What changed in this filing

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Item 1. Business

2021-02-24 compared with 2020-02-26 · 1173 added, 1169 removed, 654 unchanged (78% of the section changed)

We are an innovation-driven pharmaceutical company focused on the discovery, development and commercialization of novel, first-in-class

drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases.

We are a commercial-stage pharmaceutical company pioneering novel cancer therapies and dedicated to the discovery, development and commercialization of first-in-class

drugs directed against nuclear transport for the treatment of cancer and other diseases.

Our scientific expertise is based upon an understanding of the regulation of intracellular communication between the nucleus and the cytoplasm.

We have discovered and are developing and commercializing novel, small molecule S

nhibitor of N

) compounds that inhibit the nuclear export protein exportin 1, or XPO1.

These SINE compounds represent a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety of high unmet medical need diseases.

Our SINE compounds were the first oral XPO1 inhibitors in clinical development.

(“SINE”) compounds that inhibit the nuclear export protein exportin 1 (“XPO1”).

These SINE compounds, representing a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety of diseases with high unmet medical need, were the first oral XPO1 inhibitors to receive marketing approval.

Our lead asset, XPOVIO ®

(selinexor) tablets, was the first SINE compound to receive marketing approval by the U.S.

Food and Drug Administration, or FDA, on July 3, 2019 and is currently indicated for use in adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, or PIs, at least two immunomodulatory agents, or IMiDs, and an anti-CD38 monoclonal antibody.

We refer to myeloma that is refractory to these five agents as penta-refractory myeloma.

This indication is approved under accelerated approval based on response rate.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The ongoing, randomized Phase 3 BOSTON ( Bo

(selinexor), received its initial U.S.

approval from the U.S.

Food and Drug Administration (the “FDA”) in July 2019 and is currently approved and marketed for the following indications:

In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

Approval in this indication was supported by data from the BOSTON ( Bo

elinexor and Dexame t

e) study evaluating selinexor in combination with Velcade ®

(bortezomib) and low-dose

dexamethasone in patients with myeloma treatment with between one and three prior therapies is expected to serve as the confirmatory trial.

Our focus is on marketing XPOVIO in its currently approved indication as well as seeking the regulatory approval and potential commercialization of selinexor as an oral agent in additional cancer indications with significant unmet medical need.

We plan to conduct additional clinical trials and seek additional approvals for the use of selinexor in combination with other oncology therapies to expand the patient populations that are eligible for selinexor.

Thus, we are currently advancing the clinical development of selinexor in multiple hematological malignancies and solid tumor indications.

Studies that support submitted applications for regulatory approval include STORM ( S

e) study (the “BOSTON Study”).

In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (“PIs”), at least two immunomodulatory agents (“IMiDs”), and an anti-CD38 monoclonal antibody.

We refer to myeloma that is refractory to these five agents as penta-refractory.

Approval in this indication was supported by data from the STORM ( S

reatment of R

yeloma) and SADAL ( S

Ongoing clinical trials evaluating selinexor include the pivotal, randomized Phase 3 BOSTON study in multiple myeloma, the Phase 1b/2 STOMP ( S

elinexor and Backbone T

ultiple Myeloma P

atients) study in combination with standard therapies in multiple myeloma, the Phase 2/3 SEAL ( Se

iposarcoma) study in liposarcoma, and the Phase 3 SIENDO ( S

yeloma) study (the “STORM Study”).

For the treatment of adult patients with relapsed or refractory diffuse large B-cell

lymphoma (“DLBCL”), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.

This indication was approved under accelerated approval based on response rate and was supported by data from the SADAL ( S

ymphoma) study (the “SADAL Study”).

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The commercialization of XPOVIO, for both the multiple myeloma and DLBCL indications, is currently supported by sales representatives and nurse liaisons as well as KaryForward TM

, an extensive patient and healthcare provider support program.

Our commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers.

We plan to continue to educate physicians, healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we expand XPOVIO into the second-line plus multiple myeloma market and continue to penetrate the third-line DLBCL market.

XPOVIO also received its first regulatory approval outside the U.S.

with an approval received in February 2021 by our partner Promedico Ltd., a member of the Neopharm Group (“Promedico”), for the treatment of patients with multiple myeloma and DLBCL, in Israel.

In addition, in January 2021, the European Medicines Agency’s (“EMA”) Committee for Medicinal Products for Human Use (“CHMP”) adopted a positive opinion recommending the conditional approval of NEXPOVIO ®

(selinexor), the expected brand name for selinexor in Europe, based on the results of the Phase 2b STORM Study, which studied selinexor in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two PIs, two IMiDs and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

We expect a final decision from the European Commission (the “EC”) on our Marketing Authorization Application (“MAA”) by April 2021.

A favorable decision based on our submission through the centralized procedure would be valid in all 27 European

Union (“EU”) member countries as well as the European Economic Area countries of Iceland, Liechtenstein and Norway.

Further, we plan to submit a second regulatory filing to the EMA (Type II variation) by April 2021 based on the data from the Phase 3 BOSTON Study, which evaluated once-weekly NEXPOVIO in combination with once-weekly Velcade ®

dexamethasone in patients with multiple myeloma after at least one prior therapy with the goal of further expanding the global reach of NEXPOVIO to additional patients in need of new treatment options.

Our focus is on marketing XPOVIO in its currently approved indications as well as seeking the regulatory approval and potential commercialization of selinexor as an oral agent in additional cancer indications with significant unmet medical need.

We plan to continue to conduct clinical trials and seek additional approvals for the use of selinexor as a single agent or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor.

Thus, we are advancing our clinical development program for selinexor in the areas of multiple hematological malignancies and solid tumors, among others, including the following ongoing or planned selinexor studies:

Phase 3 SIENDO ( S

elinexor/Placebo After Combination Chemotherapy I

n Patients with Advanced or Recurrent ENDO

metrial Cancer) study evaluating selinexor as maintenance therapy in endometrial cancer.

During 2019, final data from the Phase 2b STORM study were published in the New England Journal of Medicine

August 2019).

In addition, we reported updated, positive data from the SADAL study as well as updated interim data for the STOMP study at various medical conferences.

As a result of the positive results from STORM, in addition to the FDA approval of our first New Drug Application, or NDA, we also filed a Marketing Authorization Application, or MAA, with the European Medicines Agency, or EMA, in January 2019 and expect to receive a decision on our application in the middle of 2020.

Based on the positive results of the SADAL study, we submitted a Supplemental New Drug Application, or sNDA, to the FDA in December 2019, with a request for accelerated approval for selinexor as a new treatment for adult patients with relapsed and/or refractory diffuse large B-cell

lymphoma, or DLBCL, not otherwise specified, who have received at least two prior therapies.

The FDA accepted the application for filing on February 18, 2020 and granted Priority Review with a target decision date of June 23, 2020 under the Prescription Drug User Fee Act, or PDUFA.

Selinexor has received both Orphan Drug and Fast Track designations from the FDA for this same indication.

Provided that marketing approval is granted by the FDA, we expect to be prepared to commercialize selinexor in the United States as a treatment for patients with relapsed and/or refractory DLBCL as early as the middle of 2020.

We also plan to submit a MAA to the EMA in 2020 with a request for conditional approval.

In addition to selinexor, we are also advancing a pipeline of novel drug candidates including our other oral SINE compounds eltanexor (KPT-8602)

and verdinexor (KPT-335),

as well as our oral dual PAK4/NAMPT inhibitor, KPT-9274.

We began clinical testing of eltanexor, a second-generation SINE compound, in late 2015.

Our clinical development program for eltanexor includes myelodysplastic syndrome, or MDS, colorectal cancer, or CRC, and metastatic castration-resistant prostate cancer, or CRPC.

Based on clinical results to date and resource prioritization, we plan to focus on the development of eltanexor in MDS in 2020.

We began clinical testing of KPT-9274

in patients with hematologic or solid tumors during 2016 and we plan to study its combination with an anti-PD1

monoclonal antibody in a phase 1 clinical study in the near future.

Finally, verdinexor is our lead compound that is being evaluated as a potential therapy for viral, rare disease and autoimmune indications in humans and by a collaborator as a potential therapy for cancers in companion animals.

FDA Accelerated Approval of XPOVIO

Following the positive outcome from the expanded cohort of the STORM study, on August 6, 2018, we announced the completion of the rolling submission of an NDA to the FDA with a request for accelerated approval for selinexor as a new treatment for patients with heavily pretreated, relapsed or refractory multiple myeloma.

On October 5, 2018, the FDA accepted for filing our NDA and also granted our request for priority review of the NDA and assigned an action date of April 6, 2019 under the PDUFA.

On February 26, 2019, the Oncologic Drugs Advisory Committee, or ODAC, of the FDA met to review data supporting our NDA requesting accelerated approval for selinexor.

The FDA specifically asked the ODAC to vote on whether the

committee believed the approval of selinexor should be delayed until the results from the ongoing, randomized Phase 3 BOSTON study are available.

In a vote of eight “Yes” and five “No,” the ODAC recommended that the approval decision for selinexor should be delayed until the results of the BOSTON study are available.

Following the ODAC meeting, and at the FDA’s request, we submitted additional, existing clinical information that included preliminary data from the BOSTON study as an amendment to the NDA, which allowed the FDA to extend the PDUFA action date by three months to July 6, 2019.

On July 3, 2019, the FDA approved oral XPOVIO, our first-in-class,

nuclear export inhibitor.

XPOVIO was approved in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two PIs, at least two IMiDs, and an anti-CD38 monoclonal antibody.

XPOVIO is the first SINE compound and is the first ever nuclear export inhibitor approved for human use.

The first indication is approved under accelerated approval based on response rate.

As with all accelerated approvals, continued approval for the treatment of myeloma may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The ongoing Phase 3 BOSTON study is expected to serve as the confirmatory trial for the accelerated approval of XPOVIO.

The FDA noted in its press release announcing the approval of XPOVIO that the efficacy evaluation was supported by additional information from the BOSTON study.

Commercialization of XPOVIO in the U.S.

In July 2019, XPOVIO became commercially available to patients in the U.S.

The commercial launch of XPOVIO is being supported by approximately 70 Karyopharm sales representatives and nurse liaisons as well as KaryForward TM

, an extensive patient and healthcare provider support program.

Our commercial efforts are also being supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers.

As of December 31, 2019, approximately 1,400 XPOVIO prescriptions had been fulfilled, driven by strong demand from both academic and community-based oncologists, and XPOVIO had been prescribed by more than 550 unique physicians and healthcare accounts.

Net product sales for XPOVIO were $30.5 million through December 31, 2019.

XPOVIO sales have been driven by a combination of new patient starts, prescription refills, and initial channel inventory to our distribution partners.

Patient demand for XPOVIO continued to increase during 2019 following its accelerated approval by the FDA.

Prompt insurance coverage for XPOVIO has been a key contributor to its early commercial success, with XPOVIO being added to numerous national commercial and Medicare formularies and coverage policies.

In 2020, we expect to build upon XPOVIO’s early commercial success in the late-line relapsed refractory multiple myeloma market by educating physicians, healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action.

Additionally, if results from the pivotal BOSTON trial, which are expected in early 2020, are positive, our commercial team will begin to prepare for XPOVIO’s potential expansion into the second line relapsed refractory multiple myeloma market, subject to the FDA’s review and approval of our expected sNDA.

Finally, pending FDA approval of XPOVIO in DLBCL, we expect to begin selling XPOVIO in this indication to hematologists and oncologists in the U.S with our existing field sales force.

European Marketing Authorization Application

In January 2019, we submitted a MAA to the EMA requesting conditional approval for selinexor in combination with dexamethasone as a new treatment for patients with triple class refractory multiple myeloma, meaning patients who have received at least three prior therapies and whose disease is refractory to at least one PI, one IMiD, and one anti-CD38 monoclonal antibody.

This submission was based on the positive results from the Phase 2b STORM study.

We received feedback from EMA’s Committee for Medicinal Products for Human Use, or CHMP, including the integrated inspection report, based on site audits and a sponsor inspection.

In January 2020, we were granted a three-month extension from CHMP to provide additional time to respond to the

CHMP’s outstanding questions related to the application.

We are currently working with CHMP to address the outstanding questions and expect to receive a decision on the application in mid-2020.

To commercialize selinexor following any regulatory approval outside of the U.S., we will either work with existing and potential future partners to establish the appropriate commercial infrastructure outside the U.S., or we may, in certain geographies, elect to establish the commercial infrastructure ourselves.

Randomized Confirmatory BOSTON Study in Multiple Myeloma

We are currently conducting the pivotal, randomized Phase 3 BOSTON study evaluating once-weekly selinexor in combination with once-weekly Velcade and dexamethasone (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy.

Enrollment in the BOSTON study was completed in January 2019 and top-line

data are expected in early 2020, contingent upon the occurrence of progression-free survival, or PFS, events, the primary endpoint of the study.

Data from the BOSTON study, if positive, are expected to be used to support regulatory submissions to the FDA, the EMA and other regulatory agencies requesting the use of selinexor in combination with Velcade and dexamethasone in patients with multiple myeloma who have received at least one prior line of therapy.

If approved, this combination of selinexor with Velcade and dexamethasone will be the first approved therapy using once weekly (rather than the standard twice weekly) dosing of Velcade.

Given that Velcade must be given in a healthcare setting, we believe that this once-weekly dosing regimen could be substantially more attractive to patients by potentially eliminating a significant percentage of office visits.

Summary of Karyopharm’s Pipeline and Core Clinical Trials

Key clinical trials of selinexor are summarized in the chart below.

In addition to these studies, there are several ongoing investigator-sponsored clinical trials in a variety of hematological and solid tumor malignancies.

metrial Cancer) study evaluating once weekly selinexor versus placebo as maintenance therapy in patients with endometrial cancer after first- or second-line chemotherapy (the “SIENDO Study”);

Phase 2/3 trial evaluating the combination of selinexor and R-GDP

(rituximab, gemcitabine, dexamethasone, cisplatin) in patients with relapsed or refractory DLBCL.

The Phase 3 portion of the study will evaluate the selected dose (as identified in the Phase 2 study) of selinexor or matching placebo given with the standard combination immunochemotherapy R-GDP

to patients with at least one prior therapy and who are ineligible for high dose chemotherapy and cell-based intervention such as chimeric antigen receptor T-cell

therapy (“CAR-T”)

(the “XPORT-DLBCL-030

Phase 1b/2 STOMP ( S

elinexor and Backbone T

ultiple Myeloma P

atients) multi-arm

study to evaluate combinations of selinexor with standard therapies in multiple myeloma (the “STOMP Study”);

Phase 1/2 study of selinexor in combination with standard of care therapy in patients with newly diagnosed or recurrent glioblastoma (“GBM”) (the “XPORT-GBM-029

Phase 1/2 study of selinexor in combination with ruxolitinib in treatment naïve patients with myelofibrosis (“MF”) (the “XPORT-MF-034

Phase 2 study of selinexor versus treatment per physician’s choice in participants with previously treated MF (the “XPORT-MF-035

Phase 1/2 study to assess the preliminary anti-tumor activity of selinexor in combination with docetaxel in patients with non-small cell lung cancer (“NSCLC”) and with pembrolizumab in patients with colorectal cancer (“CRC”).

(the “XPORT-STP-027 Study”).

Additionally, we expect to initiate a number of new clinical trials in 2021, including a Phase 3 study evaluating selinexor in combination with pomalidomide in patients with relapsed or refractory multiple myeloma as well as new Phase 1 and 2 studies evaluating selinexor in patients with a variety of solid tumor indications, including metastatic melanoma, lung cancer and colorectal cancer.

A number of these studies will be investigating the treatment of selinexor in combination with other standard of care anti-cancer drugs.

In addition to selinexor, we are also advancing a pipeline of other novel product candidates including the following oral SINE compounds:

We are currently focusing on the development of eltanexor to treat patients with myelodysplastic syndrome (“MDS”) as well as evaluating additional, potential solid tumor indications for future clinical development.

We are evaluating verdinexor as a potential therapy for viral, rare disease and autoimmune indications in humans, and our partner Anivive Life Sciences, Inc.

(“Anivive”) is evaluating verdinexor as a therapy for cancers in companion animals.

As discussed below, in January 2021, Anivive received conditional approval from the FDA for LAVERDIA ™

(verdinexor) as the first oral treatment of canine lymphoma.

We are evaluating KPT-9274,

an oral inhibitor of p21-activated

kinase 4 (“PAK4”) and nicotinamide phosphoribosyltransferase (“NAMPT”), to treat patients with hematologic or solid tumors.

In July 2020, the first patient was dosed in a Phase 1/2 clinical study of KPT-9274

in combination with an anti-PD1

monoclonal antibody.

Key 2020 and Recent Highlights

XPOVIO Franchise

Received FDA approval in December 2020 (three months ahead of the FDA’s Prescription Drug User Fee Act target action date) for XPOVIO to treat multiple myeloma after at least one prior therapy based on the BOSTON Study, which satisfied the post-approval requirement of a confirmatory trial for the July 2019 accelerated approval of XPOVIO based on the STORM Study.

Received FDA accelerated approval in June 2020 for XPOVIO for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.

National Comprehensive Cancer Network (“NCCN”) added three different XPOVIO combination regimens to its NCCN Guidelines for previously treated multiple myeloma in December 2020.

Recognized XPOVIO net revenue of $76.2 million in 2020.

Saw nearly 3,900 XPOVIO prescriptions filled in 2020, driven by demand across both academic and community-based physicians.

Grew prescription refill rates for XPOVIO with the average number of prescriptions per patient reaching approximately three as of December 31, 2020.

Received a positive opinion from the CHMP in January 2021 recommending the conditional approval of NEXPOVIO in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two PIs, two IMiDs and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

European Hematology Association and European Society for Medical Oncology (“ESMO”) added selinexor to European multiple myeloma treatment guidelines in November 2020.

Selinexor Pipeline

Met primary endpoint in Phase 3 SEAL ( Se

iposarcoma) study in liposarcoma (the “SEAL Study”) in November 2020 with statistically significant increase in progression free survival (“PFS”) in patients with unresectable dedifferentiated liposarcoma.

Data was presented at the Connective Tissue Oncology Society 2020 Annual Meeting.

Passed planned futility analysis in the SIENDO Study in November 2020 with a recommendation from the Data and Safety Monitoring Board (the “DSMB”) to continue without the need to add additional patients to the trial or to amend the study protocol.

Top line data is expected to be available in the second half of 2021.

Dosed first patient

in February 2021 in Phase 3 confirmatory trial in the XPORT-DLBCL-030

Dosed first patient in June 2020 in the XPORT-GBM-029

Collaborations

Entered into an exclusive distribution agreement in February 2020 with Promedico for the commercialization of XPOVIO in Israel and the Palestinian Authority.

In February 2021, Promedico received a principal approval letter from the Israeli Ministry of Health granting approval of XPOVIO for the treatment of patients with either multiple myeloma or DLBCL in Israel.

Entered into a collaboration, option and license agreement in April 2020 with Curadev Pharma Pvt Ltd (“Curadev”), a privately-owned biotechnology company, to identify and co-develop

novel small molecules against various biological targets for the treatment of cancer and other major diseases.

Amended our license agreement with Antengene Therapeutics Limited (“Antengene”) in May 2020 to expand Antengene’s development and commercial rights to our compounds in parts of Asia, Australia and New Zealand and received approximately $10.0 million in regulatory milestones from Antengene in December 2020 following certain regulatory filings by Antengene for selinexor in both multiple myeloma and DLBCL indications in Australia, Singapore and South Korea.

Entered into a Cooperative Research and Development Agreement (“CRADA”) with the National Cancer Institute’s (“NCI”) Cancer Therapy Evaluation Program in July 2020 to collaborate on studies to investigate the safety and efficacy of selinexor in various oncology indications.

Entered into an exclusive distribution agreement in December 2020 with FORUS Therapeutics Inc.

(“FORUS”) for the commercialization of XPOVIO in Canada and received a $5.0 million upfront payment in December 2020.

Received, through our partner Anivive, conditional approval from the FDA in January 2021 for LAVERDIA ™

(verdinexor) as the first oral treatment for canine lymphoma.

Entered into collaboration agreements with partners outside of the U.S.

to establish paid named patient programs to provide opportunities to reach additional patients and generate revenue from selinexor indications that have been approved in the U.S.

as a bridge to approval in certain geographies.

Corporate Highlights

Completed a follow-on

offering in March 2020 pursuant to which we issued an aggregate of 7,187,500 shares of common stock and received aggregate net proceeds of approximately $161.8 million.

Amended our Open Market Sale Agreement with Jefferies LLC, as agent, in May 2020, pursuant to which we increased the maximum aggregate offering price of shares of our common stock that we may issue and sell from time to time under the agreement from $75.0 million to up to $175.0 million.

Ended 2020 with $276.7 million in cash, cash equivalents, restricted cash and investments.

The critical components of our business strategy are to:

Maximize the Commercial Value of XPOVIO and Our Other Product Candidates.

We are executing on our U.S.

commercial capabilities and supporting the ongoing launch of XPOVIO in the U.S.

We plan to continue to penetrate the U.S.

commercial market and further educate the medical community about the clinical data that support XPOVIO as a treatment for multiple myeloma and DLBCL.

Outside of the U.S., subject to approval of selinexor, we will either work with existing and potential partners to establish the requisite commercial infrastructure.

Continue to Develop and Seek Regulatory Approvals of Selinexor Outside of the U.S.

We, or our current or future partners, continue to seek regulatory approvals of selinexor outside of the U.S.

for each indication in which we receive favorable results in a registration-enabling clinical trial.

Maintain Our Competitive Advantage and Scientific Expertise in the Field of Nuclear Transport.

To further our understanding of the role nuclear transport plays in the underlying biology of cancer, as well other diseases, we plan to continue research in the field of nuclear transport and related areas, primarily by fostering relationships with scientific advisors and physicians.

We continue to explore a variety of standard and novel combinations of other anti-cancer agents with our SINE inhibitors, and these non-clinical

studies are anticipated to provide support for new clinical investigations.

Continue Developing our Pipeline of Novel Product Candidates.

To date, we have identified several drug candidates:

our oral SINE compounds selinexor, eltanexor and verdinexor and KPT-9274.

We may also identify or in-license

novel product candidates for development in oncology or other indications in the future.

Maximize the Value of Our SINE Compounds in Non-Oncology

Indications through Collaborations.

We may seek to enter into global or regional development, marketing, and commercialization collaboration arrangements for our SINE compounds in non-oncology

Our XPOVIO Program to Treat Cancer

According to the World Health Organization, cancer is the second leading cause of death globally and in 2020 was responsible for more than one in six deaths, or an estimated 10 million deaths.

Additionally, cancer is one of the most important health issues facing patients in the U.S.

The American Cancer Society (“ACS”) estimates that in 2021 there will be nearly 1.9 million new cancer cases in the U.S., with approximately 608,000 Americans expected to die of cancer.

Cancer is a disease characterized by unregulated cell growth.

Cancer cells develop when DNA inside the nucleus of normal cells accumulates damage in genes that regulate cell growth and survival.

In healthy cells, proteins called tumor suppressor proteins located in the cell nucleus help prevent the accumulation of DNA damage (mutations, chromosomal translocations and other abnormalities) by monitoring DNA for damage, and if damage is detected, the tumor suppressor proteins will direct the cell to attempt to repair it, or if the DNA damage is too severe, the tumor suppressor proteins will direct the cell to die in a process called apoptosis.

Accumulation of tumor suppressor proteins in the nucleus of cancer cells allows them to perform their normal role of detecting DNA damage, thereby inhibiting a cancer cell’s ability to divide, and promoting apoptosis.

Many tumor suppressor proteins can only function properly when they are located inside of a cell’s nucleus.

Proteins, however, are not made inside the nucleus but rather are made outside of the nucleus in an area called the cytoplasm.

A membrane, called the nuclear membrane, separates the nucleus from the cytoplasm.

Larger nuclear proteins, including tumor suppressor proteins, must be transported from the cytoplasm where they are made into the nucleus to perform their functions in keeping a cell healthy.

Similarly, when they have completed their normal functions, these proteins are typically exported back into the cytoplasm.

Proteins move between the nucleus from the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore.

The nuclear pore works like a gate through which large molecules, including many other proteins and ribonucleic acids (“RNAs”), enter and exit the nucleus.

When molecules enter the nucleus from the cytoplasm, the process is called import, and when molecules exit from the nucleus to the cytoplasm, the process is called export.

The import and export of most proteins and other large molecules between the nucleus and cytoplasm require specific carrier proteins to chaperone their cargo molecules through the nuclear pore complex.

Carrier proteins, which mediate the import of macromolecules into the nucleus, are called importins, and those which mediate the export of macromolecules out of the nucleus are called exportins.

Therefore, the processes of import and export are carried out separately and are typically regulated independently.

One way that cancers evade detection from the body’s own defense mechanisms is by removing tumor suppressor proteins from within the cell nucleus via an overproduction of a specific chaperone protein called

XPO1 is one of eight exportins that have been identified in human cells, and it exports over 220 proteins referred to as its “cargo proteins.” In particular, XPO1 appears to be the sole exporter for most of the tumor suppressor proteins including p53, p73, p21, p27, APC, FOXO, pRB and survivin.

In addition to exporting tumor suppressor proteins out of the nucleus, XPO1 mediates the nuclear export of a protein called eukaryotic initiation factor 4E, which itself binds to the mRNAs that code for these proteins (“eIF4E” and also called the “mRNA cap binding protein”).

eIF4E binds to the mRNAs for many growth-regulating proteins, including c-myc,

and cyclin D, and depends on XPO1 to help carry these growth-promoting mRNAs from the nucleus into the cytoplasm where the mRNAs are efficiently translated into proteins.

XPO1 also exports the anti-inflammatory (and anti-tumor) protein I k

B, which inhibits a protein called NF- k

B is found in the nucleus of most cancer cells and plays a role in cancer metastasis and chemotherapy resistance, as well as in many inflammatory and autoimmune diseases.

In nearly all cancer cells, XPO1 levels are reported to be elevated when compared to their healthy cell counterparts.

Therefore, these elevated levels of XPO1 in cancer cells mediate the rapid export of tumor suppressor proteins as well as I k

B and eIF4E out of the nucleus and can lead to reduced monitoring for DNA damage, the normal triggering of apoptosis and increased NF-

Higher levels of XPO1 expression in cancer cells is also generally correlated with resistance to chemotherapy and poor prognosis in patients.

Mechanism of Action of Our SINE Compounds—Inhibition of XPO1

XPOVIO and our product candidates are novel therapies that are first-in-class,

oral SINE compounds specifically designed to force nuclear accumulation in the levels of multiple tumor suppressor and growth regulatory proteins.

One of the ways a cell regulates the function of a particular protein is by controlling that protein’s location within the cell since certain functions may only occur within a particular location in the cell.

As described above, the nuclear pore is a complex gate between the nucleus and cytoplasm, regulating the import and export of most large molecules, called macromolecules, including many proteins, into and out of the nucleus.

In healthy cells, nuclear transport, both into and out of the nucleus, is a normal and regular occurrence that is tightly regulated and requires the presence of specific carrier proteins.

XPO1 mediates the transport of the majority of tumor suppressor proteins and appears to be the only mediator of nuclear export for these proteins.

XPO1 inhibitors, such as XPOVIO, block the nuclear export of tumor suppressor, growth-regulating, and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell.

The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion.

Because normal cells have little or no DNA damage, accumulation of tumor suppressor proteins in their nucleus generally does not lead to apoptosis.

The figure below depicts the process by which our SINE compounds inhibit the XPO1-mediated nuclear export of tumor suppressor proteins and oncoprotein mRNAs.

We believe that selinexor’s novel mechanism of action, oral administration and low levels of major organ toxicities observed to date in patients treated with selinexor, along with encouraging efficacy data, support the potential for selinexor’s broad use across many cancer types, including both hematological and solid tumor malignancies.

Unlike many other targeted therapeutic approaches that only work for a specific set of cancers or in a specific subgroup of patients, we believe that by restoring tumor suppressor proteins to the nucleus where they can assess a cell’s DNA, our SINE compounds may provide therapeutic benefits across a broad range of both hematological and solid tumor malignancies and can potentially benefit a wider range of patients.

Additionally, and as supported by its mechanism of action, and preclinical, clinical and post-approval data, we believe that selinexor has shown additive or synergistic benefit with approved and experimental therapies in treating cancer patients and, therefore, has the potential to serve as a backbone therapy across multiple hematological and solid tumor malignancies as part of a variety of combination therapies.

Update to NCCN Treatment Guidelines for Patients with Previously Treated Multiple Myeloma

In December 2020, the NCCN added three different XPOVIO combination regimens to its Clinical Procedure Guidelines in Oncology for Previously Treated Myeloma (the “NCCN Guidelines”).

The NCCN Guidelines are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97% of cancers affecting patients in the U.S.

and are intended to ensure that all patients receive preventive, diagnostic, treatment and supportive services that will most likely lead to optimal outcomes.

The XPOVIO regimens added to the NCCN Guidelines include:

(i) selinexor/bortezomib/dexamethasone (once-weekly), which also received a Category 1 recommendation, which represents the highest designation assigned by NCCN, indicating the recommendation is based upon high-level evidence and that there is uniform NCCN consensus that the intervention is appropriate;

(ii) selinexor/daratumumab/dexamethasone;

and (iii) selinexor/pomalidomide/dexamethasone, which is an all-oral

treatment regimen.

Summary of Our Pipeline and Key Clinical Trials

Oral selinexor is being evaluated in multiple later-phase clinical trials in patients with hematological and solid tumor malignancies, often in the relapsed and/or refractory setting.

In general, relapsed disease refers to disease that progresses following the expiration of a specified period of time after discontinuation of therapy and

refractory disease refers to disease that progresses while the patient is on therapy or within a specified period of time after discontinuation of therapy.

In general, relapsed disease refers to disease that progresses following the expiration of a specified period of time after discontinuation of therapy and refractory disease refers to disease that progresses while the patient is on therapy or within a specified period of time after discontinuation of therapy.

Key clinical trials of selinexor are summarized in the charts below.

In addition to these studies, there are several ongoing investigator-sponsored clinical trials being conducted in a variety of hematological and solid tumor malignancies.

HEMATOLOGICAL MALIGNANCIES

We are currently evaluating XPOVIO in certain hematological malignancies, including multiple myeloma, DLBCL and MF.

Multiple Myeloma

Multiple myeloma is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, also known as M protein, in the serum or urine, bone disease, kidney disease and immunodeficiency.

It is more common in elderly patients, with a median age at diagnosis of 69 years.

According to the National Cancer Institute, or NCI, multiple myeloma is the second most common cancer of the blood in the U.S.

with more than 32,000 new cases each year and over 130,000 patients living with the disease.

Multiple myeloma is one of the most common types of blood cancer in the U.S.

According to the ACS, nearly 35,000 new cases of multiple myeloma will be diagnosed in the U.S.

It is more common in elderly patients, and most frequently diagnosed among people between ages 65 to 74 years with a median age at diagnosis of 69 years.

Despite recent therapeutic advances, there is currently no cure and most patients’ disease will typically progress following treatment with currently available therapies.

The treatment of multiple myeloma has improved in the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, which is restricted to healthier, often younger patients, and the subsequent introduction of IMiDs, such as Revlimid and Pomalyst, and the PIs Velcade, Kyprolis ®

, and Ninlaro ®

Two monoclonal antibodies, Darzalex and Empliciti ™

(elotuzumab), have also been approved, as has the histone deacetylase inhibitor Farydak ®

The treatment of multiple myeloma has improved over the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation (“ASCT”), which is restricted to healthier, often younger patients, and the subsequent introduction of IMiDs, such as Revlimid ®

(lenalidomide) and Pomalyst ®

(pomalidomide), and PIs such as Velcade ®

(bortezomib), Kyprolis ®

(carfilzomib), and Ninlaro ®

Three monoclonal antibodies, Darzalex ®

(daratumumab), SARCLISA ®

(isatuximab-irfc), and Empliciti ®

(elotuzumab), and one monoclonal antibody with a toxin conjugate, BLENREP (belantamab mafodotin-blmf), have also been approved, as has the histone deacetylase inhibitor Farydak ®

(panobinostat).

1 unchanged sentence

agents has led to a significant increase in the survival of patients with multiple myeloma.

Although a wide variety of newly approved or experimental therapies are being used in relapsed and/or refractory patients, including new proteasome inhibitors (oprozomib and marizomib), monoclonal antibodies (with or without toxin conjugates;

belantamab mafodotin, an anti-BCMA antibody-drug conjugate;

isatuximab, an anti-CD38

monoclonal antibody) and cellular therapies like chimeric antigen receptor T-cell,

Although a wide variety of newly approved or experimental therapies are being used to treat relapsed and/or refractory patients, including new PIs (oprozomib and marizomiband cellular therapies such as CAR-T

therapy), nearly all patients will eventually relapse and succumb to their disease.

With about 13,000 deaths from multiple myeloma in the United States alone expected to occur in 2020 according to the American Cancer Society, we believe that there remains a need for therapies for patients whose disease has relapsed after, or is refractory to, available therapy.

The approval of XPOVIO in patients with penta-refractory myeloma after four prior therapies further supports this perspective.

According to EvaluatePharma (January 2020), the worldwide market for prescription drugs used to treat patients with multiple myeloma exceeded $16 billion in 2018 and is projected to reach over $20 billion by 2024.

The Phase 2b STORM Study

The Phase 2b STORM study was a single-arm

clinical trial evaluating oral selinexor in combination with standard, low-dose

dexamethasone in patients with heavily pretreated, relapsed or refractory myeloma.

Based on the results of the clinical data set for Part 1 of the STORM study, which we reported in 2016, we expanded the STORM study, designated Part 2, which enrolled 122 heavily pretreated patients with triple-class refractory myeloma, of which 83 patients had penta-refractory myeloma.

The results from the STORM study served as the basis for our NDA filing and subsequent accelerated approval from the FDA.

The final data from the 122 patients treated on STORM Part 2 were published in the New England Journal of Medicine

on August 22, 2019.

With nearly 12,500 deaths from multiple myeloma in the U.S.

alone estimated for 2021 according to the ACS, we believe that there remains a need for therapies for patients whose disease has relapsed after, or is refractory to, available therapy.

Supporting Studies

The BOSTON Study

The December 2020 FDA approval of XPOVIO’s expanded indication as a treatment for patients with multiple myeloma after at least one prior therapy was supported by the results of the BOSTON Study, a multi-center, Phase 3, randomized study conducted at over 150 clinical sites internationally, which evaluated 402 adult patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy.

The study was designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly XPOVIO in combination with once-weekly Velcade ®

plus low-dose

dexamethasone (the “XVd Arm”) versus twice-weekly Velcade ®

plus dexamethasone (the “Vd Arm”).

The primary endpoint of the study was PFS and key secondary endpoints included overall response rate (“ORR”) and the rate of peripheral neuropathy (“PN”), among others.

Additionally, the BOSTON Study allowed for patients on the Vd Arm to crossover to the XVd Arm following objective (quantitative) progression of disease verified by an Independent Review Committee (“IRC”).

Although the study had one of the highest proportions of patients with high-risk cytogenetics (~50%) as compared with other Velcade ®

-based studies in previously treated multiple myeloma, the median PFS in the XVd Arm was 13.9 months compared to 9.5 months in the Vd Arm, representing a 4.4 month (47%) increase in median PFS (hazard ratio of 0.70;

The XVd Arm also demonstrated a significantly greater ORR compared to the Vd Arm (76.4% vs.

62.3%, p=0.0012).

Further, XVd therapy demonstrated a significantly higher rate of deep responses, defined as ³

Very Good Partial Response (“VGPRs”) compared to Vd therapy (44.6% vs.

32.4%) as well as a longer median duration of response (“DOR”) (20.3 months vs.

12.9 months).

Additionally, 17% of patients on the XVd arm achieved a Complete Response (“CR”) or a Stringent Complete Response (“sCR”) as compared to 10% of patients receiving Vd therapy.

All responses were confirmed by an IRC.

Rates of PN were significantly lower for patients receiving XVd therapy compared to those receiving Vd therapy (32% vs.

In addition, PN rates ³

Grade 2 were also significantly lower in the XVd Arm compared to the Vd Arm (21% vs.

The most common adverse reactions ( ³

20%) in patients with multiple myeloma who received XVd were fatigue (59%), nausea (50%), decreased appetite (35%), diarrhea (32%), peripheral neuropathy (32%), upper respiratory tract infection (29%), decreased weight (26%), cataract (22%) and vomiting (21%).

Grade 3-4 laboratory abnormalities ( ³

10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia.

In the BOSTON Study, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment.

Serious adverse reactions occurred in 52% of patients who received XVd.

Treatment discontinuation rate due to adverse reactions was 19%.

Certain subgroup populations of the BOSTON Study were evaluated and reported at the American Society of Hematology (“ASH”) 2020 Annual Meeting.

We believe these subgroup evaluations of XVd therapy showed consistent PFS benefit and higher ORR compared to Vd therapy, including in evaluations of the safety and efficacy of XPOVIO (i) in patients previously treated with PIs;

(ii) according to the number of prior lines of therapy or prior treatment with Revlimid ®

(iii) in patients with high risk cytogenetics;

and (iv) based on age (patients younger than 65 years old versus older than 65 years old) or by frailty level (frail versus fit).

The STORM Study

The July 2019 FDA approval of XPOVIO to treat patients with penta-refractory multiple myeloma was supported by the results of the STORM Study.

This indication was approved under accelerated approval based on response rate.

The BOSTON Study served as the confirmatory trial under the FDA’s Accelerated Approval Program and, therefore, the approval of the BOSTON supplemental new drug application in December 2020 fulfilled the accelerated approval requirements of the STORM FDA approval.

The STORM Study was a global, multi-center, single-arm

Phase 2b clinical trial evaluating oral selinexor in combination with standard, low-dose

dexamethasone (“Xd”) in patients with heavily pretreated, relapsed or refractory multiple myeloma.

These heavily pretreated patients had a median of seven prior therapeutic regimens, including a median of 10 unique anti-myeloma agents.

Specifically, the myeloma patients who were eligible for the study had prior treatment with the two PIs, Velcade and Kyprolis, the two IMiDs, Revlimid and Pomalyst, and the anti-CD38 monoclonal antibody Darzalex, as well as alkylating agents, and their disease was refractory to glucocorticoids, at least one PI, at least one IMiD, Darzalex, and their most recent therapy.

In all patients, this myeloma was considered “triple-class refractory.” In a subset of 83 patients, their disease was documented to be refractory to all five major agents and is designated penta-refractory myeloma.

Specifically, the myeloma patients who were eligible for the study had prior treatment with the two PIs, Velcade ®

and Kyprolis ®

, the two IMiDs, Revlimid ®

and Pomalyst ®

, and the anti-CD38 monoclonal antibody Darzalex ®

, as well as alkylating agents, and their disease was refractory to glucocorticoids, at least one PI, at least one IMiD, Darzalex ®

, and their most recent therapy.

In all patients, this myeloma was considered “triple-class refractory.” In a subset of 83 patients, their disease was designated as penta-refractory myeloma.

In addition to multiple-refractory disease, patients in the STORM Study had rapidly progressing myeloma, with a median 22% increase in disease burden in the 12 days from screening to initial therapy.

Given the rapid progression of triple-class refractory myeloma, the window of opportunity to prevent further illness and death is small.

Therefore, the regimen that was used in the STORM study began with a high dose of selinexor to achieve rapid disease control.

Each patient began treatment with 80mg oral selinexor twice weekly in combination with low-dose

dexamethasone (20mg twice weekly).

This initial dose was chosen to optimize the potential to halt disease progression and reduce tumor load.

Because most patients involved in the study had limited end-organ

reserve and were at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the study protocol.

For the STORM study’s primary endpoint, oral selinexor achieved an ORR of 26%, including two (2%) stringent complete responses, or sCRs, six (5%) very good partial responses, or VGPRs, and 24 (20%) partial responses, or PRs, and the trial therefore met its primary endpoint.

For the STORM Study’s primary endpoint, oral selinexor achieved an ORR of 26%, including two (2%) sCRs, six (5%) VGPRs, and 24 (20%) partial responses (“PRs”) and the trial therefore met its primary endpoint.

Both patients who had relapsed after CAR-T

therapy achieved PRs.

Minimal response per International Myeloma Working Group, or IMWG, criteria was observed in 16 (13%) patients and 48 patients (39%) had stable disease.

Minimal response per International Myeloma Working Group (“IMWG”) criteria was observed in 16 (13%) patients and 48 patients (39%) had stable disease.

Median time to PR or better was 4.1 weeks.

The clinical benefit rate, meaning a minimal response or better, was 39%.

All responses were adjudicated by an Independent Review Committee consisting of 4 independent experts in the treatment of multiple myeloma.

Median duration of response, or DOR, was 4.4 months.

PFS was 3.7 months and overall survival, or OS, was 8.6 months.

All responses were adjudicated by an IRC consisting of four independent experts in the treatment of multiple myeloma.

Median DOR was 4.4 months.

PFS was 3.7 months and overall survival (“OS”) was 8.6 months.

In the 39% of patients who achieved a minimal response or better, median OS was 15.6 months, compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable.

The adverse events that were observed in the study appeared to be a function of dose, schedule, and baseline clinical characteristics, including, for example, preexisting cytopenias.

The most common treatment-emergent adverse events, or AEs, were thrombocytopenia (73%), fatigue (73%), nausea (72%) and anemia (67%).

AEs are classified by severity and graded on a scale of one to five with one being the least severe and five resulting in death.

The most common Grade 3/4 treatment-emergent AEs were thrombocytopenia (59%), anemia (44%), hyponatremia (22%) and neutropenia (21%).

Importantly, most non-hematologic

AEs were limited in severity to Grades 1 or 2, with only 10% experiencing Grade 3 nausea and 3% experiencing Grade 3 vomiting.

In all, 18% of patients discontinued study treatment because of an AE considered by the investigator related to the study drug.

AEs leading to dose modification or holds occurred in 80% of patients, with the majority occurring in the first two months of treatment.

The most common AEs leading to dose reduction or interruption were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).

Supportive care, including granulocyte colony stimulating factors, thrombopoietin receptor agonists, optimization of fluid and caloric intake, appetite stimulants, psychostimulants and/or additional anti-nausea agents usually reduced the intensity and/or duration of AEs.

Side effects were reversible without evidence of toxic effects in major organs (treatment-related cardiac, pulmonary, hepatic, or renal dysfunction of Grade 3 or higher) or cumulative toxic effects, with irreversible acute kidney injury reported in one patient (1%).

Serious AEs occurred in 63% of patients, with pneumonia (11%) and sepsis (9%) being the most common.

Twenty-eight patients died during the study:

16 from disease progression and 12 from an AE.

Of these 12 patients, two were assessed by the investigator as related to treatment (one patient having pneumonia with concurrent disease progression and the other having sepsis).

The complete results of this study were published in the New England Journal of Medicine.

However, the FDA’s accelerated approval of XPOVIO was based upon the efficacy and safety in a pre-specified

analysis of the 83 patients in the STORM study with documented penta-refractory myeloma, as the benefit-risk ratio appeared to be greater in this more heavily pre-treated

The most common adverse reactions ( ³

20%) in patients with multiple myeloma who received Xd were thrombocytopenia (74%), fatigue (73%), nausea (72%), anemia (59%), decreased appetite (53%), decreased weight (47%), diarrhea (44%), vomiting (41%), hyponatremia (39%), neutropenia (34%), leukopenia (28%), constipation (25%), dyspnea (24%) and upper respiratory tract infection (21%).

In the STORM Study, fatal adverse reactions occurred in 9% of patients.

Serious adverse reactions occurred in 58% of patients.

Treatment discontinuation rate due to adverse reactions was 27%.

The FDA’s accelerated approval of XPOVIO was based upon the efficacy and safety in a pre-specified

subgroup analysis of the 83 patients in the STORM Study with documented penta-refractory myeloma, as the benefit-risk ratio appeared to be greater in this more heavily pre-treated

population than in the overall trial population.

The overall response rate in this patient population was 25.3%.

Additional data and analysis from the STORM study were also presented at key medical conferences in 2019 including the European Hematology Association, or EHA, the International Myeloma Working Group, or IMWG, and the American Society of Hematology, or ASH, annual meetings.

The Phase 1b/2 STOMP Study

The STOMP study, a multi-arm

clinical trial in patients with multiple myeloma, is evaluating selinexor and low-dose

dexamethasone plus standard therapies, such as Velcade, Kyprolis, Revlimid, Pomalyst or Darzalex.

An additional arm of the study evaluating selinexor in combination with Revlimid in patients with previously untreated myeloma was opened in June 2018.

We presented updated clinical data from the STOMP study at both the EHA 2019 annual meeting in June 2019 as well as at the ASH 2019 annual meeting in December 2019 demonstrating that selinexor and low-dose

dexamethasone plus standard anti-myeloma therapies exhibit encouraging response rates when combined with these approved therapies.

Selinexor plus Pomalyst and Low-dose

Dexamethasone (SPd) Presented at the ASH 2019 Annual Meeting

In this all oral arm of the Phase 1b/2 STOMP study, oral selinexor (60-100mg

weekly or 40-80mg

twice weekly) is being evaluated in combination with Pomalyst (3 or 4mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a PI and an IMiD, or patients with myeloma refractory to both a PI and an IMiD.

The following table is a summary of the interim efficacy data:

The ORR in this patient population was 25.3%.

Our request for conditional approval in Europe is based upon this same patient population that served as the basis for XPOVIO’s accelerated FDA approval in the U.S.

The STOMP Study

The STOMP Study, an ongoing multi-arm

Phase 1b/2 clinical trial in patients with relapsed or refractory multiple myeloma, is evaluating selinexor and low-dose

dexamethasone in combinations with standard therapies, such as Pomalyst ®

, and Darzalex ®

We presented the following updated clinical data from the STOMP Study at the ASH 2020 Annual Meeting in December 2020, demonstrating that selinexor and low-dose

dexamethasone plus standard anti-myeloma therapies exhibit encouraging response rates in these combination regimens:

Selinexor in Combination with Pomalyst ®

Dexamethasone (“XPd”) in Patients with Relapsed or Refractory Multiple Myeloma

In this all oral arm of the Phase 1b/2 STOMP Study, selinexor is being evaluated in combination with Pomalyst ®

dexamethasone in patients with relapsed or refractory multiple myeloma who received at least two prior lines of therapy, including a PI and an IMiD.

Of note, 25% of the population enrolled in the study had previously received Darzalex ®

The recommended Phase 2 dose (“RP2D”) was determined to be 60 mg of XPOVIO orally once-weekly, four mg of Pomalyst ®

orally once-daily and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally.

The following table is a summary of the efficacy results:

Best Responses 1

in Evaluable SPd Patients as of 1-Oct-2019

Prior Therapy Status

Pomalyst-naïve

and Revlimid refractory or relapsed

Pomalyst Treated and Revlimid refractory

ORR=Overall Response Rate (VGPR+PR);

VGPR=Very Good Partial Response;

PR=Partial Response

Responses were adjudicated according to the International Myeloma Working Group criteria

in Evaluable XPd Patients as of November 14, 2020 2

naïve or non-refractory

ORR = CR+VGPR+PR

Responses were adjudicated according to the IMWG criteria.

Based on interim unaudited data.

Five patients not evaluable for response:

one death unrelated to myeloma, one non-compliance

with study procedures, one withdrawal of consent before disease follow up, one death related to progressive disease, or PD;

one PD before completing one cycle of therapy

One unconfirmed VGPR

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or supportive care.

Two VGPRs were unconfirmed.

One PR was unconfirmed.

Median follow-up

time for 20 patients at the RP2D was 2.5 months;

median follow-up

time for all 60 patients was 12.2 months.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (“AEs”) were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or standard supportive care.

The most common non-hematologic

treatment-related AEs were nausea (52%), fatigue (52%) and weight loss (39%).

As expected, the most common treatment-related Grade 3 and 4 AEs were neutropenia (58%), thrombocytopenia (27%) and anemia (27%).

Selinexor plus Kyprolis and Low-dose

Dexamethasone (SKd) Presented at the ASH 2019 Annual Meeting

In this arm of the Phase 1b/2 STOMP study, oral selinexor (80 or 100mg once-weekly) is being evaluated in combination with Kyprolis (56mg/m 2

once weekly) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed refractory multiple myeloma who have received at least two prior therapies, which can include previous treatment with a PI, one or more IMiDs or Darzalex.

The median number of prior treatments was four (with a range of two to eight).

The following table is a summary of the interim efficacy data:

treatment-related AEs were nausea (60%), fatigue (51%), decreased appetite (44%), weight loss (38%) and diarrhea (29%), and were primarily grade 1 and 2 events.

The most common treatment-related Grade 3 and 4 AEs were neutropenia (54%), anemia (33%), and thrombocytopenia (32%).

Based on these Phase 2 results, we plan to initiate a Phase 3 study investigating the XPd combination in 2021.

Historical clinical trials evaluating the efficacy of Pomalyst ®

dexamethasone in less heavily pretreated populations (i.e., without prior Darzalex ®

therapy) have demonstrated an ORR of 29% and median PFS of 3.6 months, as highlighted in the Pomalyst ®

Full Prescribing Information.

Selinexor in Combination with Kyprolis ®

Dexamethasone (“XKd”) in Patients with Relapsed or Refractory Multiple Myeloma

In this arm of the Phase 1b/2 STOMP Study, oral selinexor is being evaluated in combination with Kyprolis ®

dexamethasone in patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including a PI, one or more IMiDs (e.g., Revlimid ®

or Pomalyst ®

) or Darzalex ®

In these heavily pretreated patients, 100% had previously received Velcade ®

, 96% had previously received Revlimid ®

, 67% had previously received Pomalyst ®

and 63% had previously received Darzalex ®

The RP2D was determined to be 80 mg of XPOVIO orally once-weekly, 56 mg/m 2

of Kyprolis ®

once-weekly and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally and enrollment continues using this regimen.

The median PFS was 23.7 months for all patients.

The following table is a summary of the efficacy results:

Best Responses 1

in Evaluable SKd Patients as of 1-Oct-2019

All (Kyprolis-naïve)

ORR=Overall Response Rate (CR+VGPR+PR);

CR=Complete Response;

VGPR=Very Good Partial Response;

PR=Partial Response

Responses were adjudicated according to the International Myeloma Working Group criteria

in Evaluable XKd Patients as of October 1, 2020 2

Responses were adjudicated according to the IMWG criteria.

Based on interim unaudited data.

All patients had reductions in myeloma protein, or M-protein,

from baseline, with 71% of patients experiencing a reduction of 90% or more.

As of the data cutoff date, median PFS had not yet been reached.

Among the patients evaluated for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or supportive care.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal, constitutional and other symptoms;

most were manageable with dose modifications and/or standard supportive care.

The most common non-hematologic

treatment-related AEs were nausea (71%), fatigue (43%), anorexia (36%), vomiting (36%) and weight loss (36%) and were mostly Grade 1 and 2 events.

As expected, the most common treatment-related Grade ≥

3 AEs were hematologic AEs and included thrombocytopenia (64%), anemia (14%) and leukopenia (14%).

The recommended Phase 2 dose, or RP2D, was identified as selinexor 80mg and Kyprolis 56mg/m 2

and enrollment continues using this regimen.

Selinexor plus Revlimid and Low-dose

Dexamethasone (SPd) in Newly Diagnosed Patients with Multiple Myeloma Presented at the ASH 2019 Annual Meeting

In this all oral arm of the Phase 1b/2 STOMP study in patients with newly diagnosed multiple myeloma, selinexor (60mg orally once-weekly) is being combined with Revlimid (25mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly).

The following table is a summary of the interim efficacy data:

treatment-related AEs were nausea (71%), fatigue (58%), decreased appetite (50%) and weight loss (46%), and were mostly Grade 1 and 2 events.

The most common treatment-related Grade ³

3 AEs included thrombocytopenia (58%), anemia (21%) and leukopenia (13%).

We are encouraged by these results, which indicate that the once weekly combination of XKd may induce beneficial response rates in patients with heavily pretreated double or triple class refractory multiple myeloma.

Selinexor in Combination with Revlimid ®

Dexamethasone (“XRd”) in Patients with Newly Diagnosed and Relapsed or Refractory Multiple Myeloma

In this all oral arm of the Phase 1b/2 STOMP Study, selinexor is being evaluated in combination with Revlimid ®

dexamethasone in patients with newly diagnosed or previously treated multiple myeloma.

The previously treated patients received at least one prior therapy, which may include prior Revlimid ®

, as long as the patient’s myeloma was not refractory to Revlimid ®

The RP2D was determined to be 60 mg of XPOVIO orally once-weekly, 25 mg of Revlimid ®

orally once daily, and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally.

The following table is a summary of the efficacy results:

Best Responses 1

in Evaluable SRd Patients as of 1-Oct-2019

ORR=Overall Response Rate (CR+VGPR+PR)

Responses were adjudicated according to the International Myeloma Working Group criteria

in Evaluable XRd Patients as of October 1, 2020 2

-naïve relapsed or refractory myeloma

-treated/refractory myeloma

Newly diagnosed (efficacy evaluable)

Responses were adjudicated according to the IMWG criteria.

Based on interim unaudited data.

One patient was not evaluable for response due to withdrawn consent prior to disease follow-up

One VGPR was confirmed on Oct 10, 2019 (after data cut);

two VGPR are unconfirmed

The data are early and the median PFS was not reached.

Among the patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or supportive care.

Two PRs were unconfirmed.

One patient’s efficacy not evaluable due to withdrawal of consent during cycle 1.

One VGPR was unconfirmed.

Responses were highly durable with four relapsed or refractory patients remaining on study with PFS of greater than 35 months and two newly diagnosed patients remaining on study with PFS of greater than 24 months.

Among the newly diagnosed patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or standard supportive care.

The most common non-hematologic

treatment-related AEs were diarrhea (63%), weight loss (63%), nausea (50%), constipation (38%), fatigue (38%), hypokalemia (38%) and insomnia (38%) and were mostly Grades 1 or 2.

treatment-related AEs were fatigue (63%), weight loss (63%), diarrhea (63%), nausea (50%) and insomnia (38%) and were mostly Grade 1 and 2 events.

The most common Grade ³

3 AEs were neutropenia (75%), anemia (50%) and thrombocytopenia (38%).

Among the five patients evaluable for dose limiting toxicities, or DLTs, as of the data cutoff date, there were no DLTs observed.

Selinexor plus Darzalex and Low-dose

Dexamethasone (SDd) Presented at the EHA 2019 Annual Meeting

In this arm of the Phase 1b/2 STOMP study, oral selinexor (dose escalated using either 100mg once weekly or 60mg twice weekly) is being evaluated in combination with Darzalex (16mg/kg intravenously once weekly) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a PI and an IMiD, or patients with multiple myeloma refractory to both a PI and an IMiD.

The following table is a summary of the updated interim efficacy data:

Best Responses 1

in Evaluable SDd Patients as of 1-May-2019

Darzalex naïve

ORR=Overall Response Rate (VGPR+PR);

PR= Partial Response

Responses were adjudicated according to the International Myeloma Working Group criteria

Based on interim unaudited data

Two patients were not evaluable for response as they withdrew consent prior to disease follow up

Two unconfirmed PRs

Despite the heavily pretreated nature of the patients in the study, with 100% of the patients having disease refractory to both a PI and an IMiD, only one patient (3%) did not have at least a minimal response.

As of the data cutoff date, median PFS had not been reached.

Among patients with at least a PR, the median time on treatment was 7.7 months, while the median time on study for all evaluable patients was 4.8 months.

Median time to response was 1.0 month.

Based on published data, the expected ORR for Darzalex therapy without selinexor in the PI-

and IMiD-refractory, Darzalex-naïve

population is approximately 29%, and the anticipated response rate with selinexor-dexamethasone in this population is ≤

30% based on the STORM and previous studies.

Thus, the ORR of 73% continues to provide a basis for further evaluation of the SDd combination.

Among the 31 patients evaluated for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or supportive care.

Among the relapsed or refractory patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms;

most were manageable with dose modifications and/or standard supportive care.

The most common non-hematologic

treatment-related AEs were nausea (68%), fatigue (58%), anorexia (32%), insomnia (32%), diarrhea (32%), hyponatremia (32%), and vomiting (26%) and were mostly Grade 1 and 2 events.

As expected, the most common Grade 3 and 4 treatment-related AEs were hematologic AEs and included thrombocytopenia (42%), anemia (29%), leukopenia (26%) and neutropenia (23%).

Based on these tolerability and efficacy data, the recommended RP2D of SDd is selinexor (100mg orally, once weekly), Darzalex (16mg/kg, once weekly) and dexamethasone (40mg orally, once weekly).

Selinexor plus Velcade and Low-dose

Dexamethasone (SVd) Published in Blood

In this arm of the Phase 1b/2 STOMP study, oral selinexor was studied in 42 patients who received selinexor (60, 80, or 100mg orally, once or twice weekly) plus Velcade (1.3mg/m 2

subcutaneously) and dexamethasone (20mg orally) once or twice weekly in 21-

In the dose-escalation phase, patients were randomized to one of two treatment cohorts to receive selinexor once weekly or twice weekly in 21-

cycles, depending on the bortezomib dosing schedule.

Based on long-term tolerability and efficacy, the recommended RP2D of SVd was established at 100 mg selinexor once weekly plus 40 mg dexamethasone once weekly and 1.3 mg/m 2

bortezomib once weekly in 35-day

Patients had a median of three prior lines of therapy (with a range of one to 11), and 50% were refractory to a PI.

Treatment-related Grade 3 or 4 AEs reported in ≥

10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%).

The incidence and severity of peripheral neuropathy were low, with four (10%) patients experiencing this AE at a grade limited to two or below.

The ORR for the entire population was 63% with an 84% ORR for patients with disease that was not refractory to a PI and 43% in patients with disease refractory to a PI.

The median PFS for all patients was 9.0 months;

17.8 months for PI-nonrefractory,

and 6.1 months for PI-refractory.

The results from the SVd arm of the STOMP study were published in the journal Blood

(2018 Dec 13;

The SVd arm of the STOMP study served as the basis for the design of the Phase 3 BOSTON study evaluating once-weekly selinexor, once-weekly Velcade and dexamethasone in patients who have had one to three lines of prior multiple myeloma therapy.

Non-Hodgkin’s

lymphoma, or NHL, is a cancer that starts in cells called lymphocytes, which are part of the body’s immune system.

treatment-related AEs were nausea (58%), fatigue (54%), decreased appetite (50%), weight loss (42%), and diarrhea (33%), and were mostly Grade 1 and 2 events.

The most common Grade ³

3 AEs were thrombocytopenia (63%), neutropenia (63%), anemia (17%) and fatigue (17%).

We are encouraged by these results, which indicate that the all oral regimen of weekly selinexor with standard Revlimid ®

and dexamethasone may induce high response rates with good tolerability.

Diffuse Large B-Cell

DLBCL is a form of Non-Hodgkin’s

lymphoma (“NHL”), a cancer that starts in cells called lymphocytes, which are part of the body’s immune system.

Lymphocytes are found in the lymph nodes and other lymphoid tissues, such as the spleen and bone marrow, as well as in the blood.

NHL is one of the most common cancers in the United States, accounting for about 4% of all cancers.

In 2020, the American Cancer Society, or ACS, estimates that more than 77,000 patients will be diagnosed with NHL and nearly 20,000 deaths will result from the disease.

DLBCL is the most common and the most aggressive of the different forms of NHL, making up approximately 18,000 of the new cases diagnosed annually in the United States.

Approximately 50% of newly diagnosed patients are currently cured with front-line (typically “R-CHOP”

chemotherapy) and another approximately 10% of patients are cured with second line intensive chemotherapy followed by autologous stem cell transplantation.

The remaining patients generally succumb to the disease, with the median OS of patients with relapsed or refractory

DLBCL after two prior regimens less than one year, and often less than six months.

NHL is one of the most common cancers in the U.S., accounting for approximately 4% of all cancers.

In 2021, the ACS estimates that more than 81,000 people will be diagnosed with NHL and approximately 20,000 deaths will result from the disease.

DLBCL is the most common and most aggressive type of NHL, making up approximately 18,000 of the new cases diagnosed annually in the U.S.

Most often, newly diagnosed patients are currently cured with front-line (typically “R-CHOP”

chemotherapy).

Despite the recent approval of CAR-T

therapy, many patients with relapsed/refractory DLBCL are not medically stable enough to undergo CAR-T

The FDA recently granted accelerated approval to the triplet therapy polatuzumab vedotin, bendamustine, rituximab, known as PBR, for the treatment of adult patients with relapsed or refractory diffuse large B-cell

lymphoma, not otherwise specified after at least two prior therapies.

The Phase 2b SADAL Study

The SADAL study is an open-label Phase 2b clinical trial evaluating single-agent oral selinexor (60mg, twice weekly) in patients that have relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue.

At the ASH 2018 annual meeting, we presented top-line

clinical data from the SADAL study demonstrating that selinexor, when administered as a single-agent, is clinically active and capable of producing durable responses associated with prolonged overall survival.

Updated data were presented at the 2019 International Conference on Malignant Lymphoma, or ICML, meeting on June 19, 2019.

The results presented at the ICML meeting remain consistent with those reported at the ASH 2018 annual meeting and include efficacy results from the final 12 patients who had not reached their first response assessment in time to be included in the previously released top-line

efficacy analyses.

Among the 127 patients (median of two prior treatment regimens with a range one to six) who were evaluable for response, as adjudicated by an Independent Central Radiological Review, or ICRR, committee, 36 patients responded (13 CRs and 23 PRs) for an ORR of 28.3%.

An additional 11 patients experienced stable disease, or SD, for a disease control rate, or DCR, of 37.0%.

Selinexor also demonstrated responses in patients with either GCB or non-GCB

subtypes of DLBCL:

the ORR in the 59 patients with the GCB-subtype

was 33.9% and the ORR in the 63 patients with the non-GCB

subtype was 20.6%.

In addition, there were five patients enrolled whose subtype was unclassified and one of these patients achieved a CR while two of these patients achieved a PR.

The median DOR across responding patients was 9.2 months and responses tended to occur rapidly, with most documented at the first post-baseline radiological evaluation (weeks 8-9).

Median OS for the entire patient population was 9.0 months while median OS has not yet been reached in patients who achieved either a CR or PR.

Patients whose disease progressed or had no response to selinexor had a median OS of 4.1 months, which is consistent with the expected poor prognosis (OS <six months) for patients who have relapsed or refractory DLBCL and have been previously treated with two or more lines of therapy.

All 127 patients were included in the safety analyses.

The most common treatment-related AEs were cytopenias along with gastrointestinal and constitutional symptoms and were generally reversible and most were manageable with dose modifications and/or supportive care.

The most common non-hematologic

AEs were nausea (52.8%), fatigue (37.8%), and anorexia (34.6%) and were mostly Grade 1 and 2 events.

As expected, the most common Grade 3 and 4 AEs were thrombocytopenia (39.4%), neutropenia (20.5%) and anemia (13.4%) and were generally not associated with clinical sequelae.

In November 2018, the FDA granted Fast Track designation to selinexor for the treatment of patients that have relapsed and/or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue.

Selinexor has also been granted Orphan Drug designation by the FDA in DLBCL.

Based on the positive results of the SADAL study, we submitted an sNDA to the FDA on December 23, 2019, with a request for accelerated approval for selinexor as a new treatment for adult patients with relapsed or refractory DLBCL, not otherwise specified, who have received at least two prior therapies.

The FDA filed the application on February 18, 2020 and granted Priority Review with a target decision date of June 23, 2020 under PDUFA.

We also plan to submit a MAA to the EMA in 2020 with a request for conditional approval.

We plan to initiate two studies in DLBCL during 2020.

XPORT-DLBCL-030,

which is expected to serve as a confirmatory study for the accelerated approval requested in DLBCL based on the SADAL study, is a Phase 3 trial of selinexor or matching placebo given with the standard combination immunochemotherapy R-GDP

(rituximab, gemcitabine, dexamethasone, cisplatin) to patients with at least one prior therapy and who are ineligible for high dose chemotherapy and stem cell transplantation (or CAR-T).

The primary endpoint of the study is PFS, and this study is expected to initiate in mid-2020.

XPORT-DLBCL-025

is a multi-arm

study of selinexor in combination with commonly used and approved agents for the treatment of DLBCL;

this study is expected to begin in the second half of 2020.

This study will inform the use of selinexor with a variety of additional agents for the treatment of DLBCL.

Advanced or Metastatic Solid Tumors

therapy, many patients with relapsed or refractory DLBCL are not medically stable enough to undergo CAR-T

therapy and additional treatment options are necessary to address this continued unmet medical need.

In 2019, the FDA granted accelerated approval to the triplet therapy polatuzumab vedotin, bendamustine, rituximab, known as PBR, for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified after at least two prior therapies.

The FDA also approved Monjuvi ®

(tafasitamab-cxix) in July 2020 in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for ASCT.

Supporting Studies

The SADAL Study

In June 2020, the FDA approved XPOVIO as the only single-agent oral treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.

This approval was supported by the results of the SADAL Study, an open-label Phase 2b clinical trial evaluating single-agent oral selinexor (60 mg, twice weekly) in patients that had relapsed or refractory DLBCL after at least two prior multi-agent therapies and who were ineligible for transplantation, including high dose chemotherapy with stem cell rescue.

In this population, XPOVIO demonstrated an ORR of 29%, including a CR rate of 13%.

Responses were seen in all subgroups evaluated regardless of age, gender, prior therapy, DLBCL subtype or prior stem cell transplant therapy.

Patient responses were durable with a median DOR of 9.3 months (23.0 months for patients who achieved a CR).

Importantly, responses were associated with longer survival, underscoring the potential of oral XPO1 inhibition as an oral, non-chemotherapeutic

option for patients with relapsed or refractory DLBCL.

The most common adverse reactions ( ³

20%) in patients with DLBCL who received XPOVIO were fatigue (63%), nausea (57%), diarrhea (37%), decreased appetite (37%), decreased weight (30%), constipation (29%), vomiting (28%), and pyrexia (22%).

laboratory abnormalities ( ³

15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia.

In the SADAL Study, fatal adverse reactions occurred in 3.7% of patients within 30 days of last treatment.

Serious adverse reactions occurred in 46% of patients who received XPOVIO.

Treatment discontinuation rate due to adverse reactions was 17%.

Other DLBCL Studies

During 2021, we expect to conduct the following two studies in DLBCL:

The XPORT-DLBCL-030

, which will serve as a confirmatory study for the June 2020 FDA accelerated approval of XPOVIO to treat DLBCL based on the SADAL Study, is a Phase 2/3 multi-center, randomized study evaluating the combination of selinexor and R-GDP

in patients with relapsed or refractory DLBCL.

The Phase 3 portion of the study will evaluate the selected dose (as identified in the Phase 2 study) of selinexor or matching placebo given with the standard combination immunochemotherapy R-GDP

to patients with at least one prior therapy and who are ineligible for high dose chemotherapy and cell-based intervention such as CAR-T.

The primary endpoint of the Phase 3 portion of the XPORT-DLBCL-030

Study is PFS.

The first patient in this study was dosed in February 2021.

The XPORT-DLBCL-025

is a Phase 1/2 multi-arm

study of selinexor in combination with backbone treatments or novel therapies for the treatment of DLBCL.

The first clinical trial site for the XPORT-DLBCL-025

Study was activated in November 2020 and we plan to initiate this study in 2021.

This study will inform the use of selinexor with a variety of additional agents including novel/novel combinations for the treatment of DLBCL.

Myelofibrosis

Primary MF is a rare blood cancer in which excessive scar tissue (fibrosis) forms in the bone marrow and impairs its ability to produce normal blood cells.

As a result, blood cell production may move to the spleen (causing spleen enlargement) or to other areas of the body.

The incidence of MF is estimated to be approximately 1.5 cases per 100,000 people in the U.S.

with a median OS of 69 months.

MF is more common in older patients with a median age at diagnosis of approximately 65 years.

Allogeneic hematopoietic stem cell transplantation (“HSCT”) is currently the only treatment for MF that can provide a clinical cure;

patients who are not good candidates for HSCT should receive a JAK2 inhibitor, such as ruxolitinib or fedratinib to reduce spleen volume and improve symptoms.

However, not all patients respond adequately to JAK2 inhibitors, and some patients cannot tolerate treatment or progress on treatment.

In preclinical studies, XPO1 inhibition by selinexor selectively suppressed colony formation in MF cells, including those exposed to prior JAK2 inhibitors, compared with normal CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and cancer cell death.

In an MF mouse model, the combination of selinexor and ruxolitinib improved responses compared with monotherapy, including reductions of mutant cells and restoration of splenic architecture.

This formed the preclinical rationale for investigating selinexor in patients with MF.

In 2021, we plan to initiate the XPORT-MF-034

Study, a Phase 1/2 open-label, multicenter study of selinexor to evaluate the safety and efficacy of selinexor in combination with ruxolitinib in treatment naïve patients with MF and the XPORT-MF-035

Study, a Phase 2, randomized, open-label, multicenter study to evaluate the safety and efficacy of single agent selinexor versus treatment of physician’s choice in patients with previously treated MF.

Other Hematologic Malignancies

Myelodysplastic Syndromes

MDS is a group of hematologic malignancies whereby the bone marrow does not make enough healthy blood cells (white blood cells, red blood cells, and platelets) and there are abnormal cells in the blood and/or bone marrow.

The median OS of patients with high-risk MDS refractory to hypomethylating agents is less than six months and, currently, no standard therapy for such patients exists.

In August 2020, safety and efficacy results from a single-arm

investigator sponsored Phase 2 study of selinexor in patients with MDS or oligoblastic acute myeloid leukemia refractory to hypomethylating agents were published in the journal The Lancet Haematology

According to The Lancet Haematology

publication, preclinical studies have shown that inhibition of XPO1 causes nuclear accumulation of p53 and disruption of NF-

B signaling, both relevant targets for MDS.

In the 23 patients evaluable in the clinical study, the ORR was 26% (95% CI 10 – 48);

six patients had a marrow complete remission and an additional 12 patients (52%, 95% CI 31 – 73) had stable disease.

The most common grade 3 or 4 AEs were thrombocytopenia (32%;

8/25 patients) and hyponatraemia (20%;

5/25 patients).

There were no drug-related serious AEs and no treatment-related deaths.

Based on these data and the data from a Phase 1 study of eltanexor, as discussed further below, we intend to enroll additional patients in single-agent and combination studies to evaluate eltanexor to treat MDS.

SOLID TUMOR MALIGNANCIES

Solid tumors represent the vast majority of cancer incidences.

Given the large patient population with solid tumors and the mechanistic activity of selinexor that makes it potentially suitable for treating any type of cancer, we are developing selinexor to potentially play a meaningful role across multiple solid tumor indications, either alone or in combination as a backbone therapy.

We have seen encouraging single-agent data for selinexor in a variety of solid tumors including PRs and durable SD with disease control greater than three months.

Our Phase 1b study in patients with liposarcoma and other sarcomas demonstrated durable SD with single agent selinexor, and our Phase 2 studies of selinexor in gynecological malignancies and glioblastoma multiforme, or GBM, also demonstrated anti-cancer activity, including bona fide PRs as well as prolonged SD.

We have seen encouraging single-agent data for selinexor in a variety of solid tumors including PRs and durable stable disease (“SD”) with disease control greater than three months.

Our Phase 2/3 study in patients with dedifferentiated liposarcoma demonstrated statistically significant prolonged PFS of heavily pretreated patients and our Phase 2 studies of selinexor in gynecological malignancies and GBM also demonstrated anti-cancer activity, including bona fide PRs as well as prolonged SD.

Given the promising single-agent activity in difficult-to-treat

indications and the potential to enhance activity in combination with existing therapies, we are currently developing selinexor in unmet needs like liposarcoma and endometrial cancer with plans to expand development in GBM, and to advance combination therapy development with both standard of care and emerging therapies like immune checkpoint inhibitors.

Liposarcoma represents an area of high unmet need, with currently approved treatments for aggressive disease limited to parenteral chemotherapies.

Liposarcoma arises from fat cells or their precursors and represents up to 18% of all soft tissue sarcoma, or approximately 2,500 new cases per year in the United Sates.

Liposarcoma most commonly occurs in the thigh, behind the knee, the groin, the gluteal area or behind the abdominal cavity.

Dedifferentiated liposarcoma is an aggressive form of soft tissue sarcoma that is resistant to both standard chemotherapy and radiation.

indications and the potential to enhance activity in combination with existing therapies, we are currently developing selinexor in unmet needs such as liposarcoma, endometrial cancer and GBM.

In addition, we believe that the results of clinical data from investigator-sponsored studies evaluating selinexor in combination with certain established cancer therapies warrant further research into the potential utility of selinexor in solid tumors and will help us further prioritize future clinical development activities.

For example, in September 2020, clinical data were presented at the ESMO Virtual Congress from advanced solid tumor studies evaluating selinexor in combination with established cancer therapies including combination data with (i) pembrolizumab for the treatment of melanoma;

(ii) carboplatin and paclitaxel for the treatment of advanced or metastatic solid tumors;

and (iii) topotecan for the treatment of advanced or metastatic solid tumors.

We plan to continue to develop selinexor in combination with standard of care anti-cancer drugs, including immunotherapies, with a particular interest in lung cancer, brain cancer, metastatic melanoma and colorectal cancer.

Liposarcoma is a rare cancer of connective tissues that resemble fat cells under a microscope and represents up to 18% of all soft tissue sarcoma, or approximately 2,000 new cases in the U.S.

Current treatment of liposarcoma largely includes a combination of radiation therapy and surgery, with or without chemotherapy.

Dedifferentiated liposarcoma is an aggressive form of soft tissue sarcoma that is resistant to both standard

chemotherapy and radiation.

Liposarcoma has a particularly high rate of recurrence following surgery, especially in cases involving the abdomen.

Except for cases that are cured with surgery, most patients with metastatic liposarcoma will succumb to this disease, and novel therapies are needed.

The Phase 2/3 SEAL Study in Liposarcoma

In our Phase 1b trial to evaluate the effects of food and formulation on selinexor pharmacokinetics in patients with soft tissue or bone sarcoma, 31 of 54 sarcoma patients (57%) experienced SD with single agent selinexor treatment.

Fifteen of the 54 patients had dedifferentiated liposarcoma.

Of these 15 patients with dedifferentiated liposarcoma, 13 (87%) experienced SD and seven (47%) experienced SD of four months or longer.

In light of the Phase 1b data, we are conducting the SEAL ( Se

iposarcoma) study, a multi-center, randomized, double-blind, placebo-controlled Phase 2/3 clinical trial evaluating single-agent oral selinexor in patients with advanced unresectable dedifferentiated liposarcoma who received at least one line of prior systemic therapy.

Patients are randomized to receive either 60mg of selinexor or placebo, respectively, each given twice weekly until progression or intolerability.

Patients on placebo with confirmed progressive disease are permitted to cross over to the selinexor treatment arm.

In June 2018, we reported a successful outcome from the Phase 2 portion of the SEAL study of 56 patients with previously treated, advanced unresectable dedifferentiated liposarcoma.

The median number of prior treatment regimens was two (range of two to 10 prior treatment regimens).

For the study’s primary endpoint, patients treated with selinexor achieved PFS of 5.5 months, compared to 2.7 months for placebo-treated patients with a hazard ratio of 0.67, representing a 33% reduction in

the risk of progression or death.

PFS was assessed by an ICRR committee based on RECIST v1.1.

In this randomized, blinded Phase 2 portion of the study, selinexor demonstrated a safety and tolerability profile consistent with prior studies with AEs, primarily consisting of nausea, fatigue, anorexia and weight loss, and low levels of Grade 3/4 cytopenias, and no new or unexpected safety signals were identified.

The majority of treatment-related AEs were low grade and reversible with dose modifications and/or supportive care.

The data from the Phase 2 portion of the SEAL study, which is complete, demonstrate that treatment with selinexor improves PFS (based on the RECIST v1.1 criteria) and supports the currently ongoing Phase 3 portion of the study using RECIST v1.1 response criteria, and for which top-line

data are anticipated in 2020.

The Phase 3 portion of the SEAL study is being conducted in North America and Europe.

In this blinded, placebo-controlled Phase 3 study, patients are randomized 2:1 to receive either oral selinexor (60mg twice weekly) until disease progression or intolerability, or placebo.

Patients whose disease progresses on placebo will be permitted to cross over to the selinexor arm.

The primary endpoint of the Phase 3 portion of the study is PFS as assessed by the ICRR committee based on RECIST v1.1.

The Phase 3 study design and primary endpoint of PFS were agreed to by the FDA.

data from the Phase 3 portion of the SEAL study are anticipated in 2020.

Assuming a positive outcome, these data are intended to support regulatory submissions requesting approval for oral selinexor as a new treatment for patients with advanced unresectable dedifferentiated liposarcoma.

Selinexor received Orphan Drug designation by the FDA for the patient population being evaluated in the SEAL study.

The SEAL Study

In November 2020, we announced positive top-line

results from the Phase 3 portion of the randomized, double blind, placebo-controlled, cross-over, SEAL Study conducted in North America and Europe in patients with unresectable dedifferentiated liposarcoma.

Patients in this study were randomized 2:1 to receive either oral selinexor (60 mg twice weekly) until disease progression or intolerability, or placebo.

The SEAL Study met its primary endpoint of a statistically significant increase in PFS (hazard ratio=0.70;

p=0.023) as assessed by the Independent Central Radiological Review committee based on RECIST v1.1.

We believe these data indicate that treatment with selinexor reduced the risk of disease progression by approximately 30%, compared to placebo.

The trial allowed patients on placebo with objective progression to cross over to the selinexor treatment arm.

Among those patients who received selinexor, there was a trend towards an improvement in the median OS compared to those patients who began on the placebo arm of the study and never crossed over to the selinexor treatment arm of the study.

The safety profile for selinexor was consistent with previous clinical studies with fewer hematologic and infection-related AEs as compared to selinexor studies in patients with multiple myeloma and DLBCL.

Based on preliminary regulatory feedback, expected cost, commercial potential, and strategic priorities, we are currently evaluating the optimal approach and next steps towards making selinexor available to patients with dedifferentiated liposarcoma, including potentially pursuing a strategy of presenting clinical data to support the use of selinexor in patients with unresectable dedifferentiated liposarcoma as a medically accepted indication in published drug compendia.

Endometrial Cancer

Endometrial cancer, also called endometrial carcinoma, occurs when cells in the endometrium, which is the inner lining of uterus, begin to grow out of control.

In the United States, endometrial cancer is the most common cancer of the female reproductive organs.

The NCI estimates that approximately 62,000 new cases of endometrial cancer will be diagnosed in 2020, with approximately 12,000 deaths.

Endometrial cancer affects mainly post-menopausal women and the average age of a women diagnosed with endometrial cancer is 60.

The Phase 2/3 SIENDO Study in Endometrial Cancer

SIENDO is a randomized, blinded Phase 2/3 trial evaluating selinexor versus placebo as a maintenance therapy in patients with advanced or recurrent endometrial cancer following at least one prior platinum-based combination chemotherapy treatment.

During the first quarter of 2019 an Investigational New Drug, or IND, application was submitted by us and accepted by the FDA, resulting in the transition of this study from investigator-sponsored to company-sponsored.

The overall objective of SIENDO is to obtain conclusive evidence of efficacy for maintenance selinexor in patients with advanced or recurrent endometrial cancer.

This is a multi-national, multi-center trial and is expected to enroll approximately 192 patients.

We currently expect to report topline data from the SIENDO study in 2021.

This trial was designed based on the data from our SIGN study, a Phase 2, open-label study of efficacy and safety of oral selinexor in patients with heavily pre-treated,

progressive gynecological cancers.

Endometrial cancer, also called uterine cancer, occurs when cells in the endometrium, which is the inner lining of uterus, begin to grow out of control.

In the U.S., endometrial cancer is the most common cancer of the female reproductive organs.

The ACS estimates that there will be approximately 60,000 new cases of endometrial cancer diagnosed in 2021 in the U.S., with approximately 11,600 deaths.

Endometrial cancer affects mainly post-menopausal women and the average age of women diagnosed with endometrial cancer is 60.

Endometrial cancer is often detected at an early stage because it frequently produces abnormal vaginal bleeding.

There are currently five different types of standard treatment for patients with endometrial cancer;

surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.

The SIENDO Study

The SIENDO Study is an ongoing multicenter, randomized, double-blinded Phase 3 study evaluating the efficacy and safety of selinexor versus placebo as a maintenance therapy in patients with advanced or recurrent endometrial cancer following at least one prior platinum-based combination chemotherapy treatment.

Participants with primary stage IV or recurrent disease who had a PR or CR after at least 12 weeks of standard taxane-platinum combination chemotherapy are randomized in a 2:1 manner to receive either maintenance therapy of 80 mg of XPOVIO taken once per week or placebo, until disease progression.

The primary endpoint in the study is PFS with the goal of the study demonstrating a hazard ratio of 0.6.

In November 2020, following a pre-specified

interim futility analysis for the SIENDO Study, the DSMB recommended that the study should continue, as previously planned, without the need for adding additional patients to the trial or amending the study protocol.

As of the date of the planned futility analysis, 109 patients of the expected 248 patients had been enrolled in the trial.

We currently expect to report topline data from the SIENDO Study in the second half of 2021.

This trial was designed based on the data from a Phase 2, open-label study of efficacy and safety of oral selinexor in patients with heavily pre-treated,

progressive gynecological cancers (the “SIGN Study”).

In December 2019, the full results from the SIGN Study in patients with recurrent gynecological malignancies were published in Gynecologic Oncology

Vergot et.al., Gynecologic Oncology.

December 2019).

According to the published data, the SIGN Study showed selinexor’s promising anti-tumor activity and disease control in gynecological malignancies.

Of the 66 patients with ovarian cancer, 20 patients (30%) had disease control, meaning PR or SD for at least 12 weeks, including 7 patients (11%) with a PR.

The median duration of response for patients that achieved a PR was 7.4 months.

Of the 66 patients with ovarian cancer, 20 patients (30%) had disease control, meaning PR or SD for at least 12 weeks, including seven patients (11%) with a PR.

The median DOR for patients that achieved a PR was 7.4 months.

Median PFS for all patients with ovarian cancer was 2.6 months and median OS was 7.3 months.

3 unchanged sentences

Notably, fewer Grade 3 and 4 AEs occurred in patients receiving once weekly compared to twice weekly selinexor, with equivalent efficacy.

Glioblastoma multiforme, or GBM, is an area of high unmet need, with existing treatments having very limited success in increasing overall surviving rates.

GBM is the most common and aggressive malignant primary brain tumor in humans, accounting for 60% of brain tumors in adults.

Patients facing GBM face significant morbidity and mortality rates, with over 13,000 deaths per year in the United States.

Additionally, GBM patients endure poor prognosis rates, with a 1-year

survival rate of 37.2%, a 5-year

survival rate of 5.1%, and a median survival rate of roughly 10 months.

Glioblastoma Multiforme

GBM is one of the most common and particularly aggressive forms of brain tumors of primarily glial cell origin, accounting for 48% of all primary malignant brain tumors.

Patients with GBM face significant morbidity and mortality rates, with over 10,000 deaths per year in the U.S.

GBM is an incurable disease and the prognosis for patients is typically poor due, in part, to its aggressive and extensive infiltration of surrounding central nervous system tissue and its frequent inaccessibility for surgical resection within the brain.

In addition, the blood-brain barrier presents an obstacle for many chemotherapeutic agents, with only small, lipophilic molecules able to reach the tumor.

The median age of diagnosis in patients is 64 years old, but GBM can occur at any age, including in childhood.

Median survival in patients with newly diagnosed GBM is approximately 15 months and approximately five to seven months in patients with recurrent disease.

GBM is a disease with high unmet need, with existing treatments having very limited success in increasing overall surviving rates.

The current standard of care for GBM patients includes surgery, radiation therapy, and chemotherapy.

Approved drug treatments for GBM include temozolomide and Avastin ®

Currently approved drug treatments for GBM include temozolomide and Avastin ®

(bevacizumab).

Despite these treatment options, most patients diagnosed with GBM will quickly succumb to the disease and novel therapies are needed.

The Phase 2 KING Study in Glioblastoma Multiforme

The KING study is a Phase 2 study evaluating the efficacy and safety of oral selinexor in patients with recurrent GBM.

In June 2016, we presented data at the American Society of Clinical Oncology, or ASCO, annual meeting where we showed that single-agent oral selinexor demonstrated anti-tumor activity in patients with glioblastoma that recurred after temozolomide and radiation therapy, including selinexor brain penetration at clinically relevant levels, leading to durable anti-cancer activity and disease control of up to 6 months.

Specifically, data as of May 23, 2016 from 33 surgically ineligible patients with GBM that progressed after treatment with temozolomide and radiation showed that selinexor dosed twice weekly at 50mg/m 2

(or approximately 80mg flat dosing) demonstrated anti-tumor activity with a 12% ORR (PR or better) and a 33% DCR (SD or better) with durability of up to six months in two patients.

The most common AEs were thrombocytopenia, fatigue, anorexia, and nausea, consistent with the selinexor adverse event profile.

In July 2019, updated data were presented at the ASCO 2019 annual meeting based on 76 total patients enrolled in the study as of May 2019.

While multiple doses of selinexor were tested in this study (50mg twice weekly, 60 mg twice weekly and 80mg once weekly), the dose of 80mg once per week was determined to be the recommended dose for further evaluation.

In the study, there were 30 patients treated with selinexor 80 mg once per week.

In this cohort, the rate of patients who were still alive and did not have their disease progress after six 28-day

cycles on therapy (called the six-cycle

PFS rate) was 30%, the rate of patients who were still alive and did not have their disease progress after six month on therapy (called the six-month

PFS rate) was 19%, and the ORR was 10%.

Additionally, the median OS in this arm of the trial was 9.4 months.

The most common AEs in this arm of the trial were nausea, fatigue, anorexia, leukopenia, and neutropenia and were predominately Grade 1 and 2 adverse events.

No Grade 4 treatment-related AEs were reported in ≥

10% of patients and no fatal (Grade 5) treatment-related AEs were reported.

The Phase 1/2 XPORT-GBM-029

Based on these positive findings from the KING study, during the second half of 2020, we plan to initiate XPORT-GBM-029,

a new Phase 1/2 multi-center, open-label study to evaluate selinexor in combination with standard of care therapies.

The Phase 1 portion of the study is expected to evaluate selinexor in combination with radiation with or without temozolomide in newly diagnosed GBM and selinexor in combination with lomustine chemotherapy in recurrent GBM.

The Phase 2 portion of the study is designed to be a randomized study to compare the combinations evaluated in the Phase 1 portion against standard of care therapies alone in patients with recurrent or newly diagnosed GBM.

XPO1 is frequently overexpressed in both GBM and in high-grade gliomas and therefore may be an important, novel target in the treatment of patients with GBM.

The degree of XPO1 over-expression correlates with higher tumor grade and poor overall patient survival.

Nonclinical studies indicate that selinexor has potent anti-GBM

activity as monotherapy and is synergistic when combined with radiation, temozolomide and lomustine.

Additionally, in our previous clinical study known as the KING study, selinexor demonstrated that it crosses the blood-brain barrier with adequate intra-tumoral penetration and single-agent efficacy with durable response and disease stabilization in heavily pretreated GBM patients, which we believe supports the rationale for further clinical development of selinexor to treat patients with brain cancers.

The XPORT-GBM-029

We are currently conducting a global Phase 1/2 clinical study evaluating oral selinexor in combination with standard of care therapy in patients with newly diagnosed or recurrent GBM, which is expected to enroll approximately 400 patients at clinical sites in the U.S., Europe, and Israel.

In June 2020, we dosed the first patient in this study.

This study is expected to be conducted in two phases:

a Phase 1 dose finding study followed by a Phase 2 randomized efficacy exploration study, designed to independently evaluate three different combination regimens in three treatment arms in patients with newly diagnosed GBM (Arms A and B) or with recurrent GBM (Arm C).

Arms A and B will investigate selinexor in combination with radiation therapy with or without the addition of temozolomide, while Arm C will evaluate the combination of selinexor and lomustine.

The primary endpoints in the study are PFS in patients with newly diagnosed GBM and OS in patients with recurrent GBM.

OUR OTHER PIPELINE PROGRAMS

In addition to selinexor, we are also advancing a pipeline of novel drug candidates including our other oral SINE compounds eltanexor, verdinexor and KPT-9274.

Eltanexor (KPT-8602)

Eltanexor is a second-generation SINE compound that, like selinexor, selectively blocks the nuclear export protein XPO1.

The mechanism of action for the biological (anti-cancer) activity of eltanexor is believed to be the same as selinexor.

Eltanexor differs from selinexor primarily because it was designed and confirmed to have much lower penetration into the brain in preclinical species compared with selinexor.

Following oral administration, animals treated with eltanexor show lower percentage of body weight loss and improved food consumption, as well as less “fatigue behavior,” in comparison to animals similarly treated with selinexor.

This allows more frequent dosing of eltanexor, enabling a longer period of exposure at higher levels than is possible with selinexor, which allows for greater indication diversification among our SINE compounds.

In many preclinical model systems, the more intensive dosing regimen leads to superior efficacy in comparison to selinexor treatment.

Therefore, eltanexor may cause fewer side effects which are believed to be mediated through the central nervous system such as nausea, fatigue and anorexia in humans.

As a result, we believe that eltanexor represents a second-generation SINE compound and are evaluating safety, tolerability and efficacy in humans.

We initiated our first-in-humans

Phase 1/2 clinical trial for eltanexor in patients with relapsed/refractory multiple myeloma in January 2016.

At the ASH 2017 annual meeting, we reported positive data from the ongoing Phase 1/2 study demonstrating good tolerability and promising activity in multiple myeloma.

The median time on treatment for the overall study population was greater than 130 days, with a range of 10 days to over two years.

The ORR across all 34 patients was 21% including one patient with VGPR.

No CRs were observed.

Among the 14 patients who received a starting dose of eltanexor in combination with dexamethasone, the ORR was 35.7%.

Among the 39 patients evaluable for safety, the most common Grade 1/2 AEs in the multiple myeloma patient population were nausea (54%), fatigue (46%), anemia (38%), diarrhea (38%), dysgeusia (33%), weight loss (33%) and neutropenia (31%).

As expected in this patient population, the most common Grade 3/4 AEs were thrombocytopenia (56%), neutropenia (26%), anemia (15%), leukopenia (15%) and hyponatremia (10%).

Importantly, nausea, fatigue, diarrhea and vomiting were nearly all Grade 1, generally manageable and transient, and bleeding was uncommon.

The maximum tolerated dose was not reached;

however, dose escalation was halted as responses were achieved.

Based on these data, the RP2D in this patient population has been established as 20mg eltanexor dosed five times per week with 20mg dexamethasone dosed twice weekly.

This Phase 1/2 study has been expanded to include patients with high risk MDS, metastatic CRC or metastatic CRPC to determine the safety, preliminary efficacy, and RP2D of eltanexor in patients with these advanced cancers.

These are indications where selinexor and XPO1 inhibition has shown clear activity, but where side effects such as fatigue and anorexia were problematic for patients due to the underlying malignancies.

The mechanism of action for the biological (anti-cancer) activity of eltanexor is similar to selinexor.

However, eltanexor differs from selinexor primarily because it has been confirmed to have much lower brain penetration in preclinical species, when compared with selinexor.

Therefore, eltanexor may cause fewer side effects, particularly those mediated through the central nervous system such as nausea, fatigue and anorexia in humans.

Following oral administration, animals treated with eltanexor showed a lower percentage of body weight loss and improved food consumption, as well as less “fatigue behavior,” in comparison to animals similarly treated with selinexor.

This allows for more frequent dosing of eltanexor, enabling a longer period of exposure at higher levels than is possible with selinexor.

In many preclinical studies, an extended dosing regimen led to superior efficacy in comparison to selinexor treatment.

As a result, we believe that eltanexor represents a potent, efficacious second-generation oral SINE compound and are currently evaluating its safety, tolerability and efficacy in humans.

We currently plan to focus our clinical development of eltanexor in patients with MDS and are conducting a first-in-human

Phase 1/2 clinical trial for eltanexor in patients with relapsed or refractory multiple myeloma, metastatic colorectal cancer, metastatic castration resistant prostate cancer, and higher risk refractory MDS to determine the safety, preliminary efficacy, and RP2D of eltanexor in patients with these advanced cancers.

At the ASH 2019 annual meeting, positive data was presented from the Phase 1/2 study evaluating the safety, tolerability and anti-tumor activity of single-agent oral eltanexor (10 mg or 20 mg once-daily for five days per week) in elderly patients with higher-risk MDS with disease refractory to hypomethylating agents.

Of the 20 patients evaluable for efficacy, seven patients had a complete response without marrow recovery, or mCR, indicating an ORR of 35%.

An additional five patients (25%) achieved SD as their best response.

Median OS was 10.6 months.

Of the 15 patients evaluable for efficacy, seven patients had a marrow CR indicating an ORR of 47%.

An additional five patients (33%) achieved SD as their best response for a total disease control rate of 80% in evaluable patients.

Median OS in patients receiving a 20 mg dose was 10.6 months.

The most common treatment-related AEs were hematologic, gastrointestinal and constitutional.

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This Phase 1/2 study remains ongoing.

Based on these data, we plan to either amend the existing Phase 1/2 study protocol or implement a new protocol to evaluate eltanexor in combination with cedazuridine-decitabine (ASTX727) in patients with newly diagnosed MDS.

The dose finding portion of the study evaluating this novel combination is expected to begin during the second half of 2020.

Once the RP2D of this combination is established, the study is expected to expand into a Phase 2/3 study to explore the efficacy of this combination in newly diagnosed MDS.

is a first-in-class

orally bioavailable small molecule that is a non-competitive

dual modulator of p21-activated

kinase 4, or PAK4, and nicotinamide phosphoribosyltransferase, or NAMPT, which is also known

as PBEF or visfatin.

Co-inhibition

of these targets leads to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis.

Normal cells are more resistant to inhibition by KPT-9274

due in part to their relative genomic stability and lower metabolic rates.

Hematologic and solid tumor cells become dependent on both PAK4 and NAMPT pathways and are therefore susceptible to single-agent cytotoxic effect of KPT-9274.

has shown broad evidence of anti-cancer activity against hematological and solid tumor malignant cells while showing minimal toxicity to normal cells in vitro.

In mouse xenograft studies, KPT-9274

given orally has shown evidence of anti-cancer activity and tolerability.

To our knowledge, we are the only company with an allosteric, PAK4 and/or NAMPT specific inhibitor currently in clinical development.

We initiated a first-in-humans

Phase 1 open-label clinical trial evaluating the safety, tolerability, and efficacy of KPT-9274

in patients with advanced solid malignancies or non-Hodgkin’s

results from this Phase 1 study were presented in September 2017 at the European Society of Medical Oncology, or ESMO, annual meeting.

Among the 18 patients evaluable for preliminary efficacy, there were six (33%) with SD, the longest for 7.3 months.

Tumor reductions were observed in three out of three patients with NAPRT1 deficient tumors.

Among the 21 patients evaluated for safety, the most common Grade 2 AEs across dose levels were arthralgia (43%), anemia (24%) and fatigue (24%).

The most common drug-related Grade 3 or higher AEs across dose levels include anemia (38%) and fatigue (5%).

Gastrointestinal-related AEs were infrequent and low grade.

In addition, it was determined that niacin can be safely administered with KPT-9274

and may improve tolerability, particularly with respect to anemia.

Dose escalation remains ongoing and further evaluation of effects in NAPRT1 deficient tumors is planned.

Enrollment is planned to continue based on the patients’ NAPRT1 status in a 2:1 ratio with twice as many patients with negative NAPRT1 enrolled versus those patients with positive NAPRT1.

These study findings indicate that in patients whose disease has progressed despite most available therapies, KPT-9274

can induce tumor shrinkage and disease stabilization.

In addition, we plan to evaluate the combination of KPT-9274

with an anti-PD1

monoclonal antibody in a phase 1 clinical study in the near future.

Based on these data, we plan to amend the existing Phase 1/2 study protocol to evaluate eltanexor in combination with oral hypomethylating agents in patients with newly diagnosed or previously treated MDS.

The novel combination arms are expected to begin enrollment in 2021.

Verdinexor (KPT-335)

Oral SINE Compound for Lymphoma in Companion Canines

Lymphoma in Companion Canines

We have used spontaneously occurring canine cancers as a surrogate model for human malignancies.

It is widely known that canine lymphomas display a comparable genetic profile and respond to chemotherapy in a fashion similar to their human counterparts (human NHL, most closely DLBCL).

Lymphomas are one of the most common tumors in pet dogs.

Lymphoma in dogs is very aggressive and, without treatment, the tumors are often fatal within weeks.

The majority of dog lymphomas are DLBCL and most of the others are T-cell

Given the similarities of dog and human lymphomas, prior to initiating clinical trials of selinexor in humans, we investigated verdinexor (KPT-335),

a closely related, orally available SINE compound in pet dogs with lymphomas.

Verdinexor received a Minor Use / Minor Species, or MUMS, designation from the FDA’s Center for Veterinary Medicine, or CVM, for the treatment of newly-diagnosed or first relapse after chemotherapy lymphomas in pet dogs.

Several different dog tumor cell lines, including those derived from lymphomas, exhibited growth inhibition and apoptosis in vitro upon exposure to nanomolar concentrations of verdinexor.

Data from a Phase 1 clinical trial of verdinexor as well as dose expansion study involving pet dogs with cancer, primarily with lymphoma, show efficacy of verdinexor to treat dogs with lymphoma.

Side effects included anorexia, weight loss, vomiting and diarrhea and were manageable with dose modulation and supportive care.

We conducted an owner observation-based survey and the data indicated that the overall quality of life did not change significantly in dogs treated with verdinexor.

Based on these findings, a Phase 2b clinical trial, intended to support regulatory approval under the MUMS designation in the United States, was performed in 58 pet dogs with either newly-diagnosed or first relapse after chemotherapy lymphomas.

Verdinexor was administered initially at doses ranging from 25mg/m 2

two or three days per week.

Minimal or no supportive care was given.

The results of

this Phase 2b clinical trial were published in BMC Veterinary Research

(Sadowski, A.R., et.al., August 2018).

According to the published data, the ORR among the 58 dogs was 37%.

The most common AEs related to verdinexor included anorexia, weight loss, vomiting, lethargy and diarrhea.

Most events (95%) were considered grade 1 or 2.

We submitted the safety and effectiveness sections of a New Animal Drug Application for verdinexor to the CVM in December 2013.

In May 2017, we entered into an exclusive licensing agreement with Anivive Lifesciences, Inc., or Anivive, a privately-held biotech company focused on innovations in the veterinary drug and bioinformatics space, pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals.

In exchange, we received an upfront payment and are eligible to receive future milestone payments and royalties.

If approved, we believe that verdinexor would represent the first non-chemotherapy-based

approval for the treatment of dog lymphoma.

The Potential of XPO1 in Settings Beyond Oncology

In addition to its role in cancer, XPO1 is known to play a role in neurological, inflammatory, viral, wound healing and other diseases.

In the hands of academic collaborators, SINE compounds have shown activity in a variety of non-oncology

models consistent with the biology of XPO1.

In January 2018, we entered into an Asset Purchase Agreement with Biogen MA Inc., a subsidiary of Biogen Inc., or Biogen, pursuant to which Biogen acquired KPT-350,

an investigational new drug application-ready, oral SINE compound with a preclinical data package supporting potential efficacy in a number of neuro-inflammatory conditions, as well as certain related assets with an initial focus in amyotrophic lateral sclerosis, or ALS.

According to publicly available information, an IND application for KPT-350

(now BIIB100) was filed in December 2018 and the first patient was dosed in a Phase 1 study of sporadic ALS in June 2019.

SINE compounds have also demonstrated activity in animal models of viral diseases, certain rare diseases and other indications, and we are continuing to develop programs in these areas largely through academic collaborations and non-dilutive

funding opportunities with the intent to out-license

these programs for clinical development and future commercialization.

Our Non-Oncology

Drug Candidates

Verdinexor (KPT-335):

Oral SINE Compound for Viral, Rare Disease and Autoimmune Indications

Verdinexor (KPT-335)

is an oral SINE compound and our lead compound that is being evaluated as a potential therapy for viral, inflammatory, and autoimmune indications, in addition to the canine lymphoma program described above.

It is widely known that canine lymphomas are similar in many ways to the non-Hodgkin’s

lymphomas in humans, display a comparable genetic profile and respond to chemotherapy in a fashion similar to their human counterparts.

Lymphomas are one of the most common tumors in dogs and are very aggressive where, without treatment, the tumors are often fatal within weeks.

The majority of canine lymphomas are DLBCL and most of the others are T-cell

Given the similarities of dog and human lymphomas, prior to initiating clinical trials of selinexor in humans, we investigated verdinexor, a closely related, orally available SINE compound, in dogs with lymphomas.

In May 2017, we entered into an exclusive licensing agreement with Anivive, a privately-held biotech company focused on innovations in the veterinary drug and bioinformatics space, pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals.

In January 2021, Anivive received conditional FDA approval of LAVERDIA ™

(verdinexor) to treat dogs with lymphoma through the Minor Use/Minor Species pathway, which is an option for drugs intended for minor uses in major species, such as dogs, or for minor species.

Verdinexor is the first conditionally approved oral treatment for dogs with lymphoma.

an injectable product, is currently the only other treatment for lymphoma in dogs.

Anivive has five years to complete effectiveness studies to support a full approval of verdinexor in this indication.

The recent approval of verdinexor was supported by a Phase 2b clinical trial conducted with 58 pet dogs with B-

lymphoma who were either newly-diagnosed or who were in their first relapse after chemotherapy and were followed for at least eight months.

Seventeen of the 58 dogs (29%) did not show progression of lymphoma for at least 56 days after taking verdinexor.

Three of these dogs did not show any progression for at least 182 days.

The most common adverse reactions associated with verdinexor were anorexia, vomiting, diarrhea, weight loss, lethargy, increased water intake, increased urination, elevated liver enzymes, and low platelet count.

Viral, Rare Disease and Autoimmune Indications

In addition to canine lymphoma, verdinexor is being evaluated as a potential therapy for viral, inflammatory, and autoimmune indications.

Several autoimmune indications are driven by aberrant pro-inflammatory

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cytokine expression and NF-kB

These include systemic lupus erythematosus, or SLE, a primary focus of our work with verdinexor.

Funded by a grant under the Small Business Innovation Research program, the work to complete pre-clinical

evaluation of verdinexor as a treatment for SLE is expected to finish in early 2020.

At such time, we expect to be in position to file an IND application with the FDA.

In addition to SLE, we are initiating preclinical research in spinal cord injuries.

In September 2019, we and our collaborator were awarded $2.1 million in grant funding from the U.S.

Department of Defense to cover all preclinical work required to reach IND-readiness

in the field of spinal cord injuries.

These include systemic lupus erythematosus (“SLE”), a primary focus of our work with verdinexor.

The National Institute of Health funded project completed preclinical evaluation of verdinexor as a treatment for SLE and positioned the SLE program as Investigational New Drug (“IND”) ready.

In addition, several viruses exclusively utilize XPO1 to shuttle cargos necessary for viral replication, such as viral and host proteins from the nucleus to the cytoplasm.

Due to the stability of host gene targets compared to viruses which rapidly adapt for best fitness in hosts, targeting host genes may offer an approach to limit drug resistance.

We intend to extend preclinical research in viruses that may be relevant to patients with compromised immune systems, such as cytomegalovirus, or CMV.

As such, we are conducting pre-clinical

animal studies of verdinexor in CMV-infected

mice with the National Institutes of Health.

We also intend to investigate verdinexor to treat inflammation in virally-suppressed antiretroviral therapy-receiving individuals.

In 2015, we conducted a randomized, double-blind, placebo-controlled, dose-escalating Phase 1 clinical trial of verdinexor in healthy human volunteers in Australia.

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Mild to moderate AEs of similar grade and in an equivalent percentage of patients as placebo were reported, and no serious or severe AEs were observed.

We plan to continue to explore strategies to pursue the clinical development of verdinexor as a treatment for viral, inflammatory, and autoimmune indications, including potentially partnering with a collaborator or through government-funded grant or contract opportunities.

As part of the exclusive license agreement we entered into with Antengene Therapeutics Limited, or Antengene, in May 2018, we granted Antengene exclusive rights to develop and commercialize verdinexor for the diagnosis, treatment and/or prevention of certain human non-oncology

indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam.

Summary of Mechanism of Action:

Transient XPO1 Inhibition by SINE Compounds

Certain functions may only occur within a particular location in the cell, so one of the ways a cell regulates the function of a particular protein is by controlling that protein’s location within the cell.

The nuclear pore is a complex gate between the nucleus and cytoplasm, regulating the import and export of most large molecules, called macromolecules, including many proteins, into and out of the nucleus.

In healthy cells, nuclear transport, both into and out of the nucleus, is a normal and regular occurrence that is tightly regulated and requires the presence of specific carrier proteins.

XPO1 mediates the export of over 220 mammalian cargo proteins and some growth-promoting mRNAs.

Particularly, XPO1 mediates the transport of the majority of tumor suppressor proteins and appears to be the only mediator of nuclear export for these proteins.

Cancer cells have increased levels of XPO1, causing the increased export of these tumor suppressor proteins from the nucleus.

Since the tumor suppressor proteins must be located in the nucleus to survey for DNA damage and initiate programmed cell death, or apoptosis, XPO1 overexpression in cancer cells neutralizes their tumor suppressing function by removing them from the nucleus.

By blocking XPO1, our SINE compounds inhibit the export of tumor suppressor proteins, leading to their accumulation and functional reactivation in the nucleus.

The accumulation of tumor suppressor proteins in the nucleus amplifies their natural apoptotic function in cancer cells.

Because normal cells have little or no DNA damage, accumulation of tumor suppressor proteins in their nucleus generally does not lead to apoptosis.

Further, SINE compounds reduce the translation of certain growth-promoting and anti-apoptosis proteins—often called oncoproteins—by inhibiting the XPO1-mediated nuclear to cytoplasmic transport of a protein called eIF4E (eukaryotic protein translation initiation factor 4E), which itself binds to the

mRNAs that code for these proteins.

The figure below depicts the process by which our SINE compounds inhibit the XPO1-mediated nuclear export of tumor suppressor proteins and oncoprotein mRNAs.

We believe that the XPO1-inhibiting SINE compounds that we have discovered and developed to date, including selinexor, have the potential to provide novel, oral, targeted therapies that enable tumor suppressor proteins to remain in the nucleus and promote the apoptosis of potentially any type of cancer cell.

In multiple cancer types, patient tumor biopsies have confirmed that selinexor treatment induces nuclear localization of tumor suppressor proteins and, subsequently, cancer cell death, or apoptosis.

We believe that XPOVIO is the only currently approved cancer treatment selectively targeting the restoration and increase in the levels of multiple tumor suppressor proteins in the nucleus.

We believe that selinexor’s novel mechanism of action and oral administration and low levels of major organ toxicities observed to date in patients treated with selinexor in clinical trials, along with encouraging efficacy data, support the potential for selinexor’s broad use across many cancer types, including both hematological and solid tumor malignancies.

Our SINE compounds were the first oral XPO1 inhibitors in clinical development.

We own all intellectual property rights related to the compounds that we are developing, including composition of matter and method of use patents covering selinexor issued by the U.S.

Patent and Trademark Office in 2015 and which provide patent protection through at least 2032, prior to any adjustments or extensions.

The critical components of our business strategy are to:

Maximize the Commercial Value of XPOVIO and Our Other Drug Candidates.

We are also executing on our U.S.

commercial capabilities and supporting the ongoing launch of XPOVIO in the United States.

In 2019 we launched XPOVIO in the U.S.

unique physicians and healthcare accounts.

In 2020, we plan to further penetrate the U.S.

commercial market and further educate the medical community about the clinical data that supported the accelerated approval of XPOVIO.

Outside of the United States, we will either work with existing and potential partners to establish such commercial infrastructure or may consider establishing this infrastructure ourselves on a case by base basis.

To date, we have entered into several strategic arrangements.

In October 2017, we entered into an exclusive license agreement with Ono Pharmaceutical Co., Ltd.

for the development and commercialization of selinexor and eltanexor for all human oncology indications in Japan, South Korea, Taiwan, Hong Kong, and the ASEAN countries.

In May 2018, we entered into an exclusive license agreement with Antengene under which we granted Antengene exclusive rights to develop and commercialize selinexor, eltanexor and KPT-9274,

each for the diagnosis, treatment and/or prevention of all human oncology indications, as well as verdinexor for the diagnosis, treatment and/or prevention of certain human non-oncology

We licensed the development and commercial rights to Antengene for selinexor and eltanexor in the oncology field in mainland China and Macau and licensed the development and commercial rights to Antengene for KPT-9274

in the oncology field and verdinexor in the non-oncology

field in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam.

We currently hold development, marketing, and commercialization rights for selinexor in all other countries and are developing selinexor and seeking regulatory approval for its use in oncology indications without a collaborator in North America and Europe.

Continue to Develop and Seek Regulatory Approvals of Selinexor, Our Lead Novel Drug Candidate, in North America and Europe.

We plan to seek regulatory approvals of selinexor in North America and Europe for each indication in which we receive favorable results in a trial with a survival endpoint that is registration-enabling.

As we did with XPOVIO based on results of the STORM study, we may also seek regulatory approvals where a clinical trial demonstrates significant data in a surrogate endpoint, such as overall response rate, that could allow for accelerated or conditional approval.

We or our current or future partners may seek marketing approvals in other geographies as well.

Maintain Our Competitive Advantage and Scientific Expertise in the Field of Nuclear Transport.

To further our understanding of the role nuclear transport plays in the underlying biology of cancer, as well other major diseases, we plan to continue research in the field of nuclear transport and related areas, primarily by fostering relationships with scientific advisors and physicians.

We continue to explore a variety of standard and novel combinations of other anti-cancer agents with our SINE inhibitors, and these non-clinical

studies are anticipated to provide support for new clinical investigations.

One such example includes the recently initiated combination study of selinexor with Venclexta ®

(venetoclax), an oral inhibitor of the oncoprotein bcl-2.

studies have suggested that the combination may be synergistic in killing cancer cells and a new investigator-sponsored study at Vanderbilt University was initiated to evaluate the clinical potential of this combination.

Beyond oncology, we have taken this approach in the past with KPT-350,

an oral SINE compound for which we developed a preclinical data package supporting potential efficacy in a number of neuro-inflammatory conditions, which Biogen acquired from us in early 2018.

was renamed BIIB100 and is currently in clinical evaluation to treat ALS.

We believe that investing in the recruitment of exceptional advisors, employees, and management is critical to our continued leadership in the nuclear transport field.

We are collaborating with leading patient advocacy groups to provide education on the science behind our SINE compounds and to support the development and execution of clinical trials.

We have advanced the understanding and potential application of SINE compounds in cancer treatment through a broad range of collaborations with leading institutions engaged in evaluating SINE compounds in clinical trials in the United States, Canada, many European countries, Australia, India, Israel, Singapore and elsewhere.

Continue Developing our Pipeline of Novel Drug Candidates.

To date, we have identified several drug candidates:

our oral SINE compounds selinexor, eltanexor and verdinexor and our oral dual

PAK4/NAMPT inhibitor, KPT-9274.

A fifth program, KPT-350

for ALS and other neuro-inflammatory conditions, was sold to Biogen in January 2018.

We may also identify or in-license

novel drug candidates for development in oncology in the future.

Maximize the Value of Our Other SINE Compounds in Non-Oncology Indications through Collaborations.

We may seek to enter into global or regional development, marketing, and commercialization collaboration arrangements for our other SINE compounds in non-oncology

For example, in May 2018, we licensed the development and commercial rights to Antengene for verdinexor in the non-oncology

field in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam.

As described above, in January 2018, we entered into an asset purchase agreement with Biogen pursuant to which Biogen acquired KPT-350

as well as certain related assets with an initial focus in ALS.

Nuclear Transport

Cancer is a disease characterized by unregulated cell growth.

Cancer cells develop when DNA inside the nucleus of normal cells accumulates damage in genes that regulate cell growth and survival.

In healthy cells, proteins called tumor suppressor proteins located in the cell nucleus help prevent accumulation of DNA damage (mutations, chromosomal translocations and other abnormalities) by monitoring DNA for damage, and if damage is detected, the tumor suppressor proteins direct the cell to attempt to repair it.

However, if the DNA damage is too severe, the tumor suppressor proteins direct the cell to die in a process called apoptosis.

Proteins, however, are not made inside the nucleus but rather made outside of the nucleus in an area called the cytoplasm.

A membrane, called the nuclear membrane, separates the nucleus from the cytoplasm.

Larger nuclear proteins, including tumor suppressor proteins, must be transported from the cytoplasm where they are made into the nucleus to perform their functions in keeping a cell healthy.

Similarly, when they have completed their normal functions, these proteins are typically exported back into the cytoplasm.

Proteins move between the nucleus from the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore.

The nuclear pore works like a gate through which large molecules, including many other proteins and RNAs, enter and exit the nucleus.

When molecules enter the nucleus from the cytoplasm, the process is called import, and when molecules exit from the nucleus to the cytoplasm, the process is called export.

Carrier proteins which mediate the import of macromolecules into the nucleus are called importins, and those which mediate the export of macromolecules out of the nucleus are called exportins.

Therefore, the processes of import and export are carried out separately and are typically regulated independently.

Eight exportins have been identified in human cells.

One such export carrier protein was discovered in 1999 and is called exportin 1, or XPO1 or CRM1.

XPO1 exports over 220 proteins referred to as its “cargo proteins.” In particular, XPO1 appears to be the sole exporter for most of the tumor suppressor proteins including p53, p73, p21, p27, APC, FOXO, pRB and survivin.

In addition to exporting tumor suppressor proteins out of the nucleus, XPO1 mediates the nuclear export of a protein called eukaryotic initiation factor 4E, or eIF4E, also called the “mRNA cap binding protein.” eIF4E binds to the mRNAs for many growth-regulating proteins, including c-myc,

and cyclin D.

eIF4E depends on XPO1 to help carry these growth-promoting mRNAs from the nucleus into the cytoplasm where the mRNAs are efficiently translated into proteins.

XPO1 also exports the anti-inflammatory (and anti-tumor) protein I k

B, which inhibits a protein called NF- k

B is found in the nucleus of most cancer cells and plays a role in cancer metastasis and chemotherapy resistance, as well as in many inflammatory and autoimmune diseases.

By exporting I k

B out of the nucleus, XPO1 augments NF- k

XPO1 levels are reported to be elevated in nearly all cancer cells when compared to their healthy cell counterparts.

Therefore, these elevated levels of XPO1 in cancer cells mediate the rapid export of tumor

suppressor proteins as well as I k

B and eIF4E out of the nucleus.

When compared to healthy cells, the increased export of tumor suppressor proteins in cancer cells may lead to reduced monitoring for DNA damage, the normal triggering of apoptosis and increased NF- k

Higher levels of XPO1 expression in cancer cells is also generally correlated with resistance to chemotherapy and poor prognosis of patients.

Inhibiting XPO1 leads to accumulation of tumor suppressor proteins as well as eIF4E and I k

B in the cell nucleus, which has been confirmed in a variety of preclinical models as well as in tumor biopsy tissues from patients treated with selinexor.

Nuclear retention of tumor suppressor proteins increases their efficiency in detecting DNA damage and subsequently triggering apoptosis in cancer cells.

In addition, blocking XPO1 can cause accumulation of eIF4E-bound growth-promoting mRNAs, which may cause a reduction in the levels of growth-promoting proteins in cancer cells;

this has also been confirmed in preclinical models and in patients’ tumor biopsy tissues.

Accumulation of I k

B in the nucleus inhibits NF- k

B, which may be beneficial in overcoming chemotherapy resistance and in treating autoimmune, inflammatory, and neuro-inflammatory disease;

this too has been detected in both preclinical models and in human cancer tissues from treated patients.

For these reasons, we believe blocking XPO1 is a good strategy for treating cancer as well as autoimmune, inflammatory and neuro-inflammatory diseases.

The figure below depicts the process by which XPO1 mediates the nuclear transport process.

XPO1 Mediation of Nuclear Transport

Our Approach:

Targeting Nuclear Export with SINE Compounds

XPOVIO, our approved XPO1 inhibitor, and our drug candidates are first-in-class,

SINE compounds inhibit XPO1-mediated nuclear export by strongly, yet reversibly, binding to the XPO1 cargo binding site, effectively blocking the XPO1-cargo protein interaction.

The transient XPO1 inhibition period that we have observed to date with our SINE compounds appears to be sufficient for elevation of tumor suppressor protein levels and I k

B in the nucleus.

Healthy cells also accumulate tumor suppressor proteins in the presence of a

SINE compound, but they do not undergo apoptosis after transient XPO1 inhibition because they have minimal or no DNA damage.

The figure below depicts the process by which SINE compounds inhibit the XPO1-mediated nuclear export of tumor suppressor proteins.

Transient XPO1 Inhibition by SINE Compounds

In addition to cancer, our SINE compounds have demonstrated the potential to provide therapeutic benefit in a number of other indications.

Specifically, SINE compounds have shown evidence of activity in preclinical models of viral infections, neurological disorders, inflammation and autoimmune diseases.

Our Initial Indication:

According to the World Health Organization, cancer is the second leading cause of death globally and responsible for an estimated 9.6 million deaths in 2018.

Globally, about 1 in 6 deaths is due to cancer.

Additionally, cancer is one of the most important health issues facing patients in the United States.

The American Cancer Society estimates that in the United States, more than 16.9 million Americans with a history of cancer were alive on January 1, 2019 and more than 1.8 million new cancer cases are expected to be diagnosed in 2020.

Approximately 600,000 Americans are expected to die of cancer in 2020.

The most common methods for treating patients with cancer are a combination of surgery, radiation, and drug therapy.

Locoregional therapies, such as surgery and radiation therapy, are particularly effective with localized disease.

However, in situations where the cancer has spread beyond the primary site or cannot otherwise be treated through locoregional therapies, physicians generally use systemic drug therapies.

In many cases, drug therapy includes combinations of several different drugs.

An early approach to cancer treatment was through cytotoxic drugs that kill rapidly proliferating cancer cells by nonspecific mechanisms, such as disrupting cell metabolism or causing damage to cellular components required for survival and rapid growth.

drugs have been effective in the treatment of some cancers, they act in an indiscriminate manner, killing healthy cells as well as cancer cells.

Due to their mechanism of action, many cytotoxic drugs have a narrow dose range above which the toxicity causes unacceptable or even fatal levels of damage and below which the drugs are not effective in promoting cancer cell death.

A different approach to pharmacological cancer treatment has been to develop drugs referred to as targeted therapeutics, which target specific biological molecules in the human body that play a role in the rapid cell growth and spread of cancer.

Targeted therapeutics are designed specifically to exploit vulnerabilities in cancer cells to improve efficacy and to minimize side effects.

The drugs are designed to either attack a target that causes uncontrolled growth of cancer cells because of a genetic alteration more often found in cancer cells than in healthy cells or attack a target that cancer cells are more dependent on for their growth than are healthy cells.

Our SINE compounds are novel therapies specifically designed to force nuclear accumulation in the levels of multiple tumor suppressor and growth regulatory proteins.

When tumor suppressor proteins are located in the cell nucleus, they assess the integrity of a cell’s DNA.

In cells with heavily damaged DNA, such as cancer cells, these tumor suppressor proteins induce cell death, or apoptosis.

Unlike many other targeted therapeutic approaches that only work for a specific set of cancers or in a specific subgroup of patients, we believe that by restoring tumor suppressor proteins to the nucleus where they can assess a cell’s DNA, our SINE compounds have the potential to provide therapeutic benefits across a broad range of both hematological and solid tumor malignancies and benefit a wider range of patients.

Additionally, and as supported by its mechanism of action and preclinical and clinical data, we believe that selinexor has the potential for additive or synergistic benefit with approved and experimental therapies in treating cancer patients.

As a result, we believe that selinexor has the potential to serve as a backbone therapy across multiple hematological and solid tumor malignancies as part of a variety of combination therapies.

Since our founding by Dr.

Sharon Shacham in 2008, our goal has been to establish a leading, independent oncology business.

We are led by Dr.

Shacham, our President and Chief Scientific Officer, and Dr.

Michael Kauffman, our Chief Executive Officer.

Kauffman played a leadership role in the development and approval of Velcade at Millennium Pharmaceuticals and of Kyprolis while serving as Chief Medical Officer at Proteolix and then Onyx Pharmaceuticals.

Both prior to her founding of Karyopharm and while at Karyopharm, Dr.

Shacham has played a leadership role in the discovery and development of many novel drug candidates, which have been or are being tested in human clinical trials.

Since our inception, we have devoted most of our efforts to research and development.

Beginning in July 2019, we have generated revenue from the commercial sale of XPOVIO ®

Net product sales for the year ended December 31, 2019 was $30.5 million.

As of December 31, 2019, we had an accumulated deficit of $873.3 million.

We had net losses of $199.6 million, $178.4 million and $129.0 million for the years ended December 31, 2019, 2018 and 2017, respectively.

Our Strategic Relationships

On May 23, 2018, we entered into a license agreement with Antengene Therapeutics Limited, a corporation organized and existing under the laws of Hong Kong, or Antengene, and a subsidiary of Antengene Corporation Co.

Ltd., a corporation organized and existing under the laws of the People’s Republic of China, pursuant to which we granted Antengene exclusive rights to develop and commercialize, at its own cost, selinexor, eltanexor and KPT-9274,

each for the diagnosis, treatment and/or prevention of all human oncology indications, as well as verdinexor for the diagnosis, treatment and/or prevention of certain human non-oncology

in the oncology field, as well as verdinexor in the non-oncology

field in mainland China, Taiwan, Hong Kong, Macau, South Korea, and the ASEAN countries (Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam).

Under the terms of the Antengene Agreement, we received an upfront cash payment of $11.7 million and are entitled to receive up to $105.0 million in milestone payments

from Antengene if certain development goals are achieved and up to $45.0 million in milestone payments from Antengene if certain sales milestones are achieved.

We are further eligible to receive tiered double-digit royalties based on future net sales of selinexor and eltanexor in China and Macau, and tiered single- to double-digit royalties based on future net sales of KPT-9274

and verdinexor in the licensed territories.

Antengene’s obligations under the license agreement have been guaranteed by Antengene Corporation Co.

According to publicly available information, Antengene filed Clinical Trial Applications, or CTAs, in China with the National Medical Products Administration, or NMPA, for selinexor in multiple myeloma and DLBCL in 2019.

The multiple myeloma CTA, known as MARCH, supports a clinical study of selinexor plus dexamethasone in patients whose disease is refractory to lenalidomide and bortezomib.

The first patient in this study was enrolled in September 2019.

The DLBCL CTA, known as SEARCH, supports a clinical study of selinexor both as single agent and in combination with ATG-008,

for the treatment of relapsed/refractory DLBCL.

Also, Antengene announced on January 3, 2020 that the Food and Drug Administration, Ministry of Health and Welfare, Taiwan has recently approved the commencement of a phase I open-label clinical trial for the PAK4/NAMPT dual target oral inhibitor KPT-9274

in patients with advanced solid tumors or NHL which have progressed despite standard therapy, for whom no standard therapy exists, or who have refused standard therapy.

On January 24, 2018, we entered into an asset purchase agreement with Biogen pursuant to which Biogen acquired our oral SINE compound KPT-350

and certain related assets.

As part of an exclusive license agreement we entered into with Antengene in May 2018, and as amended in May 2020, Antengene maintains the exclusive rights to develop and commercialize verdinexor for the diagnosis, treatment and/or prevention of certain human non-oncology

indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand.

Antengene has reported that it intends to conduct clinical trials of verdinexor for the treatment of chronic active Epstein Barre infection and SLE.

We plan to continue to explore strategies to pursue the clinical development of verdinexor as a treatment for viral, inflammatory, and autoimmune indications, including potentially partnering with additional collaborators or through government-funded grant or contract opportunities.

is our first-in-class

dual inhibitor of PAK4 and NAMPT.

is an orally bioavailable small molecule that we believe could play an important role in cancer development by targeting the two proteins PAK4 and NAMPT.

PAK4 is a signaling protein regulating numerous fundamental cellular processes, including

intracellular transport, cellular division, cell shape and motility, cell survival, immune defense and the development of cancer.

PAK4 interacts with many key signaling molecules involved in cancer such as beta-catenin, CDC42, Raf-1,

BAD and myosin light chain.

NAMPT, also known as PBEF or Visfatin, is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone that can be found in complex with PAK4 in the cell.

NAMPT is of interest as an oncology target because it catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide, a universal energy- and signal-carrying molecule involved in mitochondrial function, energy metabolism, calcium homeostasis, antioxidation, and paradoxically generation of oxidative stress, gene expression, immunological functions, aging, and cell death.

Co-inhibition

of PAK4 and NAMPT may lead to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis.

Normal cells are more resistant to inhibition by KPT-9274

due in part to their relative genomic stability and lower metabolic rates.

Hematologic and solid tumor cells that have become dependent on both PAK4 and NAMPT pathways may be susceptible to single-agent cytotoxicity of KPT-9274.

has shown broad evidence of anti-cancer activity against hematological and solid tumor malignant cells while showing minimal toxicity to normal cells in vitro.

In mouse xenograft studies, oral KPT-9274

has shown evidence of anti-cancer activity and tolerability.

To our knowledge, we are the only company with an allosteric PAK4 modulator and/or NAMPT specific inhibitor currently in clinical development.

is currently being evaluated in a Phase 1 open-label study in patients with advanced solid malignancies or non-Hodgkin’s

As of February 2021, patient enrollment continues in Part C of the trial evaluating the combination of KPT-9274

(nivolumab) in patients with melanoma who progressed on an anti-PD-1

or anti-PD-L1

antibody in a prior line of therapy.

The Potential of Our SINE Compounds in Settings Beyond Oncology

In addition to cancer, our SINE compounds have demonstrated the potential to provide therapeutic benefit in a number of other indications, such as viral infections, neurological disorders, inflammation and autoimmune diseases.

For example, in January 2018, we entered into an Asset Purchase Agreement with Biogen MA Inc., a subsidiary of Biogen Inc.

(“Biogen”), pursuant to which Biogen acquired KPT-350,

which has been renamed by Biogen as BIIB100, an IND application-ready, oral SINE compound with a preclinical data package supporting potential efficacy in a number of neuro-inflammatory conditions, as well as certain related assets with an initial focus in amyotrophic lateral sclerosis (“ALS”).

XPO1 mediates the nuclear export of multiple proteins that impact neurological and inflammatory processes.

Consequently, inhibition of XPO1 by KPT-350

results in a reduction in inflammation and an increase in anti-inflammatory and neuroprotective responses.

penetrates the blood brain barrier to a greater degree than other SINE compounds.

Preclinical data generated largely by external collaborators show efficacy of KPT-350

and related SINE compounds in animal models of amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, epilepsy, and other neuro-inflammatory indications.

Consequently, inhibition of XPO1 by BIIB100 has shown a reduction in inflammation and an increase in anti-inflammatory and neuroprotective responses.

BIIB100 penetrates the blood brain barrier to a greater degree than other SINE compounds.

Preclinical data generated largely by external collaborators show efficacy of BIIB100 and related SINE compounds in animal models of ALS, multiple sclerosis, traumatic brain injury, epilepsy, and other neuro-inflammatory indications.

Biogen is currently conducting a Phase 1 double-blind, placebo-controlled, single-ascending-dose study to evaluate the safety, tolerability and pharmacokinetics and pharmacodynamics of BIIB100 administered orally to adult patients with ALS.

The accumulation of I k

B in the nucleus inhibits NF-

B, which may be beneficial in overcoming chemotherapy resistance and in treating autoimmune, inflammatory, and neuro-inflammatory disease, has been detected in both preclinical models and in human cancer tissues from treated patients.

funding opportunities with the intent to out-license

these programs for clinical development and future commercialization.

Uncertainty Relating to the COVID-19

pandemic has and will continue to affect economies and businesses around the world.

We continue to closely monitor the impact of the COVID-19

pandemic on all aspects of our business, including the impact on our employees, patients and business operations.

We have and may continue to experience disruptions in the future that could impact our results of operations, including product revenue, and financial condition.

Although we do not currently expect that the ongoing COVID-19

pandemic will have a material impact on our business plans or results of operations, we are unable to predict the impact that the COVID-19

pandemic will have on our operating results and financial condition due to numerous uncertainties.

These uncertainties include the availability and effectiveness of vaccines and therapeutics, the duration and scope of the pandemic, the severity of the virus, governmental, business or other actions, travel restrictions and social distancing, business closures or business disruptions, or changes to our operations, among others.

We will continue to monitor the COVID-19

situation closely and intend to follow health and safety guidelines as they evolve.

Further, the impacts of a potential worsening of global economic conditions and the continued disruptions to, and volatility in, the credit and financial markets, as well as other unanticipated consequences remain unknown.

The situation surrounding the COVID-19

pandemic remains fluid and continues to rapidly evolve, and we are actively managing our response and assessing potential impacts to our operating results and financial condition, as well as adverse developments in our business.

Collaboration, License and Other Strategic Agreements

We have formed, and intend to continue to form, strategic alliances to develop and commercialize our products and product candidates.

We enter into collaborations when there is a strategic advantage to us and when we believe the financial terms of the collaboration are favorable for meeting our short- and long-term strategic objectives.

Currently, we maintain complete commercial rights to selinexor in the U.S., Europe, Japan, and Latin America and have entered into the following key agreements:

In May 2020, we entered into an amendment of our May 2018 license agreement with Antengene (the “Original Antengene Agreement”, and, as amended the “Amended Antengene Agreement”).

Antengene is a corporation organized and existing under the laws of Hong Kong, and a subsidiary of Antengene Corporation Co.

Ltd., a corporation organized and existing under the laws of the People’s Republic of China.

Under the terms of the Amended Antengene Agreement, Antengene has the exclusive rights to develop and commercialize, at its own cost, selinexor, eltanexor, KPT-9274,

each for the diagnosis, treatment and/or prevention of all human oncology indications, and verdinexor for the diagnosis, treatment and/or prevention of certain human non-oncology

indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand (the “Antengene Territory”).

Under the terms of the Original Antengene Agreement, in 2018 we received an upfront cash payment of $11.7 million.

In June 2020, we received an additional $11.7 million upfront payment upon execution of the Amended Antengene Agreement.

During 2020 and early 2021, Antengene has progressed its development and regulatory plans and has submitted new drug applications (“NDAs”) for selinexor to regulatory authorities in Singapore, Australia, Hong Kong, South Korea and China for relapsed or refractory multiple myeloma and/or relapsed or refractory DLBCL indications.

In addition, Antengene is currently conducting two registrational Phase 2 clinical trials of XPOVIO in China for relapsed or refractory multiple myeloma and relapsed or refractory DLBCL and has initiated clinical trials for high prevalence cancer types in the Asia Pacific region including peripheral T-cell

lymphoma and NK/T-cell

lymphoma and KRAS-mutant non-small

cell lung cancer.

In December 2020, we received approximately $10.0 million from Antengene upon the submission of certain of Antengene’s recent NDAs and are entitled to receive additional milestone payments from Antengene if

certain development, regulatory and commercialization goals are achieved in the future.

Finally, we will be eligible to receive tiered double-digit royalties based on future net sales of selinexor and eltanexor, and tiered single- to double-digit royalties based on future net sales of verdinexor and KPT-9274

in the Antengene Territory.

In December 2020, we entered into an exclusive distribution agreement for the commercialization of XPOVIO in Canada with FORUS, a Canadian biopharmaceutical company.

Under the terms of the agreement, we received an upfront payment of $5.0 million in December 2020 and are eligible to receive additional payments if certain prespecified regulatory and commercial milestones are achieved by FORUS.

We are also eligible to receive double-digit royalties on future net sales of XPOVIO in Canada.

FORUS received the exclusive rights to commercialize XPOVIO in Canada and is responsible for all regulatory filings and obligations required for registering XPOVIO.

We have retained the exclusive production rights and will supply finished product to FORUS for commercial use in Canada.

Promedico, a Neopharm Company

In February 2020, we entered into an exclusive distribution agreement with Promedico for the commercialization of XPOVIO in Israel and the Palestinian Authority (the “Promedico Territory”).

We will receive certain prespecified payments and are eligible to receive additional payments if certain regulatory and commercial milestones are achieved by Promedico.

We are also eligible to receive double-digit royalties on future net sales in the Promedico Territory.

Promedico received the exclusive rights to commercialize XPOVIO in the Promedico Territory and is responsible for all regulatory filings and obligations required for registering XPOVIO.

We have retained exclusive production rights and will supply finished product for commercial use in the Promedico Territory.

In January 2018, we entered into an asset purchase agreement with Biogen pursuant to which Biogen acquired our oral SINE compound KPT-350,

which has been renamed by Biogen as BIIB100, and certain related assets.

We received a one-time

upfront payment of $10.0 million from Biogen and are eligible to receive additional payments of up to $207 million based on the achievement by Biogen of future specified development and commercial milestones.

upfront payment of $10.0 million in 2018 from Biogen and are eligible to receive additional payments of up to $207.0 million based on the achievement by Biogen of future specified development and commercial milestones.

We are also eligible to receive tiered royalty payments that reach low double digits based on future net sales until the later of the tenth anniversary of the first commercial sale of the applicable product or the expiration of specified patent protection for the applicable product, determined on a county-by-country

According to publicly available information, an IND application for KPT-350

was filed in December 2018 and the first patient was dosed in a Phase 1 study of sporadic ALS in June 2019.

Effective October 11, 2017, we entered into an exclusive license agreement with Ono Pharmaceutical Co., Ltd., or Ono, whereby Ono received rights to develop and commercialize selinexor and eltanexor at its own cost and expense, for the diagnosis, treatment and/or prevention of all human oncology indications in Japan, South Korea, Taiwan, Hong Kong, and the ASEAN countries, which we refer to as the Ono Territory.

In exchange, we received a one-time

upfront payment of ¥2.5 billion (approximately US$21.9 million) from Ono and retain all rights to selinexor and eltanexor outside the Ono Territory.

We are eligible to receive up to an additional ¥19.15 billion (approximately US$176.2 million at the exchange rate on December 31, 2019) if specified future development and commercial milestones are achieved by Ono.

We are also eligible to receive low double-digit royalties based on future net sales of selinexor and eltanexor in the Ono Territory.

Ono will have the ability to participate in any global clinical study of selinexor and eltanexor and will bear the cost and expense for patients enrolled in clinical studies in the Ono Territory.

In May 2017, we entered into an exclusive licensing agreement with Anivive Life Sciences, Inc., or Anivive, pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals.

In exchange, we received an upfront payment of $1.0 million and a subsequent milestone of $250,000 and are eligible to receive up to $43.25 million in future regulatory, clinical and commercial milestone payments, assuming approval in both the United States and the European Union.

In addition, Anivive agreed to pay us up to low double-digit royalty payments based on future

net sales of verdinexor.

If approved, we believe that verdinexor would represent the first non-chemotherapy-

based approval for the treatment of dog lymphoma.

In May 2017, we entered into an exclusive licensing agreement with Anivive pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals.

In 2017, we received an upfront payment of $1.0 million and a subsequent milestone payment of $250,000 and are eligible to receive up to $43.25 million in future regulatory, clinical and commercial milestone payments, assuming regulatory approval of verdinexor in both the U.S.

In addition, Anivive agreed to pay us up to low double-digit royalty payments based on future net sales of verdinexor.

Verdinexor received conditional approval from the FDA in January 2021 as the first oral treatment for canine lymphoma.

This approval triggered an additional milestone obligation to us of $500,000 in January 2021.

In April 2020, we entered into a collaboration, option and license agreement with Curadev, a privately-owned biotechnology company, to identify and co-develop

novel small molecules against various biological targets for the treatment of cancer and other major diseases .

Under the terms of the agreement, we and Curadev have agreed to identify and develop small molecules against up to two targets.

Curadev will conduct exploratory research, drug discovery and development for designated programs up to the conclusion of preclinical proof of concept studies, after which we will have an option to an exclusive license to develop and commercialize each target on a global basis.

We and Curadev will co-fund

and jointly oversee development up to the option exercise period.

CRADA with NCI

In July 2020, we entered into a CRADA with the NCI’s Cancer Therapy Evaluation Program.

Under the terms of the CRADA, the NCI will collaborate with us on studies to investigate the safety and efficacy of selinexor in various oncology indications, based on encouraging anti-tumor activity observed in earlier studies.

As data from the NCI-sponsored

studies and other Karyopharm-sponsored studies emerge, we plan to collaborate with the NCI on trials to complement and support the further development of selinexor that could address important patient unmet medical needs.

The NCI may also support non-clinical

studies to explore important future combinations of selinexor with other targeted or standard of care cancer agents.

Intellectual Property

Our commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection for our drug candidates, our core technologies, and other know-how,

Our commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection for our products and product candidates, our core technologies, and other know-how,

to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary or intellectual property rights.

Our policy is to seek to protect our proprietary and intellectual property position by, among other methods, filing patent applications in the United States and in foreign jurisdictions related to our proprietary technology and drug candidates.

Our policy is to seek to protect our proprietary and intellectual property position by, among other methods, filing patent applications in the U.S.

and in foreign jurisdictions related to our proprietary technology and products and product candidates.

We also rely on trade secrets, know-how

and continuing technological innovation to develop and maintain our proprietary and intellectual property position.

We file patent applications directed to the composition of matter and methods of use and manufacture for our drug candidates.

As of February 10, 2020, we were the sole owner of 20 patents in the United States and we had 10 pending patent applications in the United States, two pending international applications filed under the Patent Cooperation Treaty, or PCT, 59 granted patents and 96 pending patent applications in foreign jurisdictions.

We file patent applications directed to the composition of matter and methods of use and manufacture for our products and product candidates.

As of February 2, 2021, we were the sole owner of 21 patents in the U.S.

and we had 16 pending patent applications in the U.S., four pending international applications filed under the Patent Cooperation Treaty (“PCT”), 77 granted patents and 71 pending patent applications in foreign jurisdictions.

The PCT is an international patent law treaty that provides a unified procedure for filing a single initial patent application to seek patent protection for an invention simultaneously in each of the member states.

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The technology underlying such pending patent applications has been developed by us and was not acquired from any in-licensing

The intellectual property portfolios for our key drug candidates as of February 10, 2020 are summarized below.

The intellectual property portfolios for our key products and product candidates as of February 2, 2021 are summarized below.

Selinexor (KPT-330)

Our selinexor patent portfolio covers the composition of matter and methods of use of selinexor, as well as methods of making selinexor, and consists of five issued U.S.

patents (two patents are specific to selinexor, two other patents cover both selinexor and verdinexor and the fifth patent covers polymorphs of selinexor), 23 issued foreign patents, 43 pending foreign patent applications, two pending U.S.

Our selinexor patent portfolio covers the composition of matter and methods of use of selinexor and verdinexor, as well as methods of making both, and consists of seven issued U.S.

patents (two patents are specific to selinexor, two patents are specific to verdinexor, two patents cover both selinexor and verdinexor and the seventh patent covers polymorphs of selinexor), 34 issued foreign patents, 39 pending foreign patent applications, two pending U.S.

non-provisional

applications, including one directed to polymorphs of selinexor and one pending U.S.

provisional patent application.

Any patents that may issue in the United States as part of our selinexor patent portfolio, with the exception of a patent directed to the polymorphs of selinexor, will expire in 2032, absent any terminal disclaimer, patent term adjustment due to administrative delays by the United States Patent and Trademark Office, or USPTO, or patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Act.

applications, one pending PCT application and four pending U.S.

provisional patent applications.

The PCT application provides the opportunity to seek protection in all PCT member states.

Any patents that may issue in the U.S.

as part of our selinexor patent portfolio, with the exception of a patent directed to the polymorphs of selinexor and a patent based on the pending PCT application, will expire in 2032, absent any terminal disclaimer, patent term adjustment due to administrative delays by the U.S.

Patent and Trademark Office (“USPTO”) or patent term extension under the Drug Price Competition and Patent

Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Act.

Any patents that may issue in foreign jurisdictions will likewise expire in 2032.

Any patents that may issue in the United States directed to the polymorphs of selinexor will expire in 2035, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patent issued in foreign jurisdictions will likewise expire in 2035.

If a non-provisional

patent application claiming the benefit of the pending U.S.

provisional patent application referenced above is filed in 2020, any patents that may issue from such applications will expire no earlier than 2040.

Any patents that may issue in the U.S.

directed to the polymorphs of selinexor will expire in 2035, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents issued in foreign jurisdictions will likewise expire in 2035.

Any patents that may issue in the U.S.

based on the pending PCT application will expire in 2040, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents issued in foreign jurisdictions will likewise expire in 2040.

If non-provisional

patent applications claiming the benefit of the pending U.S.

provisional patent applications referenced above are filed in 2021, any patents that may issue from such applications will expire no earlier than 2041.

Selinexor (Wound Healing)

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Verdinexor (KPT-335)

Our selinexor patent portfolio described above, with the exception of the applications directed to polymorphs of selinexor, also covers both the composition of matter and

methods of use of verdinexor, as well as methods of making verdinexor.

Our selinexor patent portfolio described above, with the exception of the applications directed to polymorphs of selinexor, the one pending PCT application and the four pending U.S.

provisional applications, also covers both the composition of matter and methods of use of verdinexor, as well as methods of making verdinexor.

There are four issued U.S.

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patents, one pending non-provisional

patent application, nine issued foreign patents, 20 pending foreign patent applications and one pending PCT application.

patent application, 14 issued foreign patents, 15 pending foreign patent applications and one pending PCT application.

The PCT application provides the opportunity for seeking protection in all PCT member states.

Any patents that may issue in the United States as part of our eltanexor patent portfolio, with the exception of a patent based on the pending PCT application, will expire in 2034, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents that may issue in the U.S.

as part of our eltanexor patent portfolio, with the exception of a patent based on the pending PCT application, will expire in 2034, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents issued in foreign jurisdictions will likewise expire in 2034.

Any patents that may issue in the United States based on the pending PCT application will expire in 2039, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents that may issue in the U.S.

based on the pending PCT application will expire in 2039, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents issued in foreign jurisdictions will likewise expire in 2039.

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Our PAK4/NAMPT inhibitors patent portfolio covers both the composition of matter and methods of use of the PAK4/NAMPT inhibitors described therein, such as KPT-9274,

and consists of five patent families with nine issued U.S.

patents, five issued foreign patents, two pending U.S.

and consists of five patent families with six issued U.S.

patents, 11 issued foreign patents, one pending U.S.

non-provisional

patent applications, and 28 pending foreign patent applications in total.

Any patents that may issue in the United States based on the pending U.S.

patent application, and 15 pending foreign patent applications in total.

Any patents that may issue in the U.S.

based on the pending U.S.

non-provisional

applications will expire in 2034 for the earliest filed application and 2036 for the remaining application, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents that may issue based on the pending foreign patent applications will likewise expire in 2034 or 2036.

application will expire in 2034, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents that may issue based on the pending foreign patent applications will likewise expire in 2034.

Foreign patent applications covering the composition of matter and methods of use of KPT-9274

have been filed in 22 countries/regions.

In addition to the patent portfolios covering our key drug candidates, as of February 10, 2020, our patent portfolio also includes five patents (U.S.

Biomarkers for XPO1 Inhibitors

Our patent portfolio also covers biomarkers related to treatment with XPO1 inhibitors, such as selinexor and eltanexor, and consists of seven pending U.S.

provisional applications and two pending PCT applications.

The PCT applications provide the opportunity for seeking protection in all PCT member states.

Any patents that may issue in the U.S.

based on the pending PCT Applications will expire no earlier than 2039 absent any terminal disclaimer, patent term

adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act.

Any patents issued in foreign jurisdictions will likewise expire no earlier than 2039.

If non-provisional

patent applications claiming the benefit of the pending U.S.

provisional applications referenced above are filed in 2021, any patents that may issue from such applications will expire no earlier than 2041.

In addition to the patent portfolios covering our key products and product candidates, as of February 2, 2021, our patent portfolio also includes five patents (U.S.

8,513,230, 9,428,490, 9,550,757,10,526,295 and 10,709,606) and 17 granted foreign patents and pending patent applications in the U.S.

and foreign jurisdictions relating to other XPO1 inhibitors and their use in targeted therapeutics and combination therapies and biomarkers for XPO1 inhibitors.

In the United States, we have trademark registrations for our name and logo, and a combination of the two, XPOVIO, and PORE for our online portal.

We also have pending applications to register two additional possible drug names (examination is currently suspended), and KARYFORWARD and a KARYFORWARD logo for our financial aid and charitable services.

Outside the United States, XPOVIO is registered or pending in thirty additional jurisdictions, and is registered or pending in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan.

We also have registrations or applications for eight additional possible drug names in numerous foreign jurisdictions.

and foreign jurisdictions relating to other XPO1 inhibitors and their use in targeted therapeutics and combination therapies for XPO1 inhibitors.

In the U.S., we have trademark registrations for our name and logo, and a combination of the two, XPOVIO, and PORE for our online portal.

We also have pending applications to register two additional possible product names (currently refused), and KARYFORWARD and a KARYFORWARD logo for our financial aid and charitable services.

Outside the U.S., XPOVIO is registered or pending in forty-six

additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan.

The KARYFORWARD logo is registered or pending in four jurisdictions outside the U.S.

We also have registrations or applications for eight additional possible product names in numerous foreign jurisdictions.

The term of individual patents depends upon the legal term for patents in the countries in which they are obtained.

In most countries, including the United States, the patent term is 20 years from the earliest filing date of a non-provisional

In most countries, including the U.S., the patent term is 20 years from the earliest filing date of a non-provisional

patent application.

In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent.

In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent.

The term of a patent that covers a drug may also be eligible for patent term extension when FDA approval is granted, provided statutory and regulatory requirements are met.

See “—Government Regulation—Patent Term Restoration and Extension” below for additional information on such extensions.

In the future, if and when our drug candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those drugs, depending upon the length of the clinical trials for each drug candidate and other factors.

See “ Government Regulation—Patent Term Restoration and Extension

” below for additional information on such extensions.

In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those drugs, depending upon the length of the clinical trials for each product candidate and other factors.

There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our drug candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our products and product candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted.

However, patent applications that we may file or license from third parties may not result in the issuance of patents.

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If third parties prepare and file patent applications that also claim technology or therapeutics to which we have rights, we may have to participate in interference proceedings to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us.

In addition, because of the extensive time required for clinical development and regulatory review of a drug candidate we may develop, it is possible that, before any of our drug candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.

In addition, because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.

In addition to patents, we rely upon unpatented trade secrets and know-how

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We seek to protect our proprietary information, in part, using confidentiality agreements with our collaborators, scientific advisors, employees and consultants, and invention assignment agreements with our employees.

We also have agreements with selected consultants, scientific advisors and collaborators requiring assignment of inventions.

We also have agreements with selected consultants,

scientific advisors and collaborators requiring assignment of inventions.

The confidentiality agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through our relationship with a third party.

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The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.

While we believe that our technology, knowledge, experience and scientific resources provide us with competitive advantages, we face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions.

Any drug candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.

There are several companies developing or marketing treatments for cancer and the other indications on which we currently plan to focus, including many major pharmaceutical and biotechnology companies.

To our knowledge, only one other company with an XPO1 inhibitor has enrolled patients in clinical trials at the present time.

Stemline Therapeutics, Inc.

announced in January 2015 that it had exclusively licensed the rights to develop and commercialize SL-801

(felezonexor), an oral XPO1 inhibitor, from CanBas Co., Ltd.

In December 2015, Stemline announced the opening of its IND and planned initiation of a clinical development program in multiple cancer types.

Stemline currently has a Phase 1 trial that is open and enrolling patients with advanced solid tumors.

Updates were provided at the ESMO 2019 annual meeting indicating one patient had realized a partial response and some other patients had experienced stable disease.

Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even

more resources being concentrated among a smaller number of our competitors.

While we believe that our technology, knowledge, experience and scientific resources provide us with certain competitive advantages, we face competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions.

Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.

There are numerous companies developing or marketing treatments for cancer and the other indications on which we currently plan to focus, including many major pharmaceutical and biotechnology companies.

To our knowledge, there is only one other XPO1 inhibitor in clinical development.

In June 2020, The Menarini Group acquired Stemline Therapeutics, Inc., including its oral XPO1 inhibitor, felezonexor.

The Menarini Group is continuing a Phase 1 dose-escalation trial to evaluate felezonexor in patients with advanced solid tumors.

positive coverage/reimbursement decisions than we do.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

The key competitive factors affecting the success of any approved oncology drug product, including our drug candidates, if approved, are likely to be their efficacy, safety, convenience and price, the availability of alternative cancer therapies and the availability of reimbursement from government and other third-party payors.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize drugs, or commercialize existing drugs in new indications, and those drugs are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any drugs that we may develop.

Our competitors also may obtain FDA or other regulatory approval for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

These competitors also compete with us in recruiting and retaining qualified scientific, commercial and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

The key competitive factors affecting the success of any approved oncology drug product, including our products and product candidates, if approved, are likely to be their efficacy, safety, tolerability, convenience and price, the availability of alternative cancer therapies and the availability of reimbursement from government and other third-party payors.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products, or commercialize existing products in new indications, and those products are or are perceived to be safer, more effective, more convenient, less expensive or more tolerable than any products that we have or may develop.

Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic drugs.

Generic drugs for the treatment of cancer and the other indications on which we currently plan to initially focus are currently on the market, and additional drugs are expected to become available on a generic basis over the coming years.

As we have seen with XPOVIO, and in multiple myeloma, if we obtain marketing approval for our other drug candidates or for selinexor in other indications, we expect that they will be priced at a significant premium over generic versions of older chemotherapy agents and other cancer therapies.

Generic drugs for the treatment of cancer and the other indications on which we currently plan to initially focus are currently on the market, and additional products are expected to become available on a generic basis over the coming years.

If we obtain marketing approval for our other product candidates or for XPOVIO/NEXPOVIO in other indications, we expect that they will be priced at a significant premium over generic versions of older chemotherapy agents and other cancer therapies.

The most common methods of treating patients with cancer are surgery, radiation and drug therapy.

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In many cases, these drugs are administered in combination to enhance efficacy.

While our drug candidates may compete with many existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our drug candidates will be complimentary with them.

While our products and product candidates may compete with many existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our product candidates will be complimentary with them.

Some of the currently approved drug therapies are branded and subject to patent protection, and others are available on a generic basis.

Many of these approved drugs are well-established therapies and are widely accepted by physicians, patients and third-party payors.

In addition to currently marketed therapies, there are also a number of drugs in late stage clinical development to treat cancer and the other indications on which we plan to initially focus.

These drugs in development may provide efficacy, safety, convenience and other benefits that are not provided by currently marketed therapies.

As a result, they may provide significant competition for any of our drug candidates for which we obtain marketing approval.

XPOVIO and, if approved, our other lead drug candidates may compete with the investigational therapies and currently marketed drugs discussed below.

Many of these approved products are well-established therapies and are widely accepted by physicians, patients and third-party payors.

In addition to currently marketed therapies, there are also a number of products in late-stage clinical development to treat cancer and the other indications on which we plan to focus.

These products in development may provide efficacy, safety, tolerability, convenience and other benefits that are not provided by currently marketed therapies.

As a result, they may represent significant competition for any of our products or product candidates for which we obtain marketing approval.

XPOVIO/NEXPOVIO competes with and, if approved, our other lead product candidates may compete with the investigational therapies and/or currently marketed products discussed below.

Multiple Myeloma

Over the past 15 years, ten agents have been approved in the United States for the treatment of patients with multiple myeloma:

bortezomib (Velcade ®

, Takeda), lenalidomide (Revlimid ®

, Celgene), thalidomide (Thalomid ®

, Celgene), liposomal doxorubicin (Doxil ®

, Janssen), carfilzomib (Kyprolis ®

, Amgen), pomalidomide (Pomalyst ®

, Celgene), panobinostat (Farydak ®

, Novartis), daratumumab (Darzalex ®

, Janssen), elotuzumab (Empliciti ®

, BMS), and ixazomib (Ninlaro ®

Approved indications range from the treatment of newly diagnosed patients to those with relapsed and/or refractory multiple myeloma.

Several other anti-cancer agents are in late-stage development for the treatment of patients with multiple myeloma, including anti-B

cell maturation antigen (BCMA), based CAR-T

therapies such as bb2121 and CC-93269

(Bluebird Bio/Celgene/BMS), JCHARHI25 (Juno Therapeutics/Celgene), P-BCMA-101

Johnson/Poseida Therapeutics), JNJ-4528

(LCAR-B38M, Johnson & Johnson/Legend BioTech) and CAR-T-BCMA

monocolonal antibodies such as isatuximab (Sanofi), TAK-079

antibody-drug conjugates such as belantamab mafodotin (GSK2857916, GlaxoSmithKline);

antibodies such as AMG420 (Amgen), REGN5458 (Regeneron) and PF-06863135

and other novel agents such as ibrutinib (Imbruvica ®

, Abbvie/Roche), venetoclax (Venclexta ®

, Abbvie), plitidepsin (PharMar), masitinib (AB Sciences), filanesib (Array Biopharma), oprozomib (Amgen), ricolinostat (Celgene) and melflufen (Oncopeptides).

Non-Hodgkin’s

Lymphoma (NHL)

The initial therapy for DLBCL typically consists of multi-agent cytotoxic drugs in combination with the monoclonal antibody rituximab (Rituxan ®

In patients with DLBCL who are not elderly and who have good organ function, high dose chemotherapy with stem cell transplantation is often used.

Over the past two years, three therapeutic interventions have been approved in the United States for the treatment of patients with relapsed refractory DLBCL, or RR DLBCL, who have received at least two prior therapies:

tisagenlecleucel (Kymriah ®

, Novartis) and axicabtagene ciloleucel (Yescarta ®

, Kite/Gilead), both CAR-T

therapies, and polatuzumab vedotin (Policy ®

, Genentech/Roche).

On December 30, 2019, MorphoSys announced its submission of a biologics license application (BLA) to the FDA for tafasitamab in RR DLBCL.

Newer targeted agents such as the BTK inhibitor ibrutinib (Imbruvica ®

, Pharmacyclics) and the immunomodulatory drug lenalidomide (Revlimid ®

, Celgene) have also shown activity in DLBCL.

There are also a number of other widely used anti-cancer agents that have broad labels which include NHL, and some of these are being evaluated alone or in combination for the treatment of patients with DLBCL that have relapsed after treatment with chemotherapy.

Other anti-cancer agents are also being evaluated in the treatment of DLBCL, including but not limited to, tafasitamab (MOR-208,

MorphoSys), polatuzumab vedotin (Polivy ™

, Roche), magrolimab (Hu5F9-G4,

Forty Seven, Inc.), umbralisib/ublituximab (TG Therapeutics), mosunetuzumab (Roche), ADCT-402

(ADC Therapeutics), zanubrutinib (Brukinsa ™

, Beigene), everolimus (Afinitor ®

, Novartis), venetoclax (Venclexta ®

, Abbvie), acalabrutinib (Calquence ®

, Acerta Pharma), blinatumomab (Blincyto ®

, Amgen), durvalumab (Imfinzi ®

, AstraZeneca), nivolumab (Opdivo ®

, BMS), pembrolizumab (Keytruda ®

, Merck), avelumab (Bavencio ®

, Pfizer/EMD Serono) and brentuximab vendotin (Adcetris ®

, Seattle Genetics).

In addition, other CAR-T

therapies are currently in clinical development.

Dedifferentiated Liposarcoma (DDLS)

Sarcomas are a group of cancers which arise from connective tissue and bone, of which more than 50 subtypes exist.

Liposarcoma is one of the more common types of soft tissue sarcoma.

The initial treatment for liposarcoma is surgery with or without radiotherapy when possible.

When liposarcoma is not amenable to surgery (i.e., unresectable), various systemic treatments, including multiagent and sometimes single agent chemotherapy are used.

Agents used in combination therapies include:

doxorubicin, ifosfamide, epirubicin, gemcitabine, dacarbazine, docetaxel and vinorelbine.

There are a number of anti-cancer agents that have board soft tissue sarcoma labels and are typically used as single agents after initial systemic therapy, which include liposomal doxorubicin, temozolomide, vinorelbine, pazopanib (Votrient ®

Novartis), larotrectinib (for neurotrophic tyrosine receptor kinase, or NTRK, gene fusion-positive sarcomas—Vitrakvi ®

, Bayer) and entrectinib (for NTRK gene fusion-positive sarcomas—Rozlytrek ®

, Genentech/Roche).

Selinexor in being evaluated in patients with advanced, unresectable, dedifferentiated relapsed or refractory liposarcoma who have received at least two prior therapies.

Two agents have been approved in the United States for the management of unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen:

eribulin (Halaven ®

2017) and trabectedin (Yondelis ®

, Janseen 2019).

Other anti-cancer agents are also being evaluated in the treatment of dedifferentiated liposarcoma, including but not limited to HDM201 and LEE011 (Novartis), cabazitaxel (Jevtana ®

, Sanofi), abemaciclib (Verzenio ®

, Lilly), plitidepsin (PharmaMar), Ipilimumab/Nivolumab (BMS), and Pembrolizumab (Keytruda ®

The effectiveness of existing treatments for unresectable or metastatic liposarcoma remains limited and few trials have specifically evaluated dedifferentiated liposarcoma at an advanced stage.

Competition with XPO1 Inhibitors

Drug compounds currently in preclinical studies, if developed and approved, could also be competitive with our drug candidates, if approved.

In January 2015, Stemline Therapeutics, Inc.

announced that it had exclusively licensed the rights to develop and commercialize SL-801,

an XPO1 inhibitor, from CanBas Co., Ltd.

Stemline currently has a Phase 1 trial that is open and enrolling patients with advanced solid tumors and updates were provided at the 2019 ESMO annual meeting indicating one patient had realized a partial response and some other patients had experienced stable disease.

Additionally, Kosan Biosciences Inc.

(acquired by Bristol-Myers Squibb Company) had evaluated compounds derived from leptomycin B in preclinical studies.

To our knowledge, the Kosan compounds are not currently being developed and have never entered human studies.

With respect to indications other than cancer, there are many currently marketed therapies and drugs in late-stage clinical development to treat non-oncology

indications which we may develop of our XPO1 inhibitors.

However, to our knowledge, there are no other XPO1 inhibitors in clinical development for the treatment of any diseases other than cancer, including indications such as autoimmune and inflammatory diseases or wound healing.

There is no published information on the use of the preclinical compounds that have been developed by Kosan Biosciences or CanBas Co./Stemline in models other than cancer.

Competition with PAK4/NAMPT Dual Inhibitors

Our first-in-class

PAK4/NAMPT dual inhibitor KPT-9274,

if developed and approved, would compete with currently marketed therapies and drugs in clinical development to treat cancer.

However, there are currently no marketed therapies that target PAK4 and/or NAMPT.

We are not aware of any company focusing on the development of a PAK4/NAMPT dual inhibitor.

is orally bioavailable and has demonstrated in pre-clinical

studies consistent pharmacokinetics properties, minimal brain penetration, and minimal inhibition of cytochrome P450 (CYP-450)

In early animal models, KPT-9274

has not shown the retinal and cardiac effects observed with certain NAMPT inhibitors.

developed PF-03758309,

a non-selective

PAK inhibitor, meaning that this compound inhibited several of the PAK family members, and not solely PAK4, through Phase 1 clinical development, but that compound had poor oral bioavailability in both animals and humans and, to our knowledge, development has been discontinued.

We are aware that PAK4 biology is being evaluated preclinically by AstraZeneca plc and Genentech, Inc.

(acquired by Roche Holding AG).

We are aware of a possible first in human clinical trial by Arcus Bioscience for its PAK inhibitor in 2020.

We are not aware of any other PAK4 inhibitors that are in clinical development at the present time.

In addition to KPT-9274,

we are aware of three NAMPT inhibitors that have entered phase 1/2 human clinical trials in patients with solid tumors or lymphomas.

These compounds include GMX1778 (also known as CHS-828,

Teva), GMX1777 (water-soluble derivative of GMX1778, Teva), and APO866 (also known as FK866 and WK175).

APO866 and GMX1777 was delivered as parenteral infusions, while GMX1778 was evaluated by oral dosing.

The safety and preliminary efficacy of these inhibitors as reported in the literature appeared to show unfavorable pharmacokinetics properties (limited/no oral bioavailability, poor plasma stability, high inter- and intra-patient variability, and drug-drug interactions).

To our knowledge, development of these inhibitors were discontinued.

We are also aware that OT-82

(OncoTartis) has advanced to first in human clinical development stage.

We are aware that NAMPT biology is being evaluated by Genentech, Inc., Eli Lilly & Company, Millennium/Takeda Pharmaceutical Company Ltd., OncoTartis, Inc., Arcus Bioscience, Aurigene Discovery Technologies Limited, and at some academic institutions.

We are not aware of any other NAMPT inhibitors in clinical development.

Many therapies are approved for use in patients with multiple myeloma.

Our primary competitors in this indication, including the following, currently treat patients ranging from newly diagnosed patients to those with relapsed and/or refractory multiple myeloma and are indicated for use either as single agent and/or as combination therapies:

(lenalidomide), Pomalyst ®

(pomalidomide) and Thalomid ®

(thalidomide), all marketed by Celgene Corporation (“Celgene”) /Bristol-Myers Squibb Company (“BMS”);

(bortezomib) marketed by Takeda Pharmaceutical Company Limited (“Takeda”) in the U.S.

and Janssen Pharmaceutical K.K.

(“Janssen”) outside of the U.S., Ninlaro ®

(ixazomib) marketed by Takeda and Kyprolis ®

(carfilzomib) marketed by Amgen Inc.

Monoclonal antibodies

(daratumumab) marketed by Janssen, Empliciti ®

(elotuzumab) marketed by BMS and Sarclisa ®

(isatuximab-irfc) marketed by Sanofi S.A.

Antibody Drug Conjugate

BLENREP (belantamab mafodotin-blmf) marketed by GlaxoSmithKline plc (“GSK”);

Histone Deacetylase inhibitor

(panobinostat) marketed by Novartis AG (“Novartis”);

Anthracycline

(liposomal doxorubicin) marketed by Janssen.

Several other anti-cancer agents are in mid to late-stage development for the treatment of patients with multiple myeloma, including:

Anti-BCMA directed CAR-T

ciltacabtagene autoleucel (cilta-cel,

previously known as JNJ-68284528/

from Janssen and Legend Biotech Corporation, ide-cel

(previously known as bb2121) from bluebird bio, Inc.

(“bluebird bio”)/Celgene/BMS, orvacabtagene Autoleucel (orva-cel,

previously known as JCARH125) from Juno Therapeutics, Inc./Celgene/BMS and P-BCMA-101

from Janssen/Poseida Therapeutics, Inc.;

Immunomodulator

Iberdomide (previously known as CC-220,

cereblon E3 ligase modulator) from Celgene/BMS and Opdivo ®

(nivolumab) from BMS;

Alkylating agent

(melphalan flufenamide) from Oncopeptides AB;

(venetoclax) from AbbVie Inc.

(“AbbVie”)/Genentech USA (“Genentech”);

Anti-CD38 Monocolonal antibodies

mezagitamab (previously known as TAK-079)

teclistamab (previously known as JNJ-64007957)

from Johnson & Johnson/Janssen, CC-93269

from bluebird bio/Celgene/BMS, AMG420 from Amgen, REGN5458 from Regeneron Pharmaceuticals, Inc.

(“Regeneron”) and PF-06863135

from Pfizer Inc.;

Other molecules

(ibrutinib) from Pharmacyclics LLC (“Pharmacyclics”)/AbbVie/Janssen, nirogacestat (previously known as PF 3084014) from Springworks Therapeutics, Inc./Janssen, plitidepsin from Pharma Mar S.A.

(“Pharma Mar”), masitinib from AB Science Group, filanesib from Array Biopharma Inc.

and ricolinostat from Celgene.

The initial therapy for DLBCL typically consists of multi-agent cytotoxic drugs in combination with the monoclonal antibody rituximab (or a rituximab biosimilar).

In patients with DLBCL who are not elderly and who have good organ function, high dose chemotherapy with stem cell transplantation is often used at first relapse.

Over the past five years, a number of therapeutic interventions have been approved in the U.S.

and/or Europe and/or other parts of the world for the treatment of patients with relapsed or refractory DLBCL who have received at least two prior therapies and/or are not eligible for ASCT/HSCT.

These recently approved therapeutic interventions are also being evaluated via late-stage development in earlier lines of therapy for the treatment of patients with DLBCL:

CD19-directed CAR-T

(tisagenlecleucel) marketed by Novartis, Yescarta ®

(axicabtagene ciloleucel) marketed by Kite Pharma, Inc., a Gilead Company, and Breyanzi ®

(lisocabtagene maraleucel;

marketed by BMS;

CD79b-directed antibody-drug conjugate

(polatuzumab vedotin-piiq) marketed by Genentech F.

Hoffmann-La/Roche

AG (“Roche”);

CD19-directed cytolytic antibody:

(tafasitamab-cxix, previously known as MOR208 in combination with lenalidomide) marketed by MorphoSys AG/Incyte Corporation (“Incyte”).

Other agents are listed in the NCCN and/or the ESMO guidelines for use after one to two prior therapies, although they have not been formally approved by the FDA including:

(lenalidomide), Imbruvica ®

(ibrutinib) from Pharmacyclics/Abbvie, and generic multiagent chemotherapy including gemcitabine, oxaliplatin, and bendamustine.

In addition, a number of anti-cancer agents are in mid to late-stage development for the treatment of patients with DLBCL, including:

Immune modulator:

(pembrolizumab) (“Keytruda”) from Merck & Co.

(“Merck”) and Imfinzi ®

(durvalumab) from AstraZeneca plc (“AstraZeneca”);

mosunetuzumab from Genentech/Roche, epcoritamab (previously known as GEN3013) from AbbVie/Genmab A/S, glofitamab (previously known as RG6026) from Genentech/Roche, odronextomab (previously known as REGN1979) from Regeneron, plamotamab (previously known as XmAb13676) from Xencor Inc.

and magrolimab from Gilead Sciences, Inc.;

Antibody drug conjugates:

loncastuximab tesirine (previously known as ADCT-402)

from ADC therapeutics, Adcetris ®

(brentuximab vedotin in CD30+ DLBCL) from Seagen Inc./Takeda and naratuximab emtansine (previously known as Debio1562) from DebioPharm;

Small molecules:

enzastaurin from Denovo Biopharma LLC, Calquence ®

(acalabrutinib) from Acerta Pharma, LLC/AstraZeneca, Venclexta ®

(venetoclax) from AbbVie/Genentech and Brukinsa ™

(zanubrutinib) from Beigene, Ltd;

Monoclonal antibodies:

umbralisib/ublituximab from TG Therapeutics Inc.

Endometrial Cancer

The initial treatment for endometrial cancer is surgery, radiotherapy and where applicable taxane/platinum-based chemotherapy.

Upon disease progression, various chemotherapy agents are commonly used, and recently Keytruda ®

received U.S.

and European approvals as a single agent or in combination with Lenvima ®

(lenvatinib, marketed by Esai) in a subgroup of patients with recurrent disease.

Both Keytruda ®

and Lenvima ®

are also being evaluated in other endometrial cancer lines of therapy.

Other anti-cancer agents are in late-stage development for the treatment of patients with endometrial cancer, specifically for the use of “maintenance” therapy following initial treatment, as in the SIENDO Study and/or in recurrent disease, including:

Immune checkpoints inhibitors:

dostarlimab from GSK/Tesaro, Inc.

(“Tesaro”), Tecentriq ®

(atezolizumab) from Genentech/Roche and Imfinzi ®

(durvalumab) from AstraZeneca;

PARP inhibitor:

(olaparib) from AstraZeneca and Zejula ®

(niraparib) from GSK/Tesaro.

Sales and Marketing

Following the July 2019 U.S.

commercial launch of XPOVIO in multiple myeloma and subsequent FDA approvals in 2020 in both earlier stage multiple myeloma and DLBCL, our commercial team has focused its efforts on educating health care providers on the efficacy and safety profile of XPOVIO with the goal of enabling cancer patients access to this important new medicine.

We are commercializing XPOVIO in the U.S.

with our own focused, customer-facing teams, including sales specialists, reimbursement and access support specialists, and nurse liaisons, each typically with a number of years of experience in the biopharmaceutical industry in hematology/oncology.

We have approximately 70 field-based employees in the U.S.

who call on academic and community-based healthcare professionals who treat multiple myeloma and DLBCL, as well as our reimbursement team.

We believe that the current size of our sales force is appropriate at this time to effectively reach our target audience in the specialty markets in which we currently operate.

Continued growth of our current marketed products and the launch of any future products may require further expansion of our field force and support organization within and outside the U.S.

For the foreseeable future, we intend to develop and commercialize XPOVIO and our product candidates alone in the U.S.

and expect to rely on partners to develop and commercialize our products in territories outside the U.S.

In executing our strategy, our goal is to retain oversight over the global development and commercialization of our products by playing an active role in their commercialization or finding partners who share our vision, values, and culture.

Our sales force is supported by an experienced sales leadership team and professionals in marketing, reimbursement and market access, market research and analytics, commercial operations, finance and human resources.

Our sales and marketing organization uses a variety of pharmaceutical marketing strategies to promote XPOVIO, including sales calls, peer-to-peer

education, non-personal

promotional, and digital content.

We employ third-party vendors, such as advertising agencies, market research firms and suppliers of marketing and other sales support-related services, to assist with our commercial activities.

Our patient support program, KaryForward ®

, is dedicated to providing assistance and resources to our patients with multiple myeloma and DLBCL and their caregivers throughout their XPOVIO treatment.

KaryForward ®

offers support in navigating insurance coverage issues and processes and enabling continuation of our patients’ ability to access XPOVIO in the case of delays or interruptions in the insurance process.

We also offer a copay card, which offers eligible commercial patients who have insurance to receive their prescription for as little as $5.00 per prescription.

Further, the KaryForward ®

program assists eligible patients who do not have insurance or lack coverage to be able to access XPOVIO treatment through our Patient Assistance Program.

Under our KaryForward ®

program, patients are assigned a dedicated nurse case manager, who serves as a point of contact to help patients and their caregivers navigate the treatment process, including by explaining prescription instructions, providing psychosocial support and additional nonclinical education regarding XPOVIO, highlighting expectations when taking XPOVIO and providing referrals for additional third-party support, such as transportation assistance.

Manufacturing

We do not have any manufacturing facilities or personnel.

We currently utilize and expect to continue to utilize third parties for the manufacture and testing of our preclinical, clinical, and commercial drug products.

have engaged one third-party manufacturer to obtain the active pharmaceutical ingredient for selinexor for clinical and commercial testing.

We have engaged a separate third-party manufacturer for fill-and-finish

(tableting) services and have entered into a three-year supply agreement for the manufacture of selinexor 20 mg tablets with this manufacturer.

We obtain all other selinexor supplies or materials on a purchase order basis and do not have a long-term supply arrangement in place at this time.

We currently maintain sufficient inventories to exceed our two-year

forecasts for selinexor and do not have arrangements in place for a redundant supply.

For all of our drug candidates, we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish

services as part of our long-term commercial supply plans.

All of our drug products/candidates are small molecules and are manufactured in reliable and reproducible synthetic processes from readily available starting materials.

The chemistry and formulation processes of selinexor has been developed to meet our large-scale manufacturing needs and do not require unusual equipment in the manufacturing process.

We expect to continue to develop drug candidates that can be produced cost-effectively at contract manufacturing facilities.

We do not own or operate, and have no plans to establish, any manufacturing facilities for our products or product candidates.

We currently rely, and expect to continue to rely, on third-party contract manufacturers to manufacture our products and product candidates for our commercial and clinical use.

We have long-term supply agreements with third-party contract manufacturers to manufacture clinical and commercial supplies of the drug product for XPOVIO and obtain all other supplies or materials for our other compounds on a purchase order basis.

At this time, we rely on a single source supplier for our active pharmaceutical ingredient and drug product manufacturing requirements.

All of our products and product candidates are small molecules and are manufactured in reliable and reproducible synthetic processes from readily available starting materials.

The chemistry and formulation processes of selinexor have been developed to meet our large-scale manufacturing needs and do not require unusual equipment in the manufacturing process.

We maintain sufficient inventory levels throughout our supply chain to exceed our two-year

forecasts for XPOVIO in order to minimize the risks of supply disruption.

To support the commercialization and development of our products and product candidates, we have developed a fully integrated manufacturing support system, including scientific oversight, quality assurance, quality control, regulatory affairs and inventory control policies and procedures.

These support systems are intended to enable us to maintain high standards of quality for our products.

We intend to continue to outsource the manufacture and distribution of our products for the foreseeable future, and we believe this manufacturing strategy will enable us to direct more of our financial resources to the commercialization and development of our products and product candidates.

Government Regulation

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, or EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.

The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

Review and Approval of Drugs in the United States

In the United States, the FDA regulates drug products under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations.

Government authorities in the U.S., at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.

The processes for obtaining regulatory approvals in the U.S.

and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

Review and Approval of Drugs in the U.S.

In the U.S., the FDA regulates drug products under the Federal Food, Drug, and Cosmetic Act (the “FDCA”) and implementing regulations.

The failure to comply with applicable requirements under the FDCA and other applicable laws at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.

An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following:

completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations;

An applicant seeking approval to market and distribute a new drug product in the U.S.

must typically undertake the following:

completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice (“GLP”) regulations;

submission to the FDA of an IND, which must take effect before human clinical trials may begin;

approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;

performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication;

approval by an independent institutional review board (“IRB”) representing each clinical site before each clinical trial may be initiated;

performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (“GCP”) to establish the safety and efficacy of the proposed drug product for each indication;

preparation and submission to the FDA of an NDA;

review of the product by an FDA advisory committee, where appropriate or if applicable;

satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices (“cGMP”) requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;

payment of user fees and securing FDA approval of the NDA;

compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, and post-approval studies required by the FDA.

compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies (“REMS”) and post-approval studies required by the FDA.

Preclinical Studies

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The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

Some long-term preclinical testing, such as animal tests of reproductive AEs and carcinogenicity, may continue after the IND is submitted.

In addition, companies usually must also develop additional information about the chemistry and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

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When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived.

When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with FDA certain regulatory requirements in order to use the study as support for an IND or application for marketing approval.

Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an investigational new drug application as support for an IND or an NDA.

When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as support for an IND or application for marketing approval.

Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an IND application as support for an IND or an NDA.

The final rule provides that such studies must be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects.

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An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee or DSMB.

Additionally, some trials are overseen by a DSMB, an independent group of qualified experts organized by the trial sponsor.

This group provides authorization for whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the study.

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Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.

Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on its ClinicalTrials.gov website.

Similar requirements for posting clinical trial information are present in the European Union (EudraCT) website:

Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health for public dissemination on its ClinicalTrials.gov website.

Similar requirements for posting clinical trial information are present in the EU (EudraCT) website:

https://eudract.ema.europa.eu/ and other countries, as well.

Expanded Access to an Investigational Drug for Treatment Use

Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.

Expanded access, sometimes called “compassionate use,” is the use of IND products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.

The rules and regulations related to expanded access are intended to improve access to investigational drugs for patients who may benefit from investigational therapies.

FDA regulations allow access to investigational drugs under an IND by the company or the treating physician for treatment purposes on a case-by-case

FDA regulations allow access to investigational drugs under an IND by the company or the treating physician for

treatment purposes on a case-by-case

individual patients (single-patient IND applications for treatment in emergency settings and non-emergency

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and larger populations for use of the drug under a treatment protocol or Treatment IND Application.

When considering an IND application for expanded access to an investigational product with the purpose of treating a patient or a group of patients, the sponsor and treating physicians or investigators will determine

suitability when all of the following criteria apply:

patient(s) have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;

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and the expanded use of the investigational drug for the requested treatment will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the product or otherwise compromise the potential development of the product.

On December 13, 2016, the 21st Century Cures Act established (and the 2017 Food and Drug Administration Reauthorization Act later amended) a requirement that sponsors of one or more investigational drugs for the treatment of a serious disease(s) or condition(s) make publicly available their policy for evaluating and responding to requests for expanded access for individual patients.

On December 13, 2016, the 21st Century Cures Act (the “Cures Act”) established (and the 2017 Food and Drug Administration Reauthorization Act later amended) a requirement that sponsors of one or more investigational drugs for the treatment of a serious disease(s) or condition(s) make publicly available their policy for evaluating and responding to requests for expanded access for individual patients.

Although these requirements were rolled out over time, they have now come into full effect.

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In addition, on May 30, 2018, the Right to Try Act was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase I clinical trial and that are undergoing investigation for FDA approval.

The law, among other things, provides a federal framework for certain patients to access certain IND products that have completed a Phase I clinical trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

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The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

These clinical trials are commonly referred to as “pivotal” studies, which denotes a study that presents the data that the FDA or other relevant regulatory agency will use to determine whether or not to approve a drug.

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These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious AEs occur.

In addition, IND safety reports must be submitted to the FDA for any of the following:

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Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.

Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Concurrent with clinical trials, companies often complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, must develop methods for testing the identity, strength, quality, purity, and potency of the final drug.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, purity, and potency of the final product.

Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

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inspections may cover all facilities associated with an NDA submission, including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product manufacturing, and control testing laboratories.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

The FDA will not approve an application unless it

determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

The FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain drug

applications, including applications for drugs in a shortage or drugs for which approval is dependent on remediation of conditions identified in the inspection report.

The FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain drug applications, including applications for drugs in a shortage or drugs for which approval is dependent on remediation of conditions identified in the inspection report.

In addition, as a condition of approval, the FDA may require an applicant to develop a REMS.

REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks.

To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity.

REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure safe use, or ETASU.

To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential AEs, and whether the product is a new molecular entity.

REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure safe use (“ETASU”).

ETASU may include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.

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Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

The FDA determines, on a

The FDA determines, on a case-by-case

basis, whether the proposed product represents a significant improvement when compared with other available therapies.

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A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

Finally, with passage of the 21st Century Cures Act, or Cures Act, in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies.

Finally, with passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies.

A product is eligible for this designation if it is a regenerative medicine therapy (as defined in the Cures Act) that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.

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The FDA may grant accelerated approval to a drug for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (“IMM”) and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

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As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.

Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the drug from the market on an expedited basis.

Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies,

would allow the FDA to withdraw the drug from the market on an expedited basis.

All promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the FDA.

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Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

Later discovery of previously unknown problems with a product, including AEs of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

imposition of post-market studies or clinical trials to assess new safety risks;

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After approval, a drug product generally may not be promoted for uses that are not approved by the FDA, as reflected in the product’s prescribing information.

In the United States, healthcare professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as off-label

In the U.S., healthcare professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as off-label

uses, because the FDA does not regulate the practice of medicine.

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The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, and its implementation regulations, as well as the Drug Supply Chain Security Act, or DSCSA, which regulates the distribution of and tracing of prescription drugs and prescription drug samples at the federal level, and sets minimum standards for the regulation of drug distributors by the states.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”) and its implementation regulations, as well as the Drug Supply Chain Security Act (“DSCSA”), which regulates the distribution of and tracing of prescription drugs and prescription drug samples at the federal level, and sets minimum standards for the regulation of drug distributors by the states.

The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCSA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.

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NDAs filed under Section 505(b)(2) may provide an alternate and potentially more expeditious pathway to FDA approval for new or improved formulations or new uses of previously approved products.

If the Section 505(b)(2) applicant can establish that reliance on the FDA’s previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical

or clinical studies of the new product.

If the Section 505(b)(2) applicant can establish that reliance on the FDA’s

previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies of the new product.

The FDA may also require companies to perform additional studies or measurements to support the change from the approved product.

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In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency.

In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application (“ANDA”) to the agency.

Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug.

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data exclusivity for a new drug containing a new chemical entity.

For the purposes of this provision, a new chemical entity, or NCE, is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA.

For the purposes of this provision, a new chemical entity (“NCE”) is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA.

An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance.

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The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug application within eight months for a drug that has three or fewer approved drugs listed in the Orange Book and is no longer protected by any patent or regulatory exclusivities, or is on the FDA’s drug shortage list.

The new legislation also authorizes FDA to expedite review of competitor generic therapies or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.

The new legislation also authorizes the FDA to expedite review of competitor generic therapies or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.

Hatch-Waxman Patent Certification and the 30-Month

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As a result, approval of a Section 505(b)(2) NDA can be stalled until all the listed patents claiming the referenced product have expired, until any non-patent

exclusivity, such as exclusivity for obtaining approval of a new chemical entity, listed in the Orange Book for the referenced product has expired, and, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit or a decision in the infringement case that is favorable to the Section 505(b)(2) applicant.

exclusivity, such as exclusivity for obtaining approval of an NCE, listed in the Orange Book for the referenced product has expired, and, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit or a decision in the infringement case that is favorable to the Section 505(b)(2) applicant.

Pediatric Studies and Exclusivity

Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

With enactment of the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012, sponsors must also submit pediatric study plans prior to the assessment data.

With enactment of the Food and Drug Administration Safety and Innovation Act (“FDASIA”) in 2012, sponsors must also submit pediatric study plans prior to the assessment data.

Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation.

applicant, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other, and agree upon a final plan.

The applicant, the FDA, and the FDA’s internal review committee must then review the information submitted,

consult with each other, and agree upon a final plan.

The FDA or the applicant may request an amendment to the plan at any time.

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Pediatric exclusivity is another type of non-patent

marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the non-patent

marketing exclusivity in the U.S.

and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the non-patent

and orphan exclusivity.

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Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition (generally meaning that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a drug product available in the United States for treatment of the disease or condition will be recovered from sales of the product).

Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition (generally meaning that it affects fewer than 200,000 individuals in the U.S., or more in cases in which there is no reasonable expectation that the cost of developing and making a drug product available in the U.S.

for treatment of the disease or condition will be recovered from sales of the product).

A company must request orphan product designation before submitting an NDA.

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Orphan product designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will be receiving orphan product exclusivity.

Orphan product exclusivity means that the FDA may not approve any other applications for the same product for the same indication for seven years, except in certain limited circumstances.

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If a drug or drug product designated as an orphan product ultimately receives marketing approval for an indication broader than what was designated in its orphan product application, it may not be entitled to exclusivity.

approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.

Orphan drug exclusivity will not bar approval of another orphan drug under certain circumstances, including if a subsequent product with the same drug for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.

Legislation reverses prior precedent holding that the Orphan Drug Act unambiguously required the FDA to recognize orphan exclusivity regardless of a showing of clinical superiority.

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A patent that covers multiple drugs for which approval is sought can only be extended in connection with one of the approvals.

Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

We cannot provide any assurance that any patent term extension with respect to any U.S.

patent will be obtained and, if obtained, the duration of such extension, in connection with any of our product candidates.

Review and Approval of Animal Drugs in the United States

In addition to pursuing approval of our drug candidates for use in human beings, we may also seek approval of certain drug candidates for veterinary applications.

As with new drug products for human beings, new animal drugs may not be marketed in the United States until they have been approved by the FDA as safe and effective.

Review and Approval of Animal Drugs in the U.S.

In addition to pursuing approval of our product candidates for use in human beings, we may also seek approval of certain product candidates for veterinary applications.

As with new drug products for human beings, new animal drugs may not be marketed in the U.S.

until they have been approved by the FDA as safe and effective.

The requirements and phases governing approval of a new animal drug are analogous to those for new human drugs.

Specifically, the Center for Veterinary Medicine or CVM at FDA is responsible for determining whether a new veterinary product should be approved on the basis of a NADA filed by the applicant.

Specifically, the Center for Veterinary Medicine (“CVM”) at FDA is responsible for determining whether a new veterinary product should be approved on the basis of a New Animal Drug Application (“NADA”) filed by the applicant.

A NADA must contain substantial evidence of the safety and effectiveness of the animal drug, as well as data and controls demonstrating that the product will be manufactured and studied in compliance with, among other things, applicable cGMP and GLP practices.

To begin this process, an applicant must file an Investigational New Animal Drug application, or INAD, with the CVM.

To begin this process, an applicant must file an Investigational New Animal Drug application (“INAD”) with the CVM.

The applicant will hold a pre-development

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In this context, an applicant must submit pivotal protocols to the CVM for review and concurrence prior to conducting the required studies.

The applicant will gather and submit data on safety, efficacy and chemistry, manufacturing and controls or CMC to the CVM for review, as below:

The applicant will gather and submit data on safety, efficacy and chemistry, manufacturing and controls (“CMC”) to the CVM for review, as below:

The design and review of the safety study and the study protocol are completed prior to initiation of the study to help assure that the data generated will meet FDA requirements.

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Review and Approval of Drug Products in the European Union

In order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of products.

In order to market any product outside of the U.S., a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of products.

Whether or not it obtains FDA approval for a product, the company would need to obtain the necessary approvals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions.

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Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

Procedures Governing Approval of Drug Products in the European Union

Procedures Governing Approval of Drug Products

Pursuant to the European Clinical Trials Directive, a system for the approval of clinical trials in the EU has been implemented through national legislation of the member states.

Under this system, an applicant must obtain approval from the competent national authority of a EU member state in which the clinical trial is to be conducted.

Under this system, an applicant must obtain approval from the competent national authority of an EU member state in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial after a competent ethics committee has issued a favorable opinion.

Clinical trial application must be accompanied by an investigational medicinal product dossier with supporting information prescribed by the European Clinical Trials Directive and corresponding national laws of the member states and further detailed in applicable guidance documents.

To obtain marketing approval of a product under EU regulatory systems, an applicant must submit a marketing authorization application, or MAA, either under a centralized or decentralized procedure.

The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid for all EU member states.

Clinical trial application must be accompanied by an investigational medicinal product dossier (“IMPD”) with supporting information prescribed by the European Clinical Trials Directive and corresponding national laws of the member states and further detailed in applicable guidance documents.

To obtain marketing approval of a product under EU regulatory systems, an applicant must submit an MAA either under a centralized or decentralized procedure.

The centralized procedure provides for the grant of a single marketing authorization by the EC that is valid for all EU member states.

The centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal products, advanced therapy products and products with a new active substance indicated for the treatment of certain diseases.

For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.

Under the centralized procedure, the Committee for Medicinal Products for Human Use, or the CHMP, established at the European Medicines Agency, or EMA, is responsible for conducting the initial assessment of a product.

Under the centralized procedure, the CHMP established at the EMA is responsible for conducting the initial assessment of a product.

The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

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Within 90 days of receiving the reference member state’s assessment report and related materials, each concerned member state must decide whether to approve the assessment report and related materials.

If a member state cannot approve the assessment report and related materials on the grounds of potential serious risk to public health, the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the European Commission, whose decision is binding on all member states.

Within this framework, manufacturers may seek approval of hybrid medicinal products under Article 10(3) of Directive 2001/83/EC.

Hybrid applications rely, in part, on information and data from a reference product and new data from appropriate pre-clinical

tests and clinical trials.

Hybrid applications rely, in part, on information and data from a reference product and new data from appropriate preclinical tests and clinical trials.

Such applications are necessary when the proposed product does not meet the strict definition of a generic medicinal product, or bioavailability studies cannot be used to demonstrate bioequivalence, or there are changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration of the generic product compared to the reference medicinal product.

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Where the reference product was authorized via the decentralized procedure, a hybrid application may be accepted for consideration under the centralized procedure if the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation, or the granting of a community authorization for the medicinal product is in the interest of patients at the community level.

Clinical Trial Approval in the European Union

Requirements for the conduct of clinical trials in the EU including Good Clinical Practice, or GCP, are set forth in the Clinical Trials Directive 2001/20/EC and the GCP Directive 2005/28/EC.

Clinical Trial Approval

Requirements for the conduct of clinical trials in the EU including GCP are set forth in the Clinical Trials Directive 2001/20/EC and the GCP Directive 2005/28/EC.

Pursuant to Directive 2001/20/EC and Directive 2005/28/EC, as amended, a system for the approval of clinical trials in the EU has been implemented through national legislation of the EU member states.

Under this system, approval must be obtained from the competent national authority of each EU member state in which a study is planned to be conducted.

To this end, a CTA is submitted, which must be supported by an investigational medicinal product dossier, or IMPD, and further supporting information prescribed by Directive 2001/20/EC and Directive 2005/28/EC and other applicable guidance documents.

To this end, a clinical trial application is submitted, which must be supported by an IMPD and further supporting information prescribed by Directive 2001/20/EC and Directive 2005/28/EC and other applicable guidance documents.

Furthermore, a clinical trial may only be started after a competent ethics committee has issued a favorable opinion on the clinical trial application in that country.

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The Clinical Trials Directive 2001/20/EC will, however, still apply three years from the date of entry into application of the Clinical Trials Regulation to (i) clinical trials applications submitted before the entry into application and (ii) clinical trials applications submitted within one year after the entry into application if the sponsor opts for old system.

As of January 1, 2020, the website of the European Commission reported that the implementation of the Clinical Trials Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the European Commission publishes a notice of this confirmation.

The website indicated that the audit was expected to commence in December 2020.

The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trial in the EU.

The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.

The main characteristics of the regulation include:

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and the involvement of the ethics committees in the assessment procedure in accordance with the national law of the member state concerned but within the overall timelines defined by the Clinical Trials Regulation.

PRIME Designation in the EU

The Regulation was published on June 16, 2014 but has not yet become effective.

As of January 1, 2020, the website of the EC reported that the implementation of the Clinical Trials Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the EC publishes a notice of this confirmation.

The website indicated that the audit was expected to commence in December 2020.

In late 2020, the EMA indicated that it plans to focus on the findings of a system audit;

improving the usability, quality and stability of the clinical trial information system;

and knowledge transfer to prepare users and their organizations for the new clinical trial system.

The EMA has indicated that the system will go live in December 2021.

As in the U.S., parties conducting certain clinical trials must post clinical trial information in the EU at the EudraCT website:

https://eudract.ema.europa.eu.

PRIME Designation

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure.

The PRIority Medicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure.

Products from small- and medium-sized

enterprises, or SMEs, may qualify for earlier entry into the PRIME scheme than larger companies.

Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted.

Importantly, a dedicated Agency contact and rapporteur from the CHMP or Committee for Advanced Therapies, or CAT, are appointed early in PRIME scheme facilitating increased understanding of the product at EMA’s Committee level.

enterprises (“SMEs”) may qualify for earlier entry into the PRIME scheme than larger companies.

Importantly, a dedicated Agency contact and rapporteur from the CHMP or Committee for Advanced Therapies are appointed early in PRIME scheme facilitating increased understanding of the product at EMA’s Committee level.

meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

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of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state.

To this end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.

Once renewed, the marketing authorization is valid for an unlimited period, unless the European Commission or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

Any authorization which is not followed by

the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid (the so-called

To this end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file with respect to quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.

Once renewed, the marketing authorization is valid for an unlimited period, unless the EC or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

Any authorization which is not followed by the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid (the so-called

sunset clause).

Data and Market Exclusivity in the European Union

In the EU, new chemical entities qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

Data and Market Exclusivity

In the EU, NCEs qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorizations can be submitted, and the innovator’s data may be referenced, but not approved for two years.

The overall ten-year

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Regulatory Requirements after Marketing Authorization

As in the United States, both marketing authorization holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA and the competent authorities of the individual EU Member States both before and after grant of the manufacturing and marketing authorizations.

The holder of an EU marketing authorization for a medicinal product must, for example, comply with EU pharmacovigilance legislation and its related regulations and guidelines which entail many requirements for conducting

pharmacovigilance, or the assessment and monitoring of the safety of medicinal products.

As in the U.S., both marketing authorization holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA and the competent authorities of the individual EU Member States both before and after grant of the manufacturing and marketing authorizations.

The manufacturing process for medicinal products in the EU is also highly regulated and regulators may shut down manufacturing facilities that they believe do not comply with regulations.

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In addition, other legislation adopted by individual EU Member States may apply to the advertising and promotion of medicinal products.

These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics, or SmPC, as approved by the competent authorities.

These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”) as approved by the competent authorities.

Promotion of a medicinal product that does not comply with the SmPC is considered to constitute off-label

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General Data Protection Regulation

The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to the EU General Data Protection Regulation, or GDPR, which became effective on May 25, 2018.

The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €

20 million or 4% of annual global revenues, whichever is greater.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the U.S., and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.

Brexit and the Regulatory Framework in the United Kingdom

On June 23, 2016, the electorate in the United Kingdom, or UK, voted in favor of leaving the EU, commonly referred to as Brexit.

Following protracted negotiations, the UK left the EU on January 31, 2020.

Under the withdrawal agreement, there is a transitional period until December 31, 2020 (extendable up to two years).

Discussions between the UK and the UK have so far mainly focused on finalizing withdrawal issues and transition agreements but have been extremely difficult to date.

To date, only an outline of a trade agreement has been reached.

Much remains open but the Prime Minister has indicated that the UK will not seek to extend the transitional period beyond the end of 2020.

If no trade agreement has been reached before the end of the transitional period, there may be significant market and economic disruption.

The Prime Minister has also indicated that the UK will not accept high regulatory alignment with the EU.

Since the regulatory framework for pharmaceutical products in the UK covering quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the UK.

It remains to be seen how, if at all, Brexit will impact regulatory requirements for product candidates and products in the United Kingdom.

On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the EU, commonly referred to as Brexit.

Following protracted negotiations, the United Kingdom left the EU on January 31, 2020.

Under the withdrawal agreement, there was a transitional period until December 31, 2020 (extendable by up to two years).

On December 24, 2020, the United Kingdom and the EU entered into a Trade and Cooperation Agreement.

The agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction.

Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom.

Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the GDPR, has achieved Royal Assent on May 23, 2018 and is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area (“EEA”) to the United Kingdom will remain lawful under GDPR.

The Trade and Cooperation Agreement provides for a transitional period during which the United Kingdom will be treated like an EU member state in relation to processing and transfers of personal data for four months from January 1, 2021.

This may be extended by two further months.

After such period, the United Kingdom will be a “third country” under the GDPR unless the EC adopts an adequacy decision with respect to transfers of personal data to the United Kingdom.

The United Kingdom has already determined that it considers all of the EU 27 and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the United Kingdom to the EU/EEA remain unaffected.

Pricing Decisions for Approved Products

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Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities.

Sales of products will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, such products.

Sales of products will depend, in part, on the extent to which third-party payors, including government health programs in the U.S.

such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, such products.

The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

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In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable regulatory approvals.

Payors also set other criteria to govern the uses of a drug that will be deemed medically appropriate and therefore reimbursed or otherwise covered.

In particular, many public and private health care payors limit reimbursement and coverage to the uses of a drug that are either approved by the FDA or that are supported by other appropriate evidence (for example, published medical literature) and appear in a recognized drug compendium.

Drug compendia are publications that summarize the available medical evidence for particular drug products and identify which uses of a drug are supported or not supported by the available evidence, whether or not such uses have been approved by the FDA.

Nonetheless, product candidates may not be considered medically necessary or cost effective.

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Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit a company’s revenue generated from the sale of any approved products.

Coverage policies and third-party

reimbursement rates may change at any time.

Coverage policies and third-party reimbursement rates may change at any time.

Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

In the United States, we participate in, and have certain price reporting obligations to, the Medicaid Drug Rebate program, several state Medicaid supplemental rebate programs, and other governmental pricing programs.

In the U.S., we participate in, and have certain price reporting obligations to, the Medicaid Drug Rebate program, several state Medicaid supplemental rebate programs, and other governmental pricing programs.

We also have obligations to report the average sales price for certain of our drugs to the Medicare program.

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Federal law requires that any company that participates in the Medicaid Drug Rebate program also participate in the Public Health Service’s 340B drug pricing program (the “340B program”) in order for federal funds to be available for the manufacturer’s drugs under Medicaid.

The 340B program, which is administered by the Health Resources and Services Administration, or HRSA, requires participating manufacturers to agree to charge statutorily defined covered entities no more than the 340B “ceiling price” for the manufacturer’s covered outpatient drugs.

The 340B program, which is administered by the Health Resources and Services Administration (“HRSA”) requires participating manufacturers to agree to charge statutorily defined covered entities no more than the 340B “ceiling price” for the manufacturer’s covered outpatient drugs.

Covered entities include hospitals that serve a disproportionate share of financially needy patients, community health clinics, and other entities that receive certain types of grants under the Public Health Service Act.

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HRSA issued a final regulation regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities, which became effective on January 1, 2019.

It is currently unclear how HRSA will apply its enforcement authority under the new regulation.

It is currently unclear how HRSA will apply its enforcement authority

under the new regulation.

Any charge by HRSA that we have violated the requirements of the regulation could result in civil monetary penalties.

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In addition, legislation may be introduced that, if passed, would further expand the 340B program to additional covered entities or would require participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.

Outside the United States, ensuring adequate coverage and payment for our product candidates will face challenges.

Outside the U.S., ensuring adequate coverage and payment for our product candidates will face challenges.

Pricing of prescription pharmaceuticals is subject to governmental control in many countries.

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The conduct of such a clinical trial could be expensive and result in delays in our commercialization efforts.

In the EU, pricing and reimbursement schemes vary widely from country to country.

Some countries provide that drug products may be marketed only after a reimbursement price has been agreed.

Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular drug candidate to currently available therapies.

For example, the EU provides options for its member states to restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

EU member states may approve a specific price for a drug product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the drug product on the market.

Other member states allow companies to fix their own prices for drug products, but monitor and control company profits.

The downward pressure on healthcare costs in general, particularly prescription drugs, has become intense.

As a result, increasingly high barriers are being erected to the entry of new products.

In addition, in some countries, cross-border imports from low-priced

markets exert competitive pressure that may reduce pricing within a country.

Any country that has price controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing arrangements.

Healthcare Law and Regulation

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the federal civil monetary penalty and false statement laws and regulations relating to pricing and submission of pricing information for government programs, including penalties for knowingly and intentionally overcharging 340B eligible entities and the submission of false or fraudulent pricing information to government entities;

the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal laws that prohibit, among other things, knowingly and willingly executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, which also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the U.S.

Department of Health and Human Services, information related to payments and other transfers of value to clinicians and teaching hospitals (and beginning in 2022, additional non-physician clinicians including physician assistants and nurse practitioners) and clinician ownership and investment interests;

the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), which created additional federal criminal laws that prohibit, among other things, knowingly and willingly executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

HIPAA and HITECH and their implementing regulations, which also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

Department of Health and Human Services, information related to payments and other transfers of value to clinicians and teaching hospitals (and beginning in 2022, additional non-physician

clinicians including physician assistants and nurse practitioners) and clinician ownership and investment interests;

analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by non-governmental

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Healthcare Reform

A primary trend in the United States healthcare industry and elsewhere is cost containment.

There have been a number of federal and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical products, limiting coverage and reimbursement for drugs and other medical products, government control and other changes to the healthcare system in the United States.

By way of example, the United States and state governments continue to propose and pass legislation designed to reduce the cost of healthcare.

In March 2010, Congress enacted the Patient Protection and Affordable Care Act, or ACA, which, among other things, includes changes to the coverage and payment for products under government health care programs.

Among the provisions of the ACA of importance to our potential drug candidates are:

A primary trend in the U.S.

healthcare industry and elsewhere is cost containment.

By way of example, the U.S.

and state governments continue to propose and pass legislation designed to reduce the cost of healthcare.

In March 2010, Congress enacted the Patient Protection and Affordable Care Act (“ACA”), which, among other things, includes changes to the coverage and payment for products under government health care programs.

Among the provisions of the ACA of importance to our products and product candidates are:

an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs, although this fee would not apply to sales of certain products approved exclusively for orphan indications;

expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices and extending rebate liability to prescriptions for individuals enrolled in Medicare Advantage plans;

expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price” for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices and extending rebate liability to prescriptions for individuals enrolled in Medicare Advantage plans;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

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off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

the Independent Payment Advisory Board, or IPAB, which has authority to recommend certain changes to the Medicare program to reduce expenditures by the program that could result in reduced payments for prescription drugs.

a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

the Independent Payment Advisory Board (“IPAB”), which has authority to recommend certain changes to the Medicare program to reduce expenditures by the program that could result in reduced payments for prescription drugs.

However, the IPAB implementation has been not been clearly defined.

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Funding has been allocated to support the mission of the Center for Medicare and Medicaid Innovation from 2011 to 2019.

Other legislative changes have been proposed and adopted in the United States since the ACA was enacted.

Other legislative changes have been proposed and adopted in the U.S.

since the ACA was enacted.

In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.

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This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments, will remain in effect through 2029 unless additional Congressional action is taken.

The Coronavirus Aid, Relief, and Economic Security Act (the “CARES Act”) and other COVID-19

relief legislation, suspended the 2% Medicare sequester from May 1, 2020 through March 3, 2021, and extended the sequester by one year, through 2030.

In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Since enactment of the ACA, there have been and continue to be numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

For example, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, will become effective in 2019.

Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated

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District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

The Trump administration and CMS have both stated that the ruling will have no immediate effect, and on December 30, 2018 the same judge issued an order staying the judgment pending appeal.

The Trump Administration recently represented to the Court of Appeals considering this judgment that it does not oppose the lower court’s ruling.

On July 10, 2019, the Court of Appeals for the Fifth Circuit heard oral argument in this case.

On December 18, 2019, that court affirmed the lower court’s ruling that the individual mandate portion of the ACA is unconstitutional and it remanded the case to the district court for reconsideration of the severability question and additional analysis of the provisions of the ACA.

On December 18, 2019, the Court of Appeals for the Fifth Circuit affirmed the lower court’s ruling that the individual mandate portion of the ACA is unconstitutional and it remanded the case to the district court for reconsideration of the severability question and additional analysis of the provisions of the ACA.

On January 21, 2020, the U.S.

Supreme Court declined to review this decision on an expedited basis.

Supreme Court declined to review this decision on an expedited basis but subsequently agreed to hear the case on its regular calendar.

On November 10, 2020, the Court heard oral argument.

It is expected to issue a decision sometime this year.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

The Trump Administration has also taken executive actions to undermine or delay implementation of the ACA.

Since January 2017, President Trump has signed two Executive Orders designed to delay the implementation of certain provisions of the ACA or otherwise circumvent some of the requirements for health insurance mandated by the ACA.

One Executive Order directs federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any

provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

The second Executive Order terminates the cost-sharing subsidies that reimburse insurers under the ACA.

Several state Attorneys General filed suit to stop the administration from terminating the subsidies, but their request for a restraining order was denied by a federal judge in California on October 25, 2017.

In addition, CMS has recently proposed regulations that would give states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

Further, on June 14, 2018, U.S.

Court of Appeals for the Federal Circuit ruled that the federal government was not required to pay more than $12 billion in ACA risk corridor payments to third-party payors who argued were owed to them.

This decision is under review by the U.S.

Supreme Court during its current term.

The full effects of this gap in reimbursement on third-party payors, the viability of the ACA marketplace, providers, and potentially our business, are not yet known.

The Trump Administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

On January 28, 2021, however, President Biden issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access.

Under this Order, federal agencies are directed to re-examine:

policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19;

demonstrations and waivers under Medicaid and the ACA that may reduce

coverage or undermine the programs, including work requirements;

policies that undermine the Health Insurance Marketplace or other markets for health insurance;

policies that make it more difficult to enroll in Medicaid and the ACA;

and policies that reduce affordability of coverage or financial assistance, including for dependents.

Further, there have been several recent U.S.

congressional inquiries and proposed federal and proposed and enacted state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.

For example, there have been several recent U.S.

At the federal level, Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

For example, on May 11, 2018, the Trump Administration issued a plan to lower drug prices.

Under this blueprint for action, the Trump Administration indicated that the Department of Health and Human Services, or HHS, will:

take steps to end the gaming of regulatory and patent processes by drug makers to unfairly protect monopolies;

advance biosimilars and generics to boost price competition;

evaluate the inclusion of prices in drug makers’ ads to enhance price competition;

speed access to and lower the cost of new drugs by clarifying policies for sharing information between insurers and drug makers;

avoid excessive pricing by relying more on value-based pricing by expanding outcome-based payments in Medicare and Medicaid;

work to give Part D plan sponsors more negotiation power with drug makers;

examine which Medicare Part B drugs could be negotiated for a lower price by Part D plans, and improving the design of the Part B Competitive Acquisition Program;

update Medicare’s drug-pricing dashboard to increase transparency;

prohibit Part D contracts that include “gag rules” that prevent pharmacists from informing patients when they could pay less out-of-pocket

by not using insurance;

and require that Part D plan members be provided with an annual statement of plan payments, out-of-pocket

spending, and drug price increases.

In addition, on December 23, 2019, the Trump Administration published a proposed rulemaking that, if finalized, would allow states or certain other non-federal

government entities to submit importation program proposals to FDA for review and approval.

Applicants would be required to demonstrate their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers.

In addition, the Trump Administration published a final rulemaking that allows states or certain other non-federal

government entities to submit importation program proposals to the FDA for review and approval.

Applicants would be required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers.

At the same time, FDA issued draft guidance that would allow manufacturers to import their own FDA-approved

drugs that are authorized for sale in other countries (multi-market approved products).

In addition, President Trump issued five executive orders intended to lower the costs of prescription drug products.

Several of these orders are reflected in recently promulgated regulations, and one of these regulations is currently subject to a nationwide preliminary injunction.

It remains to be seen whether these orders and resulting regulations will remain in force during the Biden Administration.

At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.

We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

As of February 14, 2020, we had 347 full-time employees.

Human Capital Resources

We believe that the success of our business is fundamentally due to our greatest asset, our employees.

To that end, we have invested significant resources towards the attraction, retention and development of personnel and the promotion and maintenance of diversity in our workforce.

To support these objectives, our human resources programs reflect our commitment to our core values (Innovation, Courage, Urgency, Resiliency and Energy) and are designed to prioritize our employees’ well-being, support their career goals, offer competitive wages and benefits, and enhance our culture through efforts aimed at making the workplace more satisfying, engaging and inclusive.

In order to attract, retain and reward our employees, we provide competitive compensation and benefits packages.

We currently offer all new employees equity in the company and as incentive awards to all our employees in connection with our annual performance reviews.

Our equity and cash incentive plans are aimed to increase stockholder value and the success of our company by motivating our employees to perform to the best of their abilities and achieve our and their objectives.

In addition, many of our employees are stockholders of the Company through participation in our Employee Stock Purchase Plan, which aligns the interests of our employees with our stockholders by providing stock ownership on a tax-deferred

We also provide a 4% match for employee contributions to our Section 401(k) retirement savings plan.

We strive to provide our employees with a safe and healthy work environment and believe that the overall health, safety and wellness of our employees is critical to our long-term success and our growth as a business.

such, we provide our employees and their families with access to a variety of innovative, flexible and convenient health and wellness programs, including benefits that provide protection and security so they can have peace of mind concerning events that may require time away from work or that impact their financial well-being.

Our full-time employees are all eligible to participate in our health, vision, dental, life, and long-term disability insurance plans.

To encourage employees to keep up with routine medical care and participate in our wellness program, we fund a Health Reimbursement Account for participating employees and to help our employees cover medical expenses pre-tax,

we also offer employees a Flexible Spending Account.

Our employees outside the U.S.

receive competitive compensation and benefits that are regularly benchmarked to ensure market norms and reflect our standards.

We encourage and support the growth and development of our employees and, wherever possible, seek to fill positions by promotion, transfer from within the organization and through our employee referral process.

Continual learning and career development is advanced through ongoing performance and development conversations with employees, training programs, customized corporate training engagements and seminars and other training events employees are encouraged to attend in connection with their job duties.

Further, we strongly believe that diversity is a key driver of success.

We strive to bring together employees with a wide variety of backgrounds, skills and culture and encourage all of our employees to maintain a work environment in which our differences are respected.

As of February 16, 2021, we had 432 employees.

None of our employees are represented by a labor union or covered by a collective bargaining agreement, nor have we experienced work stoppages.

We believe that relations with our employees are good.

Corporate Responsibility

We are highly committed to policies and practices focused on environmental, social and corporate governance (“ESG”) positively impacting our social community and maintaining and cultivating good corporate governance.

By focusing on such ESG policies and practices, we believe we can affect a meaningful and positive change in our community and maintain our open, collaborative corporate culture.

Some of the initiatives that we were most proud of in 2020 included donating thousands of personal protection equipment items to hospitals, cancer centers, veterans organizations, and various community groups across the U.S.

and around the globe in response to the COVID-19

We were also proud to actively support a number of scholarship and mentoring programs for students in underserved communities as well as those interested in pursuing degrees in science and technology.

We look forward to continuing our commitment to giving back to our local communities in 2021 and beyond.

Information about our Executive Officers

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President and Chief Scientific Officer

Christopher B.

Primiano, J.D., M.B.A.

Executive Vice President, Chief Business Officer, General Counsel and Secretary

Chief Commercial Officer

Ran Frenkel, RPh.

Chief Development Operations Officer

Jatin Shah, M.D..

Executive Vice President, Chief Medical Officer

Executive Vice President, Chief Development Officer

Tanya Lewis, M.S.

Executive Vice President, Chief Regulatory Officer and Quality Officer

Executive Vice President, Chief Regulatory Affairs and Strategic Operations

Senior Vice President, General Counsel and Secretary

Michael Mason

Senior Vice President, Chief Financial Officer and Treasurer

Stephen Mitchener

Senior Vice President, Chief Business Officer

Jatin Shah, M.D.

Executive Vice President, Chief Medical Officer

Kauffman, M.D., Ph.D

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Karyopharm with Dr.

Sharon Shacham in 2008 and served as our President from January 2011 to December 2013 and as Chief Medical Officer from December 2012 to December 2013.

Prior to joining Karyopharm, he was Chief Medical Officer of Onyx Pharmaceuticals Inc., a biopharmaceutical company, from November 2009 to December 2010.

From November 2008 to November 2009, Dr.

Kauffman was Chief Medical Officer of Proteolix Inc., which was acquired by Onyx Pharmaceuticals.

Sharon Shacham in 2008 and served as our President from 2011 to 2013 and as Chief Medical Officer from 2012 to 2013.

Prior to joining Karyopharm, he was Chief Medical Officer of Onyx Pharmaceuticals Inc.

(“Onyx”), a public biopharmaceutical company, from 2009 to 2010.

From 2008 to 2009, Dr.

Kauffman was Chief Medical Officer of Proteolix Inc., which was acquired by Onyx.

At Proteolix, he led the development of Kyprolis ®

(carfilzomib), a novel proteasome inhibitor approved in refractory myeloma by the Food and Drug Administration in July 2012.

(carfilzomib), a novel proteasome inhibitor approved in refractory myeloma by the FDA in 2012.

Kauffman was an operating partner at Bessemer Venture Partners from 2006 to 2008, where he led investments in biotechnology companies.

From 2006 to 2008, he was President and Chief Executive Officer of Epix Pharmaceuticals, Inc., a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009.

Kauffman was President and Chief Executive Officer of Predix Pharmaceuticals, Inc., a private biopharmaceutical company focused on G protein-coupled receptors (GPCR), from 2002 until its merger into Epix Pharmaceuticals in 2006.

In that role, he led the merger of Predix Pharmaceuticals and Epix Pharmaceuticals, oversaw the discovery and development of four new clinical candidates and led collaboration transactions with Amgen and GlaxoSmithKline.

From March 2000 to September 2002, Dr.

Kauffman was Vice President, Clinical at Millennium Pharmaceuticals, Inc., a biopharmaceutical company, where he led the Velcade ®

From 2006 to 2008, he was President and Chief Executive Officer of Epix Pharmaceuticals, Inc.

(“Epix”), a public biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009.

Kauffman was President and Chief Executive Officer of Predix Pharmaceuticals, Inc.

(“Predix”), a private biopharmaceutical company focused on G protein-coupled receptors, from 2002 until its merger into Epix in 2006.

In that role, he led the merger of Predix and Epix, oversaw the discovery and development of four new clinical candidates and led collaboration transactions with Amgen and GlaxoSmithKline plc.

From 2000 to 2002, Dr.

Kauffman was Vice President, Clinical at Millennium Pharmaceuticals, Inc.

(“Millennium”), a biopharmaceutical company, where he led the Velcade ®

development program.

From September 1997 to March 2000, Dr.

Kauffman held a number of senior positions at Millennium Predictive Medicine, Inc., a biopharmaceutical company and a subsidiary of Millennium Pharmaceuticals, where he led the discovery and development of novel molecular diagnostics for major cancers, including melanoma and led transactions with Becton-Dickenson and Bristol Myers Squibb.

From August 1995 to September 1997, Dr.

From 1997 to 2000, Dr.

Kauffman held a number of senior positions at Millennium Predictive Medicine, Inc., a biopharmaceutical company and a subsidiary of Millennium, where he led the discovery and development of novel molecular diagnostics for major cancers, including melanoma and led transactions with Becton-Dickenson and Bristol Myers Squibb.

From 1995 to 1997, Dr.

Kauffman held a number of senior positions at Biogen Idec, Inc., a biopharmaceutical company, where he led the clinical development of anti-CD40L antibodies in autoimmune and inflammatory diseases, and acted as the main medical advisor to the Biogen business development group.

Kauffman currently serves on the board of directors, nominating and governance committee and research and development committee of Infinity Pharmaceuticals, Inc., a public biopharmaceutical company, on the board of directors and audit committee and as chairman of the compensation committee of Kezar Life Sciences, Inc., also a public biopharmaceutical company, and is the lead director and serves on the board of directors and compensation committee of Verastem Inc., also a public biopharmaceutical company.

Kauffman previously served on the board of directors and compensation and audit committees of Zalicus Inc., a biotechnology company.

Kauffman has served on the Board of Directors, the Audit Committee and as Chairman of the Compensation Committee of Kezar Life Sciences, Inc., a public biopharmaceutical company, since December 2016 and has been the lead director and a member of the Compensation Committee of Verastem Inc., a public biopharmaceutical company, since 2012.

Kauffman previously served on the Board of Directors, Nominating and Governance Committee and Research and Development Committee of Infinity Pharmaceuticals, Inc., a public biopharmaceutical company, from April 2017 to March 2020.

Kauffman received his B.A.

in Biochemistry

from Amherst College and his M.D.

in Biochemistry from Amherst College and his M.D.

from Johns Hopkins Medical School, and he trained in internal medicine and rheumatology at Beth Israel Hospital (now Beth Israel Deaconess Medical Center) and Massachusetts General Hospital.

He is board certified in internal medicine.

Sharon Shacham, Ph.D., M.B.A.

Shacham founded Karyopharm in 2008 and has served as our President since December 2013, and as our Chief Scientific Officer since October 2010.

Shacham served as our President of Research and Development from December 2012 to December 2013, as our Head of Research and Development from October 2010 to December 2012 and as our President and Chief Executive Officer from October 2010 to January 2011.

, Ph.D., M.B.A.

Shacham founded Karyopharm in 2008, has served as our Chief Scientific Officer since 2010 and as our President since 2013.

Shacham served as our President of Research and Development from 2012 to 2013, as our Head of Research and Development from 2010 to 2012 and as our President and Chief Executive Officer from 2010 to 2011.

Shacham established the company to focus on the discovery and development of small molecule inhibitors of nuclear export and has led our scientific progress since inception.

Her computational drug discovery algorithms formed a critical part of the technological basis for our drug discovery and optimization expertise, which was used for the discovery of selinexor, our lead drug candidate.

Shacham co-chairs

our Scientific Advisory Board.

Prior to founding Karyopharm, from 2006 to April 2009, she was Senior Vice President of Drug Development at Epix Pharmaceuticals, Inc., a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009.

She was Director, Algorithm and Software Development at Predix Pharmaceuticals Inc.

from July 2000 until Predix’s merger into Epix Pharmaceuticals in 2006, where she led the company’s efforts in GPCR modeling, computational chemistry, lead optimization and development of clinical trials.

Prior to founding Karyopharm, from 2006 to 2009, she was Senior Vice President of Drug Development at Epix, a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009.

She was Director, Algorithm and Software Development at Predix from 2000 until Predix’s merger into Epix in 2006, where she led the company’s efforts in GPCR modeling, computational chemistry, lead optimization and development of clinical trials.

Shacham received her B.Sc.

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from Tel Aviv University.

Christopher B.

Primiano, J.D., M.B.A.

Primiano joined Karyopharm in March 2014 as Vice President, Corporate Development, General Counsel and Secretary, and was appointed Senior Vice President, Corporate Development, General Counsel and Secretary in September 2015;

Senior Vice President, Operations, Business Development, General Counsel and Secretary in November 2016 and Executive Vice President, Chief Business Officer, General Counsel and Secretary in January 2018.

John Demaree, M.B.A.

has served as our Chief Commercial Officer since March 2020.

Prior to joining Karyopharm, Mr.

Primiano was a Counsel at Wilmer Cutler Pickering Hale and Dorr LLP, where he had practiced law since October 2012.

From August 2010 to August 2012, he served as Vice President, Corporate Development, General Counsel and Secretary of GlassHouse Technologies, Inc., an information technology consulting company, where he led global legal operations and managed asset and subsidiary acquisition and sale activity.

Primiano began his career at Gunderson Dettmer Stough Villeneuve Franklin & Hachigian LLP, where he practiced law from August 2006 to July 2010.

Primiano received a B.A.

in Political Economy and English from Georgetown University, an M.B.A.

from the Boston College Carroll School of Management and a J.D.

from Boston College Law School.

served as Chief Commercial Officer at G1 Therapeutics, Inc.

(“G1”), a biopharmaceutical company, from July 2018 to March 2020 led its integrated commercial functions.

Prior to G1, Mr.

Demaree served as Vice President, Oncology Marketing at Astellas Pharma US, a pharmaceutical company, from July 2016 to July 2018 and as Executive Director from 2011 to July 2016, where he was responsible for establishing and leading the oncology marketing function, including the successful launch of XTANDI ®

(enzalutamide).

Previously, Mr.

Demaree led oncology business development and alliance management at Abbott Laboratories.

He began his career serving in marketing leadership positions at Novartis and Eli Lilly.

holds an M.B.A.

in marketing and finance and a B.S.

in marketing from Indiana University.

Ran Frenkel, RPh.

Frenkel was appointed Executive Vice President, Worldwide Development Operations of Karyopharm in October 2014 and was appointed Chief Development Operations Officer in January 2015.

Frenkel was appointed Executive Vice President, Worldwide Development Operations of Karyopharm in 2014, Executive Vice President, Chief Development Operations Officer from 2015 to August 2020 and EVP, Chief Development Officer in August 2020.

Prior to joining Karyopharm, Mr.

Frenkel held a number of senior management roles in Europe, Israel and the United States, most recently as Managing Director EMEA from January 2013 to October 2014 for Clinipace Worldwide, an international clinical research organization, where he had responsibility for the overall management of the organization in Europe, the Middle East and Africa.

Frenkel held a number of senior management roles in Europe, Israel and the U.S., most recently as Managing Director EMEA from 2013 to 2014 for Clinipace Worldwide, an international clinical research organization, where he had responsibility for the overall management of the organization in Europe, the Middle East and Africa.

Prior to becoming Managing Director EMEA, Mr.

Frenkel was VP International Business Development at Clinipace Worldwide from July 2011 to January 2013.

Prior to joining Clinipace Worldwide, from January 2007 to August 2011, Mr.

Frenkel was Vice President of International Business Development at Clinipace Worldwide from 2011 to 2013.

Prior to joining Clinipace Worldwide, from 2007 to 2011, Mr.

Frenkel established and managed the Israeli office of PFC Pharma Focus AG, which was acquired by Clinipace Worldwide in 2011, and from 2004 to 2007, he held the position of Managing Director at Actelion Pharmaceuticals with responsibility for all science and business affairs of the company in Israel.

Frenkel received a BPharm from Hebrew University.

Jatin Shah, M.D.

Shah joined Karyopharm in May 2017 as Vice President, Clinical Strategy, and was appointed Senior Vice President, Clinical Development in April 2018 and Executive Vice President, Chief Medical Officer in July 2019.

Prior to joining Karyopharm, Dr.

Shah held numerous roles at The University of Texas MD Anderson Cancer Center.

From September 2007 to August 2016, Dr.

Shah served as an Assistant Professor, Associate Professor, and Associate Program Director of the Malignant Hematology Fellowship, as well as Director of Myeloma Clinical and Translational Research in the Department of Lymphoma/Myeloma, Division of Cancer Medicine.

Shah received his M.D.

from The Ohio State University College of Medicine, Columbus, Ohio and holds a degree in Mechanical Engineering from The Ohio State University.

completed his residency in internal medicine at the Cleveland Clinic Foundation, Cleveland, Ohio, and a fellowship in hematology/oncology at the University of Alabama at Birmingham.

Shah holds board certification in hematology and oncology from the American Board of Internal Medicine.

Tanya Lewis, M.S.

Lewis joined Karyopharm in October 2018 as Senior Vice President, Regulatory and Quality Affairs and was appointed Executive Vice President, Chief Regulatory Officer and Quality Officer in November 2019.

Lewis joined Karyopharm in November 2018 as Senior Vice President, Regulatory and Quality Affairs and was appointed Executive Vice President, Chief Regulatory and Quality Officer in October 2019 and Executive Vice President, Chief Regulatory Affairs and Strategic Operations in October 2020.

Prior to joining Karyopharm, Ms.

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Most recently Ms.

Lewis served as Vice President, Regulatory and Quality Affairs for Syros Pharmaceuticals, a pharmaceutical company, from January 2017 to July 2018.

Prior to joining Syros Pharmaceuticals, Inc., Ms.

Lewis served as Vice President, Regulatory Affairs and Quality Assurance for Idera Pharmaceuticals, Inc., a pharmaceutical company, from October 2015 to December 2016.

Prior to joining Idera Pharmaceuticals, Ms.

Lewis served as Vice President, Regulatory Affairs for Tesaro, Inc., a pharmaceutical company, from October 2011 to June 2015.

Lewis served as Vice President, Regulatory and Quality Affairs for Syros Pharmaceuticals, Inc.

(“Syros”), a pharmaceutical company, from January 2017 to July 2018.

Prior to joining Syros, Ms.

Lewis served as Vice President, Regulatory Affairs and Quality Assurance for Idera Pharmaceuticals, Inc.

(“Idera”), a pharmaceutical company, from 2015 to December 2016.

Prior to joining Idera, Ms.

Lewis served as Vice President, Regulatory Affairs for Tesaro, Inc., a pharmaceutical company, from 2011 to 2015.

Lewis has served on the board of directors of Replimune, Inc., a biotechnology company, since November 2020.

Lewis holds a B.S.

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in Regulatory Affairs and Public Health from Massachusetts College of Pharmacy and Allied Health Science.

Michael Mano, J.D.

Mano joined Karyopharm as Senior Vice President, General Counsel and Secretary in December 2020 with over 15 years of legal experience.

Prior to joining Karyopharm, Mr.

Mano served as

Counsel, Business Development for Biogen Inc., a biotechnology company, from January 2018 to December 2020, where he supported Biogen’s global business development platform.

Prior to that he was Senior Counsel at Proskauer Rose LLP, an international law firm, from 2013 to January 2018 where he represented clients in a broad range of corporate matters.

Prior to Proskauer Rose LLP, Mr.

Mano was in private legal practice where he represented clients in the life sciences industry in a broad range of corporate matters.

Mano received a B.A.

in Political Science and Sociology from Saint Michael’s College and a Juris Doctor from Washington University School of Law.

Michael Mason, C.P.A., M.B.A.

Mason has served as our Senior Vice President, Chief Financial Officer and Treasurer since February 2019.

Mason served as Vice President of Finance and Treasurer of Alnylam Pharmaceuticals, Inc., a public biopharmaceutical company, from February 2011 until February 2019, as its Principal Accounting Officer from February 2011 to October 2018, and as its Principal Financial Officer from February 2011 to June 2016 and from January 2017 to May 2017.

From December 2005 to February 2011, Mr.

Mason served as Alynylam’s Corporate Controller.

From May 2000 through November 2005, Mr.

Mason served in several finance and commercial roles at Praecis Pharmaceuticals Incorporated, a public biotechnology company, most recently as Corporate Controller.

Mason served as Vice President of Finance and Treasurer of Alnylam Pharmaceuticals, Inc., a public biopharmaceutical company, from 2011 until February 2019, as its Principal Accounting Officer from 2011 to October 2018, and as its Principal Financial Officer from 2011 to June 2016 and from January 2017 to May 2017.

From 2005 to 2011, Mr.

Mason served as Alnylam’s Corporate Controller.

From 2000 through 2005, Mr.

Mason served in several finance and commercial roles at Praecis Pharmaceuticals Incorporated (“Praecis”), a public biotechnology company, most recently as Corporate Controller.

Prior to Praecis, Mr.

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from Babson College and is a certified public accountant.

Our Corporate Information

Karyopharm was incorporated under the laws of the state of Delaware on December 22, 2008 under the name Karyopharm Therapeutics Inc.

Our principal executive offices are located at 85 Wells Avenue, 2 nd

Floor, Newton, Massachusetts 02459.

Our telephone number is (617) 658-0600,

and our website is located at www.karyopharm.com.

References to our website are inactive textual references only and the content of our website should not be deemed incorporated by reference into this Annual Report on Form 10-K.

Stephen Mitchener, Pharm.D.

Mitchener has served as our Chief Business Officer since December 2020.

Prior to joining Karyopharm, Dr.

Mitchener served as Chief Business Officer and Head, Strategic Finance from August 2019 to December 2020 and as Senior Vice President, Chief Business Officer from September 2018 to August 2019 at Axcella Health Inc.

(“Axcella”), a biotechnology company.

Before joining Axcella, Dr.

Mitchener spent 15 years at Novartis, a pharmaceutical company, in roles of increasing responsibility, in both U.S.

and international roles within its Oncology Business.

He served as Head of Strategy, Partnering and Operations from July 2016 to August 2018 and as Oncology Franchise Head for Australia and New Zealand from 2013 to June 2016.

During his tenure at Novartis, he also held various commercial, medical and business development roles, including Business Franchise Head, Oncology, Global Pharma Strategy Director, and Global New Product Director.

Mitchener was involved in securing partnerships in oncology with multiple big pharma, technology, academic and healthcare partners.

Mitchener received a PharmD from the University of North Carolina at Chapel Hill.

Jatin Shah, M.D.

Prior to joining Karyopharm, Dr.

Shah held numerous roles at The University of Texas MD Anderson Cancer Center.

From 2007 to August 2016, Dr.

Shah received his M.D.

from The Ohio State University College of Medicine, Columbus, Ohio and holds a degree in Mechanical Engineering from The Ohio State University.

Shah completed his residency in internal medicine at the Cleveland Clinic Foundation, Cleveland, Ohio, and a fellowship in hematology/oncology at the University of Alabama at Birmingham.

Shah holds board certification in hematology and oncology from the American Board of Internal Medicine.

Information about our Directors

The following table lists the positions, names and ages of our current directors:

Kauffman, M.D., Ph.D.

Chief Executive Officer of Karyopharm

Chief Executive Officer of Sage Therapeutics, Inc., a biopharmaceutical company

Former Executive Vice President of Constellation Pharmaceuticals, Inc., a biopharmaceutical company

Mikael Dolsten, M.D., Ph.D.

President of Worldwide Research, Development and Medical, Chief Scientific Officer and Executive Vice President of Pfizer Inc., a pharmaceutical company

Mansoor Raza Mirza, M.D.

Chief Oncologist at the Department of Oncology, Rigshopitalet – the Copenhagen University Hospital, Denmark and Medical Director of the Nordic Society of Gynaecological Oncology

Christy Oliger

Former Senior Vice President of the Oncology Business Unit at Genentech, Inc., a biotechnology company

Pakianathan, Ph.D.

Managing Member at Delphi Ventures, a venture capital firm focused on biotechnology and medical device investments

Richard Paulson.

Executive Vice President of Ipsen Pharmaceuticals, Inc., a biopharmaceutical company, and Chief Executive Officer of Ipsen North America

President, Chief Executive Officer and Director of Adicet Bio, Inc., a biotechnology company

Available Information

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current reports on Form 8-K

and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act.

and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended.

We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the U.S.

Securities and Exchange Commission, or SEC.

Securities and Exchange Commission.

In addition, we regularly use our website to post information regarding our business, development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “Investors” as a source of information about us.

Our Code of Business Conduct and Ethics, Corporate Governance Guidelines and the charters of the Audit, Compensation, Nominating and Corporate Governance and Compliance Committees of our board of directors are all available on our website at http://www.karyopharm.com at the “Investors” section under “Corporate Governance”.

Stockholders may request a free copy of any of these documents by writing to Investor Relations, Karyopharm Therapeutics Inc., 85 Wells Avenue, 2 nd

References to our website are inactive textual references only and the content of our website should not be deemed incorporated by reference into this Annual Report on Form 10-K.

Our Code of Business Conduct and Ethics, Corporate Governance Guidelines and the charters of the Audit, Compensation, Nominating, Corporate Governance & Compliance Committees of our Board of Directors are all available on our website at http://www.karyopharm.com at the “Investors” section under “Corporate Governance.” Stockholders may request a free copy of any of these documents by writing to Investor Relations, Karyopharm Therapeutics Inc., 85 Wells Avenue, 2 nd

floor, Newton, Massachusetts 02459, U.S.A.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business