What changed in this filing

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Item 1A. Risk Factors

2020-11-02 compared with 2020-08-04 · 96 added, 87 removed, 1246 unchanged (13% of the section changed)

Risk Factors.

Careful consideration should be given to the following risk factors, in addition to the other information set forth in this Quarterly Report on Form 10-Q and in other documents that we file with the Securities and Exchange Commission, or SEC, in evaluating us and our business.

Securities and Exchange Commission, or SEC, in evaluating us and our business.

Investing in our common stock involves a high degree of risk.

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New risk factors can emerge from time to time, and it is not possible to predict the impact that any factor or combination of factors may have on our business, prospects, financial condition and results of operations.

Risks Related to the Discovery, Development and Commercialization of Our Drugs and Drug Candidates

The COVID-19 pandemic has adversely disrupted, and is expected to continue to adversely disrupt, our operations, including our clinical trial activities and commercial operations, which could have an adverse effect on our business and financial results.

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negative impact to revenue for XPOVIO ® (selinexor) tablets, which may continue as the COVID-19 pandemic persists, including as a result of decreased new patient starts due to the inability of our sales force and our patients to meet with healthcare professionals;

delays or difficulties in enrolling patients in our clinical trials, including our SEAL, SIENDO and STOMP trials;

delays or difficulties in enrolling patients in our clinical trials, including our SIENDO and STOMP trials;

delays or difficulties in initiating new clinical studies, including clinical site initiation and difficulties in recruiting clinical site investigators and clinical site staff;

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Food and Drug Administration, or FDA, and comparable foreign regulatory agencies, including the European Medicines Agency, or EMA, which may impact regulatory review and approval timelines, such as the EMA review of our Marketing Authorization Application, or MAA, for selinexor in multiple myeloma based on the results on the STORM study and any resulting impact to the timing of our expected submission of an MAA for selinexor in multiple myeloma supported by the results of the BOSTON study or any future MAA submission;

negative impacts on any or all aspects of our operations due business disruptions related to COVID-19 at our third-party vendors who we rely upon in the conduct of our business;

negative impacts on any or all aspects of our operations due to business disruptions related to COVID-19 at our third-party vendors who we rely upon in the conduct of our business;

limitations on employee resources that would otherwise be focused on the conduct of our business, including because of sickness of employees or their families, the desire of employees to avoid contact with large groups of people, and an increased reliance on working from home.

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and other countries to contain and treat the disease.

Our pursuit of a treatment for severe COVID-19 in hospitalized patients is at an early stage.

We have not previously tested selinexor in this capacity and cannot assure you that selinexor will prove to be an effective treatment of severe COVID-19 or approved for marketing by the FDA, EMA or other regulatory authorities.

In April 2020, we announced the initiation of a global, randomized clinical trial to evaluate the use of selinexor to treat hospitalized patients with severe COVID-19.

In May 2020, the protocol was amended to allow enrollment of patients with more severe disease.

Following a planned interim analysis (115 patients included in the efficacy analysis and 113 patients included in the safety analysis), the Data Safety Monitoring Board, or DSMB, for the study recommended that we discontinue the trial as it is unlikely to demonstrate a statistically significant efficacy benefit across the entire heterogenous patient population studied.

However, the DSMB concluded that the trial was likely to show a benefit in a subpopulation of patients <75 years old who have a COVID-GRAM non-high-risk score (a clinical risk score for disease severity), which represented approximately 75% of these 115 patients.

Preliminary results indicate that in the specific subpopulation, a two-point improvement in Ordinal Score at Day 14 (the primary endpoint for the entire study) reached statistical significance, as did the two-point improvement in Ordinal Score by Day 28 and the rate of hospital discharge by Day 14 (all p≤0.05).

Fatalities were similar across the two arms in this subpopulation (4/49 on selinexor and 2/37 on placebo).

There was also a significant improvement in conversion to SARS-CoV2 PCR negative status on the selinexor arm as compared with the placebo arm across the entire population (p≤0.05).

In patients ≥75 years old or with a COVID-GRAM high risk score, there was no improvement in clinical outcomes;

fatalities were higher in the selinexor arm (6/15) than the placebo arm (1/12).

While the rate of fatalities in the study was imbalanced in the patients ≥75 years old or with a COVID-GRAM high risk score, after a detailed review, the DSMB considered that the fatalities on study were due to severe COVID-19 disease and/or underlying comorbidities without a clear contribution of selinexor.

After reviewing the safety and efficacy data that was shared with the DSMB, the FDA’s opinion was that the benefit-risk ratio was not favorable in the heterogenous patient population evaluated under the latest protocol for XPORT-CoV-1001, which included the patients with more severe disease as described above.

We will continue to analyze the data to further characterize the specific subpopulation that will likely benefit from selinexor and will work with the FDA to identify a path forward for future clinical development.

We will also seek potential partners and external funding to advance future clinical studies.

Although we believe that selinexor has the potential to provide anti-viral and/or anti-inflammatory benefits to patients with severe COVID-19, selinexor has not previously been tested as a treatment for patients with severe viral infections and, therefore, we cannot predict its efficacy or whether we will be able to obtain marketing approval from the FDA, EMA or other regulatory authorities.

Our development of this potential treatment is in early stages, and we may be unable to provide a treatment that successfully treats the virus and/or its symptoms in a timely manner, if at all, particularly in light of our recent decision to discontinue the current trial.

In addition, we may not be able to enter into an arrangement with a third party or obtain external funding to advance future clinical studies in COIVD-19 in a timely manner, or at all.

If the pandemic is effectively contained or the risk of COVID-19 infection is diminished or eliminated before we can successfully complete clinical development and obtain regulatory approval of selinexor as a treatment for COVID-19, we may be unable to recoup any costs we incur in the development of this additional indication for selinexor and we may never recognize any revenue from the sale of selinexor to treat COVID-19, even if we do receive one or more regulatory approvals.

Furthermore, the biotechnology market is highly competitive and there are numerous companies that are currently pursuing a treatment or vaccine for COVID-19.

Our competitors may develop these products more rapidly or more effectively than us.

If our competitors are more successful in developing, obtaining regulatory approval or commercializing their products than us, their success could adversely affect our competitive position in this area and harm our business prospects.

We depend heavily on the success of XPOVIO.

If we are unable to successfully commercialize our current and future indications of XPOVIO or successfully develop our other drug candidates within or outside of the U.S.

, or if we experience significant delays in doing so, our business will be materially harmed.

If we are unable to successfully commercialize our current and future indications of XPOVIO or successfully develop our other drug candidates within or outside of the U.S., or if we experience significant delays in doing so, our business will be materially harmed.

We have invested a significant portion of our efforts and financial resources in the research and development of our lead drug, selinexor.

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regulatory authorities may disagree with our trial design and our interpretation of data from preclinical studies and clinical trials.

For example, on November 2, 2020, we announced top-line data from the Phase 3 portion of the randomized, double blind, placebo controlled, cross-over SEAL study of selinexor versus placebo in advanced unresectable dedifferentiated liposarcoma following at least two prior therapies.

Although we believe these data are positive, top-line data includes certain assumptions, estimations, calculations and conclusions as part of our analyses of the top-line data and the data remains subject to audit and verification procedures that may cause final data to differ, even materially.

If the FDA, or other regulatory authorities, disagree about the overall benefit-risk assessment and data analyses, we may not obtain approval for XPOVIO to treat advanced unresectable dedifferentiated liposarcoma, which could harm our business, financial condition, results of operations and prospects, including our ability to advance our solid tumor programs for selinexor.

In addition, any of these regulatory authorities may change the requirements for the approval of a drug candidate even after providing a positive opinion on, or otherwise reviewing and providing comments or advice on, a protocol for a clinical trial that has the potential to result in approval by the FDA or another regulatory authority.

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regulatory authorities regarding the design of our later phase clinical trials for selinexor, including the BOSTON, STORM, SADAL and SEAL studies.

In July 2019 and June 2020, the FDA approved the multiple myeloma indication and the DLBCL indication, respectively, under its Accelerated Approval program based on response rate from the STORM and SADAL studies, respectively.

In July 2019 and June 2020, the FDA approved the multiple myeloma indication and the DLBCL indication, respectively, under its A ccelerated A pproval program based on response rate from the STORM and SADAL studies, respectively.

We plan to seek additional regulatory approvals of selinexor in North America and Europe in each indication with respect to which such later phase clinical trial is being conducted and with respect to which we receive positive results that may support full or accelerated approval, as the case may be.

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For example, in our STORM study, the primary endpoint of overall response rate was determined based on efficacy adjudications by an independent review committee, or IRC, comprised of physicians who are expert in treating and evaluating patients with multiple myeloma.

While the FDA agreed with the assessments of the IRC for the STORM study in conducting its review of those data, we cannot be certain that other regulatory authorities will agree with the assessments of the IRC for STORM or any other study for which we may submit data to support a request for regulatory approval.

While the FDA agreed with the assessments of the IRC for the STORM study in conducting its review of those data, we cannot be certain that the European Union and other regulatory authorities will agree with the assessments of the IRC for STORM or any other study for which we may submit data to support a request for regulatory approval.

We may not be successful in our efforts to identify or discover additional potential drug candidates.

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any partners and collaborators that help conduct clinical trials may face any of the above issues, and may conduct clinical trials in ways they view as advantageous to them but that are suboptimal for us.

As we seek to advance our clinical programs, we remain in close contact with our contract research organizations, clinical sites and suppliers to attempt to assess the impacts that the COVID-19 pandemic has had and may continue to have on our clinical trials, current timelines and costs and to consider whether we can implement appropriate mitigating measures to help to lessen such impacts.

As we seek to advance our clinical programs, we remain in close contact with our contract research organizations, clinical sites and suppliers to attempt to assess the impacts that the COVID-19 pandemic ha s had and may continue to have on our clinical trials, current timelines and costs and to consider whether we can implement appropriate mitigating measures to help to lessen such impacts.

At this time, however, we cannot fully forecast the scope of impacts that the COVID-19 pandemic may have on our ability to initiate trial sites, enroll and assess patients, supply study drug and report trial results .

To date, we have incurred delays in enrollment for our SEAL, SIENDO and STOMP clinical trials.

In addition, we may experience delays in certain regulatory filings, which may impact our approval timelines, such as the EMA review of our MAA for selinexor in multiple myeloma based on the results on the STORM study and any resulting impact to the timing of our expected submission of an MAA for selinexor in multiple myeloma supported by the results of the BOSTON study or any future MAA submission.

In addition, we have and may continue to experience delays in certain regulatory filings, which may impact our approval timelines, such as the EMA review of our MAA for selinexor in multiple myeloma based on the results on the STORM study and any resulting impact to the timing of our expected submission of an MAA for selinexor in multiple myeloma supported by the results of the BOSTON study or any future MAA submission .

Further, in response to the COVID-19 pandemic, the FDA issued guidance on March 18, 2020, and updated it on July 2, 2020, to address the conduct of clinical trials during the pandemic.

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restrictions on our ability to conduct clinical trials, including full or partial clinical holds on ongoing or planned trials;

external negative impacts to our efforts to facilitate timely enrollment in clinical trials, such as the ongoing governmental “stay at home” orders related to the COVID-19 pandemic;

external negative impacts to our efforts to facilitate timely enrollment in clinical trials, such as the ongoing governmental “stay at home” or “safer at home” orders related to the COVID-19 pandemic;

patient referral practices of physicians;

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If serious adverse or unacceptable side effects are identified or we observe limited efficacy of our drugs or drug candidates, we may need to abandon or limit the development or commercialization of one or more of our drugs or drug candidates, and such findings may delay or prevent regulatory approval, limit commercial viability, or result in significant negative consequences following any marketing approval.

Four of our drug candidates are in clinical development for treatment of human diseases.

Four of our drug candidates are in clinical development for the treatment of human diseases.

Their risk of failure is high.

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Adverse events, or AEs, in our clinical trials to date have been generally predictable and typically manageable, including through prophylactic care or dose reductions, although some patients have experienced more serious AEs.

The most common drug-related AEs in our clinical trials for XPOVIO included gastrointestinal, such as nausea, anorexia, diarrhea, vomiting, cytopenias, hyponatremia, constitutional symptoms of anorexia/weight loss, fatigue and neurological adverse reactions, including dizziness, syncope, depressed level of consciousness, and mental status changes.

The most common drug-related AEs in our clinical trials for XPOVIO were gastrointestinal, such as nausea, anorexia, diarrhea, vomiting, cytopenias, hyponatremia, constitutional symptoms of anorexia/weight loss, fatigue and neurological adverse reactions, including dizziness, syncope, depressed level of consciousness, and mental status changes.

These side effects were generally mild or moderate in severity.

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If we do not accurately evaluate the commercial potential or target market for a particular drug candidate, we may relinquish valuable rights to that drug candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such drug candidate.

XPOVIO or any of our drug candidates that receives marketing approval may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success.

XPOVIO or any of our drug candidates that receive marketing approval may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success.

XPOVIO or any of our drug candidates that receive marketing approval may fail to gain sufficient market acceptance by physicians, patients, third-party payors and others in the medical community.

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Since inception, we have incurred significant operating losses.

Our net loss was $99.4 million for the six months ended June 30, 2020.

As of June 30, 2020, we had an accumulated deficit of $972.7 million.

Our net loss was $152.9 million for the nine months ended September 30, 2020.

As of September 30, 2020, we had an accumulated deficit of $1.0 billion.

With the launch of our first FDA-approved product, XPOVIO, in July 2019, we have had limited revenues to date from product sales and have historically financed our operations principally through private placements of our preferred stock, proceeds from our initial public offering and follow-on offerings of common stock, issuance of convertible debt, proceeds from a revenue interest financing agreement and cash generated from our business development activities.

We have devoted substantially all of our efforts to research and development, including preclinical studies and clinical trials, pursuing regulatory approvals and engaging in activities to commercially launch XPOVIO for its two FDA-approved indications.

We have and continue to devote substantially all of our efforts to research and development, including preclinical studies and clinical trials, pursuing regulatory approvals and engaging in activities to commercially support XPOVIO in its two FDA-approved indications.

Other than the FDA’s two accelerated approvals of XPOVIO, our lead drug, oral selinexor (for indications not yet approved), as well as eltanexor, verdinexor, and KPT-9274, are in clinical development.

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Such disruptions have resulted, and could in the future result, in diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability.

For example, in the past few months, the spread of COVID-19 has resulted in businesses suspending or terminating global operations and travel, self-imposed or government-mandated quarantines, and an overall slowdown of economic activity in many areas.

For example, the COVID-19 pandemic has resulted in businesses suspending or terminating global operations and travel, self-imposed or government-mandated quarantines, and an overall slowdown of economic activity in many areas.

Our general business strategy may be compromised by economic downturns, a volatile business environment and unpredictable and unstable market conditions, such as the current global situation resulting from the COVID-19 pandemic.

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we may lose certain valuable rights under circumstances identified in any collaboration arrangement that we enter into, such as if we undergo a change of control;

collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development, marketing and/or commercialization of the applicable drug candidates;

collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development, marketing and/or commercialization of the applicable drugs or drug candidates;

collaborators may learn about our discoveries and use this knowledge to compete with us in the future;

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If these facilities are not approved for commercial manufacture, we may need to find alternative manufacturing facilities, which could result in delays in obtaining approval for the applicable drug candidate as alternative qualified manufacturing facilities may not be available on a timely basis, or at all.

In addition, our manufacturers are subject to ongoing periodic unannounced inspections by the FDA and corresponding state and foreign agencies

for compliance with cGMPs and similar regulatory requirements.

In addition, our manufacturers are subject to ongoing periodic unannounced inspections by the FDA and corresponding state and foreign agencies for compliance with cGMPs and similar regulatory requirements.

Failure by any of our manufacturers to comply with applicable cGMPs or other regulatory requirements could result in sanctions being imposed on us or the contract manufacturer, including fines, injunctions, civil penalties, delays, suspensions or withdrawals of approvals, operating restrictions, interruptions in supply and criminal prosecutions, any of which could significantly and adversely affect supplies of our drug candidates and have a material adverse impact on our business, financial condition and results of operations.

Any drugs that we may develop may compete with other drug candidates and drugs for access to manufacturing facilities.

Any performance failure on the part of our existing or future manufacturers could delay clinical development, marketing approval or commercialization.

Any performance failure on the part of our existing or future manufacturers could delay clinical development, marketing approval or commercialization of our drugs or drug candidates.

For example, as a result of the COVID-19 pandemic, our suppliers and contract manufacturers could be disrupted by worker absenteeism, quarantines, or other travel or health-related restrictions or could incur increased costs associated with ensuring the safety and health of their personnel.

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Continued approval for these indications may be contingent upon verification and description of clinical benefit in one or more confirmatory trials.

For example, the FDA has agreed that the randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade ® (bortezomib) and low-dose dexamethasone could serve as the confirmatory trial for the multiple myeloma indication and the XPORT-DLBCL-030 study will serve as the confirmatory trial for evaluating selinexor in DLBCL.

For example, the FDA has agreed that the randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade ® (bortezomib) and low-dose dexamethasone and the XPORT-DLBCL-030 study could serve as the confirmatory trials for the multiple myeloma and DLBCL indications, respectively.

The BOSTON and XPORT-DLBCL-030 studies are post-marketing requirements for continued marketing authorization under the FDA’s Accelerated Approval program issued by the FDA in July 2019 and June 2020, respectively, for XPOVIO based on the results of the STORM study and SADAL study, respectively.

If the FDA does not approve our supplemental New Drug Application, or sNDA, submission based on the data from the BOSTON study, we will suffer substantial harm, including potential loss of the accelerated approval for XPOVIO based on the results of the STORM and SADAL studies.

In addition, we submitted a MAA to the EMA in January 2019 with a request for conditional approval of selinexor as a treatment for patients with heavily pretreated multiple myeloma based on the results of the STORM study.

In addition, in January 2019, we submitted a n MAA to the EMA with a request for conditional approval of selinexor as a treatment for patients with heavily pretreated multiple myeloma based on the results of the STORM study.

During March 2019, the EMA had inspectors conduct a Good Clinical Practices, or GCP, inspection at our headquarters, which was also attended by the FDA, as well as inspections of two clinical sites that participated in Part 2 of the STORM study.

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First, CHMP requested that we reconfirm the IRC adjudicated response rate to justify a positive benefit-risk assessment and, second, CHMP requested that we address the findings from the GCP inspection and our corrective measures taken to justify that the clinical trial data are of sufficient quality to support a benefit-risk assessment.

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

We are currently working with CHMP to address the outstanding questions;

however, due to reduced access to clinical trial sites as a result of the COVID-19 pandemic, and, therefore, have requested, and the EMA has granted us, additional time to submit our response.

In January 2020, we were granted a three-month extension to respond to t he CHMP’s outstanding questions related to the application.

In September 2020, we submitted our responses following an additional extension of time due to the impact of the COVID-19 pandemic.

In October 2020, we received a further updated list of outstanding issues, or LOI, from CHMP summarizing the remaining topics for us to address and indicating that, as part of its assessment of the safety and efficacy of selinexor based on the STORM study, the CHMP intends to consult its Scientific Advisory Group for additional advice in the fourth quarter of 2020.

The LOI indicates that the CHMP is continuing to assess the IRC’s adjudicated responses from the STORM study and asks us to justify the positive benefit-risk in the intended indication, which CHMP has also requested that we update to be more closely aligned with the patient population evaluated in the STORM study.

The LOI further requests that we demonstrate that selinexor provides an advantage over approved therapies in the relevant indication and that we provide a summary of top - line data from the BOSTON study and the context of such data for the current application.

We are currently in the process of preparing responses to the LOI ;

however , the CHMP may not be satisfied by our responses, might disagree with our responses or might request additional information, which may delay an opinion from the CHMP or result in a negative opinion by the CHMP, and ultimately the EMA, for selinexor in this indication.

With the exception of our sNDA submission to the FDA requesting approval of selinexor to treat multiple myeloma after at least one prior line of therapy, we have not submitted any other application for, or received any marketing approval of, any of our drug candidates in the U.S.

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and abroad, is a lengthy, expensive and uncertain process.

It may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the

type, complexity and novelty of the drug candidates involved.

It may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the drug candidates involved.

In addition, we may experience delays in the regulatory review process for our drug candidates as a result of the ongoing COVID-19 pandemic, such as the EMA review of our MAA for selinexor in multiple myeloma based on the results on the STORM study and any resulting impact to the timing of our expected submission of an MAA for selinexor in multiple myeloma supported by the results of the BOSTON study or any future MAA submission.

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These confirmatory trials must be completed with due diligence.

As a condition of the accelerated approval of XPOVIO for the multiple myeloma indication, we are required to (i) complete and submit a final report with full datasets from the BOSTON study following completion of the study, (ii) conduct a randomized phase 2 clinical trial of selinexor plus dexamethasone with three doses of selinexor including the approved dose of 80 mg on days 1 and 3 of each week and two doses that are lower than the approved dose, in a similar patient population for which XPOVIO is indicated (which we plan to conduct outside of the U.S.), (iii) conduct a trial with selinexor in patients who have mild, moderate or severe hepatic impairment, and (iv) conduct a drug interaction trial with selinexor in patients to evaluate the effect of co-administration of a strong CYP3A4 inhibitor on the pharmacokinetics of selinexor.

As a condition of the accelerated approval of XPOVIO for the multiple myeloma indication, we are required to (i) complete and submit a final report with full datasets from the BOSTON study following completion of the study, (ii) conduct a randomized Phase 2 clinical trial of selinexor plus dexamethasone with three doses of selinexor including the approved dose of 80 mg on days one and three of each week and two doses that are lower than the approved dose, in a similar patient population for which XPOVIO is indicated (which we plan to conduct outside of the U.S.), (iii) conduct a trial with selinexor in patients who have mild, moderate or severe hepatic impairment, and (iv) conduct a drug interaction trial with selinexor in patients to evaluate the effect of co-administration of a strong CYP3A4 inhibitor on the pharmacokinetics of selinexor.

As a condition of the accelerated approval of XPOVIO for the DLBCL indication, we are required to (i) complete and submit a final report with full datasets from a randomized, double-blind, placebo-controlled Phase 3 trial that verifies and describes the clinical benefit of selinexor in patients with relapsed or refractory DLBCL and (ii) provide the interim and final analyses of a randomized Phase 2 clinical trial of selinexor to characterize the safety and efficacy of at least two different dosing regimens of selinexor monotherapy in patients with relapsed or refractory DLBCL after at least two prior lines of systemic therapy.

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does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA.

However, a failure or delay in obtaining regulatory approval in

one country may have a negative effect on the regulatory process in other countries.

However, a failure or delay in obtaining regulatory approval in one country may have a negative effect on the regulatory process in other countries.

We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any market.

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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 European Union directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the UK.

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The FDA imposes stringent restrictions on manufacturers’ communications regarding off-label use, and if we or our collaborators do not market any of our drug candidates for which we, or they, receive marketing approval for only their approved indications, we, or they, may be subject to warnings or enforcement action for off-label marketing.

Violation of the FDCA and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to investigations or allegations of violations of federal and state health care fraud and abuse laws and state consumer protection laws.

Violation of the FDCA and other statutes, including the False Claims Act, relating to the promotion and

advertising of prescription drugs may lead to investigations or allegations of violations of federal and state health care fraud and abuse laws and state consumer protection laws.

In addition, later discovery of previously unknown AEs or other problems with our drugs or their manufacturers or manufacturing processes, data integrity issues with regulatory filings, or failure to comply with regulatory requirements, may yield various results, including:

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For fiscal years 2018 and beyond, the executive order requires agencies to identify regulations to offset any incremental cost of a new regulation and approximate the total costs or savings associated with each new regulation or repealed regulation.

In interim guidance issued by the Office of Information and Regulatory Affairs within the Office of Management and Budget in February 2017, the administration indicates that the “two-for-one” provisions may apply not only to agency regulations, but also to significant agency guidance documents.

In interim guidance issued by the Office of Information and Regulatory Affairs within the Office of Management and Budget in February 2017, the Trump Administration indicated that the “two-for-one” provisions may apply not only to agency regulations, but also to significant agency guidance documents.

In addition, on February 24, 2017, President Trump issued an executive order directing each affected agency to designate an agency official as a “Regulatory Reform Officer” and establish a “Regulatory Reform Task Force” to implement the two-for-one provisions and other previously issued executive orders relating to the review of federal regulations.

More recently, on October 9, 2019, President Trump issued another executive order (“Executive Order on Promoting the Rule of Law Through Improved Agency Guidance Documents”).

The order is meant to ensure that agency guidance documents do not establish legally binding requirements and it directs each agency to rescind guidance documents that it determines should no longer be in effect.

In response to the COVID-19 pandemic, the Trump Administration is looking for additional ways to provide regulatory relief.

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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, 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 January 21, 2020, the U.S.

Supreme Court declined to review this decision on an expedited basis.

On March 3, 2020, the Supreme Court agreed to hear this case.

More recently, the Trump Administration filed a brief in this case supporting the decision of the Court of Appeals.

Supreme Court declined to review this decision on an expedited basis , but, on March 3, 2020, the Court agreed to hear the case .

Subsequently, on June 25, 2020, the Trump A dministration and a coalition of 18 states asked the court to strike down the entirety of the ACA.

Oral argument before the Supreme Court is scheduled for November 10, 2020.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

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A bipartisan bill to appropriate funds for CSR payments was introduced in the Senate, but the future of that bill is uncertain.

Further, in July 2018 following a federal district court decision from New Mexico, the Administration announced that it would be freezing payments to insurers under the ACA to cover sicker patients until it or Congress can address the appropriate methodology for calculating and making such payments.

Further, in July 2018 following a federal district court decision from New Mexico, the Trump Administration announced that it would be freezing payments to insurers under the ACA to cover sicker patients until it or Congress can address the appropriate methodology for calculating and making such payments.

It remains to be seen how this action will affect the implementation of the ACA.

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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.

At the federal level, Congress and the current 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 current administration issued a plan to lower drug prices.

Under this blueprint for action, the current 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 Medicare Part D plan sponsors more negotiation power with drug makers, examine which Medicare Part B drug prices could be negotiated by Medicare Part D plans, improve the design of the Medicare Part B Competitive Acquisition Program, update Medicare’s drug-pricing dashboard to increase transparency, prohibit Medicare 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 Medicare Part D plan members be provided with an annual statement of plan payments, out-of-pocket spending, and drug price increases.

Finally, the current presidential administration’s budget proposal for fiscal year 2021 includes a $135.0 billion allowance to support legislative proposals seeking to reduce drug prices, increase competition, lower out-of-pocket drug costs for patients, and increase patient access to lower-cost generic and biosimilar drugs.

More recently, on July 24, 2020, President Trump issued four executive orders that are intended to lower the costs of prescription drug products.

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 Medicare Part D plan sponsors more negotiation power with drug makers, examine which Medicare Part B drug prices could be negotiated by Medicare Part D plans, improve the design of the Medicare Part B Competitive Acquisition Program, update Medicare’s drug-pricing dashboard to increase transparency, prohibit Medicare 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 Medicare Part D plan members be provided with an annual statement of plan payments, out-of-pocket spending, and drug price increases.

On July 24, 2020, President Trump issued four executive orders that are intended to lower the costs of prescription drug products.

The first order would require all federally qualified health centers to pass on to patients the discounts the health centers receive on insulin and epinephrine through Medicare's 340B Drug Discount Program.

The second order would establish an international pricing index that would set the price Medicare Part B pays for the costliest medications covered under the program to the lowest price in other economically advanced countries.

The President has indicated that this order will be held until August 24, 2020, because the administration may not implement it.

The third order is intended to reduce the costs of drugs by supporting the safe importation of prescription drugs.

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Each of these orders directs the federal government to implement the initiatives outlined in the orders, meaning they will not have immediate effects.

Finally, and more recently, President Trump issued a fifth order , which instructs the federal government to develop a list of “essential” medicines and then buy them and other medical supplies from U.S.

manufacturers instead of from companies around the world, including especially China.

The order is intended to reduce regulatory barriers to domestic pharmaceutical manufacturing and catalyze manufacturing technologies needed to keep drug prices low and the production of drug products in the U.S .

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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State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not pre-empted by HIPAA, thus complicating compliance efforts.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations involve substantial costs.

It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.

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and, as a result, increases the scrutiny that clinical trial sites located in the EEA should apply to transfers of personal data from such sites to countries that are considered to lack an adequate level of data protection, such as the U.S.

associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

The GDPR also permits data protection authorities to require destruction of improperly gathered or used personal information and/or impose substantial fines for violations of the GDPR, which can be up to four percent of global revenues or 20 million Euros, whichever is greater, and it 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.

In addition, the GDPR provides that European Union member states may make their own further laws and regulations limiting the processing of personal data, including genetic, biometric or health data.

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New laws also are being considered at both the state and federal levels.

For example, the California Consumer Privacy Act, which went into effect on January 1, 2020, is creating similar risks and obligations as those created by GDPR, though the Act does exempt certain information collected as part of a clinical trial subject to the Federal Policy for the Protection of Human Subjects (the Common Rule).

For example, the California Consumer Privacy Act, which went into effect on January 1, 2020, is creating similar risks and obligations as those created by GDPR, though the California Consumer Privacy Act does exempt certain information collected as part of a clinical trial subject to the Federal Policy for the Protection of Human Subjects (the Common Rule).

Many other states are considering similar legislation.

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and abroad related to our novel drug candidates and other discoveries that are important to our business.

As of July 15, 2020, 72 patents were in force that relate to XPO1 inhibitors, including composition of matter patents for selinexor, verdinexor and eltanexor in the U.S., and their use in targeted therapeutics.

As of October 15, 2020, 79 patents were in force that relate to XPO1 inhibitors, including composition of matter patents for selinexor, verdinexor and eltanexor in the U.S., and their use in targeted therapeutics.

In addition, 16 patents were in force that relate to our PAK4/NAMPT inhibitors, including two composition of matter patents for KPT-9274 in the U.S.

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To the extent that we are unable to timely enter into confidentiality and invention or patent assignment agreements with our employees and consultants, our ability to protect our business through trade secrets and patents may be harmed.

Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable.

Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is

difficult, expensive and time-consuming, and the outcome is unpredictable.

In addition, some courts inside and outside of the U.S.

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Failure to secure those registrations could adversely affect our business.

As of July 15, 2020, we have trademark registrations in the U.S.

As of October 15, 2020, we have trademark registrations in the U.S.

for our name and logo, and a combination of the two, XPOVIO, and PORE for our online portal.

We also have pending applications in the U.S.

to register two additional drug names (examination is currently suspended), and KARYFORWARD and a KARYFORWARD logo for our financial aid and charitable services.

Outside the U.S., XPOVIO is registered or pending in thirty-seven additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan.

to register two additional drug 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-five additional jurisdictions, and is registered 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.

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The loss of the services of any of our key employees could impede the achievement of our research, development, commercialization and other business objectives.

Recruiting and retaining qualified scientific, clinical, manufacturing and sales and marketing personnel will also be critical to our success.

Recruiting and retaining qualified scientific, clinical, manufacturing and sales and marketing personnel is critical to our success.

We may not be able to attract and retain these personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel.

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Our executive officers, directors and principal stockholders maintain the ability to control all matters submitted to stockholders for approval.

As of July 15, 2020, our executive officers, directors and a small number of stockholders own more than a majority of our outstanding common stock.

As of October 15, 2020, our executive officers, directors and a small number of stockholders own more than a majority of our outstanding common stock.

As a result, if these stockholders were to choose to act together, they would be able to control all matters submitted to our stockholders for approval, as well as our management and affairs.

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Our stock price has been and is likely to be volatile and may fluctuate substantially.

For example, since July 15, 2019, our common stock has traded at prices per share as high as $29.61 and as low as $7.55.

On July 31, 2020, the closing sale price of our common stock on The Nasdaq Global Select Market was $16.05 per share.

For example, since October 15, 2019, our common stock has traded at prices per share as high as $29.61 and as low as $10.12.

On October 30, 2020, the closing sale price of our common stock on The Nasdaq Global Select Market was $14.82 per share.

The stock market in general and the market for pharmaceutical and biotechnology companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies, such as the recent response to the ongoing COVID-19 pandemic and related world-wide economic disruptions.

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In addition, it is uncertain if and to what extent various states will conform to the TCJA, the FFCR Act or the CARES Act.

Exhibit Number

Description of Exhibit

Amendment to License Agreement, dated May 1, 2020, by and between Antengene Therapeutics Limited and the Registrant.

Amendment No.

1 to the Open Market Sale Agreement, by and between the Registrant and Jefferies LLC, dated May 5, 2020 (incorporated by reference to Exhibit 10.1 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on May 5, 2020)

Fifth Amendment to Lease, dated as of August 13, 2020, by and between the Registrant and AG-JCM Wells Avenue Property Owner, LLC.

Amended and Restated Letter Agreement, dated as of August 31, 2020, between the Registrant and Michael Kauffman, M.D., Ph.D.

(incorporated by reference to Exhibit 10.1 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on August 31, 2020).

Amended and Restated Letter Agreement, dated as of August 31, 2020, between the Registrant and Sharon Shacham, Ph.D., M.B.A.

(incorporated by reference to Exhibit 10.2 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on August 31, 2020).

Amended and Restated Letter Agreement, dated as of August 31, 2020, between the Registrant and Christopher B.

Primiano (incorporated by reference to Exhibit 10.3 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on August 31, 2020).

Letter Agreement, dated as of August 31, 2020, between the Registrant and Michael Mason (incorporated by reference to Exhibit 10.4 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on August 31, 2020).

Transition Agreement, dated as of September 25, 2020, between the Registrant and Christopher B.

Primiano (incorporated by reference to Exhibit 10.1 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on September 25, 2020).

Consulting Agreement, dated as of September 25, 2020, between the Registrant and Christopher B.

Primiano (incorporated by reference to Exhibit 10.2 to the Registrant’s Current Report on Form 8-K (File No.

001-36167) filed with the Commission on September 25, 2020).

Letter Agreement, dated as of October 1, 2020, between the Registrant and Ran Frenkel.

Form of Incentive Stock Option Agreement under 2013 Stock Incentive Plan adopted August 25, 2020.

Form of Nonstatutory Stock Option Agreement under 2013 Stock Incentive Plan adopted August 25, 2020.

Form of Restricted Stock Unit Agreement under 2013 Stock Incentive Plan adopted August 25, 2020.

Form of Nonstatutory Stock Option Agreement for Inducement Grants adopted August 25, 2020.

2020 Israeli Equity Incentive Sub Plan to the 2013 Stock Incentive Plan.

Form of Option Agreement under 2020 Israeli Equity Incentive Sub Plan to the 2013 Stock Incentive Plan.

Form of Restricted Stock Unit Agreement under 2020 Israeli Equity Incentive Sub Plan to the 2013 Stock Incentive Plan.

Certification of principal executive officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

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Cover Page Interactive Data File (formatted as inline XBRL with applicable taxonomy extension information contained in Exhibits 101)

Certain portions of this exhibit (indicated by “[***]”) have been omitted pursuant to Item 601(b)(10)(iv) of Regulation S-K.

Filed herewith.

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KARYOPHARM THERAPEUTICS INC.

August 4, 2020

November 2, 2020

/s/ MICHAEL KAUFFMAN

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(Principal executive officer)

August 4, 2020

November 2, 2020

/s/ MICHAEL MASON

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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-Q

Item 1A. Risk Factors