What changed in this filing

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Item 1A. Risk Factors

2020-08-04 compared with 2020-05-05 · 260 added, 349 removed, 1073 unchanged (36% of the section changed)

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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.

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.

The outbreak of the novel coronavirus disease, or COVID-19,

is a global pandemic that has affected many segments of the global economy.

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.

The outbreak of the novel coronavirus disease, or COVID-19, is a global pandemic that has affected many segments of the global economy.

As a result, we have experienced, and we expect to continue to experience, disruptions that could adversely impact our business, clinical trial activities and commercial operations, including:

decreased revenue for XPOVIO ®

(selinexor) tablets in the current quarter, 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, such as our SEAL, SIENDO and STOMP trials;

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

reduction or diversion of healthcare resources away from the conduct of clinical trials, including the diversion of hospitals serving as our clinical trial sites and hospital staff supporting the conduct of our clinical trials;

interruption of key clinical trial activities, such as clinical trial site data monitoring, due to limitations on travel imposed or recommended by government officials or entities, employers and others or interruption of clinical trial patient visits and study procedures (particularly any procedures that may be deemed non-essential),

which may impact the integrity of clinical trial data and clinical study endpoints;

interruption or delays in the operations of the U.S.

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;

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 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.

outbreak continues to rapidly evolve, and its ultimate scope, duration and effects are unknown.

The extent of the impact of the disruptions to our business, including commercial sales and clinical trials, as a result of the outbreak will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as the ultimate geographic spread of the disease, the duration of the outbreak, travel restrictions and actions to contain the outbreak or treat its impact, including social distancing and quarantines or lock-downs in the U.S.

The COVID-19 pandemic continues to evolve, and its ultimate scope, duration and effects are unknown.

The extent of the impact of the disruptions to our business, including commercial sales and clinical trials, as a result of the pandemic will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as the ultimate geographic spread of the disease, the duration of the pandemic , travel restrictions and actions to contain the pandemic or treat its impact, including social distancing and quarantines or lock-downs in the U.S.

and other countries, business closures or business disruptions and the effectiveness of actions taken in the U.S.

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.

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.

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.

If the outbreak 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.

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.

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We depend heavily on the success of XPOVIO.

If we are unable to successfully commercialize XPOVIO or successfully develop selinexor for additional indications, 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 candidate, selinexor.

In July 2019, the FDA granted accelerated approval for XPOVIO in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma, or RRMM, who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Our ability to generate revenues from the sale of drugs that treat cancer and other diseases in humans will depend heavily on the successful development, regulatory approval and commercialization of selinexor.

For example, 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.

Although we believe that selinexor has the potential to provide anti-viral and anti-inflammatory activities to patients with severe COVID-19,

selinexor has not previously been tested as an inhibitor in patients with severe viral infections and therefore we cannot predict its efficacy or whether we will be able to obtain the necessary regulatory approval from the FDA or other non-U.S.

regulatory authorities.

The commercial success of XPOVIO and the successful clinical development of selinexor and our other drug candidates will depend on several factors, including the following:

successful commercialization of XPOVIO in the U.S., including maintaining sales, marketing and distribution capabilities for XPOVIO;

the consistency of any new data we collect and analyses we conduct with prior results, whether they support a favorable safety, efficacy and effectiveness profile of XPOVIO and any potential impact on our FDA accelerated approval and/or FDA package insert for XPOVIO;

our ability to comply with FDA post-marketing requirements and commitments, including through successfully conducting additional studies that confirm clinical efficacy, effectiveness and safety of XPOVIO and acceptance of the same by the FDA and medical community since continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials;

acceptance of XPOVIO and, if and when approved, our other drug candidates, by patients, the medical community and third-party payors;

obtaining and maintaining coverage, adequate pricing and adequate reimbursement by third-party payors, including government payors, for XPOVIO and our drug candidates;

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.

In July 2019, the FDA granted accelerated approval for XPOVIO 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, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, or the multiple myeloma indication.

In June 2020, the FDA granted accelerated approval for XPOVIO f or the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, or DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy, or the DLBCL indication .

Our ability to generate revenues from the sale of drugs that treat cancer and other diseases in humans will depend heavily on the successful development, additional regulatory approvals and commercialization of selinexor.

The commercial success of our current and future indications of XPOVIO and the successful clinical development of our other drug candidates will depend on several factors, including the following:

our ability to successfully launch our approved products, including the recently approved DLBCL indication for XPOVIO, or any drug candidates for which we obtain marketing approval, whether alone or in collaboration with others;

our ability to comply with FDA post-marketing requirements and commitments, including through successfully conducting additional studies that confirm clinical efficacy, effectiveness and safety of XPOVIO and acceptance of the same by the FDA and the medical community since continued approval for our current indications may be contingent upon verification of a clinical benefit in confirmatory trials;

acceptance of our current and future indications of XPOVIO and, if and when approved, our other drug candidates, by patients, the medical community and third-party payors;

obtaining and maintaining coverage, adequate pricing and reimbursement by third-party payors, including government payors, for XPOVIO and our drug candidates, if approved;

successful and timely completion of preclinical studies;

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establishing and maintaining commercial manufacturing capabilities or making arrangements with third-party manufacturers;

obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our drug candidates;

establishing sales, marketing, manufacturing and distribution capabilities to commercialize any drug candidates for which we may obtain marketing approval, whether alone or in collaboration with others;

launching commercial sales of any drug candidates for which we obtain marketing approval, whether alone or in collaboration with others;

obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our drugs and drug candidates;

establishing and maintaining sales, marketing, manufacturing and distribution capabilities to commercialize our currently approved drugs and any drug candidates for which we obtain marketing approval, whether alone or in collaboration with others;

effectively competing with other therapies;

maintaining an acceptable safety profile of our drugs following approval;

compliance with existing and new health care laws and regulations currently being considered or implemented in the U.S., including government pricing, price reporting and other disclosure requirements of such laws and regulations and the potential impact of such requirements on physician prescribing practices and payor coverage;

maintaining an acceptable safety profile of our approved drugs;

compliance with existing and new health care laws and regulations currently being considered or implemented in the U.S., including government pricing, price reporting and other disclosure requirements related to such laws and regulations and the potential impact of such requirements on physician prescribing practices and payor coverage;

enforcing and defending intellectual property rights and claims;

maintaining and growing an organization of scientists and business people, including collaborators, who can develop and commercialize our drug candidates;

the impact of the COVID-19

pandemic on the above factors, including the limitation of our sales professionals to meet with

healthcare professionals as the result of travel restrictions or hospital limitations on access for non-patients.

If we do not achieve one or more of these factors in a timely manner, or at all, we could experience significant delays or an inability to successfully commercialize XPOVIO or our drug candidates, which would materially harm our business.

the impact of the COVID-19 pandemic on the above factors, including the limitation of our sales professionals to meet with healthcare professionals as the result of travel restrictions or hospital limitations on access for non-patients.

The results of previous clinical trials may not be predictive of future results and the results of our current and planned clinical trials may not satisfy the requirements of the FDA or non-U.S.

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Drug candidates that have shown promising results in early-stage clinical trials may still suffer significant setbacks in subsequent registration clinical trials.

Additionally, the outcome of preclinical studies and early-stage clinical trials may not be predictive of the success of later-stage clinical trials, and interim results of a clinical trial are not necessarily indicative of final results.

Additionally, interim results of a clinical trial are not necessarily indicative of final results.

In addition, the design of a clinical trial can determine whether its results will support approval of a drug, and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced.

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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, the FDA approved, under accelerated approval based on response rate from the STORM study, XPOVIO in combination with dexamethasone for the treatment of adult patients with RRMM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

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.

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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The FDA and non-U.S.

regulatory authorities retain broad discretion in evaluating the results of our clinical trials and in determining whether the results demonstrate that selinexor is safe and effective.

If we are required to conduct additional clinical trials of selinexor prior to approval of additional indications in earlier lines of therapy or in combination with other drugs, including additional earlier phase clinical trials that may be required prior to commencing any later phase clinical trials, or additional clinical trials following completion of our current and planned later phase clinical trials, we may need substantial additional funds, and there is no assurance that the results of any such additional clinical trials will be sufficient for approval.

regulatory authorities retain broad discretion in evaluating the results of our clinical trials and in determining whether the results demonstrate that selinexor or any of our other drug candidates is safe and effective.

If we are required to conduct additional clinical trials of selinexor or our other drug candidates prior to approval of additional indications in earlier lines of therapy or in combination with other drugs, including additional earlier phase clinical trials that may be required prior to commencing any later phase clinical trials, or additional clinical trials following completion of our current and planned later phase clinical trials, we may need substantial additional funds, and there is no assurance that the results of any such additional clinical trials will be sufficient for approval.

The results to date in preclinical and early clinical studies conducted by us or our academic collaborators and in Phase 1 and Phase 2 clinical trials that we are currently conducting include the response of tumors to selinexor.

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For some types of cancer, we may use overall response rate as a primary endpoint, as we did in our SADAL study and our STORM study.

These clinical trials will not be randomized against control arms and the primary endpoints of these trials are overall response rate.

If selinexor does not demonstrate sufficient overall response rates in these indications, or any other indication for which a clinical trial has overall response rate as a primary endpoint, or if the FDA or non-U.S.

regulatory authorities do not deem overall response rate a sufficient endpoint, or deem a positive overall response rate to be insufficient, it will likely not be approved for that indication based on the applicable study.

With respect to the STORM and SADAL studies, the FDA has reiterated to us that it recommends, in general, a randomized trial with a progression-free survival endpoint as an initial registration approach.

Finally, independent review committees are typically implemented to adjudicate efficacy outcomes in clinical studies that are intended to support requests for marketing authorization.

These clinical trials were not randomized against control arms and the primary endpoints of these trials were overall response rate.

If selinexor does not demonstrate sufficient overall response rates for any other indication for which a clinical trial has overall response rate as a primary endpoint, or if the FDA or non-U.S.

regulatory authorities do not deem overall response rate a sufficient endpoint, or deem a positive overall response rate to be insufficient, selinexor will likely not be approved for that indication based on the applicable study.

Finally, independent review committees are typically implemented to adjudicate efficacy outcomes in clinical studies that are intended to support requests for regulatory approval.

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 marketing authorization.

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

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The outcome of preclinical studies and early-stage clinical trials may not be predictive of the success of later stage clinical trials, and interim results of a clinical trial do not necessarily predict final results.

For example, certain data from our Phase 1 and Phase 2 clinical trials of selinexor to date are based on unaudited data provided by our clinical trial investigators.

For example, certain data from our Phase 1 and Phase 2 clinical trials of selinexor are based on unaudited data provided by our clinical trial investigators.

An audit of this data may change the conclusions drawn from this unaudited data provided by our clinical trial investigators indicating less promising results than we currently anticipate.

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We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize our drug candidates, including:

delays associated with the COVID-19

pandemic, including impacts to healthcare systems, our trial sites’ ability to conduct trials, and interruption or unavailability of clinical supplies, regulatory reviews, site monitors and patient enrollment;

delays associated with the COVID-19 pandemic, including impacts to healthcare systems, our trial sites’ ability to conduct trials, and interruption or unavailability of clinical supplies, regulatory reviews, site monitors and patient enrollment;

regulatory authorities or institutional review boards may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;

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our third-party contractors, including those manufacturing our drug candidates or conducting clinical trials on our behalf, may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all;

we or our investigators might have to suspend or terminate clinical trials of our drug candidates for various reasons, including non-compliance

with regulatory requirements, a finding that our drug candidates have undesirable side effects or other unexpected characteristics, or a finding that the participants are being exposed to unacceptable health risks;

we or our investigators might have to suspend or terminate clinical trials of our drug candidates for various reasons, including non-compliance with regulatory requirements, a finding that our drug candidates have undesirable side effects or other unexpected characteristics, or a finding that the participants are being exposed to unacceptable health risks;

regulators may recommend or require us to perform additional or unanticipated clinical trials to obtain approval;

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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 COVID-19

may 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 COVID-19

may have on our ability to initiate trial sites, enroll and assess patients, supply study drug and report trial results.

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.

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 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.

Further, in response to the COVID-19

pandemic, the FDA issued guidance on March 18, 2020, to address the conduct of clinical trials during the pandemic.

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.

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.

The guidance sets out a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical study report (or as a separate document) contingency measures implemented to manage the study, and any disruption of the study as a result of COVID-19;

a list of all study participants affected by COVID-19-related

study disruption by unique subject identifier and by investigational site, and a description of how the individual’s participation was altered;

a list of all study participants affected by COVID-19-related study disruption by unique subject identifier and by investigational site, and a description of how the individual’s participation was altered;

and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study.

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Our drug development costs will also increase if we experience delays in testing or marketing approvals.

We do not know whether clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all, particularly as a result of the COVID-19

We do not know whether clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all, particularly as a result of the COVID-19 pandemic.

Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our drug candidates, allow our competitors to bring drugs to market before we do or impair our ability to successfully commercialize our drug candidates, which would harm our business and results of operations.

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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

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;

patient referral practices of physicians;

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Enrollment delays in our clinical trials may also result in increased development costs for our drug candidates, which could cause the value of our company to decline and limit our ability to obtain additional financing.

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

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.

Their risk of failure is high.

If XPOVIO or any of our drug candidates are associated with undesirable side effects or have characteristics that are unexpected in clinical trials or following approval and/or commercialization, we may need to abandon their development or limit development or marketing to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

Adverse events, or AEs, in our clinical trials to date have been generally predictable and manageable, 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 and vomiting, and fatigue.

If our current or future indications of XPOVIO or any of our drug candidates are associated with undesirable side effects or have characteristics that are unexpected in clinical trials or following approval and/or commercialization, we may need to abandon their development or limit development or marketing to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

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.

These side effects were generally mild or moderate in severity.

The most common AEs that were Grade 3 or Grade 4, meaning they were more than mild or moderate in severity, included thrombocytopenia, or low count of platelets in the blood, and neutropenia, or low neutrophil counts.

To date, the most common AEs have been managed with supportive care and dose modifications.

To date, the most common AEs in the multiple myeloma patient population have been managed with supportive care and dose modifications.

However, a number of patients have withdrawn from our clinical trials as a result of AEs.

For example, amongst the 202 patients enrolled in Parts 1 and 2 of the STORM study who were treated with selinexor in combination with dexamethasone, the most common AEs (incidence ≥

20%) were thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infections.

The treatment discontinuation rate due to AEs was 27%;

For example, among the 202 patients enrolled in Parts 1 and 2 of the STORM study who were treated with selinexor in combination with dexamethasone, the most common AEs (incidence ≥20%) were thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infections.

The treatment discontinuation rate in the STORM study due to AEs was 27%;

53% of patients had a reduction in the selinexor dose, and 65.3% had the dose of selinexor interrupted.

In this group of patients, the most frequent AEs requiring permanent discontinuation in 4% or greater of patients who received selinexor included fatigue, nausea, and thrombocytopenia.

Similarly, in the SADAL study, as of April 3, 2019, among the 127 patients included in the safety analysis, the most common AEs (incidence ≥

20%) were thrombocytopenia, nausea, fatigue, anemia, anorexia, diarrhea, constipation, weight loss, neutropenia, vomiting, pyrexia and asthenia.

Similarly, in the SADAL study, among the 134 patients included in the safety analysis, the most common AEs (incidence ≥20%) in patients with DLBCL were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia.

Grade 3-4 laboratory abnormalities (≥15%) were thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia.

The treatment discontinuation rate in the SADAL study due to AEs was 17%;

49% of patients had a reduction in the selinexor dose, and 61% had the dose of selinexor interrupted.

Some patients across our clinical trials have experienced serious adverse events, or SAEs, deemed by us and the clinical investigator to be related to selinexor.

SAEs generally refer to AEs that result in death, are life threatening, require hospitalization or prolonging of hospitalization, or cause a significant and permanent disruption of normal life functions, congenital anomalies or birth defects, or require intervention to prevent such an outcome.

These AEs and the resulting dose modification and/or treatment discontinuation rates or safety or toxicity issues that we may experience in our clinical trials in the future could result in a more restrictive label for any drug candidates approved for marketing or could result in the delay or denial of approval to market any drug candidates by the FDA or comparable foreign regulatory authorities,

which could prevent us from ever generating revenue from the sale of drugs or achieving profitability.

The occurrence of AEs in either our clinical trials or following regulatory approval could result in a more restrictive label for any drug candidates approved for marketing or could result in the delay or denial of approval to market any drug candidates by the FDA or comparable foreign regulatory authorities, which could prevent us from generating sufficient revenue from the sale of drugs or achieving profitability.

Results of our trials could reveal an unacceptably high severity and prevalence of side effects.

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our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of the affected drug candidate, if approved, or could substantially increase commercialization costs and expenses, which could delay or prevent us from generating revenues from the sale of our drugs and harm our business and results of operations.

Any of these events could prevent us from achieving or maintaining market acceptance of the affected drug candidate, if approved, or could substantially increase commercialization costs and expenses, which could delay or prevent us from generating sufficient revenue from the sale of our drugs and harm our business and results of operations.

The FDA or non-U.S.

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Our resource allocation decisions may cause us to fail to capitalize on viable commercial drugs or profitable market opportunities.

Our spending on current and future research and development programs and drug candidates for specific indications may not yield any commercially-viable drugs.

Our spending on current and future research and development programs and drug candidates for specific indications may not yield any additional commercially-viable drugs.

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.

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If XPOVIO or our drug candidates do not achieve an adequate level of acceptance, we may not generate significant revenues from sales of drugs and we may not become profitable.

The degree of market acceptance of XPOVIO and our drug candidates, if approved for commercial sale, will depend on a number of factors, including:

The degree of market acceptance of XPOVIO for each approved indication and for our drug candidates, if approved for commercial sale, will depend on a number of factors, including:

efficacy and potential advantages compared to alternative treatments;

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any restrictions on the use of our drugs together with other medications;

inability of certain types of patients to take our drugs.

the inability of certain types of patients to take our drugs.

Our estimates of the potential market opportunities for XPOVIO and our drug candidates include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and fail to accurately reflect market opportunities.

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If we are unable to maintain or expand our sales, marketing and distribution capabilities or maintain current agreements or enter into additional sales, marketing and distribution agreements with third parties, we may not be successful in commercializing XPOVIO or any of our drug candidates that we may develop if and when they are approved.

We have built a sales and marketing infrastructure for XPOVIO, our first commercial product, and our company does not have any prior experience in the sales, marketing or distribution of pharmaceutical drugs.

To achieve commercial success for any approved drug for which sales and marketing is not the responsibility of any strategic collaborator that we have or may have in the future, we must either develop a sales, marketing and distribution organization or outsource these functions to other third parties.

In the future, we may choose to build a sales, marketing and distribution infrastructure to market or co-promote

one or more of our drug candidates, if and when they are approved, or enter into additional collaborations with respect to the sale, marketing and distribution of our drug candidates.

We have built a sales and marketing infrastructure for XPOVIO, our first commercial product, in hematological malignancies and our company did not previously have any prior experience in the sales, marketing or distribution of pharmaceutical drugs.

If XPOVIO or any of our other drug candidates is approved for additional indications beyond hematological malignancies, we will need to substantially evolve our sales, marketing and distribution capabilities and we may not do be able to do so successfully.

In the future, we may choose to expand our sales, marketing and distribution infrastructure to market or co-promote one or more of our drug candidates, if and when they are approved, or enter into additional collaborations with respect to the sale, marketing and distribution of our drug candidates.

We intend to work with existing and potential partners to establish the commercial infrastructure to support a potential launch of selinexor outside of the U.S.

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Further, we may underestimate the size of the sales force required for a successful product launch and we may need to expand our sales force earlier and at a higher cost than we anticipated.

If the commercial launch of any of our drug candidates for which we establish a commercial infrastructure is delayed or does not occur for any reason, including if we do not receive marketing approval on the timeframe we expect, we would have prematurely or unnecessarily incurred these commercialization expenses.

If the commercial launch of any of our drug candidates for which we establish a commercial infrastructure is delayed or does not occur for any reason, including if we do not receive marketing approval in the timeframe we expect, we would have prematurely or unnecessarily incurred these commercialization expenses.

This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.

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our inability to recruit, train and retain adequate numbers of effective sales and marketing personnel;

the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future drugs;

the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe current or future drugs;

the lack of complementary drugs to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive drug lines;

unforeseen costs and expenses associated with creating an independent sales, marketing and distribution organization;

inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies.

our inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies;

existing or new competitors taking share from XPOVIO or preventing XPOVIO from gaining share in its approved indications.

Entering into arrangements with third parties to perform sales and marketing services may result in lower revenues from the sale of drug or the profitability of these revenues to us than if we were to market and sell any drugs that we develop ourselves.

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We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our drugs effectively.

Furthermore, we may be unable to enter into an arrangement with a third party if the current restrictions relating to COVID-19

continue to restrict travel, limit the ability of us or potential partners to negotiate and consummate a transaction in a timely manner, or if COVID-19

causes a prolonged economic downturn.

The extent to which COVID-19

impacts our search for a partner will depend on future developments, which are highly uncertain and cannot be predicted, including new information which may emerge concerning the severity of COVID-19

and the actions to contain COVID-19

or treat its impact, among others.

If the disruptions posed by COVID-19

or other matters of global concern continue for an extensive period of time, our ability to consummate an arrangement may be materially adversely affected.

If we do not establish sales, marketing and distribution capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing XPOVIO or any of our drug candidates for which we obtain marketing approval.

Furthermore, we may be unable to enter into an arrangement with a third party if the current restrictions relating to COVID-19 continue to restrict travel, limit the ability of us or potential partners to negotiate and consummate a transaction in a timely manner, or if the COVID-19 pandemic causes a prolonged economic downturn.

The extent to which the pandemic impacts our search for a partner will depend on future developments, which are highly uncertain and cannot be predicted, including additional information which may emerge concerning the severity of COVID-19 and the actions to contain COVID-19 or treat its impact, among others.

If the disruptions posed by the COVID-19 pandemic or other matters of global concern continue for an extensive period of time, our ability to consummate an arrangement may be materially adversely affected.

If we do not successfully establish and maintain sales, marketing and distribution capabilities, either on our own or in collaboration with third parties, we will not be successful in commercializing XPOVIO or any of our drug candidates for which we obtain marketing approval.

We have a limited number of contractual arrangements with specialty pharmacies and specialty distributors.

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We may not receive royalty or milestone revenue under our partnership agreements for several years, or at all.

Certain of our partnership agreements provide for payments on achievement of development and/or commercialization milestones and for royalties on product sales.

Certain of our partnership agreements provide for payments on achievement of development, regulatory and/or commercialization milestones and for royalties on product sales.

However, because drug development entails a high risk of failure, we may never realize any material portion of the milestone revenue provided in our partnership agreements and we do not expect to receive any royalty revenue for several years, if at all.

We face substantial competition, which may result in others discovering, developing or commercializing drugs before or more successfully than we do.

The discovery, development and commercialization of new drugs is highly competitive.

The discovery, development and commercialization of new drugs is highly competitive, particularly in the cancer field.

We face competition with respect to XPOVIO and our drug candidates and will face competition with respect to any drug candidates that we may seek to discover and develop or commercialize in the future, from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide.

There are a number of major pharmaceutical, specialty pharmaceutical and biotechnology companies that currently market and sell drugs or are pursuing the development of drugs for the treatment of cancer and the other disease indications for which we are developing our drug candidates, although we believe that to date, none of these competitive drugs and therapies currently in development are based on scientific approaches that are the same as our approach.

In addition, there are a large number of companies that are currently developing potential treatments for COVID-19.

Even if we are able to obtain regulatory approval of XPOVIO for the treatment of severe COVID-19

in hospitalized patients following the completion of our recently initiated global clinical trial, we may not be able to compete with other companies, who may have greater financial, sales and marketing capabilities or other competitive advantages.

There are a number of major pharmaceutical, specialty pharmaceutical and biotechnology companies that currently market and sell drugs and/or are pursuing the development of drugs for the treatment of cancer and the other disease indications for which we are developing our drug candidates.

Potential competitors also include academic institutions and governmental agencies and public and private research institutions.

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In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.

In the U.S., approval and reimbursement decisions are not linked directly, but there is increasing scrutiny from the Congress and regulatory authorities of the pricing of pharmaceutical products.

As a result, we might obtain marketing approval for a drug in a particular country, but then be subject to price regulations that delay our commercial launch of the drug, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the drug in that country.

Adverse pricing limitations may hinder our ability to recoup our investment in one or more drug candidates, even if our drug candidates obtain marketing approval.

Our ability to effectively commercialize XPOVIO or any of our product candidates that we may develop successfully will depend, in part, on the extent to which reimbursement for these drugs and related treatments will be available from government health administration authorities, private health insurers and other organizations.

In the U.S., approval and reimbursement decisions are not linked directly, but there is increasing scrutiny from the Congress and regulatory authorities of the pricing of pharmaceutical products.

Adverse pricing limitations may also hinder our ability to recoup our investment in one or more drug candidates, even if our drug candidates obtain marketing approval.

Our ability to effectively commercialize XPOVIO or any of our product candidates that we may develop successfully will depend, in part, on the extent to which reimbursement for these drugs and related treatments is available from government health administration authorities, private health insurers and other organizations.

Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.

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They may require such evidence to demonstrate clinical benefits and value in specific patient populations or they may call for costly pharmaceutical studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies before covering our products.

Accordingly, we cannot be sure that reimbursement will or continue to be available for XPOVIO and any drug candidate that we commercialize and, if reimbursement is available, we cannot be sure as to the level of reimbursement and whether it will be adequate.

Accordingly, we cannot be sure that reimbursement will be or will continue to be available for XPOVIO and any drug candidate that we commercialize and, if reimbursement is available, we cannot be sure as to the level of reimbursement and whether it will be adequate.

Coverage and reimbursement may impact the demand for, or the price of, XPOVIO or any drug candidate for which we obtain marketing approval.

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The business that we conduct outside of the U.S.

may be adversely affected by international risk and uncertainties.

may be adversely affected by international risks and uncertainties.

Although our operations are based in the U.S., we conduct business outside of the U.S.

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For instance, many of the sites at which our clinical trials are being conducted are located outside of the U.S.

In addition, we plan to seek approvals to sell our products in foreign countries.

In addition, we are seeking and continue to plan to seek approvals to sell our products in foreign countries.

Any business that we conduct outside of the U.S.

will be subject to additional risks that may materially adversely affect our ability to conduct business in international markets, including:

potentially reduced protection for intellectual property rights;

the potential for so-called

parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts to import goods from a foreign market (with low or lower prices) rather than buying them locally;

unexpected changes in tariffs, trade barriers and regulatory requirements;

economic weakness, including inflation, volatility in currency exchange rates or political instability in particular foreign economies and markets, including as a result of the current economic situation stemming from the COVID-19

potentially reduced protection of our intellectual property rights;

the potential for so-called parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts to import goods from a foreign market (with low or lower prices) rather than buying them locally;

unexpected changes in tariffs, trade barriers or regulatory requirements;

workforce uncertainty in countries where labor unrest is more common than in the U.S.;

production shortages resulting from any events affecting a product candidate and/or finished drug product supply or manufacturing capabilities abroad;

business interruptions resulting from pandemics (including the COVID-19

outbreak), geo-political

actions, including war and terrorism, or natural disasters, including earthquakes, hurricanes, typhoons, floods and fires;

business interruptions resulting from pandemics (including the COVID-19 pandemic), geo-political actions, including war and terrorism, or natural disasters, including earthquakes, hurricanes, typhoons, floods and fires;

failure to comply with Office of Foreign Asset Control rules and regulations and the Foreign Corrupt Practices Act, or FCPA.

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Since inception, we have incurred significant operating losses.

Our net loss was $52.9 million for the three months ended March 31, 2020.

As of March 31, 2020, we had an accumulated deficit of $926.3 million.

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 the treatment of adult patients with RRMM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Other than the FDA’s accelerated approval of XPOVIO, our lead drug candidate, oral selinexor (for indications not yet approved), as well as eltanexor, verdinexor, and KPT-9274,

are in clinical development.

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.

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.

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.

Although we expect to continue to generate revenue from sales of XPOVIO, there can be no assurance as to the amount or timing of any such revenue, and we expect to continue to incur significant expenses and operating losses.

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We anticipate that our expenses will increase substantially if and as we:

continue to commercialize XPOVIO in the U.S.

and seek regulatory approval for XPOVIO outside of the U.S.;

continue to commercialize XPOVIO in the U.S., including the commercial launch of the recently approved DLBCL indication, and seek regulatory approval for XPOVIO outside of the U.S.;

continue to grow our sales, marketing and distribution infrastructure to support the commercialization of XPOVIO and any drug candidates for which we may obtain marketing approval, prior to or upon receiving marketing approval in the U.S.

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identify additional drug candidates;

acquire or in-license

other drugs and technologies;

acquire or in-license other drugs and technologies;

add operational, financial and management information systems and personnel, including personnel to support our drug development, any commercialization efforts and our other operations as a public company;

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hiring and building a full commercial organization required for the marketing, selling and distribution for those drugs for which we obtain marketing approval;

navigating the negative impacts resulting from the ongoing COVID-19

pandemic to the healthcare systems and the ability of our clinical trial sites to conduct current or future trials;

navigating the negative impacts resulting from the ongoing COVID-19 pandemic to the healthcare systems and the ability of our clinical trial sites to conduct current or future trials;

obtaining, maintaining and protecting our intellectual property rights.

Because of the numerous risks and uncertainties associated with pharmaceutical product development, we are unable to accurately predict the timing or amount of increased expenses or when, or if, we will be able to achieve profitability.

Our expenses could increase if we are required by the FDA or other regulatory authorities to perform clinical trials and non-clinical

studies in addition to those that have been conducted or are currently expected, or if there are any delays in the development of our drug candidates or the manufacture of any of our drug candidates.

Our expenses could increase if we are required by the FDA or other regulatory authorities to perform clinical trials and non-clinical studies in addition to those that have been conducted or are currently expected, or if there are any delays in the development of our drug candidates or the manufacture of any of our drug candidates.

XPOVIO is our only product that has been approved for sale and it has only been approved in the U.S.

for the treatment of adult patients with RRMM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Our ability to become and remain profitable will depend, in part, on the timing and success of commercial sales of XPOVIO, which we commercially launched in the U.S.

in July 2019.

Our ability to become and remain profitable will depend, in part, on the timing and success of commercial sales of XPOVIO for its two currently approved indications, which were commercially launched in the U.S.

in July 2019 and June 2020, respectively.

However, the successful commercialization of XPOVIO in the U.S.

is subject to many risks.

We do not anticipate our revenue from sales of XPOVIO alone, in the currently approved indication, will be sufficient for us to become profitable for several years, if at all.

We do not anticipate that our revenue from sales of XPOVIO alone, in the currently approved indications, will be sufficient for us to become profitable for several years, if at all.

We may never succeed in these activities and may never generate revenues that are significant or large enough to achieve profitability.

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We were incorporated in 2008 and commenced operations in 2009.

Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, developing our platform, identifying potential drug candidates, conducting preclinical studies and early-phase and later-phase clinical trials of our drug candidates and establishing a commercial infrastructure to launch XPOVIO.

To date, we have not generated significant revenue from the sale of XPOVIO.

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In addition, as a business with a short operating history, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors.

We will need to transition from a company with a research and development focus to a company capable of supporting commercial activities.

We need to continue to successfully transition from a company with a research and development focus to a company capable of supporting commercial activities.

We may not be successful in such a transition.

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If we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate our research and drug development programs or commercialization efforts.

We expect our expenses to increase in connection with our ongoing activities, particularly as we commercialize XPOVIO and continue the clinical trials of, and seek marketing approval and prepare for commercialization of, selinexor in additional indications and our other drug candidates, including as a potential treatment for hospitalized patients with severe COVID-19.

Our expenses have increased as we continue to commercialize XPOVIO, including costs associated with our sales force and increased marketing and

distribution capabilities.

If we obtain marketing approval for any drug candidates that we develop, we expect to incur significant additional commercialization expenses for such drug candidate to the extent that such sales, marketing, manufacturing and distribution are not the responsibility of any collaborator that we may have at such time for any such drug candidate.

We expect our expenses to increase in connection with our ongoing activities, particularly as we commercialize XPOVIO, including in the recently approved DLBCL indication, and continue the clinical trials of, and seek marketing approval and prepare for commercialization of, selinexor in additional indications and our other drug candidates.

Our expenses have increased as we continue to commercialize XPOVIO, including costs associated with our sales force and increased marketing and distribution capabilities.

If we obtain marketing approval for any drug candidates that we develop, we expect to incur significant additional commercialization expenses for such drug candidate to the extent that such sales, marketing, manufacturing and distribution functions are not the responsibility of any collaborator that we may have at such time for any such drug candidate.

Furthermore, we will continue to incur additional costs associated with operating as a public company, hiring additional personnel and expanding our facilities.

Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations.

Further, any sustained disruption in the capital markets from the COVID-19

pandemic could negatively impact our ability to raise capital and we cannot predict the extent or duration of the macro-economic disruption stemming from the COVID-19

If the macro-economic disruption continues for pro-longed

periods we may need to raise additional capital and capital may not be available on acceptable terms, or at all.

Further, any sustained disruption in the capital markets from the COVID-19 pandemic could negatively impact our ability to raise capital and we cannot predict the extent or duration of the macro-economic disruption stemming from the COVID-19 pandemic.

If the macro-economic disruption continues for pro-longed periods, we may need to raise additional capital and capital may not be available on acceptable terms, or at all.

If we are unable to raise capital when needed or on attractive terms, we could be forced to delay, reduce or eliminate our research and drug development programs or any current or future commercialization efforts.

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Our future capital requirements will depend on many factors, including:

our ability to successfully commercialize and sell XPOVIO in the U.S.;

our ability to successfully commercialize XPOVIO in the U.S.;

the cost of, and our ability to expand and maintain, the commercial infrastructure required to support the commercialization of XPOVIO and any other drug for which we receive marketing approval, including product sales, medical affairs, marketing and distribution;

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the success of any collaborations that we have entered into and may enter into with third parties;

the extent to which we acquire or in-license

other drugs and technologies;

the costs of commercialization activities, including drug sales, marketing, manufacturing and distribution, for any of our drug candidates for which we receive marketing approval, and pre-commercialization

costs for our drug candidates incurred prior to receiving any such marketing approval, including the costs and timing of establishing product sales, marketing, manufacturing and distribution capabilities that are not the responsibility of any collaborator that we may have at such time;

the extent to which we acquire or in-license other drugs and technologies;

the costs of commercialization activities, including costs related to product sales, marketing, manufacturing and distribution functions, for XPOVIO or any of our drug candidates for which we receive marketing approval, and pre-commercialization costs for our drug candidates incurred prior to receiving any such marketing approval, including the costs and timing of establishing product sales, marketing, manufacturing and distribution capabilities that are not the responsibility of any collaborator that we may have at such time;

the amount of revenue, if any, received from commercial sales of our drug candidates, if approved;

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Identifying potential drug candidates, conducting preclinical studies and clinical trials, seeking marketing approvals and commercializing products are time-consuming, expensive and uncertain processes that take years to complete.

Although we commercially launched XPOVIO in July 2019, we do not anticipate that our revenue from product sales of XPOVIO will be sufficient for us to become profitable for several years, if at all.

Although we commercially launched XPOVIO in its two approved indications in July 2019 and June 2020, respectively, we do not anticipate that our revenue from product sales of XPOVIO will be sufficient for us to become profitable for several years, if at all.

In addition, we may never generate the necessary data or results required to obtain marketing approval of our drug candidates.

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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.

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

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.

If the equity and credit markets continue to deteriorate, it may make any necessary equity or debt financing more difficult to secure, more costly or more dilutive.

Failure to secure any necessary financing in a timely manner and on favorable terms could harm our growth strategy, financial performance and stock price and could require us to delay or abandon plans with respect to our business, including clinical development plans.

In addition, there is a risk that one or more of our current service providers, manufacturers or other third parties with which we conduct business may not survive difficult economic times, including the current global situation resulting from the COVID-19

pandemic, which could directly affect our ability to attain our operating goals on schedule and on budget.

Our indebtedness could limit cash flow available for our operations, expose us to risks that could adversely affect our business, financial condition and results of operations and impair our ability to satisfy our obligations under the Convertible Senior Notes due 2025, or Notes.

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Our business may not generate cash flow from operations in the future sufficient to service the Notes or other future indebtedness and make necessary capital expenditures.

In addition, if the impact of the COVID-19

pandemic to our results of operations and business prospects is more severe and prolonged than we currently anticipate, our ability to repay the Notes could be impaired.

In addition, if the impact of the COVID-19 pandemic to our results of operations and business prospects is more severe and prolonged than we currently anticipate, our ability to repay the Notes could be impaired.

If we are unable to generate such cash flow, we may be required to adopt one or more alternatives, such as selling assets, restructuring indebtedness or obtaining additional debt financing or equity capital on terms that may be onerous or highly dilutive.

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In May 2008, the Financial Accounting Standards Board, or FASB, issued FASB Staff Position No.

Accounting for Convertible Debt Instruments That May Be Settled in Cash upon Conversion (Including Partial Cash Settlement), which has subsequently been codified as Accounting Standards Codification 470-20,

Debt with Conversion and Other Options, or ASC 470-20.

Under ASC 470-20,

an entity must separately account for the liability and equity components of the convertible debt instruments (such as the Notes) that may be settled entirely or partially in cash upon conversion in a manner that reflects the issuer’s economic interest cost.

The effect of ASC 470-20

on the accounting for the Notes is that the equity component is required to be included in the additional paid-in

capital section of stockholders’ equity at the issuance date, and the value of the equity component would be treated as debt discount for purposes of accounting for the debt component of the Notes.

As a result, we will be required to record a greater amount of non-cash

interest expense as a result of the amortization of the discounted carrying value of the Notes to their face amount over the term of the Notes.

We will report a larger net loss in our financial results because ASC 470-20

will require interest to include both the amortization of the value of the debt discount and the instrument’s coupon interest rate, which could adversely affect our future financial results, the market price of our common stock and the trading price of the Notes.

APB 14-1, Accounting for Convertible Debt Instruments That May Be Settled in Cash upon Conversion (Including Partial Cash Settlement), which has subsequently been codified as Accounting Standards Codification 470-20, Debt with Conversion and Other Options, or ASC 470-20.

Under ASC 470-20, an entity must separately account for the liability and equity components of the convertible debt instruments (such as the Notes) that may be settled entirely or partially in cash upon conversion in a manner that reflects the issuer’s economic interest cost.

The effect of ASC 470-20 on the accounting for the Notes is that the equity component is required to be included in the additional paid-in capital section of stockholders’ equity at the issuance date, and the value of the equity component would be treated as debt discount for purposes of accounting for the debt component of the Notes.

As a result, we will be required to record a greater amount of non-cash interest expense as a result of the amortization of the discounted carrying value of the Notes to their face amount over the term of the Notes.

We will report a larger net loss in our financial results because ASC 470-20 will require interest to include both the amortization of the value of the debt discount and the instrument’s coupon interest rate, which could adversely affect our future financial results, the market price of our common stock and the trading price of the Notes.

In addition, under certain circumstances, convertible debt instruments (such as the Notes) that may be settled entirely or partly in cash are currently eligible to be accounted for utilizing the treasury stock method, the effect of which is that the shares issuable upon conversion of the Notes are not included in the calculation of diluted earnings per share except to the extent that the conversion value of the Notes exceeds their principal amount.

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On September 14, 2019, we entered into the Revenue Interest Agreement with HCR.

incur or prepay indebtedness, create or incur liens, pay dividends on or repurchase outstanding shares of our capital stock or dispose of assets.

In addition, the Revenue Interest Agreement includes customary events of default upon the occurrence of enumerated events, including non-payment

of revenue interests, failure to perform certain covenants and the occurrence of insolvency proceedings, specified judgments, specified cross-defaults or specified revocations, withdrawals or cancellations of regulatory approval for XPOVIO.

Pursuant to the Revenue Interest Agreement, we are required to comply with various covenants relating to the conduct of our business and the commercialization of XPOVIO, including obligations to use commercially reasonable efforts to commercialize our products and limits on our ability to incur or prepay indebtedness, create or incur liens, pay dividends on or repurchase outstanding shares of our capital stock or dispose of assets.

In addition, the Revenue Interest Agreement includes customary events of default upon the occurrence of enumerated events, including non-payment of revenue interests, failure to perform certain covenants and the occurrence of insolvency proceedings, specified judgments, specified cross-defaults or specified revocations, or withdrawals or cancellations of regulatory approval for XPOVIO.

Upon the occurrence of an event of default and in the event of a change of control, HCR may accelerate payments due under the Revenue Interest Agreement up to $138.8 million, less the aggregate of all of the payments previously paid to HCR.

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In addition, we intend to seek one or more collaborators to aid in the further development, marketing and/or commercialization of selinexor and our other SINE compounds for indications outside of oncology.

Potential collaborators for any collaboration arrangements include large and mid-size

pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies.

Potential collaborators for any collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies.

In connection with any such arrangements with third parties, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development, marketing and/or commercialization of our drug candidates.

Our ability to generate revenues from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements.

In addition, the third-parties upon whom we rely to develop, market and commercialize XPOVIO and our drug candidates could be negatively impacted by the COVID-19

pandemic, including as a result of businesses suspending or terminating global operations and travel, self-imposed or government-mandated quarantines, and an overall slowdown of economic activity.

In addition, the third-parties upon whom we rely to develop, market and commercialize XPOVIO and our drug candidates could be negatively impacted by the COVID-19 pandemic, including as a result of businesses suspending or terminating global operations and travel, self-imposed or government-mandated quarantines, and an overall slowdown of economic activity.

If our third-party collaborators are so affected, our business prospects and results of operations could be severely adversely impacted.

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If we do not receive the funding we expect under these agreements, our development of our product candidates could be delayed and we may need additional resources to develop product candidates.

All of the risks relating to product development, regulatory approval and commercialization described in this Quarterly Report on Form 10-Q

also apply to the activities of our collaborators.

All of the risks relating to product development, regulatory approval and commercialization described in this Quarterly Report on Form 10-Q also apply to the activities of our collaborators.

If we are unable to establish and maintain our agreements with third parties to distribute XPOVIO to patients, our results of operations and business could be adversely affected.

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If we or any of the third parties that we rely on in connection with our clinical trials fail to comply with applicable requirements, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, EMA or other comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications.

We cannot assure you that upon inspection by a given regulatory authority, such

regulatory authority will determine that any of our clinical trials comply with such requirements.

We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with such requirements.

We also are required to register ongoing clinical trials and post the results of completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within certain timeframes.

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Any failure by a third party to meet its obligations with respect to the clinical development of our drug candidates may delay or impair our ability to obtain regulatory approval for selinexor and our other drug candidates.

We rely on academic and private non-academic

institutions to conduct and sponsor clinical trials relating to selinexor and our other drug candidates.

We rely on academic and private non-academic institutions to conduct and sponsor clinical trials relating to selinexor and our other drug candidates.

We do not control the design or conduct of the investigator-sponsored trials, and it is possible that the FDA or non-U.S.

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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.

There are a limited number of manufacturers that operate under cGMP regulations and that might be capable of manufacturing for us.

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

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.

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.

If our suppliers or contract manufacturers are so affected, our supply chain could be disrupted, our product shipments could be delayed, our costs could be increased and our business could be adversely affected.

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or in other countries until we or any of our collaborators receive approval of an NDA from the FDA or marketing approval from applicable regulatory authorities outside of the U.S.

In July 2019, the FDA approved XPOVIO in combination with dexamethasone for the treatment of adult patients with RRMM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

This indication was 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 randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade ®

(bortezomib) and low-dose

dexamethasone is expected to serve as the confirmatory trial based on positive topline data announced in March 2020.

The BOSTON study is one of the post-marketing requirements for continued marketing authorization under the accelerated approval issued by the FDA for XPOVIO based on the results of the STORM study.

If the FDA does not approve our planned 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 study.

In addition, we submitted a Marketing Authorization Application, or 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 July 2019 and June 2020, the FDA approved XPOVIO in the multiple myeloma indication and the DLBCL indication, respectively.

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.

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.

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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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, we have not yet been able to complete certain re-monitoring

activities and, therefore, have requested, and the EMA has granted us, additional time to submit our response.

As a result, we currently expect to receive a decision on the application during late 2020.

With the exception of our sNDA submission to the FDA requesting approval of selinexor to treat relapsed or refractory diffuse large B-cell

lymphoma, or DLBCL, we have not submitted any other application for, or received any marketing approval of, any of our drug candidates in the U.S.

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.

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.

or in any other jurisdiction.

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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.

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, as discussed above, 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.

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 .

Further, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes in regulatory review for each submitted drug application, may cause delays in the approval or rejection of an application.

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Any delay in obtaining or failure to obtain required approvals could materially adversely affect our ability or that of any of our collaborators to generate revenue from the particular drug candidate, which likely would result in significant harm to our financial position and adversely impact our stock price.

Under the FDA’s accelerated approval regulations, we must still comply with post-approval development and regulatory requirements to maintain our approval of XPOVIO and, if we fail to do so, the FDA could withdraw its approval of XPOVIO, which would lead to substantially lower revenues.

For drugs granted accelerated approval, the FDA typically requires post-marketing confirmatory trials to evaluate the anticipated effect on irreversible morbidity or mortality or other clinical benefit.

Under the FDA’s accelerated approval regulations, we must still comply with post-approval development and regulatory requirements to maintain our approval of XPOVIO and, if we fail to do so, the FDA could withdraw its approval of XPOVIO for either of the currently approved indications, which would lead to substantially lower revenues.

For drugs approved under the FDA’s Accelerated Approval Program, the FDA typically requires post-marketing confirmatory trials to evaluate the anticipated effect on irreversible morbidity or mortality or other clinical benefit.

These confirmatory trials must be completed with due diligence.

As a condition of the accelerated approval of XPOVIO, 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.

The FDA may withdraw approval of XPOVIO if, for example, the trial required to verify the predicted clinical benefit of XPOVIO fails to verify such benefit or does not demonstrate sufficient clinical benefit to justify the risks associated with the drug.

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 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.

The FDA may withdraw approval of XPOVIO for either approved indication if, for example, a trial required to verify the predicted clinical benefit of XPOVIO fails to verify such benefit or does not demonstrate sufficient clinical benefit to justify the risks associated with the drug.

The FDA may also withdraw approval if other evidence demonstrates that XPOVIO is not shown to be safe or effective under the conditions of use, we fail to conduct any required post approval trial of our product candidate with due diligence or we disseminate false or misleading promotional materials relating to our product candidate.

Similar risks to those described above are also applicable to any application that we have submitted or may submit to the EMA to support conditional approval of selinexor to treat heavily pretreated multiple myeloma, relapsed/refractory DLBCL, or any other cancer indication.

There can be no assurance that the FDA or any similar regulatory authority will determine that the BOSTON study, which was conducted as part of our post-marketing obligations, will confirm that the surrogate marker used for accelerated approval of XPOVIO showed an adequate correlation with clinical outcomes.

If the FDA or any similar regulatory authority determines that the BOSTON study fails to show such adequate correlation, we may not be able to maintain our previously granted marketing approval of XPOVIO.

There can be no assurance that the FDA or any similar regulatory authority will determine that any confirmatory trial we conduct as part of our post-marketing obligations, will confirm that the surrogate marker used for accelerated approval of XPOVIO showed an adequate correlation with clinical outcomes.

If the FDA or any similar regulatory authority determines that our confirmatory trials fail to show such adequate correlation, we may not be able to maintain our previously granted marketing approvals of XPOVIO.

Our failure to obtain marketing approval in foreign jurisdictions would prevent our product candidates from being marketed abroad, and any approval we are granted for our product candidates in the U.S.

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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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We may seek approval from the FDA or comparable non-U.S.

regulatory authorities to use accelerated development pathways for our product candidates, including for selinexor in diffuse large B-cell

regulatory authorities to use accelerated development pathways for our product candidates.

If we are not able to use such pathways, we may be required to conduct additional clinical trials beyond those that we contemplate and that would increase the expense of obtaining, and delay the receipt of, necessary marketing approvals, if we receive them at all.

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Prior to seeking such accelerated approval, we will continue to seek feedback from the FDA and otherwise evaluate our ability to seek and receive such accelerated approval.

Based on the positive results of the SADAL study, we submitted a 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 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.

In November 2018, the FDA granted fast track designation to selinexor for this indication.

While the FDA agreed that the trial design and indication appear appropriate for accelerated approval, they reiterated to us in their feedback that the availability of accelerated approval will depend on the trial results and available therapies at the time of regulatory action.

The FDA also has reiterated to us that it recommends, in general, a randomized trial with a progression-free survival endpoint as an initial registration approach and, for DLBCL, recommended two randomized trials that isolate the treatment effect of selinexor for a DLBCL indication.

During a pre-sNDA

meeting with the FDA in November 2019, the FDA noted that the sufficiency of efficacy, tolerability and dose optimization data would be a review issue.

Although we believe that our SADAL study presents an opportunity for us to request that the FDA grant accelerated approval for selinexor in relapsed and/or refractory DLBCL, there can be no assurance that the FDA will grant such approval, whether on an accelerated basis, or at all.

There can also be no assurance that the FDA will agree with our surrogate endpoints or intermediate clinical endpoints, or that we will decide to pursue or submit any additional NDAs for accelerated approval or any other form of expedited development, review or approval.

There can be no assurance that the FDA will agree with our surrogate endpoints or intermediate clinical endpoints in any of our clinical trials, or that we will decide to pursue or submit any additional NDAs for accelerated approval or any other form of expedited development, review or approval.

Similarly, there can be no assurance that, after feedback from FDA, we will continue to pursue or apply for accelerated approval or any other form of expedited development, review or approval, even if we initially decide to do so.

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Moreover, even if we do receive such a designation, we may not experience a faster development process, review or approval compared to conventional FDA procedures and there is no assurance that our product candidate will be approved by the FDA.

In April 2018, the FDA granted fast track designation to selinexor for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy that include regimens comprised of an alkylating agent, a glucocorticoid, Velcade ®

(bortezomib), Kyprolis ®

(carfilzomib), Revlimid ®

(lenalidomide), Pomalyst ®

(pomalidomide) and Darzalex ®

(daratumumab) and whose disease is refractory to at least one proteasome inhibitor (Velcade or Kyprolis), one immunomodulatory agent (Revlimid or Pomalyst), glucocorticoids and to Darzalex, as well as to the most recent therapy.

In addition, 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.

However, even with these fast track designations, we may not experience a faster development process, review or approval compared to conventional FDA procedures and there is no assurance that selinexor will be approved by the FDA for additional indications.

For example, in connection with our NDA for XPOVIO, in March 2019, the FDA extended the PDUFA action date by three months following our submission of additional, existing clinical information as an amendment to the NDA, which resulted in a nine-month review cycle despite the fast track designation.

For example, in connection with our NDA for XPOVIO, in March 2019, the FDA extended the Prescription Drug User Fee Act, or PDUFA, action date by three months following our submission of additional, existing clinical information as an amendment to the NDA, which resulted in a nine-month review cycle despite the fast track designation.

The FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program.

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Receiving priority review from the FDA does not guarantee approval within the six-month

review cycle or thereafter.

Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or thereafter.

We may not be able to obtain orphan drug exclusivity for our product candidates.

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On August 3, 2017, Congress passed the FDA Reauthorization Act of 2017, or FDARA.

FDARA, among other things, codified the FDA’s pre-existing

regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.

FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.

The new legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority.

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These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, requirements regarding the distribution of samples to physicians and recordkeeping.

For example, as a condition of the XPOVIO approval, we are required to complete certain post-marketing commitments, as described above.

For example, as a condition of the XPOVIO approval for the multiple myeloma and DLBCL indications, we are required to complete certain post-marketing commitments, as described above.

Even if marketing approval of a drug candidate is granted, the approval may be subject to limitations on the indicated uses for which the drug may be marketed or to the conditions of approval, including the requirement to implement a Risk Evaluation and Mitigation Strategy, which could include requirements for a restricted distribution system.

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The FDA and other agencies, including the Department of Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of drugs to ensure that they are manufactured, marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling.

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

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.

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Under the Cures Act and the Trump Administration’s regulatory reform initiatives, the FDA’s policies, regulations and guidance may be revised or revoked and that could prevent, limit or delay regulatory approval of our product candidates, which would impact our ability to generate revenue.

In December 2016, the 21 st

Century Cures Act, or Cures Act, was signed into law.

In December 2016, the 21 st Century Cures Act, or Cures Act, was signed into law.

The Cures Act, among other things, is intended to modernize the regulation of drugs and spur innovation.

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In January 2017, President Trump issued an executive order, applicable to all executive agencies including the FDA, which requires that for each notice of proposed rulemaking or final regulation to be issued in fiscal year 2017, the agency shall identify at least two existing regulations to be repealed, unless prohibited by law.

These requirements are referred to as the “two-for-one”

These requirements are referred to as the “two-for-one” provisions.

This executive order includes a budget neutrality provision that requires the total incremental cost of all new regulations in the 2017 fiscal year, including repealed regulations, to be no greater than zero, except in limited circumstances.

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 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.

In response to the COVID-19

pandemic, the Trump Administration is looking for additional ways to provide regulatory relief.

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

It is difficult to predict how these various requirements will be implemented, and the extent to which they will impact the FDA’s ability to exercise its regulatory authority.

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Among the provisions of the Patient Protection and Affordable Care Act, or ACA, of potential importance to our business, including, without limitation, our ability to commercialize our drugs and the prices we may obtain for any of our drug candidates that are approved for sale, are the following:

an annual, non-deductible

fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;

an annual, non-deductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;

an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;

expansion of healthcare fraud and abuse laws, including the civil False Claims Act and the federal Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;

a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer point-of-sale

discounts off negotiated prices to eligible beneficiaries during their coverage gap period, as a condition for a manufacturer’s outpatient drugs to be covered under Medicare Part D;

a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer point-of-sale discounts off negotiated prices to eligible beneficiaries during their coverage gap period, as a condition for a manufacturer’s outpatient drugs to be covered under Medicare Part D;

extension of manufacturers’ Medicaid rebate liability;

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These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions to Medicare payments to providers of up to 2% per fiscal year that started in April 2013 and, due to subsequent legislative amendments, will stay in effect through 2029 unless additional Congressional action is taken, and the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

These laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for XPOVIO and for any of our product candidates for which we may obtain regulatory approval or the frequency with which XPOVIO or any such product candidate is prescribed or used.

The CARES Act, which was signed into law on March 27, 2020 and designed to provide financial support and resources to individuals and businesses affected by the COVID-19 pandemic, suspended the 2% Medicare sequester from May 1, 2020 to December 31, 2020 and extended the sequester by one year, through 2030, in order to offset the added expense of the 2020 cancellation.

Further, there have been several recent U.S.

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While Congress has not passed comprehensive repeal legislation, two bills affecting the implementation of certain taxes under the ACA have been signed into law.

The Tax Cuts and Jobs Act of 2017, or the TCJA, includes a provision repealing, effective January 1, 2019, the tax-based

shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate”.

Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated

“Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminates the health insurer tax.

The Tax Cuts and Jobs Act of 2017, or the TCJA, includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate”.

Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminates the health insurer tax.

The Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole”.

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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.

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

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In January 2017, President Trump signed an executive order 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.

October 2017, the President signed a second executive order allowing for the use of association health plans and short-term health insurance, which may provide fewer health benefits than the plans sold through the ACA exchanges.

In October 2017, the President signed a second executive order allowing for the use of association health plans and short-term health insurance, which may provide fewer health benefits than the plans sold through the ACA exchanges.

At the same time, the Trump Administration announced that it will discontinue the payment of cost-sharing reduction, or CSR, payments to insurance companies until Congress approves the appropriation of funds for such CSR payments.

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congressional inquiries and proposed and enacted federal and 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, the Trump administration’s budget proposal contains further drug price control measures that could be enacted during the budget process or in other future legislation, including, for example, measures to permit Medicare Part D plans to negotiate the price of certain drugs under Medicare Part B, to allow some states to negotiate drug prices under Medicaid, and to eliminate cost sharing for generic drugs for low-income

Specifically, the Trump Administration’s 2021 budget proposal includes a $135 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 drugs and biosimilars.

While any proposed measures will require authorization through additional legislation to become effective, Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

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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.

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 the FDA for review and approval.

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.

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.

Specifically, the order calls upon the Department of Health and Human Services, or HHS, to facilitate grants to individuals of waivers of the prohibition of importation of prescription drugs that would allow patients to import FDA - approved drug products from abroad, so long as doing so would result in lower costs.

In addition, the order would allow wholesalers and pharmacies to re-import both biological drugs and insulin that were originally manufactured in the U.S.

and then exported for international sale.

This action follows the publication of a proposed rulemaking on December 23, 2020, that, if finalized, would allow 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, the 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).

At the same time, the 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).

Finally, the fourth order would end drug rebates used by health plan sponsors, pharmacies or pharmacy benefit managers, or PBMs, in operating the Medicare Part D program.

Specifically, the order directs HHS to exclude from safe harbor protections under the federal anti-kickback statute retroactive price reductions that are not applied at the point-of-sale.

Instead, the order requires HHS to establish new safe harbors that would allow health plan sponsors, pharmacies, and PBMs to pass on those discounts to consumers at point-of-sale in order to “ lower the patient's out-of-pocket costs ” and “ permit the use of certain bona fide PBM service fees ” .

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

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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In addition, increased scrutiny by the Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as subject us and any collaborators to more stringent drug labeling and post-marketing testing and other requirements.

Our relationships with healthcare providers and physicians and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and third party payors will play a primary role in the recommendation and prescription of any drugs for which we obtain marketing approval.

Our future arrangements with third party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any drugs for which we obtain marketing approval.

Our relationships with healthcare providers and physicians and third-party payors are subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and third party payors play a primary role in the recommendation and prescription of any drugs for which we obtain marketing approval.

Our arrangements with third party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any drugs for which we obtain marketing approval.

These include the following:

Anti-Kickback Statute

—the federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation or arranging of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;

False Claims Act

—the federal False Claims Act imposes criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim

penalties, currently set at a minimum of $11,181 and a maximum of $22,363 per false claim;

—the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters, and, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, also imposes obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and transmission of individually identifiable health information;

Transparency Requirements

—federal laws require applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals;

Analogous State and Foreign Laws

—analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, can apply to sales or marketing arrangements and claims involving healthcare items or services and are generally broad and are enforced by many different federal and state agencies as well as through private actions.

Anti-Kickback Statute —the federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation or arranging of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;

False Claims Act —the federal False Claims Act imposes criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties, currently set at a minimum of $11,181 and a maximum of $22,363 per false claim;

HIPAA —the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters, and, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, also imposes obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and transmission of individually identifiable health information;

Transparency Requirements —federal laws require applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals;

Analogous State and Foreign Laws —analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, can apply to sales or marketing arrangements and claims involving healthcare items or services and are generally broad and are enforced by many different federal and state agencies as well as through private actions.

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures.

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.

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.

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If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.

If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

If any of the physicians or other healthcare providers or entities with whom we do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union.

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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.

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.

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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Even if we are not determined to have violated these laws, government investigations into these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our reputation and our business.

Our employees, independent contractors, consultants and vendors may engage in misconduct or other improper activities, including non-compliance

with regulatory standards and requirements and insider trading, which could cause significant liability for us and harm our reputation.

Our employees, independent contractors, consultants and vendors may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements and insider trading, which could cause significant liability for us and harm our reputation.

We are exposed to the risk of fraud or other misconduct by our employees, independent contractors, consultants and vendors.

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Disruptions at the FDA and other agencies may also slow the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.

For example, over the last several years, including in recent months, the U.S.

For example, over the last several years, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical FDA, SEC and other government employees and stop critical activities.

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

As of April 15, 2020, 65 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, 15 patents are in force that relate to our PAK4/NAMPT inhibitors, including two composition of matter patents for KPT-9274

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.

In addition, 15 patents were in force that relate to our PAK4/NAMPT inhibitors, including two composition of matter patents for KPT-9274 in the U.S.

and its use in targeted therapeutics.

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In March 2013, the U.S.

transitioned to a first-inventor-to-file

system in which, assuming the other requirements for patentability are met, the first inventor to file a patent application is entitled to the patent.

transitioned to a first-inventor-to-file system in which, assuming the other requirements for patentability are met, the first inventor to file a patent application is entitled to the patent.

We may be subject to a third-party preissuance submission of prior art to the U.S.

Patent and Trademark Office, or USPTO, or become involved in opposition, derivation, revocation, reexamination, or post-grant or inter partes

review or interference proceedings challenging our patent rights or the patent rights of others.

Patent and Trademark Office, or USPTO, or become involved in opposition, derivation, revocation, reexamination, or post-grant or inter partes review or interference proceedings challenging our patent rights or the patent rights of others.

An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our discoveries or drugs and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize drugs without infringing third-party patent rights.

Even if our patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage.

Our competitors may be able to circumvent our patents by developing similar or alternative discoveries or drugs in a non-infringing

Our competitors may be able to circumvent our patents by developing similar or alternative discoveries or drugs in a non-infringing manner.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our patents may be challenged in the courts or patent offices in the U.S.

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However, we may not be able to obtain any required license on commercially reasonable terms, or at all.

Even if we were able to obtain a license, it could be non-exclusive,

thereby giving our competitors access to the same intellectual property licensed to us.

Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same intellectual property licensed to us.

We could be forced, including by court order, to cease commercializing the infringing intellectual property or drug or to cease using the infringing technology.

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Many of our employees were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors.

Although we try to ensure that our employees do not use the proprietary information or know-how

of others in their work for us, we may be subject to claims that we or these employees have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such employee’s former employer.

Although we try to ensure that our employees do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these employees have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such employee’s former employer.

Although we have no knowledge of any such claims being alleged to date, if such claims were to arise, litigation may be necessary to defend against any such claims.

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Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.

Obtaining and maintaining our patent protection depends on compliance with various procedural, documentary, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance

with these requirements.

Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or applications will be due to the USPTO and various foreign patent offices at various points over the lifetime of the patents and/or applications.

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We employ reputable law firms and other professionals to help us comply with such provisions, and in many cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with rules applicable to the particular jurisdiction.

However, there are situations in which non-compliance

can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.

However, there are situations in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.

If such an event were to occur, it could have a material adverse effect on our business.

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Laws governing analogous patent term extensions in foreign jurisdictions vary widely, as do laws governing the ability to obtain multiple patents from a single patent family.

Because both selinexor and verdinexor are protected by a single family of patents and applications, we may not be able to secure patent term extensions for both of these drug candidates in all jurisdictions where these drug candidates are approved, if ever.

If we are unable to obtain a patent term extension for a drug candidate or the term of any such extension is less than we request, the period during which we can enforce our patent rights for that drug candidate, if any, in that jurisdiction will be shortened and our competitors may obtain approval to market competing products sooner.

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If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to seeking patents for our drugs, drug candidates and other discoveries, we also rely on trade secrets, including unpatented know-how,

technology and other proprietary information, to maintain our competitive position.

We seek to protect these trade secrets, in part, by entering into non-disclosure

and confidentiality agreements with parties who have access to them, such as our employees, outside scientific collaborators, contract research organizations, contract manufacturers, consultants, advisors and other third parties.

In addition to seeking patents for our drugs, drug candidates and other discoveries, we also rely on trade secrets, including unpatented know-how, technology and other proprietary information, to maintain our competitive position.

We seek to protect these trade secrets, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, outside scientific collaborators, contract research organizations, contract manufacturers, consultants, advisors and other third parties.

We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants.

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Failure to secure those registrations could adversely affect our business.

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

As of July 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.

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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 additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan.

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.

We also have registrations or applications for eight additional possible drug names in numerous foreign jurisdictions.

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We may also be vulnerable to cyber attacks by hackers, or other malfeasance.

This type of breach of our cybersecurity may compromise our confidential information and/or our financial information and adversely affect our business or

result in legal proceedings.

This type of breach of our cybersecurity may compromise our confidential information and/or our financial information and adversely affect our business or result in legal proceedings.

In addition, the cost and operational consequences of implementing further data protection measures could be significant.

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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 April 30, 2020, our executive officers, directors and a small number of stockholders own more than a majority of our outstanding common stock.

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 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 April 15, 2019, our common stock has traded at prices per share as high as $29.61 and as low as $4.26.

On April 30, 2020, the closing sale price of our common stock on The Nasdaq Global Select Market was $22.05

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

outbreak and related world-wide economic disruptions.

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.

The market price for our common stock may be influenced by many factors, including:

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the level of expenses related to the commercialization of XPOVIO and clinical development programs for any of our drug candidates;

the results of our efforts to discover, develop, acquire or in-license

additional drug candidates or drugs;

the results of our efforts to discover, develop, acquire or in-license additional drug candidates or drugs;

actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;

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changes in the structure of healthcare payment systems;

market conditions in the pharmaceutical and biotechnology sectors, including as the result of uncertainties due to the ongoing COVID-19

market conditions in the pharmaceutical and biotechnology sectors, including as the result of uncertainties due to the ongoing COVID-19 pandemic;

general economic, industry and market conditions;

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We are a target of this type of litigation.

See Part II, Item 1, “Legal Proceedings” in this Quarterly Report on Form 10-Q

for information concerning securities litigation recently initiated against us and certain of our executive officers and directors and certain other defendants.

See Part II, Item 1, “Legal Proceedings” in this Quarterly Report on Form 10-Q for information concerning securities litigation recently initiated against us and certain of our executive officers and directors and certain other defendants.

We may become the target of additional securities litigation in the future.

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We currently maintain insurance coverage for some of these potential liabilities.

Other potential liabilities may not be covered by insurance, insurers may

dispute coverage or the amount of insurance may not be enough to cover damages awarded.

Other potential liabilities may not be covered by insurance, insurers may dispute coverage or the amount of insurance may not be enough to cover damages awarded.

In addition, certain types of damages may not be covered by insurance, and insurance coverage for all or certain forms of liability may become unavailable or prohibitively expensive in the future.

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Under the provisions of the Internal Revenue Code of 1986, as amended, or the Code, our net operating loss and tax credit carryforwards are subject to review and possible adjustment by the Internal Revenue Service (and state tax authorities under relevant state tax rules).

In addition, as described below in “ Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition

,” the TCJA (as amended by the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act,) includes changes to U.S.

In addition, as described below in “ Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition ,” the TCJA (as amended by the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act) includes changes to U.S.

federal tax rates and the rules governing net operating loss carryforwards that may significantly impact our ability to utilize our net operating losses to offset taxable income in the future.

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tax on foreign earnings (subject to certain important exceptions), immediate deductions for certain new investments instead of deductions for depreciation expense over time, and modifying or repealing many business deductions and credits.

As part of Congress’ response to the COVID-19

pandemic, the Families First Coronavirus Response Act, or FFCR Act, was enacted on March 18, 2020, and the CARES Act was enacted on March 27, 2020.

As part of Congress’ response to the COVID-19 pandemic, the Families First Coronavirus Response Act, or FFCR Act, was enacted on March 18, 2020, and the CARES Act was enacted on March 27, 2020.

Both contain numerous tax provisions.

In particular, the CARES Act retroactively and temporarily (for taxable years beginning before January 1, 2021) suspends application of the 80%-of-income

limitation on the use of net operating losses, which was enacted as part of the TCJA.

In particular, the CARES Act retroactively and temporarily (for taxable years beginning before January 1, 2021) suspends application of the 80%-of-income limitation on the use of net operating losses, which was enacted as part of the TCJA.

It also provides that net operating losses arising in any taxable year beginning after December 31, 2017, and before January 1, 2021 are generally eligible to be carried back up to five years.

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Regulatory guidance under the TCJA, the FFCR Act and the CARES Act is and continues to be forthcoming, and such guidance could ultimately increase or lessen their impact on our business and financial condition.

It is also likely that Congress will enact additional legislation in connection with the COVID-19

pandemic, some of which could have an impact on us.

It is also likely that Congress will enact additional legislation in connection with the COVID-19 pandemic, some of which could have an impact on us.

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

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)

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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Inline XBRL Instance Document.

Inline XBRL Schema Document

Inline XBRL Calculation Linkbase Document

Inline XBRL Definition Linkbase Document

Inline XBRL Label Linkbase Document

Inline XBRL Presentation Linkbase Document

The instance document does not appear in the Interactive Data File because its XBRL tags are embedded within the Inline XBRL document.

Inline XBRL Taxonomy Extension Schema Document.

Inline XBRL Taxonomy Extension Calculation Linkbase Document.

Inline XBRL Taxonomy Extension Definition Linkbase Document.

Inline XBRL Taxonomy Extension Label Linkbase Document.

Inline XBRL Taxonomy Extension Presentation Linkbase Document.

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

/s/ MICHAEL KAUFFMAN

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(Principal executive officer)

August 4, 2020

/s/ MICHAEL MASON

Michael Mason

Senior Vice President,

Chief Financial Officer and Treasurer

Senior Vice President, Chief Financial Officer and Treasurer

(Principal financial and accounting officer)

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