Karyopharm Therapeutics Inc. - Annual Report: 2020 (Form 10-K)

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files).    Yes  ☒    No  ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in of the Exchange Act.

Indicate by check mark whether the registrant is a shell company (as defined in the Exchange Act).    Yes ☐    No ☒

The aggregate market value of the registrant’s voting and common stock held by of the registrant (without admitting that any person whose shares are not included in such calculation is an affiliate) computed by reference to the price at which the common stock was last sold on June 30, 2020 was approximately $1.32 billion. Shares of common stock held by each executive officer and director and by each holder of 10% or more of the outstanding common stock have been excluded in that such persons may be deemed to be affiliates. This determination of affiliate status is not necessarily a conclusive determination for other purposes.

Portions of the registrant’s Proxy Statement for its 2021 Annual Meeting of Stockholders, which the registrant intends to file with the Securities and Exchange Commission no later than 120 days after the registrant’s fiscal year end of December 31, 2020, are incorporated by reference into Part III of this Annual Report on

Table of Contents 

We are a commercial-stage pharmaceutical company pioneering novel cancer therapies and dedicated to the discovery, development and commercialization of drugs directed against nuclear transport for the treatment of cancer and other diseases. Our scientific expertise is based upon an understanding of the regulation of intracellular communication between the nucleus and the cytoplasm. We have discovered and are developing and commercializing novel, small molecule (“SINE”) compounds that inhibit the nuclear export protein exportin 1 (“XPO1”). These SINE compounds, representing a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety of diseases with high unmet medical need, were the first oral XPO1 inhibitors to receive marketing approval. Our lead asset, XPOVIO (selinexor), received its initial U.S. approval from the U.S. Food and Drug Administration (the “FDA”) in July 2019 and is currently approved and marketed for the following indications:

Union (“EU”) member countries as well as the European Economic Area countries of Iceland, Liechtenstein and Norway. Further, we plan to submit a second regulatory filing to the EMA (Type II variation) by April 2021 based on the data from the Phase 3 BOSTON Study, which evaluated once-weekly NEXPOVIO in combination with once-weekly Velcade and dexamethasone in patients with multiple myeloma after at least one prior therapy with the goal of further expanding the global reach of NEXPOVIO to additional patients in need of new treatment options.

Cancer is a disease characterized by unregulated cell growth. Cancer cells develop when DNA inside the nucleus of normal cells accumulates damage in genes that regulate cell growth and survival. In healthy cells, proteins called tumor suppressor proteins located in the cell nucleus help prevent the accumulation of DNA damage (mutations, chromosomal translocations and other abnormalities) by monitoring DNA for damage, and if damage is detected, the tumor suppressor proteins will direct the cell to attempt to repair it, or if the DNA damage is too severe, the tumor suppressor proteins will direct the cell to die in a process called apoptosis. Accumulation of tumor suppressor proteins in the nucleus of cancer cells allows them to perform their normal role of detecting DNA damage, thereby inhibiting a cancer cell’s ability to divide, and promoting apoptosis.

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The STOMP Study, an ongoing Phase 1b/2 clinical trial in patients with relapsed or refractory multiple myeloma, is evaluating selinexor and dexamethasone in combinations with standard therapies, such as Pomalyst, Kyprolis, Revlimid, Velcade, and Darzalex. We presented the following updated clinical data from the STOMP Study at the ASH 2020 Annual Meeting in December 2020, demonstrating that selinexor and dexamethasone plus standard anti-myeloma therapies exhibit encouraging response rates in these combination regimens:

In this all oral arm of the Phase 1b/2 STOMP Study, selinexor is being evaluated in combination with Pomalyst and dexamethasone in patients with relapsed or refractory multiple myeloma who received at least two prior lines of therapy, including a PI and an IMiD. Of note, 25% of the population enrolled in the study had previously received Darzalex. The recommended Phase 2 dose (“RP2D”) was determined to be 60 mg of XPOVIO orally once-weekly, four mg of Pomalystorally once-daily and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally. The following table is a summary of the efficacy results:

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (“AEs”) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common treatment-related AEs were nausea (60%), fatigue (51%), decreased appetite (44%), weight loss (38%) and diarrhea (29%), and were primarily grade 1 and 2 events. The most common treatment-related Grade 3 and 4 AEs were neutropenia (54%), anemia (33%), and thrombocytopenia (32%).

Based on these Phase 2 results, we plan to initiate a Phase 3 study investigating the XPd combination in 2021. Historical clinical trials evaluating the efficacy of Pomalyst and dexamethasone in less heavily pretreated populations (i.e., without prior Darzalex therapy) have demonstrated an ORR of 29% and median PFS of 3.6 months, as highlighted in the Pomalyst U.S. Full Prescribing Information.

In this arm of the Phase 1b/2 STOMP Study, oral selinexor is being evaluated in combination with Kyprolis and dexamethasone in patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including a PI, one or more IMiDs (e.g., Revlimid or Pomalyst) or Darzalex. In these heavily pretreated patients, 100% had previously received Velcade, 96% had previously received Revlimid, 67% had previously received Pomalyst and 63% had previously received Darzalex. The RP2D was determined to be 80 mg of XPOVIO orally once-weekly, 56 mg/m of Kyprolisonce-weekly and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally and enrollment continues using this regimen. The median PFS was 23.7 months for all patients. The following table is a summary of the efficacy results:

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal, constitutional and other symptoms; most were manageable with dose modifications and/or standard supportive care. The most common treatment-related AEs were nausea (71%), fatigue (58%), decreased appetite (50%) and weight loss (46%), and were mostly Grade 1 and 2 events. The most common treatment-related Grade 3 AEs included thrombocytopenia (58%), anemia (21%) and leukopenia (13%).

In this all oral arm of the Phase 1b/2 STOMP Study, selinexor is being evaluated in combination with Revlimid and dexamethasone in patients with newly diagnosed or previously treated multiple myeloma. The previously treated patients received at least one prior therapy, which may include prior Revlimid, as long as the patient’s myeloma was not refractory to Revlimid. The RP2D was determined to be 60 mg of XPOVIO orally once-weekly, 25 mg of Revlimidorally once daily, and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally. The following table is a summary of the efficacy results:

Among the newly diagnosed patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common treatment-related AEs were fatigue (63%), weight loss (63%), diarrhea (63%), nausea (50%) and insomnia (38%) and were mostly Grade 1 and 2 events. The most common Grade 3 AEs were neutropenia (75%), anemia (50%) and thrombocytopenia (38%).

Among the relapsed or refractory patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common treatment-related AEs were nausea (58%), fatigue (54%), decreased appetite (50%), weight loss (42%), and diarrhea (33%), and were mostly Grade 1 and 2 events. The most common Grade 3 AEs were thrombocytopenia (63%), neutropenia (63%), anemia (17%) and fatigue (17%).

DLBCL is a form of lymphoma (“NHL”), a cancer that starts in cells called lymphocytes, which are part of the body’s immune system. Lymphocytes are found in the lymph nodes and other lymphoid tissues, such as the spleen and bone marrow, as well as in the blood. NHL is one of the most common cancers in the U.S., accounting for approximately 4% of all cancers. In 2021, the ACS estimates that more than 81,000 people will be diagnosed with NHL and approximately 20,000 deaths will result from the disease. DLBCL is the most common and most aggressive type of NHL, making up approximately 18,000 of the new cases diagnosed annually in the U.S. Most often, newly diagnosed patients are currently cured with front-line (typically chemotherapy). Despite the recent approval of therapy, many patients with relapsed or refractory DLBCL are not medically stable enough to undergo therapy and additional treatment options are necessary to address this continued unmet medical need.

In June 2020, the FDA approved XPOVIO as the only single-agent oral treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This approval was supported by the results of the SADAL Study, an open-label Phase 2b clinical trial evaluating single-agent oral selinexor (60 mg, twice weekly) in patients that had relapsed or refractory DLBCL after at least two prior multi-agent therapies and who were ineligible for transplantation, including high dose chemotherapy with stem cell rescue. In this population, XPOVIO demonstrated an ORR of 29%, including a CR rate of 13%. Responses were seen in all subgroups evaluated regardless of age, gender, prior therapy, DLBCL subtype or prior stem cell transplant therapy. Patient responses were durable with a median DOR of 9.3 months (23.0 months for patients who achieved a CR). Importantly, responses were associated with longer survival, underscoring the potential of oral XPO1 inhibition as an oral, option for patients with relapsed or refractory DLBCL.

The most common adverse reactions (20%) in patients with DLBCL who received XPOVIO were fatigue (63%), nausea (57%), diarrhea (37%), decreased appetite (37%), decreased weight (30%), constipation (29%), vomiting (28%), and pyrexia (22%). laboratory abnormalities (15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL Study, fatal adverse reactions occurred in 3.7% of patients within 30 days of last treatment. Serious adverse reactions occurred in 46% of patients who received XPOVIO. Treatment discontinuation rate due to adverse reactions was 17%.

In preclinical studies, XPO1 inhibition by selinexor selectively suppressed colony formation in MF cells, including those exposed to prior JAK2 inhibitors, compared with normal CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and cancer cell death. In an MF mouse model, the combination of selinexor and ruxolitinib improved responses compared with monotherapy, including reductions of mutant cells and restoration of splenic architecture. This formed the preclinical rationale for investigating selinexor in patients with MF. In 2021, we plan to initiate the Study, a Phase 1/2 open-label, multicenter study of selinexor to evaluate the safety and efficacy of selinexor in combination with ruxolitinib in treatment naïve patients with MF and the Study, a Phase 2, randomized, open-label, multicenter study to evaluate the safety and efficacy of single agent selinexor versus treatment of physician’s choice in patients with previously treated MF.

MDS is a group of hematologic malignancies whereby the bone marrow does not make enough healthy blood cells (white blood cells, red blood cells, and platelets) and there are abnormal cells in the blood and/or bone marrow. The median OS of patients with high-risk MDS refractory to hypomethylating agents is less than six months and, currently, no standard therapy for such patients exists. In August 2020, safety and efficacy results from a investigator sponsored Phase 2 study of selinexor in patients with MDS or oligoblastic acute myeloid leukemia refractory to hypomethylating agents were published in the journal . According to publication, preclinical studies have shown that inhibition of XPO1 causes nuclear accumulation of p53 and disruption of B signaling, both relevant targets for MDS. In the 23 patients evaluable in the clinical study, the ORR was 26% (95% CI 10 – 48); six patients had a marrow complete remission and an additional 12 patients (52%, 95% CI 31 – 73) had stable disease. The most common grade 3 or 4 AEs were thrombocytopenia (32%; 8/25 patients) and hyponatraemia (20%; 5/25 patients). There were no drug-related serious AEs and no treatment-related deaths. Based on these data and the data from a Phase 1 study of eltanexor, as discussed further below, we intend to enroll additional patients in single-agent and combination studies to evaluate eltanexor to treat MDS.

Solid tumors represent the vast majority of cancer incidences. Given the large patient population with solid tumors and the mechanistic activity of selinexor that makes it potentially suitable for treating any type of cancer, we are developing selinexor to potentially play a meaningful role across multiple solid tumor indications, either alone or in combination as a backbone therapy. We have seen encouraging single-agent data for selinexor in a variety of solid tumors including PRs and durable stable disease (“SD”) with disease control greater than three months. Our Phase 2/3 study in patients with dedifferentiated liposarcoma demonstrated statistically significant prolonged PFS of heavily pretreated patients and our Phase 2 studies of selinexor in gynecological malignancies and GBM also demonstrated anti-cancer activity, including bona fide PRs as well as prolonged SD. Given the promising single-agent activity in indications and the potential to enhance activity in combination with existing therapies, we are currently developing selinexor in unmet needs such as liposarcoma, endometrial cancer and GBM.

In November 2020, we announced positive results from the Phase 3 portion of the randomized, double blind, placebo-controlled, cross-over, SEAL Study conducted in North America and Europe in patients with unresectable dedifferentiated liposarcoma. Patients in this study were randomized 2:1 to receive either oral selinexor (60 mg twice weekly) until disease progression or intolerability, or placebo. The SEAL Study met its primary endpoint of a statistically significant increase in PFS (hazard ratio=0.70; p=0.023) as assessed by the Independent Central Radiological Review committee based on RECIST v1.1. We believe these data indicate that treatment with selinexor reduced the risk of disease progression by approximately 30%, compared to placebo. The trial allowed patients on placebo with objective progression to cross over to the selinexor treatment arm. Among those patients who received selinexor, there was a trend towards an improvement in the median OS compared to those patients who began on the placebo arm of the study and never crossed over to the selinexor treatment arm of the study. The safety profile for selinexor was consistent with previous clinical studies with fewer hematologic and infection-related AEs as compared to selinexor studies in patients with multiple myeloma and DLBCL.

In November 2020, following a interim futility analysis for the SIENDO Study, the DSMB recommended that the study should continue, as previously planned, without the need for adding additional patients to the trial or amending the study protocol. As of the date of the planned futility analysis, 109 patients of the expected 248 patients had been enrolled in the trial. We currently expect to report topline data from the SIENDO Study in the second half of 2021.

This trial was designed based on the data from a Phase 2, open-label study of efficacy and safety of oral selinexor in patients with heavily progressive gynecological cancers (the “SIGN Study”). In December 2019, the full results from the SIGN Study in patients with recurrent gynecological malignancies were published in. According to the published data, the SIGN Study showed selinexor’s promising anti-tumor activity and disease control in gynecological malignancies. Of the 66 patients with ovarian cancer, 20 patients (30%) had disease control, meaning PR or SD for at least 12 weeks, including seven patients (11%) with a PR. The median DOR for patients that achieved a PR was 7.4 months. Median PFS for all patients with ovarian cancer was 2.6 months and median OS was 7.3 months. Of the 23 patients with endometrial cancer, eight (35%) had disease control (three PRs and five with SD for at least 12 weeks). Median PFS for the endometrial cancer arm was 2.8 months and median OS was 7.0 months. Across all arms, the most common AEs were nausea (71%), fatigue (68%), decreased appetite (57%), vomiting (53%), weight loss (48%), anemia (36%), and thrombocytopenia (34%), which were managed with supportive care and dose modifications. Notably, fewer Grade 3 and 4 AEs occurred in patients receiving once weekly compared to twice weekly selinexor, with equivalent efficacy.

XPO1 is frequently overexpressed in both GBM and in high-grade gliomas and therefore may be an important, novel target in the treatment of patients with GBM. The degree of XPO1 over-expression correlates with higher tumor grade and poor overall patient survival. Nonclinical studies indicate that selinexor has potent activity as monotherapy and is synergistic when combined with radiation, temozolomide and lomustine. Additionally, in our previous clinical study known as the KING study, selinexor demonstrated that it crosses the blood-brain barrier with adequate intra-tumoral penetration and single-agent efficacy with durable response and disease stabilization in heavily pretreated GBM patients, which we believe supports the rationale for further clinical development of selinexor to treat patients with brain cancers.

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

Eltanexor is a second-generation SINE compound that, like selinexor, selectively blocks the nuclear export protein XPO1. The mechanism of action for the biological (anti-cancer) activity of eltanexor is similar to selinexor. However, eltanexor differs from selinexor primarily because it has been confirmed to have much lower brain penetration in preclinical species, when compared with selinexor. Therefore, eltanexor may cause fewer side effects, particularly those mediated through the central nervous system such as nausea, fatigue and anorexia in humans. Following oral administration, animals treated with eltanexor showed a lower percentage of body weight loss and improved food consumption, as well as less “fatigue behavior,” in comparison to animals similarly treated with selinexor. This allows for more frequent dosing of eltanexor, enabling a longer period of exposure at higher levels than is possible with selinexor.In many preclinical studies, an extended dosing regimen led to superior efficacy in comparison to selinexor treatment.As a result, we believe that eltanexor represents a potent, efficacious second-generation oral SINE compound and are currently evaluating its safety, tolerability and efficacy in humans.

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

At the ASH 2019 annual meeting, positive data was presented from the Phase 1/2 study evaluating the safety, tolerability and anti-tumor activity of single-agent oral eltanexor (10 mg or 20 mg once-daily for five days per week) in elderly patients with higher-risk MDS with disease refractory to hypomethylating agents. Of the 15 patients evaluable for efficacy, seven patients had a marrow CR indicating an ORR of 47%. An additional five patients (33%) achieved SD as their best response for a total disease control rate of 80% in evaluable patients. Median OS in patients receiving a 20 mg dose was 10.6 months. The most common treatment-related AEs were hematologic, gastrointestinal and constitutional. The most common treatment-related AEs were nausea (45%), decreased appetite (40%), fatigue (35%), diarrhea (35%) and dysgeusia (25%); the vast majority were Grade 1 or 2. The most common Grade 3 AEs were anemia (30%), neutropenia (25%), thrombocytopenia (20%) and leukopenia (15%). AEs were dose-dependent and generally managed with supportive care and dose modification. This Phase 1/2 study remains ongoing. Based on these data, we plan to amend the existing Phase 1/2 study protocol to evaluate eltanexor in combination with oral hypomethylating agents in patients with newly diagnosed or previously treated MDS. The novel combination arms are expected to begin enrollment in 2021.

We have used spontaneously occurring canine cancers as a surrogate model for human malignancies. It is widely known that canine lymphomas are similar in many ways to the lymphomas in humans, display a comparable genetic profile and respond to chemotherapy in a fashion similar to their human counterparts. Lymphomas are one of the most common tumors in dogs and are very aggressive where, without treatment, the tumors are often fatal within weeks. The majority of canine lymphomas are DLBCL and most of the others are lymphomas. Given the similarities of dog and human lymphomas, prior to initiating clinical trials of selinexor in humans, we investigated verdinexor, a closely related, orally available SINE compound, in dogs with lymphomas.

In May 2017, we entered into an exclusive licensing agreement with Anivive, a privately-held biotech company focused on innovations in the veterinary drug and bioinformatics space, pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals. In January 2021, Anivive received conditional FDA approval of LAVERDIA (verdinexor) to treat dogs with lymphoma through the Minor Use/Minor Species pathway, which is an option for drugs intended for minor uses in major species, such as dogs, or for minor species. Verdinexor is the first conditionally approved oral treatment for dogs with lymphoma. an injectable product, is currently the only other treatment for lymphoma in dogs. Anivive has five years to complete effectiveness studies to support a full approval of verdinexor in this indication.

The recent approval of verdinexor was supported by a Phase 2b clinical trial conducted with 58 pet dogs with or lymphoma who were either newly-diagnosed or who were in their first relapse after chemotherapy and were followed for at least eight months. Seventeen of the 58 dogs (29%) did not show progression of lymphoma for at least 56 days after taking verdinexor. Three of these dogs did not show any progression for at least 182 days. The most common adverse reactions associated with verdinexor were anorexia, vomiting, diarrhea, weight loss, lethargy, increased water intake, increased urination, elevated liver enzymes, and low platelet count.

In addition to canine lymphoma, verdinexor is being evaluated as a potential therapy for viral, inflammatory, and autoimmune indications. Several autoimmune indications are driven by aberrant responses, particularly uncontrolled cytokine expression and activation. These include systemic lupus erythematosus (“SLE”), a primary focus of our work with verdinexor. The National Institute of Health funded project completed preclinical evaluation of verdinexor as a treatment for SLE and positioned the SLE program as Investigational New Drug (“IND”) ready.

As part of an exclusive license agreement we entered into with Antengene in May 2018, and as amended in May 2020, Antengene maintains the exclusive rights to develop and commercialize verdinexor for the diagnosis, treatment and/or prevention of certain human indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand. Antengene has reported that it intends to conduct clinical trials of verdinexor for the treatment of chronic active Epstein Barre infection and SLE.

is our dual inhibitor of PAK4 and NAMPT. is an orally bioavailable small molecule that we believe could play an important role in cancer development by targeting the two proteins PAK4 and NAMPT. PAK4 is a signaling protein regulating numerous fundamental cellular processes, including

intracellular transport, cellular division, cell shape and motility, cell survival, immune defense and the development of cancer. PAK4 interacts with many key signaling molecules involved in cancer such as beta-catenin, CDC42, BAD and myosin light chain. NAMPT, also known as PBEF or Visfatin, is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone that can be found in complex with PAK4 in the cell. NAMPT is of interest as an oncology target because it catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide, a universal energy- and signal-carrying molecule involved in mitochondrial function, energy metabolism, calcium homeostasis, antioxidation, and paradoxically generation of oxidative stress, gene expression, immunological functions, aging, and cell death.

of PAK4 and NAMPT may lead to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells are more resistant to inhibition by due in part to their relative genomic stability and lower metabolic rates. Hematologic and solid tumor cells that have become dependent on both PAK4 and NAMPT pathways may be susceptible to single-agent cytotoxicity of

has shown broad evidence of anti-cancer activity against hematological and solid tumor malignant cells while showing minimal toxicity to normal cells in vitro. In mouse xenograft studies, oral has shown evidence of anti-cancer activity and tolerability. To our knowledge, we are the only company with an allosteric PAK4 modulator and/or NAMPT specific inhibitor currently in clinical development.

is currently being evaluated in a Phase 1 open-label study in patients with advanced solid malignancies or lymphoma. As of February 2021, patient enrollment continues in Part C of the trial evaluating the combination of and Opdivo (nivolumab) in patients with melanoma who progressed on an or antibody in a prior line of therapy.

In addition to cancer, our SINE compounds have demonstrated the potential to provide therapeutic benefit in a number of other indications, such as viral infections, neurological disorders, inflammation and autoimmune diseases. For example, in January 2018, we entered into an Asset Purchase Agreement with Biogen MA Inc., a subsidiary of Biogen Inc. (“Biogen”), pursuant to which Biogen acquired which has been renamed by Biogen as BIIB100, an IND application-ready, oral SINE compound with a preclinical data package supporting potential efficacy in a number of neuro-inflammatory conditions, as well as certain related assets with an initial focus in amyotrophic lateral sclerosis (“ALS”). XPO1 mediates the nuclear export of multiple proteins that impact neurological and inflammatory processes. Consequently, inhibition of XPO1 by BIIB100 has shown a reduction in inflammation and an increase in anti-inflammatory and neuroprotective responses. BIIB100 penetrates the blood brain barrier to a greater degree than other SINE compounds. Preclinical data generated largely by external collaborators show efficacy of BIIB100 and related SINE compounds in animal models of ALS, multiple sclerosis, traumatic brain injury, epilepsy, and other neuro-inflammatory indications. Biogen is currently conducting a Phase 1 double-blind, placebo-controlled, single-ascending-dose study to evaluate the safety, tolerability and pharmacokinetics and pharmacodynamics of BIIB100 administered orally to adult patients with ALS.

The accumulation of IB in the nucleus inhibits B, which may be beneficial in overcoming chemotherapy resistance and in treating autoimmune, inflammatory, and neuro-inflammatory disease, has been detected in both preclinical models and in human cancer tissues from treated patients.

SINE compounds have also demonstrated activity in animal models of viral diseases, certain rare diseases and other indications, and we are continuing to develop programs in these areas largely through academic collaborations and funding opportunities with the intent to these programs for clinical development and future commercialization.

pandemic has and will continue to affect economies and businesses around the world. We continue to closely monitor the impact of the pandemic on all aspects of our business, including the impact on our employees, patients and business operations. We have and may continue to experience disruptions in the future that could impact our results of operations, including product revenue, and financial condition. Although we do not currently expect that the ongoing pandemic will have a material impact on our business plans or results of operations, we are unable to predict the impact that the pandemic will have on our operating results and financial condition due to numerous uncertainties. These uncertainties include the availability and effectiveness of vaccines and therapeutics, the duration and scope of the pandemic, the severity of the virus, governmental, business or other actions, travel restrictions and social distancing, business closures or business disruptions, or changes to our operations, among others. We will continue to monitor situation closely and intend to follow health and safety guidelines as they evolve. Further, the impacts of a potential worsening of global economic conditions and the continued disruptions to, and volatility in, the credit and financial markets, as well as other unanticipated consequences remain unknown. The situation surrounding pandemic remains fluid and continues to rapidly evolve, and we are actively managing our response and assessing potential impacts to our operating results and financial condition, as well as adverse developments in our business.

In May 2020, we entered into an amendment of our May 2018 license agreement with Antengene (the “Original Antengene Agreement”, and, as amended the “Amended Antengene Agreement”). Antengene is a corporation organized and existing under the laws of Hong Kong, and a subsidiary of Antengene Corporation Co. Ltd., a corporation organized and existing under the laws of the People’s Republic of China. Under the terms of the Amended Antengene Agreement, Antengene has the exclusive rights to develop and commercialize, at its own cost, selinexor, eltanexor, each for the diagnosis, treatment and/or prevention of all human oncology indications, and verdinexor for the diagnosis, treatment and/or prevention of certain human indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand (the “Antengene Territory”). Under the terms of the Original Antengene Agreement, in 2018 we received an upfront cash payment of $11.7 million. In June 2020, we received an additional $11.7 million upfront payment upon execution of the Amended Antengene Agreement.

During 2020 and early 2021, Antengene has progressed its development and regulatory plans and has submitted new drug applications (“NDAs”) for selinexor to regulatory authorities in Singapore, Australia, Hong Kong, South Korea and China for relapsed or refractory multiple myeloma and/or relapsed or refractory DLBCL indications. In addition, Antengene is currently conducting two registrational Phase 2 clinical trials of XPOVIO in China for relapsed or refractory multiple myeloma and relapsed or refractory DLBCL and has initiated clinical trials for high prevalence cancer types in the Asia Pacific region including peripheral lymphoma and lymphoma and KRAS-mutant cell lung cancer.

certain development, regulatory and commercialization goals are achieved in the future. Finally, we will be eligible to receive tiered double-digit royalties based on future net sales of selinexor and eltanexor, and tiered single- to double-digit royalties based on future net sales of verdinexor and in the Antengene Territory.

In January 2018, we entered into an asset purchase agreement with Biogen pursuant to which Biogen acquired our oral SINE compound which has been renamed by Biogen as BIIB100, and certain related assets. We received a upfront payment of $10.0 million in 2018 from Biogen and are eligible to receive additional payments of up to $207.0 million based on the achievement by Biogen of future specified development and commercial milestones. We are also eligible to receive tiered royalty payments that reach low double digits based on future net sales until the later of the tenth anniversary of the first commercial sale of the applicable product or the expiration of specified patent protection for the applicable product, determined on a basis.

In April 2020, we entered into a collaboration, option and license agreement with Curadev, a privately-owned biotechnology company, to identify and novel small molecules against various biological targets for the treatment of cancer and other major diseasesUnder the terms of the agreement, we and Curadev have agreed to identify and develop small molecules against up to two targets. Curadev will conduct exploratory research, drug discovery and development for designated programs up to the conclusion of preclinical proof of concept studies, after which we will have an option to an exclusive license to develop and commercialize each target on a global basis. We and Curadev will and jointly oversee development up to the option exercise period.

In July 2020, we entered into a CRADA with the NCI’s Cancer Therapy Evaluation Program. Under the terms of the CRADA, the NCI will collaborate with us on studies to investigate the safety and efficacy of selinexor in various oncology indications, based on encouraging anti-tumor activity observed in earlier studies. As data from the studies and other Karyopharm-sponsored studies emerge, we plan to collaborate with the NCI on trials to complement and support the further development of selinexor that could address important patient unmet medical needs. The NCI may also support studies to explore important future combinations of selinexor with other targeted or standard of care cancer agents.

Our commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection for our products and product candidates, our core technologies, and other to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary or intellectual property rights. Our policy is to seek to protect our proprietary and intellectual property position by, among other methods, filing patent applications in the U.S. and in foreign jurisdictions related to our proprietary technology and products and product candidates. We also rely on trade secrets, and continuing technological innovation to develop and maintain our proprietary and intellectual property position.

We file patent applications directed to the composition of matter and methods of use and manufacture for our products and product candidates. As of February 2, 2021, we were the sole owner of 21 patents in the U.S. and we had 16 pending patent applications in the U.S., four pending international applications filed under the Patent Cooperation Treaty (“PCT”), 77 granted patents and 71 pending patent applications in foreign jurisdictions. The PCT is an international patent law treaty that provides a unified procedure for filing a single initial patent application to seek patent protection for an invention simultaneously in each of the member states. Although a PCT application is not itself examined and cannot issue as a patent, it allows the applicant to seek protection in any of the member states through national-phase applications. The technology underlying such pending patent applications has been developed by us and was not acquired from any agreement.

In the U.S., we have trademark registrations for our name and logo, and a combination of the two, XPOVIO, and PORE for our online portal. We also have pending applications to register two additional possible product names (currently refused), and KARYFORWARD and a KARYFORWARD logo for our financial aid and charitable services. Outside the U.S., XPOVIO is registered or pending in additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan. The KARYFORWARD logo is registered or pending in four jurisdictions outside the U.S. We also have registrations or applications for eight additional possible product names in numerous foreign jurisdictions.

The term of individual patents depends upon the legal term for patents in the countries in which they are obtained. In most countries, including the U.S., the patent term is 20 years from the earliest filing date of a patent application. In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The term of a patent that covers a drug may also be eligible for patent term extension when FDA approval is granted, provided statutory and regulatory requirements are met. See “” below for additional information on such extensions. In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those drugs, depending upon the length of the clinical trials for each product candidate and other factors. There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

In addition to patents, we rely upon unpatented trade secrets and and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary information, in part, using confidentiality agreements with our collaborators, scientific advisors, employees and consultants, and invention assignment agreements with our employees. We also have agreements with selected consultants,

With respect to our proprietary drug discovery and optimization platform, we consider trade secrets and to be our primary intellectual property. Trade secrets and can be difficult to protect. We anticipate that with respect to this technology platform, these trade secrets and may over time be disseminated within the industry through independent development, the publication of journal articles describing the methodology, and the movement of personnel skilled in the art from academic to industry scientific positions.

Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, marketing approved products and achieving positive coverage/reimbursement decisions than we do. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific, commercial and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Our sales force is supported by an experienced sales leadership team and professionals in marketing, reimbursement and market access, market research and analytics, commercial operations, finance and human resources. Our sales and marketing organization uses a variety of pharmaceutical marketing strategies to promote XPOVIO, including sales calls, education, promotional, and digital content. We employ third-party vendors, such as advertising agencies, market research firms and suppliers of marketing and other sales support-related services, to assist with our commercial activities.

All of our products and product candidates are small molecules and are manufactured in reliable and reproducible synthetic processes from readily available starting materials. The chemistry and formulation processes of selinexor have been developed to meet our large-scale manufacturing needs and do not require unusual equipment in the manufacturing process. We maintain sufficient inventory levels throughout our supply chain to exceed our forecasts for XPOVIO in order to minimize the risks of supply disruption.

Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug product, as well as and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations. The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. Some long-term preclinical testing, such as animal tests of reproductive AEs and carcinogenicity, may continue after the IND is submitted.

An IND is an exemption from the FDCA that allows an unapproved drug to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer an investigational drug to humans. Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved NDA. In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. The FDA requires a waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At any time during this period, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.

A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived. When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as support for an IND or application for marketing approval. Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an IND application as support for an IND or an NDA. The final rule provides that such studies must be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects. The GCP requirements in the final rule encompass both ethical and data integrity standards for clinical studies. The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in foreign clinical studies, as well as the quality and integrity of the resulting data. They further help ensure that foreign studies are conducted in a manner comparable to that required for IND studies.

treatment purposes on a basis for: individual patients (single-patient IND applications for treatment in emergency settings and settings); patient populations; and larger populations for use of the drug under a treatment protocol or Treatment IND Application.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious AEs occur. In addition, IND safety reports must be submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or testing that suggest a significant risk in humans exposed to the drug; and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

The FDA conducts a preliminary review of an NDA within 60 days of its receipt and strives to inform the sponsor by the 74th day after the FDA’s receipt of the submission to determine whether the application is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an substantive review. The FDA has agreed to certain performance goals in the review process of NDAs. Most such applications are meant to be reviewed within ten months from the date of filing, and most applications for “priority review” products are meant to be reviewed within six months of filing. The review process may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These inspections may cover all facilities associated with an NDA submission, including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product manufacturing, and control testing laboratories. The FDA will not approve an application unless it

Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a basis, whether the proposed product represents a significant improvement when compared with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market. This regulation includes, among other things, standards and regulations for advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, and promotional activities involving the Internet and social media. Promotional claims about a drug’s safety or effectiveness are prohibited before the drug is approved. After approval, a drug product generally may not be promoted for uses that are not approved by the FDA, as reflected in the product’s prescribing information.

In the U.S., healthcare professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as uses, because the FDA does not regulate the practice of medicine. However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of uses. It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, communication regarding information, such as distributing scientific or medical journal information. If a company is found to have promoted uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities. This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

Under the Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of exclusivity for the RLD has expired. The FDCA provides a period of five years of data exclusivity for a new drug containing a new chemical entity. For the purposes of this provision, a new chemical entity (“NCE”) is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA. An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance. In cases where such NCE exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.

To the extent that the Section 505(b)(2) applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would. As a result, approval of a Section 505(b)(2) NDA can be stalled until all the listed patents claiming the referenced product have expired, until any exclusivity, such as exclusivity for obtaining approval of an NCE, listed in the Orange Book for the referenced product has expired, and, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit or a decision in the infringement case that is favorable to the Section 505(b)(2) applicant.

consult with each other, and agree upon a final plan. The FDA or the applicant may request an amendment to the plan at any time. For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of an applicant, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments. In addition, FDA will meet early in the development process to discuss pediatric study plans with drug sponsors. The legislation requires FDA to meet with drug sponsors by no later than the 1 meeting for serious or life-threatening diseases and by no later than ninety days after FDA’s receipt of the study plan.

Pediatric exclusivity is another type of marketing exclusivity in the U.S. and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the and orphan exclusivity. This exclusivity may be granted if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data. The data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months. This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another application. With regard to patents, the pediatric exclusivity period will not attach to any patents for which a generic (ANDA or 505(b)(2) NDA) applicant submitted a paragraph IV patent certification, unless the NDA sponsor or patent owner first obtains a court determination that the patent is valid and infringed by a proposed generic product.

A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost during product development and the FDA regulatory review. The restoration period granted is typically the time between the effective date of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved drug product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question. A patent that covers multiple drugs for which approval is sought can only be extended in connection with one of the approvals. The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA. We cannot provide any assurance that any patent term extension with respect to any U.S. patent will be obtained and, if obtained, the duration of such extension, in connection with any of our product candidates.

To begin this process, an applicant must file an Investigational New Animal Drug application (“INAD”) with the CVM. The applicant will hold a meeting with the CVM to reach general agreement on the plans for providing the data necessary to fulfill requirements for a NADA. In this context, an applicant must submit pivotal protocols to the CVM for review and concurrence prior to conducting the required studies. The applicant will gather and submit data on safety, efficacy and chemistry, manufacturing and controls (“CMC”) to the CVM for review, as below:

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist. The PRIority Medicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and enterprises (“SMEs”) may qualify for earlier entry into the PRIME scheme than larger companies. Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated MAA assessment once a dossier has been submitted. Importantly, a dedicated Agency contact and rapporteur from the CHMP or Committee for Advanced Therapies are appointed early in PRIME scheme facilitating increased understanding of the product at EMA’s Committee level. A meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

Marketing authorization is valid for five years in principle and the marketing authorization may be renewed after five years on the basis of a of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state. To this end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file with respect to quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid. Once renewed, the marketing authorization is valid for an unlimited period, unless the EC or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. Any authorization which is not followed by the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid (the sunset clause).

In the EU, NCEs qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity. This data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorizations can be submitted, and the innovator’s data may be referenced, but not approved for two years. The overall period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. Even if a compound is considered to be a new chemical entity and the sponsor is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the product if such company can complete a full MAA with a complete database of pharmaceutical test, preclinical tests and clinical trials and obtain marketing approval of its product.

Regulation 847/2000 sets out criteria and procedures governing designation of orphan drugs in the EU. Specifically, an application for designation as an orphan product can be made any time prior to the filing of an application for approval to market the product. Marketing authorization for an orphan drug leads to a period of market exclusivity. This period may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation, for example because the product is sufficiently profitable not to justify market exclusivity. Market exclusivity can be revoked only in very selected cases, such as consent from the marketing authorization holder, inability to supply sufficient quantities of the product, demonstration of “clinically relevant superiority” by a similar medicinal product, or, after a review by the Committee for Orphan Medicinal Products, requested by a member state in the fifth year of the marketing exclusivity period (if the designation criteria are believed to no longer apply). Medicinal products designated as orphan drugs pursuant to Regulation 141/2000 shall be eligible for incentives made available by the European Community and by the member states to support research into, and the development and availability of, orphan drugs.

In the EU, the advertising and promotion of approved products are subject to EU Member States’ laws governing promotion of medicinal products, interactions with clinicians, misleading and comparative advertising and unfair commercial practices. In addition, other legislation adopted by individual EU Member States may apply to the advertising and promotion of medicinal products. These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”) as approved by the competent authorities. Promotion of a medicinal product that does not comply with the SmPC is considered to constitute promotion, which is prohibited in the EU.

In the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies or health technology assessments, in order to obtain reimbursement or pricing approval. For example, EU Member States have the option to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. EU Member States may approve a specific price for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market. Other EU Member States allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions. Recently, many countries in the EU have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage health care expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU. The downward pressure on health care costs in general, particularly prescription products, has become intense. As a result, increasingly high barriers are being erected to the entry of new products. Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU Member States, and parallel trade, i.e., arbitrage between and high-priced EU Member States, can further reduce prices. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.

Other legislative changes have been proposed and adopted in the U.S. since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments, will remain in effect through 2029 unless additional Congressional action is taken. The Coronavirus Aid, Relief, and Economic Security Act (the “CARES Act”) and other relief legislation, suspended the 2% Medicare sequester from May 1, 2020 through March 3, 2021, and extended the sequester by one year, through 2030. In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Since enactment of the ACA, there have been and continue to be numerous legal challenges and Congressional actions to repeal and replace provisions of the law. For example, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019. Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminates the health insurer tax. Further, the Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to increase from 50 percent to 70 percent the discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole”. The Congress will likely consider other legislation to replace elements of the ACA during the next Congressional session.

Further, there have been several recent U.S. congressional inquiries and proposed federal and proposed and enacted state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products. For example, on May 11, 2018, the Trump Administration issued a plan to lower drug prices. In addition, the Trump Administration published a final rulemaking that allows states or certain other government entities to submit importation program proposals to the FDA for review and approval. Applicants would be required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers. At the same time, FDA issued draft guidance that would allow manufacturers to import their own drugs that are authorized for sale in other countries (multi-market approved products). In addition, President Trump issued five executive orders intended to lower the costs of prescription drug products. Several of these orders are reflected in recently promulgated regulations, and one of these regulations is currently subject to a nationwide preliminary injunction. It remains to be seen whether these orders and resulting regulations will remain in force during the Biden Administration.

In order to attract, retain and reward our employees, we provide competitive compensation and benefits packages. We currently offer all new employees equity in the company and as incentive awards to all our employees in connection with our annual performance reviews. Our equity and cash incentive plans are aimed to increase stockholder value and the success of our company by motivating our employees to perform to the best of their abilities and achieve our and their objectives. In addition, many of our employees are stockholders of the Company through participation in our Employee Stock Purchase Plan, which aligns the interests of our employees with our stockholders by providing stock ownership on a basis. We also provide a 4% match for employee contributions to our Section 401(k) retirement savings plan.

such, we provide our employees and their families with access to a variety of innovative, flexible and convenient health and wellness programs, including benefits that provide protection and security so they can have peace of mind concerning events that may require time away from work or that impact their financial well-being. Our full-time employees are all eligible to participate in our health, vision, dental, life, and long-term disability insurance plans. To encourage employees to keep up with routine medical care and participate in our wellness program, we fund a Health Reimbursement Account for participating employees and to help our employees cover medical expenses we also offer employees a Flexible Spending Account. Our employees outside the U.S. receive competitive compensation and benefits that are regularly benchmarked to ensure market norms and reflect our standards.

We are highly committed to policies and practices focused on environmental, social and corporate governance (“ESG”) positively impacting our social community and maintaining and cultivating good corporate governance. By focusing on such ESG policies and practices, we believe we can affect a meaningful and positive change in our community and maintain our open, collaborative corporate culture. Some of the initiatives that we were most proud of in 2020 included donating thousands of personal protection equipment items to hospitals, cancer centers, veterans organizations, and various community groups across the U.S. and around the globe in response to the pandemic. We were also proud to actively support a number of scholarship and mentoring programs for students in underserved communities as well as those interested in pursuing degrees in science and technology.

. Dr. Kauffman has served as Karyopharm’s Chief Executive Officer since January 2011 and has been one of our directors since 2008. Dr. Kauffman Karyopharm with Dr. Sharon Shacham in 2008 and served as our President from 2011 to 2013 and as Chief Medical Officer from 2012 to 2013. Prior to joining Karyopharm, he was Chief Medical Officer of Onyx Pharmaceuticals Inc. (“Onyx”), a public biopharmaceutical company, from 2009 to 2010. From 2008 to 2009, Dr. Kauffman was Chief Medical Officer of Proteolix Inc., which was acquired by Onyx. At Proteolix, he led the development of Kyprolis (carfilzomib), a novel proteasome inhibitor approved in refractory myeloma by the FDA in 2012. Dr. Kauffman was an operating partner at Bessemer Venture Partners from 2006 to 2008, where he led investments in biotechnology companies. From 2006 to 2008, he was President and Chief Executive Officer of Epix Pharmaceuticals, Inc. (“Epix”), a public biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009. Dr. Kauffman was President and Chief Executive Officer of Predix Pharmaceuticals, Inc. (“Predix”), a private biopharmaceutical company focused on G protein-coupled receptors, from 2002 until its merger into Epix in 2006. In that role, he led the merger of Predix and Epix, oversaw the discovery and development of four new clinical candidates and led collaboration transactions with Amgen and GlaxoSmithKline plc. From 2000 to 2002, Dr. Kauffman was Vice President, Clinical at Millennium Pharmaceuticals, Inc. (“Millennium”), a biopharmaceutical company, where he led the Velcade development program. From 1997 to 2000, Dr. Kauffman held a number of senior positions at Millennium Predictive Medicine, Inc., a biopharmaceutical company and a subsidiary of Millennium, where he led the discovery and development of novel molecular diagnostics for major cancers, including melanoma and led transactions with Becton-Dickenson and Bristol Myers Squibb. From 1995 to 1997, Dr. Kauffman held a number of senior positions at Biogen Idec, Inc., a biopharmaceutical company, where he led the clinical development of anti-CD40L antibodies in autoimmune and inflammatory diseases, and acted as the main medical advisor to the Biogen business development group. Dr. Kauffman has served on the Board of Directors, the Audit Committee and as Chairman of the Compensation Committee of Kezar Life Sciences, Inc., a public biopharmaceutical company, since December 2016 and has been the lead director and a member of the Compensation Committee of Verastem Inc., a public biopharmaceutical company, since 2012. Dr. Kauffman previously served on the Board of Directors, Nominating and Governance Committee and Research and Development Committee of Infinity Pharmaceuticals, Inc., a public biopharmaceutical company, from April 2017 to March 2020. Dr. Kauffman received his B.A. in Biochemistry from Amherst College and his M.D. and Ph.D. from Johns Hopkins Medical School, and he trained in internal medicine and rheumatology at Beth Israel Hospital (now Beth Israel Deaconess Medical Center) and Massachusetts General Hospital. He is board certified in internal medicine.

Dr. Shacham founded Karyopharm in 2008, has served as our Chief Scientific Officer since 2010 and as our President since 2013. Dr. Shacham served as our President of Research and Development from 2012 to 2013, as our Head of Research and Development from 2010 to 2012 and as our President and Chief Executive Officer from 2010 to 2011. Dr. Shacham established the company to focus on the discovery and development of small molecule inhibitors of nuclear export and has led our scientific progress since inception. Her computational drug discovery algorithms formed a critical part of the technological basis for our drug discovery and optimization expertise, which was used for the discovery of selinexor, our lead product. Dr. Shacham our Scientific Advisory Board. Prior to founding Karyopharm, from 2006 to 2009, she was Senior Vice President of Drug Development at Epix, a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009. She was Director, Algorithm and Software Development at Predix from 2000 until Predix’s merger into Epix in 2006, where she led the company’s efforts in GPCR modeling, computational chemistry, lead optimization and development of clinical trials. Dr. Shacham received her B.Sc. in Chemistry, Ph.D. and M.B.A. from Tel Aviv University.

Mr. Demareehas served as our Chief Commercial Officer since March 2020. Prior to joining Karyopharm, Mr. Demareeserved as Chief Commercial Officer at G1 Therapeutics, Inc. (“G1”), a biopharmaceutical company, from July 2018 to March 2020 led its integrated commercial functions. Prior to G1, Mr. Demaree served as Vice President, Oncology Marketing at Astellas Pharma US, a pharmaceutical company, from July 2016 to July 2018 and as Executive Director from 2011 to July 2016, where he was responsible for establishing and leading the oncology marketing function, including the successful launch of XTANDI (enzalutamide). Previously, Mr. Demaree led oncology business development and alliance management at Abbott Laboratories. He began his career serving in marketing leadership positions at Novartis and Eli Lilly. Mr. Demareeholds an M.B.A. in marketing and finance and a B.S. in marketing from Indiana University.

Mr. Frenkel was appointed Executive Vice President, Worldwide Development Operations of Karyopharm in 2014, Executive Vice President, Chief Development Operations Officer from 2015 to August 2020 and EVP, Chief Development Officer in August 2020. Prior to joining Karyopharm, Mr. Frenkel held a number of senior management roles in Europe, Israel and the U.S., most recently as Managing Director EMEA from 2013 to 2014 for Clinipace Worldwide, an international clinical research organization, where he had responsibility for the overall management of the organization in Europe, the Middle East and Africa. Prior to becoming Managing Director EMEA, Mr. Frenkel was Vice President of International Business Development at Clinipace Worldwide from 2011 to 2013. Prior to joining Clinipace Worldwide, from 2007 to 2011, Mr. Frenkel established and managed the Israeli office of PFC Pharma Focus AG, which was acquired by Clinipace Worldwide in 2011, and from 2004 to 2007, he held the position of Managing Director at Actelion Pharmaceuticals with responsibility for all science and business affairs of the company in Israel. Mr. Frenkel received a BPharm from Hebrew University.

Ms. Lewis joined Karyopharm in November 2018 as Senior Vice President, Regulatory and Quality Affairs and was appointed Executive Vice President, Chief Regulatory and Quality Officer in October 2019 and Executive Vice President, Chief Regulatory Affairs and Strategic Operations in October 2020. Prior to joining Karyopharm, Ms. Lewis held several leadership roles across the biopharmaceutical industry where she was instrumental in the successful negotiations for registration trial designs, approval, and/or commercialization of Velcade, Varubi, Integrilin and Zejula. Most recently Ms. Lewis served as Vice President, Regulatory and Quality Affairs for Syros Pharmaceuticals, Inc. (“Syros”), a pharmaceutical company, from January 2017 to July 2018. Prior to joining Syros, Ms. Lewis served as Vice President, Regulatory Affairs and Quality Assurance for Idera Pharmaceuticals, Inc. (“Idera”), a pharmaceutical company, from 2015 to December 2016. Prior to joining Idera, Ms. Lewis served as Vice President, Regulatory Affairs for Tesaro, Inc., a pharmaceutical company, from 2011 to 2015. Ms. Lewis has served on the board of directors of Replimune, Inc., a biotechnology company, since November 2020. Ms. Lewis holds a B.S. in Biology from Northeastern University and a M.S. in Regulatory Affairs and Public Health from Massachusetts College of Pharmacy and Allied Health Science.

Mr. Mano joined Karyopharm as Senior Vice President, General Counsel and Secretary in December 2020 with over 15 years of legal experience. Prior to joining Karyopharm, Mr. Mano served as

Mr. Mason has served as our Senior Vice President, Chief Financial Officer and Treasurer since February 2019. Mr. Mason served as Vice President of Finance and Treasurer of Alnylam Pharmaceuticals, Inc., a public biopharmaceutical company, from 2011 until February 2019, as its Principal Accounting Officer from 2011 to October 2018, and as its Principal Financial Officer from 2011 to June 2016 and from January 2017 to May 2017. From 2005 to 2011, Mr. Mason served as Alnylam’s Corporate Controller. From 2000 through 2005, Mr. Mason served in several finance and commercial roles at Praecis Pharmaceuticals Incorporated (“Praecis”), a public biotechnology company, most recently as Corporate Controller. Prior to Praecis, Mr. Mason worked in the audit practice at KPMG LLP, a national audit, tax and advisory services firm. Mr. Mason received a B.A. in Business Administration from Stetson University and an M.B.A. from Babson College and is a certified public accountant.

Dr. Mitchener has served as our Chief Business Officer since December 2020. Prior to joining Karyopharm, Dr. Mitchener served as Chief Business Officer and Head, Strategic Finance from August 2019 to December 2020 and as Senior Vice President, Chief Business Officer from September 2018 to August 2019 at Axcella Health Inc. (“Axcella”), a biotechnology company. Before joining Axcella, Dr. Mitchener spent 15 years at Novartis, a pharmaceutical company, in roles of increasing responsibility, in both U.S. and international roles within its Oncology Business. He served as Head of Strategy, Partnering and Operations from July 2016 to August 2018 and as Oncology Franchise Head for Australia and New Zealand from 2013 to June 2016. During his tenure at Novartis, he also held various commercial, medical and business development roles, including Business Franchise Head, Oncology, Global Pharma Strategy Director, and Global New Product Director. Dr. Mitchener was involved in securing partnerships in oncology with multiple big pharma, technology, academic and healthcare partners. Dr. Mitchener received a PharmD from the University of North Carolina at Chapel Hill.

Dr. Shah joined Karyopharm in May 2017 as Vice President, Clinical Strategy, and was appointed Senior Vice President, Clinical Development in April 2018 and Executive Vice President, Chief Medical Officer in July 2019. Prior to joining Karyopharm, Dr. Shah held numerous roles at The University of Texas MD Anderson Cancer Center. From 2007 to August 2016, Dr. Shah served as an Assistant Professor, Associate Professor, and Associate Program Director of the Malignant Hematology Fellowship, as well as Director of Myeloma Clinical and Translational Research in the Department of Lymphoma/Myeloma, Division of Cancer Medicine. Dr. Shah received his M.D. from The Ohio State University College of Medicine, Columbus, Ohio and holds a degree in Mechanical Engineering from The Ohio State University. Dr. Shah completed his residency in internal medicine at the Cleveland Clinic Foundation, Cleveland, Ohio, and a fellowship in hematology/oncology at the University of Alabama at Birmingham. Dr. Shah holds board certification in hematology and oncology from the American Board of Internal Medicine.

Our Internet website is http://www.karyopharm.com. We make available free of charge through our website our annual report on quarterly reports on current reports on and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended. We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the U.S. Securities and Exchange Commission. In addition, we regularly use our website to post information regarding our business, development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “Investors” as a source of information about us. References to our website are inactive textual references only and the content of our website should not be deemed incorporated by reference into this Annual Report on

Our business and our ability to generate product revenue from the sales of drugs that treat cancer and other diseases in humans depend heavily on our ability to successfully commercialize our lead drug, XPOVIO (selinexor) on a global basis, in currently approved and future indications and the level of market adoption for, and the continued use of, our products and product candidates, if approved. XPOVIO is currently approved in the U.S. in multiple hematologic malignancy indications, including in combination with Velcade (bortezomib) and dexamethasone for the treatment of patients with multiple myeloma after at least one prior therapy, in combination with dexamethasone for the treatment of patients with heavily pretreated multiple myeloma and as a monotherapy for the treatment of patients with relapsed or refractory diffuse large lymphoma (“DLBCL”). Efforts to drive adoption within the medical community and third-party payors based on the benefits of our products and product candidates require significant resources and may not be successful. The success of XPOVIO and any current or future product candidates, whether alone or in collaboration with third-parties, including achieving and maintaining an adequate level of market adoption, depends on several factors, including:

significantly greater financial resources and expertise in research and development, manufacturing, preclinical studies, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. 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 product candidates. For example, BLENREP and Monjuvi were approved by the FDA in August and July 2020, respectively. In addition, several new mechanism of actions may be introduced into the multiple myeloma market, including therapies, which may have a significant impact on the multiple myeloma landscape and our product revenues. See Item 1 under the heading in this Annual Report on Form for more information on competition.

Further, our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize drugs that are or are perceived to be more effective, safer, more tolerable, more convenient and/or less costly than any of our currently approved products or product candidates or that would render our products obsolete or Our competitors may also obtain marketing approval from the FDA or other regulatory authorities for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a stronger market position before we are able to enter the market or preventing us from entering into a particular indication at all.

The pandemic may continue to have an impact on our clinical trials. At this time, however, we cannot fully forecast the scope of the impact that pandemic may have on our ability to, among other things, initiate trial sites, enroll and assess patients, supply study drug and report trial results. In addition, we have and may continue to experience delays in the regulatory process as a result of the pandemic, which may impact our approval timelines, such as delays we encountered related to our reduced access to clinical trial sites in order to complete remonitoring activities associated with our Marketing Authorization Application (“MAA”) for selinexor in multiple myeloma based on the results on the STORM study. Further, in response to the pandemic, the FDA issued guidance on March 18, 2020, and updated it on July 2, 2020 and January 27, 2021, 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 a list of all study participants affected by study disruptions by a 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.

Further, 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 pandemic. Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our products, allow our competitors to bring products to market before we do or impair our ability to successfully commercialize our products, which would harm our business and results of operations. In addition, many of the factors that cause, or lead to, clinical trial delays may ultimately lead to the denial of regulatory approval of our product candidates.

We currently have four product candidates in clinical development for the treatment of human diseases: selinexor, eltanexor, verdinexor and Their risk of failure is high. If our current or future indications of XPOVIO or any of our product 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 or limit their development or limit 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.

As a result of the pandemic that has affected many segments of the global economy, we have experienced, and we expect to continue to experience, disruptions that could adversely impact our business, clinical trial activities and commercial operations, including:

pandemic continues to evolve, and its ultimate scope, duration and effects remain 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 the availability and effectiveness of vaccines and therapeutics and future developments, which are highly uncertain and cannot be predicted with confidence, such as the duration and scope of the pandemic, and the effectiveness of actions taken in the U.S. and other countries to contain and treat the disease, such as travel restrictions, social distancing and quarantines or lock-downs in the U.S. and other countries, business closures or business disruptions.

We may publicly disclose preliminary, interim or data from our clinical trials. These interim updates are based on a preliminary analysis of then-available data, and the results and related findings and conclusions are subject to change as further patient data become available and following a more comprehensive review of the data related to the particular study or trial. For example, in November 2020, we announced that our ongoing Phase 3 SIENDO study passed its planned interim futility analysis without the need to modify the study protocol or add additional patients. For this study or any other that we report preliminary, interim or

data, we make assumptions, estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data. Consequently, the preliminary, interim or data results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated. Preliminary, interim or data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, these early data points should be viewed with caution until the final data are available.

We have built a commercial infrastructure in the U.S. 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 product candidates is approved for additional indications beyond hematological malignancies, such as solid tumors, we will need to substantially evolve our sales, marketing and distribution capabilities and we may not be able to do so successfully or on a timely basis. In the future, we may choose to expand our sales, marketing and distribution infrastructure to market or one or more of our product candidates, if and when they are approved, or enter into additional collaborations with respect to the sale, marketing and distribution of our product 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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decreased demand for XPOVIO and any other products that we may develop or acquire;

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injury to our reputation and significant negative media attention;

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withdrawal of clinical trial participants;

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initiation of investigations by regulators;

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product recalls, withdrawals or labeling, marketing or promotional restrictions;

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significant costs to defend the related litigation;

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substantial monetary awards to trial participants or patients;

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loss of revenue;

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reduced resources of our management to pursue our business strategy; and

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the inability to successfully commercialize XPOVIO and any other products that we may develop or acquire.

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potentially reduced protection of our intellectual property rights;

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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;

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unexpected changes in tariffs, trade barriers or regulatory requirements;

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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 pandemic;

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

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

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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; and

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failure to comply with Office of Foreign Asset Control rules and regulations and the Foreign Corrupt Practices Act (“FCPA”).

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litigation involving patients taking our drug;

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restrictions on our manufacturers or manufacturing processes;

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restrictions on the labeling or marketing of our products;

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restrictions on the distribution or use of our products;

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requirements to conduct post-marketing studies or clinical trials;

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warning letters or untitled letters;

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withdrawal, recall or seizure of our products from the market;

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refusal to approve pending applications or supplements to approved applications that we submit;

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fines, restitution or disgorgement of profits or revenues;

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suspension or withdrawal of marketing approvals;

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damage to relationships with our current or potential collaborators;

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unfavorable press coverage and damage to our reputation;

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refusal to permit the import or export of our products; or

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injunctions or the imposition of civil or criminal penalties.

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compliance with the EU’s stringent pharmacovigilance or safety reporting rules must be ensured. These rules can impose post-authorization studies and additional monitoring obligations.

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the manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice. These requirements include compliance with EU current Good Manufacturing Practice (“cGMP”) standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU.

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the marketing and promotion of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the EU notably under Directive 2001/83EC, as amended, and are also subject to EU Member State laws. Direct-to-consumer advertising of prescription medicines is prohibited across the EU.

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The FDA may also designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For Fast Track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a Fast Track product’s application before the application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective.

The Trump Administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices. On January 28, 2021, however, President Biden issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access. Under this Order, federal agencies are directed to policies that undermine protections for people with conditions, including complications related to demonstrations and waivers under Medicaid and the ACA that may reduce coverage or undermine the programs, including work requirements; policies that undermine the Health Insurance Marketplace or other markets for health insurance; policies that make it more difficult to enroll in Medicaid and the ACA; and policies that reduce affordability of coverage or financial assistance, including for dependents.

The containment of healthcare costs has become a priority of federal, state and foreign governments and the prices of pharmaceutical products have been a focus in this effort. Governments have shown significant interest in implementing cost-containment programs, including rebate programs, price controls, restrictions on reimbursement and requirements for substitution of generic products. Controlling drug pricing has garnered bipartisan support in U.S. Congress. To that end, the Trump Administration published final rules that would allow states or certain other government entities to submit importation program proposals to the FDA for review and approval. Applicants would be required to demonstrate their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers. Earlier, the FDA had issued draft guidance that would allow manufacturers to import their own drugs that are authorized for sale in other countries (multi-market approved products). Further, President Trump issued five executive orders intended to lower the costs of prescription drug products. Several of these orders are reflected in recently promulgated regulations, and one of these regulations is currently subject to a nationwide preliminary injunction.

branded, biologic, and certain generic drugs by referencing the price of these drugs in other developed countries. At the same time, the administration may seek to limit Medicare Part D and public option drug prices through a tax penalty on manufacturers for increases in the cost of drugs and biologics above the general inflation rate. The Biden Administration may also seek to amend existing law that currently bans Medicare from negotiating lower prices with drug manufacturers.

Healthcare providers, physicians and third-party payors play a primary role in the recommendation and prescription of our approved products. 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 approved product. These include the Federal Anti-Kickback Statute, the FCA and federal transparency requirements (and their state analogues), as discussed above in Item 1 under the heading “” in this Annual Report on Form

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 by the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), thus complicating compliance efforts.

Like the FCPA, the UK Bribery Act and other anti-corruption laws throughout the world similarly prohibit offers and payments made to obtain improper business advantages, including offers or payments to healthcare professionals and other government and officials. These other anti-corruption laws also can result in substantial financial penalties and other collateral consequences.

Various laws, regulations and executive orders also restrict the use and dissemination outside of the U.S., or the sharing with certain nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products. Our expansion outside of the U.S., has required, and will continue to require, us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain drugs and product candidates outside of the U.S., which could limit our growth potential and increase our development costs.

Since inception, we have incurred significant operating losses. Our net loss was $196.3 million for the year ended December 31, 2020. As of December 31, 2020, we had an accumulated deficit of $1.1 billion. Although we received our first for XPOVIO in July 2019, we may never attain profitability or positive cash flows from operations. We have historically financed our operations principally through private placements of

our preferred stock, proceeds from our initial public offering and offerings of common stock, issuance of convertible debt, proceeds from a revenue interest financing agreement and cash generated from our business development activities. Substantially all of our operating losses have resulted from costs incurred in connection with our research and development programs, the pursuit of regulatory approvals within and outside of the U.S., and the commercialization of XPOVIO. We expect to continue to incur significant expenses and operating losses as we continue to commercialize XPOVIO in the U.S. and potentially outside of the U.S. and engage in activities to prepare for the potential approval and commercialization of additional indications for selinexor as well as our other product candidates. The net losses we incur may fluctuate significantly from quarter to quarter.

As of December 31, 2020, we believe that our existing cash, cash equivalents and investments will enable us to fund our current operating and capital expenditure plans for at least twelve months from the date of issuance of the financial statements contained in this Annual Report on The amount and timing of our future capital requirements will depend on many factors, including, but not limited to:

Even if we believe we have sufficient funds for our current or future operating plans, we may seek additional capital due to favorable market conditions or strategic considerations. Any future fundraising efforts could divert our management’s attention away from their activities. Further, adequate additional financing may not be available to us on acceptable terms, or at all. In addition, raising funds in the current economic environment may present additional challenges. For example, any sustained disruption in the capital markets from 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 pandemic. If adequate funds are not available to us on a timely basis or on attractive terms, we may be required to delay, reduce or eliminate our research and development programs or any current or future commercialization efforts for one or more of our products or product candidates, any of which could have a material adverse effect on our business, operating results and prospects.

In September 2019, we entered into the Revenue Interest Financing Agreement (“Revenue Interest Agreement”) with HealthCare Royalty Partners III, L.P. and HealthCare Royalty Partners IV, L.P. (“HCR”). 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 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. Upon the occurrence of specified material adverse events or the material breach of specified representations and warranties, which will not be considered events of default, HCR may elect to terminate the Revenue Interest Agreement and require us to make payments necessary for HCR to receive $75.0 million, less the aggregate of all of the payments made to date, plus a specified annual rate of return. In the event that we are unable to make such payment, then HCR may be able to foreclose on the collateral that was pledged to HCR, which consists of all of our present and future assets relating to XPOVIO. Any such foreclosure remedy would significantly and adversely affect us and could result in us losing our interest in such assets.

Our ability to pay the principal of or interest on the Notes or to make cash payments in connection with any conversion of the Notes depends on our future performance, which is subject to economic, financial, competitive and other factors beyond our control. 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 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 May 2008, the Financial Accounting Standards Board (“FASB”) issued FASB Staff Position No. APB , which has subsequently been codified as Accounting Standards Codification (“ASC Under 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 on the accounting for the Notes is that the equity component is required to be included in the additional 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 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 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.

Effective January 1, 2021, we are adopting Accounting Standards Update No.  that eliminates the requirement for the equity component to be bifurcated from the debt instrument and included in the additional capital section of stockholders’ equity. Upon adoption, we will reclassify the equity component out of additional capital into the long-term liability. As a result, the equity component will no longer be treated as a debt discount for purposes of accounting for the debt, and interest expense related to amortizing the equity component will be eliminated in 2021 and beyond.

Global credit and financial markets have experienced extreme disruptions over the past several years. 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, the pandemic has resulted in businesses suspending or terminating global operations and travel, self-imposed or government-mandated quarantines, and an overall slowdown of economic activity in many areas. Our general business strategy may be compromised by economic downturns, a volatile business environment and unpredictable and unstable market conditions, such as the current global situation resulting from the pandemic. If the equity and credit markets 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 pandemic, which could directly affect our ability to attain our operating goals on schedule and on budget.

Promedico Ltd. and FORUS Therapeutics Inc. for the development, marketing and/or commercialization of selinexor in certain geographies outside of the U.S. 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. For example, we expect to rely on partners to develop and commercialize our products outside of the U.S. All of the risks relating to product development, regulatory approval and commercialization described in this Annual Report on also apply to the activities of our collaborators.

Potential collaborators include large and pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies and we face significant competition in seeking appropriate collaborators, including as a result of a significant number of recent business combinations among large pharmaceutical companies that have reduced the number of potential collaborators. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or foreign regulatory authorities, the potential market for the product or product candidate, the costs and complexities of manufacturing and delivering such product or product candidate to patients, the potential of competing products, the existence of uncertainty with respect to our ownership of intellectual property, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally. The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us.

Further, our ability to enter into new collaboration arrangements and the successful execution of our current arrangements by our collaborators could be negatively impacted by the pandemic, including as a result of businesses suspending or terminating global operations and travel, self-imposed or government-mandated quarantines, and a prolonged economic downturn. If our or our third-party collaborators are so affected, our business prospects and results of operations could be severely adversely impacted.

Our reliance on these third parties for research and development activities reduces our control over these activities but does not relieve us of our responsibilities. For example, we remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the trial. Moreover, the FDA requires us to comply with GCP standards when conducting, recording and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected. The EMA also requires us to comply with comparable standards. Regulatory authorities ensure compliance with these requirements through periodic inspections of trial sponsors, principal investigators and trial sites. Our reliance on third parties that we do not control does not relieve us of these responsibilities and requirements. 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 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. Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.

In addition, as discussed above, the third-parties upon whom we rely to conduct our clinical trials could be negatively impacted as a result of disruptions caused by pandemic, including difficulties in initiating clinical sites or enrolling participants, diversion of healthcare resources away from clinical trials, travel or quarantine policies, and other factors. If these third parties are so affected, our business prospects and results of operations could be severely adversely impacted.

We rely on academic and private institutions to conduct and sponsor clinical trials relating to selinexor and our other product candidates. We do not control the design or conduct of the investigator-sponsored trials, and it is possible that the FDA or foreign regulatory authorities will not view these investigator-sponsored trials as providing adequate support for future clinical trials, whether controlled by us or third parties, for any one or more reasons, including elements of the design, execution of the trials, safety concerns or other trial results.