10-K

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM

10-K

(Mark One)

For the fiscal year ended:

December 31

, 2020

For the transition period from

Commission file number:

001-36167

KARYOPHARM THERAPEUTICS INC.

(Exact name of registrant as specified in its charter)

85 Wells Avenue, 2

Floor, Newton, Massachusetts

02459

(Address of principal executive offices) (zip code)

Registrant’s telephone number, including area code:

(617) 658-0600

Securities registered pursuant to Section 12(b) of the Act:

Title of each class Trading Symbol(s) Name of each exchange on which listed

Common Stock, $0.0001 par value KPTI Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No ☐

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of

Regulation S-T(§232.405

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

non-accelerated

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

Rule 12b-2

of the Exchange Act.

Large accelerated filer ☒ Accelerated filer ☐

Non-accelerated filer ☐ Smaller reporting company ☒

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report.☒

Indicate by check mark whether the registrant is a shell company (as defined in

Rule 12b-2of

the Exchange Act). Yes ☐ No ☒

The aggregate market value of the registrant’s voting and

non-voting

common stock held by

non-affiliates

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.

Number of shares outstanding of the registrant’s Common Stock as of February 16, 2021: 74,634,291.

Documents incorporated by reference:

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

Form 10-K.

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TABLE OF CONTENTS

Page No.

PART I 6

Item 1. Business 6

Item 1A. Risk Factors 64

Item 1B. Unresolved Staff Comments 112

Item 2. Properties 112

Item 3. Legal Proceedings 112

Item 4. Mine Safety Disclosures 112

Item 6. Selected Financial Data 113

Item 7A. Quantitative and Qualitative Disclosures about Market Risk 127

Item 8. Financial Statements and Supplementary Data 127

Item 9A. Controls and Procedures 128

Item 9B. Other Information 130

Item 10. Directors, Executive Officers and Corporate Governance 131

Item 11. Executive Compensation 131

Item 14. Principal Accountant Fees and Services 131

Item 15. Exhibits and Financial Statement Schedules 132

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Forward-Looking Information

This Annual Report on

Form 10-K

contains forward-looking statements regarding the expectations of Karyopharm Therapeutics Inc., herein referred to as “Karyopharm,” the “Company,” “we,” or “our,” with respect to the possible achievement of discovery and development milestones, our future discovery and development efforts, including regulatory submissions and approvals, our commercialization efforts, our partnerships and collaborations with third parties, our future operating results and financial position, our business strategy, and other objectives for future operations. We often use words such as “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and other words and terms of similar meaning to help identify forward-looking statements, although not all forward-looking statements contain these identifying words. You also can identify these forward-looking statements by the fact that they do not relate strictly to historical or current facts. There are a number of important risks and uncertainties that could cause actual results or events to differ materially from those indicated by forward-looking statements. These risks and uncertainties include, but are not limited to, those described in “Part I—Item 1A. Risk Factors” of this Annual Report on Form 10-K and under the heading “Summary of Risk Factors” below. As a result of these and other factors, we may not actually achieve the plans, intentions, expectations or results disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

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Summary of Risk Factors

Below is a summary of the principal factors that make an investment in our common stock speculative or risky. This summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, and other risks that we face, can be found below under the heading “Risk Factors” and should be carefully considered, together with other information in this Annual Report on Form

10-K

and our other filings with the SEC, before making an investment decision regarding our common stock.

Risks Related to Commercialization and Product Development

• XPOVIO faces substantial competition.

Risks Related to Regulatory Matters

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Risks Related to Our Financial Position and Capital Requirements

Risks Related to Our Dependence on Third Parties

Risks Related to Our Intellectual Property

Risks Related to Employee Matters and Managing Growth

Risks Related to Our Common Stock

• The price of our common stock has been and may continue to be volatile.

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PART I

Item 1. Business

Overview

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

first-in-class

drugs directed against nuclear transport for the treatment of cancer and other diseases. Our scientific expertise is based upon an understanding of the regulation of intracellular communication between the nucleus and the cytoplasm. We have discovered and are developing and commercializing novel, small molecule

elective

nhibitor of

uclear

xport

(“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:

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

, an extensive patient and healthcare provider support program. Our commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers. We plan to continue to educate physicians, healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we expand XPOVIO into the second-line plus multiple myeloma market and continue to penetrate the third-line DLBCL market.

XPOVIO also received its first regulatory approval outside the U.S. with an approval received in February 2021 by our partner Promedico Ltd., a member of the Neopharm Group (“Promedico”), for the treatment of patients with multiple myeloma and DLBCL, in Israel. In addition, in January 2021, the European Medicines Agency’s (“EMA”) Committee for Medicinal Products for Human Use (“CHMP”) adopted a positive opinion recommending the conditional approval of NEXPOVIO

(selinexor), the expected brand name for selinexor in Europe, based on the results of the Phase 2b STORM Study, which studied selinexor in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two PIs, two IMiDs and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy. We expect a final decision from the European Commission (the “EC”) on our Marketing Authorization Application (“MAA”) by April 2021. A favorable decision based on our submission through the centralized procedure would be valid in all 27 European

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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

low-dose

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

Our focus is on marketing XPOVIO in its currently approved indications as well as seeking the regulatory approval and potential commercialization of selinexor as an oral agent in additional cancer indications with significant unmet medical need. We plan to continue to conduct clinical trials and seek additional approvals for the use of selinexor as a single agent or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor. Thus, we are advancing our clinical development program for selinexor in the areas of multiple hematological malignancies and solid tumors, among others, including the following ongoing or planned selinexor studies:

Additionally, we expect to initiate a number of new clinical trials in 2021, including a Phase 3 study evaluating selinexor in combination with pomalidomide in patients with relapsed or refractory multiple myeloma as well as new Phase 1 and 2 studies evaluating selinexor in patients with a variety of solid tumor indications, including metastatic melanoma, lung cancer and colorectal cancer. A number of these studies will be investigating the treatment of selinexor in combination with other standard of care anti-cancer drugs.

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

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Key 2020 and Recent Highlights

XPOVIO Franchise

• Recognized XPOVIO net revenue of $76.2 million in 2020.

Selinexor Pipeline

• Dosed first patient in June 2020 in the XPORT-GBM-029 Study.

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Collaborations

Corporate Highlights

Our Strategy

The critical components of our business strategy are to:

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Our XPOVIO Program to Treat Cancer

Overview

According to the World Health Organization, cancer is the second leading cause of death globally and in 2020 was responsible for more than one in six deaths, or an estimated 10 million deaths. Additionally, cancer is one of the most important health issues facing patients in the U.S. The American Cancer Society (“ACS”) estimates that in 2021 there will be nearly 1.9 million new cancer cases in the U.S., with approximately 608,000 Americans expected to die of cancer.

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

Many tumor suppressor proteins can only function properly when they are located inside of a cell’s nucleus. Proteins, however, are not made inside the nucleus but rather are made outside of the nucleus in an area called the cytoplasm. A membrane, called the nuclear membrane, separates the nucleus from the cytoplasm. Larger nuclear proteins, including tumor suppressor proteins, must be transported from the cytoplasm where they are made into the nucleus to perform their functions in keeping a cell healthy. Similarly, when they have completed their normal functions, these proteins are typically exported back into the cytoplasm. Proteins move between the nucleus from the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore. The nuclear pore works like a gate through which large molecules, including many other proteins and ribonucleic acids (“RNAs”), enter and exit the nucleus. When molecules enter the nucleus from the cytoplasm, the process is called import, and when molecules exit from the nucleus to the cytoplasm, the process is called export. The import and export of most proteins and other large molecules between the nucleus and cytoplasm require specific carrier proteins to chaperone their cargo molecules through the nuclear pore complex. Carrier proteins, which mediate the import of macromolecules into the nucleus, are called importins, and those which mediate the export of macromolecules out of the nucleus are called exportins. Therefore, the processes of import and export are carried out separately and are typically regulated independently.

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

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XPO1. XPO1 is one of eight exportins that have been identified in human cells, and it exports over 220 proteins referred to as its “cargo proteins.” In particular, XPO1 appears to be the sole exporter for most of the tumor suppressor proteins including p53, p73, p21, p27, APC, FOXO, pRB and survivin. In addition to exporting tumor suppressor proteins out of the nucleus, XPO1 mediates the nuclear export of a protein called eukaryotic initiation factor 4E, which itself binds to the mRNAs that code for these proteins (“eIF4E” and also called the “mRNA cap binding protein”). eIF4E binds to the mRNAs for many growth-regulating proteins, including

c-myc,

bcl-2,

bcl-6

and cyclin D, and depends on XPO1 to help carry these growth-promoting mRNAs from the nucleus into the cytoplasm where the mRNAs are efficiently translated into proteins. XPO1 also exports the anti-inflammatory (and anti-tumor) protein I

B, which inhibits a protein called NF-

B. NF-

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

In nearly all cancer cells, XPO1 levels are reported to be elevated when compared to their healthy cell counterparts. Therefore, these elevated levels of XPO1 in cancer cells mediate the rapid export of tumor suppressor proteins as well as I

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

NF-

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

Mechanism of Action of Our SINE Compounds—Inhibition of XPO1

XPOVIO and our product candidates are novel therapies that are

first-in-class,

oral SINE compounds specifically designed to force nuclear accumulation in the levels of multiple tumor suppressor and growth regulatory proteins. One of the ways a cell regulates the function of a particular protein is by controlling that protein’s location within the cell since certain functions may only occur within a particular location in the cell. As described above, the nuclear pore is a complex gate between the nucleus and cytoplasm, regulating the import and export of most large molecules, called macromolecules, including many proteins, into and out of the nucleus. In healthy cells, nuclear transport, both into and out of the nucleus, is a normal and regular occurrence that is tightly regulated and requires the presence of specific carrier proteins. XPO1 mediates the transport of the majority of tumor suppressor proteins and appears to be the only mediator of nuclear export for these proteins.

XPO1 inhibitors, such as XPOVIO, block the nuclear export of tumor suppressor, growth-regulating, and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Because normal cells have little or no DNA damage, accumulation of tumor suppressor proteins in their nucleus generally does not lead to apoptosis. The figure below depicts the process by which our SINE compounds inhibit the XPO1-mediated nuclear export of tumor suppressor proteins and oncoprotein mRNAs.

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We believe that selinexor’s novel mechanism of action, oral administration and low levels of major organ toxicities observed to date in patients treated with selinexor, along with encouraging efficacy data, support the potential for selinexor’s broad use across many cancer types, including both hematological and solid tumor malignancies. Unlike many other targeted therapeutic approaches that only work for a specific set of cancers or in a specific subgroup of patients, we believe that by restoring tumor suppressor proteins to the nucleus where they can assess a cell’s DNA, our SINE compounds may provide therapeutic benefits across a broad range of both hematological and solid tumor malignancies and can potentially benefit a wider range of patients.

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

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

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

The NCCN Guidelines are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97% of cancers affecting patients in the U.S. and are intended to ensure that all patients receive preventive, diagnostic, treatment and supportive services that will most likely lead to optimal outcomes. The XPOVIO regimens added to the NCCN Guidelines include: (i) selinexor/bortezomib/dexamethasone (once-weekly), which also received a Category 1 recommendation, which represents the highest designation assigned by NCCN, indicating the recommendation is based upon high-level evidence and that there is uniform NCCN consensus that the intervention is appropriate; (ii) selinexor/daratumumab/dexamethasone; and (iii) selinexor/pomalidomide/dexamethasone, which is an

all-oral

treatment regimen.

Summary of Our Pipeline and Key Clinical Trials

Oral selinexor is being evaluated in multiple later-phase clinical trials in patients with hematological and solid tumor malignancies, often in the relapsed and/or refractory setting. In general, relapsed disease refers to disease that progresses following the expiration of a specified period of time after discontinuation of therapy and refractory disease refers to disease that progresses while the patient is on therapy or within a specified period of time after discontinuation of therapy. Key clinical trials of selinexor are summarized in the charts below. In addition to these studies, there are several ongoing investigator-sponsored clinical trials being conducted in a variety of hematological and solid tumor malignancies.

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HEMATOLOGICAL MALIGNANCIES

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

Multiple Myeloma

Overview

Multiple myeloma is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, also known as M protein, in the serum or urine, bone disease, kidney disease and immunodeficiency. Multiple myeloma is one of the most common types of blood cancer in the U.S. According to the ACS, nearly 35,000 new cases of multiple myeloma will be diagnosed in the U.S. in 2021. It is more common in elderly patients, and most frequently diagnosed among people between ages 65 to 74 years with a median age at diagnosis of 69 years. Despite recent therapeutic advances, there is currently no cure and most patients’ disease will typically progress following treatment with currently available therapies.

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

(lenalidomide) and Pomalyst

(pomalidomide), and PIs such as Velcade

(bortezomib), Kyprolis

(carfilzomib), and Ninlaro

(ixazomib). Three monoclonal antibodies, Darzalex

(daratumumab), SARCLISA

(isatuximab-irfc), and Empliciti

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

(panobinostat). The introduction of

non-chemotherapeutic

agents has led to a significant increase in the survival of patients with multiple myeloma. Although a wide variety of newly approved or experimental therapies are being used to treat relapsed and/or refractory patients, including new PIs (oprozomib and marizomiband cellular therapies such as

CAR-T

therapy), nearly all patients will eventually relapse and succumb to their disease. With nearly 12,500 deaths from multiple myeloma in the U.S. alone estimated for 2021 according to the ACS, we believe that there remains a need for therapies for patients whose disease has relapsed after, or is refractory to, available therapy.

Supporting Studies

The BOSTON Study

The December 2020 FDA approval of XPOVIO’s expanded indication as a treatment for patients with multiple myeloma after at least one prior therapy was supported by the results of the BOSTON Study, a multi-center, Phase 3, randomized study conducted at over 150 clinical sites internationally, which evaluated 402 adult patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy. The study was designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly XPOVIO in combination with once-weekly Velcade

plus

low-dose

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

plus dexamethasone (the “Vd Arm”). The primary endpoint of the study was PFS and key secondary endpoints included overall response rate (“ORR”) and the rate of peripheral neuropathy (“PN”), among others. Additionally, the BOSTON Study allowed for patients on the Vd Arm to crossover to the XVd Arm following objective (quantitative) progression of disease verified by an Independent Review Committee (“IRC”).

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

-based studies in previously treated multiple myeloma, the median PFS in the XVd Arm was 13.9 months compared to 9.5 months in the Vd Arm, representing a 4.4 month (47%) increase in median PFS (hazard ratio of 0.70; p=0.0075). The XVd Arm also demonstrated a significantly greater ORR compared to the Vd Arm (76.4% vs. 62.3%, p=0.0012).

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

Very Good Partial Response (“VGPRs”) compared to Vd therapy (44.6% vs. 32.4%) as well as a longer median duration of response (“DOR”) (20.3 months vs. 12.9 months). Additionally, 17% of patients on the XVd arm achieved a Complete Response (“CR”) or a Stringent Complete Response (“sCR”) as compared to 10% of patients receiving Vd therapy. All responses were confirmed by an IRC. Rates of PN were significantly lower for patients receiving XVd therapy compared to those receiving Vd therapy (32% vs. 47%). In addition, PN rates

Grade 2 were also significantly lower in the XVd Arm compared to the Vd Arm (21% vs. 34%).

The most common adverse reactions (

20%) in patients with multiple myeloma who received XVd were fatigue (59%), nausea (50%), decreased appetite (35%), diarrhea (32%), peripheral neuropathy (32%), upper respiratory tract infection (29%), decreased weight (26%), cataract (22%) and vomiting (21%). Grade 3-4 laboratory abnormalities (

10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON Study, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients who received XVd. Treatment discontinuation rate due to adverse reactions was 19%.

Certain subgroup populations of the BOSTON Study were evaluated and reported at the American Society of Hematology (“ASH”) 2020 Annual Meeting. We believe these subgroup evaluations of XVd therapy showed consistent PFS benefit and higher ORR compared to Vd therapy, including in evaluations of the safety and efficacy of XPOVIO (i) in patients previously treated with PIs; (ii) according to the number of prior lines of therapy or prior treatment with Revlimid

; (iii) in patients with high risk cytogenetics; and (iv) based on age (patients younger than 65 years old versus older than 65 years old) or by frailty level (frail versus fit).

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The STORM Study

The July 2019 FDA approval of XPOVIO to treat patients with penta-refractory multiple myeloma was supported by the results of the STORM Study. This indication was approved under accelerated approval based on response rate. The BOSTON Study served as the confirmatory trial under the FDA’s Accelerated Approval Program and, therefore, the approval of the BOSTON supplemental new drug application in December 2020 fulfilled the accelerated approval requirements of the STORM FDA approval.

The STORM Study was a global, multi-center,

single-arm

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

low-dose

dexamethasone (“Xd”) in patients with heavily pretreated, relapsed or refractory multiple myeloma. These heavily pretreated patients had a median of seven prior therapeutic regimens, including a median of 10 unique anti-myeloma agents. Specifically, the myeloma patients who were eligible for the study had prior treatment with the two PIs, Velcade

and Kyprolis

, the two IMiDs, Revlimid

and Pomalyst

, and the anti-CD38 monoclonal antibody Darzalex

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

, and their most recent therapy. In all patients, this myeloma was considered “triple-class refractory.” In a subset of 83 patients, their disease was designated as penta-refractory myeloma. In addition to multiple-refractory disease, patients in the STORM Study had rapidly progressing myeloma, with a median 22% increase in disease burden in the 12 days from screening to initial therapy.

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

CAR-T

therapy achieved PRs. Minimal response per International Myeloma Working Group (“IMWG”) criteria was observed in 16 (13%) patients and 48 patients (39%) had stable disease. Median time to PR or better was 4.1 weeks. The clinical benefit rate, meaning a minimal response or better, was 39%. All responses were adjudicated by an IRC consisting of four independent experts in the treatment of multiple myeloma.

Median DOR was 4.4 months. PFS was 3.7 months and overall survival (“OS”) was 8.6 months. In the 39% of patients who achieved a minimal response or better, median OS was 15.6 months, compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable.

The most common adverse reactions (

20%) in patients with multiple myeloma who received Xd were thrombocytopenia (74%), fatigue (73%), nausea (72%), anemia (59%), decreased appetite (53%), decreased weight (47%), diarrhea (44%), vomiting (41%), hyponatremia (39%), neutropenia (34%), leukopenia (28%), constipation (25%), dyspnea (24%) and upper respiratory tract infection (21%). In the STORM Study, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.

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

pre-specified

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

pre-treated

population than in the overall trial population. The ORR in this patient population was 25.3%. Our request for conditional approval in Europe is based upon this same patient population that served as the basis for XPOVIO’s accelerated FDA approval in the U.S.

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The STOMP Study

The STOMP Study, an ongoing

multi-arm

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

low-dose

dexamethasone in combinations with standard therapies, such as Pomalyst

, 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

low-dose

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

low-dose

dexamethasone in patients with relapsed or refractory multiple myeloma who received at least two prior lines of therapy, including a PI and an IMiD. Of note, 25% of the population enrolled in the study had previously received Darzalex

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

orally once-daily and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable XPd Patients as of November 14, 20202

Category N ORR* CR VGPR PR Median PFS

Pomalyst® refractory 14 5 (36%) — 1 (7%) 4 (29%) Not reported

* ORR = CR+VGPR+PR

1 Responses were adjudicated according to the IMWG criteria.

2 Based on interim unaudited data.

3 Two VGPRs were unconfirmed.

4 One PR was unconfirmed.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (“AEs”) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common

non-hematologic

treatment-related AEs were nausea (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

low-dose

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.

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

and

low-dose

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 Kyprolis

once-weekly and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally and enrollment continues using this regimen. The median PFS was 23.7 months for all patients. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable XKd Patients as of October 1, 20202

Category N ORR CR VGPR PR

1 Responses were adjudicated according to the IMWG criteria.

2 Based on interim unaudited data.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal, constitutional and other symptoms; most were manageable with dose modifications and/or standard supportive care. The most common

non-hematologic

treatment-related AEs were nausea (71%), fatigue (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%).

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

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

and

low-dose

dexamethasone in patients with newly diagnosed or previously treated multiple myeloma. The previously treated patients received at least one prior therapy, which may include prior Revlimid

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

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

orally once daily, and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable XRd Patients as of October 1, 20202

Category N ORR CR VGPR PR

Revlimid®-treated/refractory myeloma 8 1 (13%) — — 1 (13%)

1 Responses were adjudicated according to the IMWG criteria.

2 Based on interim unaudited data.

3 Two PRs were unconfirmed.

5 One VGPR was unconfirmed.

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

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Among the newly diagnosed patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common

non-hematologic

treatment-related AEs were 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

non-hematologic

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%).

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

and dexamethasone may induce high response rates with good tolerability.

Diffuse Large

B-Cell

Lymphoma

Overview

DLBCL is a form of

Non-Hodgkin’s

lymphoma (“NHL”), a cancer that starts in cells called lymphocytes, which are part of the body’s immune system. Lymphocytes are found in the lymph nodes and other lymphoid tissues, such as the spleen and bone marrow, as well as in the blood. NHL is one of the most common cancers in the U.S., accounting for approximately 4% of all cancers. In 2021, the ACS estimates that more than 81,000 people will be diagnosed with NHL and approximately 20,000 deaths will result from the disease. DLBCL is the most common and most aggressive type of NHL, making up approximately 18,000 of the new cases diagnosed annually in the U.S. Most often, newly diagnosed patients are currently cured with front-line (typically

“R-CHOP”

chemotherapy). Despite the recent approval of

CAR-T

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

CAR-T

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

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

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

Supporting Studies

The SADAL Study

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

non-chemotherapeutic

option for patients with relapsed or refractory DLBCL.

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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%).

Grade 3-4

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%.

Other DLBCL Studies

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

Myelofibrosis

Primary MF is a rare blood cancer in which excessive scar tissue (fibrosis) forms in the bone marrow and impairs its ability to produce normal blood cells. As a result, blood cell production may move to the spleen (causing spleen enlargement) or to other areas of the body. The incidence of MF is estimated to be approximately 1.5 cases per 100,000 people in the U.S. with a median OS of 69 months. MF is more common in older patients with a median age at diagnosis of approximately 65 years.

Allogeneic hematopoietic stem cell transplantation (“HSCT”) is currently the only treatment for MF that can provide a clinical cure; patients who are not good candidates for HSCT should receive a JAK2 inhibitor, such as ruxolitinib or fedratinib to reduce spleen volume and improve symptoms. However, not all patients respond adequately to JAK2 inhibitors, and some patients cannot tolerate treatment or progress on treatment.

In preclinical studies, XPO1 inhibition by selinexor selectively suppressed colony formation in MF cells, including those exposed to prior JAK2 inhibitors, compared with normal CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and cancer cell death. In an MF mouse model, the combination of selinexor and ruxolitinib improved responses compared with monotherapy, including reductions of mutant cells and restoration of splenic architecture. This formed the preclinical rationale for investigating selinexor in patients with MF. In 2021, we plan to initiate the

XPORT-MF-034

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

XPORT-MF-035

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

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Other Hematologic Malignancies

Myelodysplastic Syndromes

MDS is a group of hematologic malignancies whereby the bone marrow does not make enough healthy blood cells (white blood cells, red blood cells, and platelets) and there are abnormal cells in the blood and/or bone marrow. The median OS of patients with high-risk MDS refractory to hypomethylating agents is less than six months and, currently, no standard therapy for such patients exists. In August 2020, safety and efficacy results from a

single-arm

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

The Lancet Haematology

. According to

The Lancet Haematology

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

NF-

B signaling, both relevant targets for MDS. In the 23 patients evaluable in the clinical study, the ORR was 26% (95% CI 10 – 48); six patients had a marrow complete remission and an additional 12 patients (52%, 95% CI 31 – 73) had stable disease. The most common grade 3 or 4 AEs were thrombocytopenia (32%; 8/25 patients) and hyponatraemia (20%; 5/25 patients). There were no drug-related serious AEs and no treatment-related deaths. Based on these data and the data from a Phase 1 study of eltanexor, as discussed further below, we intend to enroll additional patients in single-agent and combination studies to evaluate eltanexor to treat MDS.

SOLID TUMOR MALIGNANCIES

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

difficult-to-treat

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

In addition, we believe that the results of clinical data from investigator-sponsored studies evaluating selinexor in combination with certain established cancer therapies warrant further research into the potential utility of selinexor in solid tumors and will help us further prioritize future clinical development activities. For example, in September 2020, clinical data were presented at the ESMO Virtual Congress from advanced solid tumor studies evaluating selinexor in combination with established cancer therapies including combination data with (i) pembrolizumab for the treatment of melanoma; (ii) carboplatin and paclitaxel for the treatment of advanced or metastatic solid tumors; and (iii) topotecan for the treatment of advanced or metastatic solid tumors.

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

Liposarcoma

Overview

Liposarcoma is a rare cancer of connective tissues that resemble fat cells under a microscope and represents up to 18% of all soft tissue sarcoma, or approximately 2,000 new cases in the U.S. per year. Current treatment of liposarcoma largely includes a combination of radiation therapy and surgery, with or without chemotherapy. Dedifferentiated liposarcoma is an aggressive form of soft tissue sarcoma that is resistant to both standard

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chemotherapy and radiation. Liposarcoma has a particularly high rate of recurrence following surgery, especially in cases involving the abdomen. Except for cases that are cured with surgery, most patients with metastatic liposarcoma will succumb to this disease, and novel therapies are needed.

The SEAL Study

In November 2020, we announced positive

top-line

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

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

Endometrial Cancer

Overview

Endometrial cancer, also called uterine cancer, occurs when cells in the endometrium, which is the inner lining of uterus, begin to grow out of control. In the U.S., endometrial cancer is the most common cancer of the female reproductive organs. The ACS estimates that there will be approximately 60,000 new cases of endometrial cancer diagnosed in 2021 in the U.S., with approximately 11,600 deaths. Endometrial cancer affects mainly post-menopausal women and the average age of women diagnosed with endometrial cancer is 60. Endometrial cancer is often detected at an early stage because it frequently produces abnormal vaginal bleeding. There are currently five different types of standard treatment for patients with endometrial cancer; surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.

The SIENDO Study

The SIENDO Study is an ongoing multicenter, randomized, double-blinded Phase 3 study evaluating the efficacy and safety of selinexor versus placebo as a maintenance therapy in patients with advanced or recurrent endometrial cancer following at least one prior platinum-based combination chemotherapy treatment. Participants with primary stage IV or recurrent disease who had a PR or CR after at least 12 weeks of standard taxane-platinum combination chemotherapy are randomized in a 2:1 manner to receive either maintenance therapy of 80 mg of XPOVIO taken once per week or placebo, until disease progression. The primary endpoint in the study is PFS with the goal of the study demonstrating a hazard ratio of 0.6.

In November 2020, following a

pre-specified

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

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

pre-treated,

progressive gynecological cancers (the “SIGN Study”). In December 2019, the full results from the SIGN Study in patients with recurrent gynecological malignancies were published in

Gynecologic Oncology

. 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.

Glioblastoma Multiforme

Overview

GBM is one of the most common and particularly aggressive forms of brain tumors of primarily glial cell origin, accounting for 48% of all primary malignant brain tumors. Patients with GBM face significant morbidity and mortality rates, with over 10,000 deaths per year in the U.S. GBM is an incurable disease and the prognosis for patients is typically poor due, in part, to its aggressive and extensive infiltration of surrounding central nervous system tissue and its frequent inaccessibility for surgical resection within the brain. In addition, the blood-brain barrier presents an obstacle for many chemotherapeutic agents, with only small, lipophilic molecules able to reach the tumor. The median age of diagnosis in patients is 64 years old, but GBM can occur at any age, including in childhood. Median survival in patients with newly diagnosed GBM is approximately 15 months and approximately five to seven months in patients with recurrent disease. GBM is a disease with high unmet need, with existing treatments having very limited success in increasing overall surviving rates. The current standard of care for GBM patients includes surgery, radiation therapy, and chemotherapy. Currently approved drug treatments for GBM include temozolomide and Avastin

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

XPO1 is frequently overexpressed in both GBM and in high-grade gliomas and therefore may be an important, novel target in the treatment of patients with GBM. The degree of XPO1 over-expression correlates with higher tumor grade and poor overall patient survival. Nonclinical studies indicate that selinexor has potent

anti-GBM

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

The

XPORT-GBM-029

Study

We are currently conducting a global Phase 1/2 clinical study evaluating oral selinexor in combination with standard of care therapy in patients with newly diagnosed or recurrent GBM, which is expected to enroll approximately 400 patients at clinical sites in the U.S., Europe, and Israel. In June 2020, we dosed the first patient in this study. This study is expected to be conducted in two phases: a Phase 1 dose finding study followed by a Phase 2 randomized efficacy exploration study, designed to independently evaluate three different combination regimens in three treatment arms in patients with newly diagnosed GBM (Arms A and B) or with recurrent GBM (Arm C). Arms A and B will investigate selinexor in combination with radiation therapy with or without the addition of temozolomide, while Arm C will evaluate the combination of selinexor and lomustine. The primary endpoints in the study are PFS in patients with newly diagnosed GBM and OS in patients with recurrent GBM.

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OUR OTHER PIPELINE PROGRAMS

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

KPT-9274.

Eltanexor

(KPT-8602)

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

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

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

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

first-in-human

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

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

non-hematologic

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.

Verdinexor

(KPT-335)

Lymphoma in Companion Canines

We have used spontaneously occurring canine cancers as a surrogate model for human malignancies. It is widely known that canine lymphomas are similar in many ways to the

non-Hodgkin’s

lymphomas in humans, display a comparable genetic profile and respond to chemotherapy in a fashion similar to their human counterparts. Lymphomas are one of the most common tumors in dogs and are very aggressive where, without treatment, the tumors are often fatal within weeks. The majority of canine lymphomas are DLBCL and most of the others are

T-cell

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.

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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

-CA1

(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.

Tanovea-CA1,

an injectable product, is currently the only other treatment for lymphoma in dogs. Anivive has five years to complete effectiveness studies to support a full approval of verdinexor in this indication.

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

B-

T-cell

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

Viral, Rare Disease and Autoimmune Indications

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

pro-inflammatory

responses, particularly uncontrolled

pro-inflammatory

cytokine expression and

NF-kB

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.

In addition, several viruses exclusively utilize XPO1 to shuttle cargos necessary for viral replication, such as viral and host proteins from the nucleus to the cytoplasm. Due to the stability of host gene targets compared to viruses which rapidly adapt for best fitness in hosts, targeting host genes may offer an approach to limit drug resistance.

In 2015, we conducted a randomized, double-blind, placebo-controlled, dose-escalating Phase 1 clinical trial of verdinexor in healthy human volunteers in Australia. This study was designed to evaluate the safety and tolerability of verdinexor in healthy adult subjects. Mild to moderate AEs of similar grade and in an equivalent percentage of patients as placebo were reported, and no serious or severe AEs were observed.

As part of an exclusive license agreement we entered into with Antengene in May 2018, and as amended in May 2020, Antengene maintains the exclusive rights to develop and commercialize verdinexor for the diagnosis, treatment and/or prevention of certain human

non-oncology

indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand. Antengene has reported that it intends to conduct clinical trials of verdinexor for the treatment of chronic active Epstein Barre infection and SLE.

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

KPT-9274

is our

first-in-class

dual inhibitor of PAK4 and NAMPT.

KPT-9274

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

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intracellular transport, cellular division, cell shape and motility, cell survival, immune defense and the development of cancer. PAK4 interacts with many key signaling molecules involved in cancer such as beta-catenin, CDC42,

Raf-1,

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

Co-inhibition

of PAK4 and NAMPT may lead to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells are more resistant to inhibition by

KPT-9274

due in part to their relative genomic stability and lower metabolic rates. Hematologic and solid tumor cells that have become dependent on both PAK4 and NAMPT pathways may be susceptible to single-agent cytotoxicity of

KPT-9274.

KPT-9274

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

KPT-9274

has shown evidence of anti-cancer activity and tolerability. To our knowledge, we are the only company with an allosteric PAK4 modulator and/or NAMPT specific inhibitor currently in clinical development.

KPT-9274

is currently being evaluated in a Phase 1 open-label study in patients with advanced solid malignancies or

non-Hodgkin’s

lymphoma. As of February 2021, patient enrollment continues in Part C of the trial evaluating the combination of

KPT-9274

and Opdivo

(nivolumab) in patients with melanoma who progressed on an

anti-PD-1

anti-PD-L1

antibody in a prior line of therapy.

The Potential of Our SINE Compounds in Settings Beyond Oncology

In addition to cancer, our SINE compounds have demonstrated the potential to provide therapeutic benefit in a number of other indications, such as viral infections, neurological disorders, inflammation and autoimmune diseases. For example, in January 2018, we entered into an Asset Purchase Agreement with Biogen MA Inc., a subsidiary of Biogen Inc. (“Biogen”), pursuant to which Biogen acquired

KPT-350,

which has been renamed by Biogen as BIIB100, an IND application-ready, oral SINE compound with a preclinical data package supporting potential efficacy in a number of neuro-inflammatory conditions, as well as certain related assets with an initial focus in amyotrophic lateral sclerosis (“ALS”). XPO1 mediates the nuclear export of multiple proteins that impact neurological and inflammatory processes. Consequently, inhibition of XPO1 by BIIB100 has shown a reduction in inflammation and an increase in anti-inflammatory and neuroprotective responses. BIIB100 penetrates the blood brain barrier to a greater degree than other SINE compounds. Preclinical data generated largely by external collaborators show efficacy of BIIB100 and related SINE compounds in animal models of ALS, multiple sclerosis, traumatic brain injury, epilepsy, and other neuro-inflammatory indications. Biogen is currently conducting a Phase 1 double-blind, placebo-controlled, single-ascending-dose study to evaluate the safety, tolerability and pharmacokinetics and pharmacodynamics of BIIB100 administered orally to adult patients with ALS.

The accumulation of I

B in the nucleus inhibits

NF-

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

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

non-dilutive

funding opportunities with the intent to

out-license

these programs for clinical development and future commercialization.

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