Background Analysis: US FDA Advisory Committee to Review Karyopharm’s Selinexor for Relapsed Refractory Multiple Myeloma – FEB 26, 2019 (ODAC)

Announcement

The US FDA has scheduled a half-day (afternoon) meeting of the Oncologic Drugs Advisory Committee (ODAC) for Tuesday, February 26, 2019. The committee will discuss a new drug application (NDA) for selinexor tablets, application submitted by Karyopharm Therapeutics, Inc. (Karyopharm), for use, in combination with dexamethasone, in the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Indication Background

Description of Indication

Multiple myeloma is a form of blood cancer that begins in a type of white blood cell called a plasma cell. Multiple myeloma causes plasma cells to rapidly multiply and crowd out other healthy blood cells from the bone marrow.

Karyopharm’s proposed indication for selinexor is use in combination with dexamethasone, for the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Product Background

Description of Product

Selinexor is a selective inhibitor of nuclear export (SINE) that inhibits a nuclear export protein called exportin 1 (XPO1). Disruption of XPO1 functioning is intended to cause an accumulation of tumor suppressor proteins in the nucleus and overwhelm the transcription of oncogenes, which suppresses the expression of cancer.

Clinical Trials

The NDA is based on results of the open-label, Phase 2b STORM trial (ClinicalTrials.Gov ID: NCT02336815). The trial evaluated oral selinexor (80 mg) in combination with low-dose dexamethasone (20 mg), taken twice weekly, in patients with penta-refractory multiple myeloma (N = 202 enrolled). Penta-refractory myeloma is defined as having previously received the two proteasome inhibitors (PIs), Velcade (bortezomib) and Kyprolis (carfilzomib), the two immunomodulatory drugs (IMiDs), Revlimid (lenalidomide) and Pomalyst (pomalidomide), and the anti-CD38 monoclonal antibody Darzalex (daratumumab) as well as alkylating agents, and their disease is refractory to at least one PI, at least one IMiD, Darzalex and their most recent therapy.

A summary of the outcomes from the STORM study is presented below, based on information from company press releases. Comprehensive data and detailed analyses by both the company and the FDA will be presented two days prior to the meeting in meeting materials posted by FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

For the STORM trial’s primary objective, selinexor achieved a 26.2% overall response rate (ORR), which included two stringent complete responses (sCRs), six very good partial responses (VGPRs) and 24 partial responses (PRs). The two sCRs were negative for minimal residual disease (MRD), one at the level of 1x10-6 and one at 1x10-4; Karyopharm says this is particularly significant in this penta-refractory population. Both patients had relapsed after chimeric antigen receptor therapy (CAR-T) therapy achieved PRs. The ORR in patients who had previously received Darzalex combination therapy (n=86) was 29.1%. The disease control rate for patients who had achieved stable disease or better was 78.7%.  All responses were confirmed by an independent review committee (IRC). Median progression-free survival (PFS) was 3.7 months and the median duration of response (DOR) was 4.4 months.  Median overall survival (OS) across the study was 8.6 months. Median OS in the approximately 40% of patients with at least a minimum response (MR) on selinexor + dexamethasone was 15.6 months compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable (p<0.0001). Karyopharm says the short median OS of patients with no response to selinexor is consistent with the lack of available effective therapies for the very heavily pretreated population who entered the study. Real world OS data were also obtained from the Flatiron Health Analytic Database (FHAD). The company reports that these results further highlight the limited life-expectancy in patients with highly refractory multiple myeloma. OS data from the FHAD indicate that patients with triple-class refractory myeloma (n=69) had a median OS of 3.5 months, also consistent with previously reported data from the literature.

The most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from Part 1 of this study (Vogl et al., J Clin Oncol, 2018) and from other selinexor studies. Most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (69%), fatigue (56%), anorexia (52%), and weight loss (47%), and were mostly Grade 1 and 2 events.  As expected, the most common Grade 3 and 4 treatment-related AEs were thrombocytopenia (54%), anemia (29%), neutropenia (19%), and fatigue (19%). No significant major organ toxicities were observed, and bleeding and infection rates were low.

Karyopharm has submitted the selinexor NDA using the FDA’s accelerated approval pathway. The company is conducting an open-label, randomized Phase 3 trial, named BOSTON (ClinicalTrials.Gov ID: NCT03110562), which evaluates selinexor in combination with Velcade and dexamethasone, compared to only Velcade and dexamethasone in adult patients (N = 364) with relapsed or refractory multiple myeloma who have received 1 to 3 prior anti-multiple myeloma regimens. The company plans to submit the results of the BOSTON trial, if they are supportive, to obtain full approval of selinexor in relapsed/refractory multiple myeloma. The primary outcome measure is progression-free survival. Karyopharm says top-line data are anticipated by the end of the year (2019). According to ClinicalTrials.Gov, the trial is estimated to be fully completed by June 2020.

Regulatory Considerations

When the company announced the NDA submission, they noted input from the FDA regarding the accelerated approval pathway, as follows in the company press release:

The FDA instituted its Accelerated Approval Program to allow for expedited approval of drugs that treat serious conditions and that fill an unmet medical need based on a surrogate endpoint or an intermediate clinical endpoint thought to predict clinical benefit, like overall response rate (ORR). Accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments at the time of consideration of the application for accelerated approval, which the FDA has reiterated in its feedback to the Company. Particularly in disease areas with multiple available and potential new therapies, such as multiple myeloma, accelerated approval carries a high regulatory threshold.  Consistent with its general guidance, the FDA has noted to the Company its preference for randomized studies geared toward full approval, which the Company has undertaken with the ongoing pivotal, Phase 3 BOSTON study, and has reminded the Company that accelerated approval requires patients to have exhausted all available approved therapies. FDA’s Fast Track designation is available to therapeutics treating an unmet medical need in a serious condition; the Company has received Fast Track designation from the FDA specifically for the population treated in the STORM trial. In light of this recognition that the STORM patient population represents an unmet medical need and the positive top-line data reported in April 2018, the Company believes that the STORM study should support its request to the FDA for accelerated approval.

Based on this statement, it appears the appropriateness of accelerated approval may be in question. One concern may be that differences in the patient population and interventions in the BOSTON trial compared to the STORM trial may make it difficult to confirm benefit for the proposed use. The STORM trial was a single-arm, open-label, non-randomized trial evaluating selinexor plus dexamethasone in patients with penta-refractory myeloma, whereas the BOSTON trial is a two-arm, open-label, randomized trial evaluating selinexor plus dexamethasone plus Velcade, compared to dexamethasone plus Velcade in patients who have received 1 to 3 prior anti-multiple myeloma regimens.

Regulatory Background

US Regulatory Background

April 6, 2019 – PDUFA date

August 6, 2018 – Karyopharm announced the completion of their rolling NDA submission (NDA 212306), requesting accelerated approval of selinexor for relapsed/refractory myeloma.

Orphan Drug Designation, Fast Track Designation, Priority Review

Ex-US Regulatory Background

Jan 8, 2019 – Karyopharm announced their submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for selinexor, requesting conditional approval for the treatment of patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody (mAb).

Accelerated Assessment

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Karyopharm Therapeutics, Inc. Drug Name: selinexor Drug Class: selective inhibitor of nuclear export Indication: multiple myeloma

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.