On August 28, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported that clinical data from the Phase 2b STORM study evaluating the Company’s lead, oral Selective Inhibitor of Nuclear Export (SINE) compound selinexor in heavily pretreated patients with refractory multiple myeloma, has been selected for oral presentation at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting, taking place September 12-15, 2018 in Houston (Press release, Karyopharm, AUG 28, 2018, View Source [SID1234529102]).
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"The clinical results from the STORM study further support selinexor’s potential role in advancing the treatment options available to patients with refractory multiple myeloma. In addition to the 25.4% overall response rate (ORR), including two patients who achieved stringent complete responses (sCRs) with minimum residual disease (MRD) negativity, patients treated with oral selinexor and dexamethasone (dex; Sd) also achieved median duration of response (DOR) of 4.4 months and median overall survival (OS) of 8.6 months," said Sundar Jagannath, MD, Director of the Multiple Myeloma Program, Professor of Medicine (Hematology and Medical Oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine, and principal investigator of the STORM study. "The importance of achieving MRD negativity and extending overall survival rates in this heavily pretreated patient population is very encouraging. Notably, patients with any response to Sd, including minimal, partial, very good partial and complete responses, experienced significantly prolonged OS compared to patients who did not respond, and the median OS had not yet been reached in this population."
"Despite recent advances in myeloma treatment, an increasing number of patients will require additional therapeutic options for this progressive and fatal disease," said Sharon Shacham, PhD, Founder, President and Chief Scientific Officer of Karyopharm. "The 27.3% ORR observed in patients who had previously received Darzalex in combination regimens is particularly compelling as these patients are especially difficult to treat. Additionally, we are increasingly encouraged by the improvement in overall survival demonstrated in patients who had a response of stable disease or better. We look forward to presenting additional data from what is covered in the abstract at the SOHO 2018 Annual Meeting in mid-September. Finally, we remain tremendously excited by the recent submission of our first New Drug Application to the U.S. Food and Drug Administration seeking accelerated approved for selinexor in patients with penta-refractory myeloma, and we look forward to submitting a Marketing Authorization Application (MAA) with the EMA in the first quarter of 2019."
Phase 2b STORM Results
These clinical results are from Part 2 of the international, multi-center, single-arm Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) study, which enrolled 122 heavily pretreated patients (median of seven prior treatment regiments) with penta-refractory myeloma. Each patient received 80mg oral selinexor twice weekly in combination with low-dose dexamethasone (dex; 20mg twice weekly). Patients with penta-refractory myeloma have 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.
For the STORM study’s primary objective, oral selinexor achieved a 25.4% ORR, which included two stringent complete responses (sCRs), eight very good partial responses (VGPRs) and 21 partial responses (PRs) in these patients with penta-refractory myeloma. The two sCRs were negative for minimal residual disease, one at 1:10-6 and one at 1:10-4, which is particularly significant in this penta-refractory population. The ORR in patients who had previously received Darzalex combination therapy (n=85) was 27.3%. Median progression-free survival (PFS) was 3.7 months and the median DOR was 4.4 months (range <1 to 8 months). Median OS was 8.6 months. Median OS in patients with at least a minor response (MR) to selinexor + dex was not reached and was significantly longer than the median OS of 6.3 months in patients that did not respond (≤ stable disease; p=0.0018). All responses were confirmed by an Independent Review Committee (IRC).
Across the relevant patient population, side effects of oral selinexor were generally predictable and often managed with dose adjustments or supportive care, with safety results that were consistent with those previously reported from Part 1 of this study (Vogl et al., J Clin Oncol, 2018) and from other selinexor studies. As anticipated, the most common non-hematologic treatment-related adverse events (AEs) were largely Grade 1/2 and included nausea (66%), fatigue (54%), anorexia (47%) and weight loss (43%). The most common Grade 3/4 AEs were cytopenias (thrombocytopenia (52%) and anemia (25%)) and were generally not associated with clinical sequelae.
Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), with a request for accelerated approval for oral selinexor as a new treatment for patients with penta-refractory multiple myeloma. The Company also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in Q1 2019 with a request for conditional approval. In parallel, Karyopharm is also conducting the pivotal, randomized Phase 3 BOSTON study evaluating selinexor in combination with the proteasome inhibitor Velcade and dex (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy. The Company is expecting to complete enrollment in the BOSTON study by the end of 2018, with top-line data anticipated in 2019. Assuming a positive outcome, Karyopharm plans to use the results from the BOSTON study to support an application for full approval in the U.S.
Details for the oral presentation at SOHO 2018:
Title: Phase 2b Results of the STORM Study: Oral Selinexor plus Low Dose Dexamethasone (Sd) in Patients with Penta-Refractory Myeloma (penta-MM)
Presenter: Sundar Jagannath, MD, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Session: Session VI – Multiple Myeloma
Date and Time: Thursday, September 13, 2018 at 5:55 PM CT
About Selinexor
Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,600 patients have been treated with selinexor. In April 2018, Karyopharm reported positive top-line data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), with a request for accelerated approval for oral selinexor as a new treatment for patients with penta-refractory multiple myeloma. The Company also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval. Selinexor is also being evaluated in several other mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.
Further Information About Potential Accelerated Approval for Selinexor in Multiple Myeloma
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.