On February 28, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, today reported financial results for the fourth quarter and full year 2018 and provided a business update and an overview of recent accomplishments for selinexor, its first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound (Press release, Karyopharm, FEB 28, 2019, View Source [SID1234533807]).
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"Earlier this week, the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5, recommending that the FDA wait for the results from the ongoing Phase 3 BOSTON study before making a final approval decision regarding selinexor for the treatment of patients with triple class refractory multiple myeloma who have received at least three prior therapies," said Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm. "While we are disappointed with the ODAC’s recommendation, we are encouraged by the support communicated by a number of ODAC members. We intend to work closely with the FDA to evaluate the best path forward as they complete their review of our New Drug Application (NDA). We remain committed to delivering on our vision of bringing selinexor into the hands of the physicians and patients who are battling highly refractory multiple myeloma."
Fourth Quarter 2018 and Recent Events
Selinexor in Multiple Myeloma
FDA Advisory Committee Recommends that the FDA Should Wait for Results from the Ongoing Phase 3 BOSTON Study Before Making an Approval Decision. On February 26, 2019, the Oncologic Drugs Advisory Committee (ODAC) of the FDA met to review data supporting Karyopharm’s NDA requesting accelerated approval for selinexor. The proposed indication discussed was for selinexor 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, one immunomodulatory agent, and one anti-CD38 monoclonal antibody. The FDA specifically asked the ODAC to vote on whether the committee believed the approval of selinexor should be delayed until the results from the ongoing, randomized Phase 3 BOSTON study, are available. In a vote of 8 Yes and 5 No, the ODAC recommended that the approval decision for selinexor should be delayed until the results of the BOSTON study are available. Karyopharm’s NDA is under Priority Review by the FDA with an action date of April 6, 2019, under the PDUFA.
The ODAC is an independent panel of experts that evaluates data concerning the efficacy and safety of marketed and investigational products for use in the treatment of cancer and makes appropriate recommendations to the FDA. Although the FDA will consider the recommendation of the panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding.
FDA Accepts Selinexor New Drug Application and Grants Priority Review. On October 5, 2018, the FDA accepted for filing with Priority Review Karyopharm’s NDA seeking accelerated approval for selinexor, its first-in-class, oral SINE compound, as a new treatment for patients with triple class refractory multiple myeloma. The FDA also assigned a PDUFA action date of April 6, 2019.
Submitted Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). A MAA was submitted to the EMA on January 8, 2019 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, one immunomodulatory agent, and one anti-CD38 monoclonal antibody. Karyopharm also announced that the selinexor MAA has been granted accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use.
Updated Phase 2b STORM Data Presented at American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting (ASH 2018). Additional results from Part 2 of the Phase 2b STORM study were highlighted in an oral presentation at ASH (Free ASH Whitepaper) 2018. For the STORM study’s primary objective, the overall response rate (ORR) was 26.2%, which included two stringent complete responses (sCRs), six very good partial responses (VGPRs) and 24 partial responses (PRs) in patients with triple class refractory myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. The two sCRs were negative for minimal residual disease, one at the level of 1×10-6 and one at 1×10-4; this is particularly significant in this highly refractory population. 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. 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 minimal response (MR) on selinexor and dexamethasone was 15.6 months compared to a median OS of 1.7 months in patients whose disease progressed or was not evaluable (p<0.0001). 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. The most common adverse events (AEs) included thrombocytopenia, nausea/vomiting, fatigue and decreased appetite. Each patient on STORM experienced at least one AE. AEs were generally predictable and manageable with dose adjustments and/or supportive care, and treatment-emergent AEs leading to treatment discontinuation occurred in 26.8% of patients and these were considered by the Investigator to be treatment-related in 17.9% of patients. Major organ toxicities were not prominent in this study and safety results were consistent with those previously reported from Part 1 of the STORM study (Vogl et al., J Clin Oncol, 2018) and from other selinexor studies.
Updated Phase 1b/2 STOMP Data Presented at ASH (Free ASH Whitepaper) 2018. Two abstracts featuring clinical data from two treatment arms of the ongoing Phase 1b/2 STOMP study in patients with relapsed or refractory multiple myeloma were selected for oral and poster presentations at ASH (Free ASH Whitepaper) 2018. The oral presentation highlighted updated data from the arm evaluating selinexor in combination with Darzalex (daratumumab) and low-dose dexamethasone (SDd). In this arm, the combination demonstrated an ORR of 79% in patients with heavily pretreated, Darzalex-naïve multiple myeloma and an ORR of 73% in the overall study population. The poster presentation described updated data from the arm evaluating selinexor in combination with Pomalyst (pomalidomide) and low-dose dexamethasone (SPd). In this arm, the combination demonstrated an ORR of 54% in patients with Pomalyst-naïve and Revlimid-relapsed or -refractory multiple myeloma, with PFS of 12.2 months. The combination demonstrated an ORR of 50% in the overall study population. Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most manageable with dose modifications and/or standard supportive care.
Pivotal Phase 3 BOSTON Study in Progress. Karyopharm’s pivotal, randomized Phase 3 BOSTON study is progressing and in January 2019, the Company announced the completion of enrollment in the study. Top-line data is expected at the earliest by the end of 2019 or into 2020 contingent upon the occurrence of PFS events, the primary endpoint in the study. The BOSTON study is evaluating 100mg of selinexor dosed once weekly in combination with the proteasome inhibitor Velcade (once weekly) and low dose dexamethasone (SVd), compared to standard twice weekly Velcade and low dose dexamethasone (Vd) in patients with multiple myeloma who have had one to three prior lines of therapy. Data from the BOSTON study, if positive, would be used to support regulatory submissions to the FDA and EMA requesting the use of selinexor in second line multiple myeloma, and confirming the Company’s requests for accelerated and conditional approvals, respectively, using data from the Phase 2b STORM study.
Selinexor in Diffuse Large B-Cell Lymphoma (DLBCL)
Received Fast Track Designation from FDA for the Treatment of Patients with Relapsed or Refractory DLBCL. In addition to Orphan Drug Designation, selinexor was recently granted Fast Track designation by the FDA for the treatment of patients with diffuse large B-cell lymphoma (DLBCL) who have received at least two prior therapies and are not eligible for high dose chemotherapy with stem cell rescue or CAR-T therapy.
Top-Line Phase 2b SADAL Data in DLBCL Presented at ASH (Free ASH Whitepaper) 2018. Top-line results from the fully enrolled Phase 2b SADAL study was presented at ASH (Free ASH Whitepaper) 2018. The SADAL study is designed to evaluate single agent oral selinexor 60mg for patients with relapsed or refractory DLBCL who are not eligible for stem cell transplantation. Based on the modified intention-to-treat analysis from the first 115 of 127 patients, as adjudicated by an independent central radiological committee, selinexor achieved an ORR of 29.6%. The median DOR across responding patients was 9.2 months. Patients with a complete response (CR) had a median DOR of 23.0 months and patients with a PR had a median DOR of 7.8 months. The median OS was 9.1 months for all patients in the study. As of the data cutoff date, median survival for the patients with a CR or PR was 29.7 months. The median survival for patients with best response of progressive disease or who were not evaluable for response was 3.2 months. Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were gastrointestinal and constitutional symptoms, along with cytopenias; most AEs were manageable with dose modifications and/or supportive care. Based on the results from the Phase 2b SADAL study, Karyopharm plans to submit an NDA to the FDA with a request for accelerated approval for oral selinexor in this relapsed or refractory DLBCL patient population and the Company is working closely with the FDA to determine the appropriate timeline. Karyopharm is also planning to submit a MAA to the EMA with a request for conditional approval in the same indication.
Selinexor in Solid Tumors
Ongoing Phase 3 Portion of the Phase 2/3 SEAL Study in Liposarcoma. Karyopharm previously reported results from the successful Phase 2 portion of the blinded, randomized Phase 2/3 SEAL study evaluating single-agent selinexor versus placebo in patients with previously treated, advanced unresectable dedifferentiated liposarcoma. Enrollment and dosing are currently ongoing in the Phase 3 portion of the SEAL study and, assuming a positive outcome on the primary end point of PFS, the Company intends to use the data from the SEAL study to support a NDA and a MAA submission requesting approval for oral selinexor for patients with advanced unresectable dedifferentiated liposarcoma. Top-line data from the Phase 3 portion of the SEAL study are anticipated in 2020.
Ongoing Investigator Sponsored Phase 2/3 Trial as Maintenance Therapy in Endometrial Cancer. A randomized Phase 2/3 study of selinexor versus placebo as maintenance therapy in patients with one or two prior platinum-based treatments for advanced endometrial cancer, led by Dr. Ignace Vergote, Head of the Department of Obstetrics and Gynaecology and Gynaecologic Oncology at the Catholic University of Leuven, Belgium, is currently ongoing. Top-line data from this study are anticipated in 2020.
Corporate Updates
Michael P. Mason Appointed Chief Financial Officer. Karyopharm announced the appointment of Michael P. Mason as Chief Financial Officer. Mr. Mason formerly served as Vice President of Finance and Treasurer at Alnylam Pharmaceuticals, Inc., a public biopharmaceutical company. He brings over 18 years of diversified financial experience to Karyopharm and has deep expertise in global financial operations and controls, financing transactions, business planning and supporting pharmaceutical product launches.
Full Year and Fourth Quarter 2018 Financial Results
Cash, cash equivalents and investments as of December 31, 2018, including restricted cash, totaled $330.9 million, compared to $176.4 million as of December 31, 2017.
On October 26, 2018, Karyopharm completed a private offering of $172.5 million aggregate principal amount of 3.00% convertible senior notes due in 2025, including the full exercise of the initial purchasers’ option to purchase additional notes. After deducting the initial purchasers’ discounts and commissions and other offering expenses the net proceeds were $166.9 million.
License and other revenue for the year ended December 31, 2018 was $30.3 million, compared to $1.6 million for the year ended December 31, 2017, primarily related to the Company’s license agreements with Biogen and ONO.
For the year ended December 31, 2018, research and development expense was $161.4 million compared to $107.3 million for the year ended December 31, 2017. For the year ended December 31, 2018, general and administrative expense was $48.8 million compared to $24.9 million for the year ended December 31, 2017.
Karyopharm reported a net loss of $178.4 million, or $3.14 per share, for the year ended December 31, 2018, compared to a net loss of $129.0 million, or $2.81 per share, for the year ended December 31, 2017. Net loss includes stock-based compensation expense of $17.3 million and $20.4 million for the years ended December 31, 2018 and December 31, 2017, respectively.
For the quarter ended December 31, 2018, research and development expense was $38.9 million, compared to $34.8 million for the quarter ended December 31, 2017. For the quarter ended December 31, 2018, general and administrative expense $18.8 million, compared to $6.2 million for the quarter ended December 31, 2017.
Karyopharm reported a net loss of $58.2 million, or $0.96 per share for the quarter ended December 31, 2018, compared to a net loss of $39.0 million, or $0.80 per share for the quarter ended December 31, 2017. Net loss includes stock-based compensation expense of $3.9 million and $4.5 million for the quarters ended December 31, 2018 and December 31, 2017, respectively.
Financial Outlook
Based on its current operating plans, Karyopharm expects that its existing cash, cash equivalents and investments will be sufficient to fund its operations into the second half of 2020, which currently assumes the commercial launch of selinexor in the U.S. in the second quarter of 2019. If the FDA decides to delay its approval decision for selinexor until the BOSTON data is available, Karyopharm will re-evaluate its spending expectations for 2019. Additional key activities expected in 2019 include supporting the ongoing multiple myeloma regulatory filings for selinexor in the U.S. and Europe, progressing the pivotal Phase 3 BOSTON study in multiple myeloma and potentially submitting an NDA and MAA, in the U.S. and Europe, respectively, in DLBCL.
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. 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.
Conference Call Information
Karyopharm will host a conference call today, Thursday, February 28, 2019, at 8:30 a.m. Eastern Time, to discuss the fourth quarter and full year 2018 financial results, recent accomplishments, clinical developments and business plans. To access the conference call, please dial (855) 437-4406 (local) or (484) 756-4292 (international) at least 10 minutes prior to the start time and refer to conference ID 4246798. A live audio webcast of the call will be available under "Events & Presentations" in the Investor section of the Company’s website, View Source An archived webcast will be available on the Company’s website approximately two hours after the event.