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NEWTON, Mass., April 20, 2020 (GLOBE NEWSWIRE) -- Karyopharm Therapeutics Inc. (KPTI) today announced dosing of the first patient in a randomized Phase 2 clinical study evaluating low dose oral selinexor in hospitalized patients with severe COVID-19. This global study is expected to enroll approximately 230 patients at clinical sites in the U.S., Europe, and Israel. Selinexor is an oral selective inhibitor of nuclear export (SINE) compound which blocks the cellular protein XPO1 which is involved in both the replication of SARS-CoV-2, the virus that causes COVID-19, and in the inflammatory response to the virus.
The randomized, multi-center, placebo-controlled Phase 2 study (XPORT-CoV-1001/NCT04349098) of low dose selinexor is designed to assess the activity and safety of 20mg of selinexor given orally three times a week for two weeks. Patients tolerating therapy well and experiencing clinical benefit may be eligible to continue treatment for an additional two weeks at the discretion of the treating physician. The primary endpoint of the study is time to clinical improvement based on improvement in the Ordinal Scale, consistent with the COVID-19 trial recommendations by the World Health Organization and the U.S. Food and Drug Administration (FDA). Additional secondary endpoints in the study include the overall death rate at day 28 as well as the rate of, and time to, mechanical ventilation.
“In less than two weeks since announcing our intention to study selinexor in patients with severe COVID-19, we have quickly mobilized our team to activate clinical trial sites across the globe and are proud to announce the dosing of the first patient in our randomized study,” said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. “This important milestone marks the first study of an XPO1 inhibitor in patients with severe viral infections. We remain highly encouraged by the potential anti-viral and anti-inflammatory activity of XPO1 inhibition with selinexor and look forward to working with the medical community of regulators, treating physicians and patients on advancing this important study as quickly as possible.”
SINE compounds have been identified as having the potential to interfere with key host protein interactions with influenza, RSV and other viruses including SARS-CoV-2.1 Furthermore, XPO1 (also called CRM1) was identified as one of the host proteins with the highest number of functional connections with SARS-CoV proteins.2 Finally, SINE compounds, including selinexor, have demonstrated potent anti-inflammatory activity through the inhibition of Nuclear Factor kB (NF-kB), leading to reductions in cytokines such as IL6, IL1, IFNg and others in a variety of models, which may be particularly beneficial to hospitalized patients with COVID-19 and other severe viral infections.
“In my laboratory, we have now used two different approaches to investigate selinexor’s ability to inhibit the viral propagation of the SARS-CoV-2 virus in Vero cells, which are monkey cells commonly used in modeling human viral infections. In our first experiment, with the assistance of Jackelyn Murray in my lab, we demonstrated that selinexor inhibited the production of new virus by 90% at a low concentration (100 nM) from cells that were already infected with SARS-CoV2. This is very exciting as low oral doses of selinexor are expected to deliver levels over 300 nM. In the second experiment, we showed that even lower levels of selinexor, only 10nM, could reduce the ability of the virus to infect new cells by about 99%. I am highly encouraged by these results and thrilled to see how quickly Karyopharm is able to test these scientific findings in patients so dramatically impacted by the current COVID-19 pandemic,” said Ralph Tripp, PhD, a Georgia Research Alliance Eminent Scholar and Professor in the Department of Infectious Diseases in the College of Veterinary Medicine at the University of Georgia.”
Selinexor, marketed as XPOVIO®, is currently approved at higher doses by the FDA as a treatment for patients with relapsed or refractory multiple myeloma. Selinexor is currently the only XPO1 inhibitor approved for commercial use by the FDA and has been extensively tested in clinical trials across numerous cancer indications worldwide since 2012. Karyopharm has sufficient supply of selinexor for current and expected commercial patients with multiple myeloma, for ongoing clinical trials in patients with various cancers, as well as for this study in patients with COVID-19.
About XPOVIO® (selinexor)
XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory 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, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. A supplemental New Drug Application was recently accepted by the FDA seeking accelerated approval for selinexor as a new treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and selinexor has received Fast Track and Orphan designation and Priority Review from the FDA with a scheduled PDUFA date of June 23, 2020 for this patient population. 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), for which Karyopharm announced positive top-line results in March 2020. Additional, ongoing trials for selinexor include as a potential backbone therapy in combination with approved myeloma therapies (STOMP), in liposarcoma (SEAL) and 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.
For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:
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IMPORTANT SAFETY INFORMATION
XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.
Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.
XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.
Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.
Gastrointestinal toxicities occurred in patients treated with XPOVIO.
Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.
Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.
Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.
Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.
Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.
Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.
Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.
Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.
XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.
Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.
In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.
Neurological toxicities occurred in patients treated with XPOVIO.
Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.
Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.
Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.
The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.
The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.
Please see XPOVIO Full Prescribing Information available at www.XPOVIO.com.
1 Gordon, D. et al. A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing. bioRxiv. 2020. 03.22.002386. https://doi.org/10.1101/2020.03.22.002386
2 Zhou, Y. et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020. 6:14. https://doi.org/10.1038/s41421-020-0153-3
About Karyopharm Therapeutics
Karyopharm Therapeutics Inc. (KPTI) is an oncology-focused pharmaceutical company dedicated to the discovery, development, and commercialization of novel first-in-class drugs directed against nuclear export and related targets for the treatment of cancer and other major diseases. Karyopharm's Selective Inhibitor of Nuclear Export (SINE) compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). Karyopharm’s lead compound, XPOVIO® (selinexor), received accelerated approval from the U.S. Food and Drug Administration (FDA) in July 2019 in combination with dexamethasone as a treatment for patients with heavily pretreated multiple myeloma. A Marketing Authorization Application for selinexor is also currently under review by the European Medicines Agency. A supplemental New Drug Application was recently accepted by the FDA seeking accelerated approval for selinexor as a new treatment for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm has several investigational programs in clinical or preclinical development. For more information, please visit www.karyopharm.com.
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Karyopharm’s expectations and plans relating to selinexor as a potential treatment for hospitalized patients with severe COVID-19; the design and execution of a global randomized clinical trial to study this potential application of selinexor, including the dosing regimen; the potential anti-viral and anti-inflammatory properties of selinexor; submissions to, and the review and potential approval of selinexor in this indication by, regulatory authorities, including the anticipated availability of data to support such submissions, timing of such submissions and actions by regulatory authorities and the potential availability of accelerated approval pathways; the sufficiency of selinexor supply for commercial demand and clinical trial use; and the therapeutic potential of and potential clinical development plans for Karyopharm’s drug candidates, including the impact of a selinexor clinical trial on the timing or prioritization of other key company milestones, such as its expected submission of a supplemental new drug application in the second quarter of 2020 for XPOVIO in combination with once-weekly Velcade® and low dose dexamethasone. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully complete necessary clinical development phases of selinexor in this indication; that data from a clinical trial of selinexor would support its use in treatment of hospitalized patients with severe COVID-19; that regulators will approve the use of selinexor in hospitalized patients with severe COVID-19, or that such approval will be made on an accelerated timeline. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm’s drug candidate portfolio will result in stock price appreciation. Management’s expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the risk that the COVID-19 pandemic could disrupt Karyopharm’s business more severely than it currently anticipates, including by reducing sales of XPOVIO, interrupting or delaying research and development efforts, impacting the ability to procure sufficient supply for the development and commercialization of selinexor or other product candidates, delaying ongoing or planned clinical trials, impeding the execution of business plans, planned regulatory milestones and timelines, or inconveniencing patients; the adoption of selinexor for treatment of COVID-19 in the commercial marketplace, the timing and costs involved in commercializing selinexor for such indication or any of Karyopharm’s drug candidates that receive regulatory approval; the ability to retain regulatory approval of selinexor for such indication or any of Karyopharm’s drug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to obtain and maintain requisite regulatory approvals and to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development of drug candidates by Karyopharm’s competitors for indications in which Karyopharm is currently developing its drug candidates; and Karyopharm’s ability to obtain, maintain and enforce patent and other intellectual property protection for any drug candidates it is developing. These and other risks are described under the caption "Risk Factors" in Karyopharm’s Annual Report on Form 10-K for the year ended December 31, 2019, which was filed with the Securities and Exchange Commission (SEC) on February 26, 2020, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.
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