Karyopharm Announces Selinexor Clinical Data to be Presented at the International Society for Influenza and Other Respiratory Virus Diseases Antiviral Group Virtual Conference on Therapeutics for COVID-19
NEWTON, Mass., Oct. 6, 2020 /PRNewswire/ -- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced an oral presentation at the International Society for Influenza and Other Respiratory Virus Diseases Antiviral Group (ISIRV-AVG) Virtual Conference on Therapeutics for COVID-19 taking place from October 6 - 8, 2020. The presentation will feature data from a Phase 2 clinical study evaluating low dose oral selinexor in hospitalized patients with severe COVID-19 (NCT04349098).
While an interim analysis indicated that the trial was unlikely to meet its pre-specified primary endpoint across the entire patient population studied, and has since been discontinued, the results demonstrated encouraging anti-viral and anti-inflammatory activity in an important subset of treated patients. The randomized, multi-center, placebo-controlled Phase 2 study was designed to assess the activity and safety of 20mg of selinexor given orally three times a week for two weeks, a dosing level significantly lower than the U.S. Food and Drug Administration (FDA) approved dose of selinexor, marketed as XPOVIO®, to treat patients with relapsed or refractory multiple myeloma or relapsed or refractory diffuse large B-cell lymphoma.
A post-hoc analysis of 66 patients with either baseline serum lactate dehydrogenase (LDH) ≤370 U/L or D-dimer ≤600 mcg/L FEU (Low LDH/DD) showed that treatment with selinexor (n=38) compared to placebo (n=28) was associated with a significantly higher percentage of patients discharged by Day 14 (78.9% vs 57.1%; p=0.029) with a trend towards superior ≥2-point improvement in the Ordinal Scale (OSI-2) on Day 14 (78.9% vs 64.3%; p=0.095). Additionally, a positive trend was observed in patients treated with selinexor to convert to a negative COVID-19 PCR test as compared to placebo (42.1% vs 28.6%; p=0.13) and a significant reduction in IL1-RA, IL-6, IL-7, IP-10, and TNF-a levels, measurements of inflammation, was also seen within eight days of selinexor treatment (p<0.05). Adverse events occurred in 63.2% of patients treated with selinexor and 51.9% of patients with placebo in the subset, with similar occurrences of deaths across the treatment arms (2 vs. 1). Blood levels of LDH and D-dimer are important prognostic markers for in-hospital mortality in patients admitted for COVID-19.
"We are encouraged by the promising results observed following low dose oral administration of selinexor in hospitalized patients with severe COVID-19 and Low LDH/DD and believe they warrant the need for additional clinical studies. Additionally, we believe non-hospitalized patients with moderate COVID-19 may also benefit from this treatment regimen and should be considered for future evaluation," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "We plan to continue ongoing discussions with potential clinical development partners, including U.S. and international government and academic organizations advancing COVID-19 clinical studies, to further evaluate selinexor in patients with COVID-19."
In addition to data from the Phase 2 selinexor study being presented at the ISIRV-AVG Conference, a case report from one of the clinical investigators in this trial has been published in the Annals of Case Reports and can be found online, here. In this case report, Marcelo Gareca, MD, an Infectious Disease specialist at Lehigh Valley Hospital, Allentown, PA, provides details of a patient with severe COVID-19 and progressive hypoxia who demonstrated marked clinical improvements following selinexor treatment without any reported adverse effects.
XPO1 inhibitors, including selinexor, have demonstrated activity against over 20 different viruses, including the RNA viruses, influenza, respiratory syncytial virus (RSV) and other common causes of respiratory infection. XPO1 inhibition has been identified in several assays as having potential activity specifically against SARS-CoV-2. One of the most important aspects of COVID-19 is the marked pulmonary inflammation with high levels of cytokines such as IL6, IL1, IFNg and others. Selinexor and other Selective Inhibitor of Nuclear Export (SINE) compounds have demonstrated potent anti-inflammatory activity through the inhibition of Nuclear Factor kB (NF-kB), leading to reductions in all of these cytokines in a variety of models, which may be particularly beneficial to hospitalized patients with COVID-19.
Details for the ISIRV-AVG oral presentation are as follows:
Title: Treatment of Severe COVID-19 with Low-Dose Selinexor: Demonstration of Anti-Viral and Anti-Inflammatory Activities in a Randomized, International, Multicenter, Placebo-Controlled Phase 2 Clinical Trial
About XPOVIO® (selinexor)
IMPORTANT SAFETY INFORMATION
Thrombocytopenia: XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma (MM) and developed or worsened in patients with DLBCL.
Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 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, reduce dose, or permanently discontinue based on severity of adverse reaction.
Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection. Neutropenia and febrile neutropenia occurred in patients with MM and in patients with DLBCL.
Obtain white blood cell counts with differential at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction (AR).
Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients with MM and DLBCL.
Nausea/Vomiting: Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonists and other anti-nausea agents prior to and during treatment with XPOVIO. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.
Diarrhea: Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide standard anti-diarrheal agents, administer intravenous fluids to prevent dehydration, and replace electrolytes as clinically indicated.
Anorexia/Weight Loss: Monitor weight, nutritional status, and volume status at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide nutritional support, fluids, and electrolyte repletion as clinically indicated.
Hyponatremia: XPOVIO can cause severe or life-threatening hyponatremia. Hyponatremia developed in patients with MM and in patients with DLBCL.
Monitor sodium level at baseline and throughout treatment. Monitor more frequently during the first 2 months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Assess hydration status and manage hyponatremia per clinical guidelines, including intravenous saline and/or salt tablets as appropriate and dietary review. Interrupt, reduce dose, or permanently discontinue based on severity of the AR.
Serious Infection: XPOVIO can cause serious and fatal infections. Most infections were not associated with Grade 3 or higher neutropenia. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.
Monitor for signs and symptoms of infection, and evaluate and treat promptly.
Neurological Toxicity: XPOVIO can cause life-threatening neurological toxicities.
Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.
Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.
Embryo-Fetal Toxicity: XPOVIO can cause fetal harm when administered to a pregnant woman.
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 ARs, excluding laboratory abnormalities, in ≥20% of patients with DLBCL are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities in ≥15% of patients included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopenia, lymphopenia, and neutropenia.
In patients with MM, fatal ARs occurred in 9% of patients. Serious ARs occurred in 58% of patients. Treatment discontinuation rate due to ARs was 27%. The most frequent ARs requiring permanent discontinuation in ≥4% of patients included fatigue, nausea, and thrombocytopenia.
In patients with DLBCL, fatal ARs occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal AR was infection (4.5% of patients). Serious ARs occurred in 46% of patients; the most frequent serious AR was infection. Discontinuation due to ARs occurred in 17% of patients.
USE IN SPECIFIC POPULATIONS
Clinical studies in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see XPOVIO Full Prescribing Information available at www.XPOVIO.com.
About Karyopharm Therapeutics
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SOURCE Karyopharm Therapeutics Inc.
Company Codes: NASDAQ-NMS:KPTI