Newton, MA (Press Release) – Karyo­pharm Thera­peutics Inc. (Nasdaq: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 cur­rent approved at higher doses by the FDA as a treat­ment for patients with re­lapsed or re­frac­tory multiple myeloma. Selinexor is cur­rent 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 cur­rent 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:

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

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.

Neutropenia

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 Toxicity

Gastrointestinal toxicities oc­curred in patients treated with XPOVIO.

Nausea / Vomiting

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

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 / Weight Loss

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.

Hyponatremia

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.

Infections

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 Toxicity

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.

Embryo-Fetal Toxicity

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.

ADVERSE REACTIONS

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.

About Karyo­pharm Thera­peutics

Karyopharm Thera­peutics Inc. (Nasdaq: 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 cur­rent 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.

Forward-Looking State­ments

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 cur­rent 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 cur­rent 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.

Velcade® is a registered trademark of Takeda Pharma­ceu­tical Com­pany Limited.

References

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

Source: Karyo­pharm.