Newton, MA (Press Release) – Karyo­pharm Thera­peutics Inc. (Nasdaq:KPTI), an inno­va­tion-driven pharma­ceu­tical com­pany, to­day an­nounced it has sub­mitted a supple­mental New Drug Appli­ca­tion (sNDA) to the U.S. Food and Drug Admin­istra­tion (FDA) seek­ing ap­prov­al for XPOVIO® (seli­nexor), its first-in-class, oral Sel­ective Inhibitor of Nuclear Export (SINE) com­pound, as a new treat­ment for pa­tients with pre­vi­ously treated mul­ti­ple myeloma.

“Earlier this year, we reported pos­i­tive top-line results from the pivotal Phase 3 BOSTON study eval­u­ating the com­bi­na­tion of XPOVIO (seli­nexor), once-weekly Velcade® (bor­tez­o­mib) and low-dose dexa­meth­a­sone (SVd) as a sec­ond line treat­ment for patients with re­lapsed or re­frac­tory mul­ti­ple myeloma,” said Sharon Shacham, PhD, MBA, Founder, Pres­i­dent and Chief Scientific Officer of Karyo­pharm. “The full study results, which were in­cluded in the sNDA, will be pre­sented on May 29, 2020 at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. In the BOSTON study, the SVd arm dem­onstrated a statistically sig­nif­i­cant re­duc­tion in the risk of dis­ease pro­gres­sion or death, along with a 47% in­crease in median pro­gres­sion-free sur­vival, as well as a sig­nif­i­cantly higher over­all re­sponse rate, as com­pared to the standard Velcade and dexa­meth­a­sone (Vd) regi­men. If approved, we be­lieve XPOVIO could be­come an im­por­tant addi­tion to the treat­ment par­a­digm for patients with re­lapsed or re­frac­tory mul­ti­ple myeloma, and we look for­ward to work­ing with the FDA during the review process.”

Karyopharm also plans to submit a Marketing Authori­za­tion Appli­ca­tion to the Euro­pean Medicines Agency re­quest­ing ap­prov­al for XPOVIO in this same in­di­ca­tion later this year. The abstract for the Phase 3 BOSTON clin­i­cal data to be pre­sented at the 2020 ASCO annual meeting and can be found on ASCO’s website, here.

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 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. In May 2020, Karyo­pharm sub­mitted a supple­mental New Drug Appli­ca­tion based on the data from BOSTON. 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.

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 inno­va­tion driven 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 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 beliefs re­gard­ing XPOVIO’s ability to treat patients with re­lapsed or re­frac­tory mul­ti­ple myeloma and ex­pec­ta­tions related to other XPOVIO regu­la­tory sub­missions. 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 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 XPOVIO in the com­mer­cial mar­ket­place, the timing and costs in­volved in com­mer­cializing XPOVIO or any of Karyo­pharm’s drug can­di­dates that re­ceive regu­la­tory ap­prov­al; the ability to retain regu­la­tory ap­prov­al of XPOVIO 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 Quar­ter­ly Report on Form 10-Q for the quarter ended March 31, 2020, which was filed with the Se­cu­ri­ties and Ex­change Com­mis­sion (SEC) on May 5, 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.

Source: Karyo­pharm Thera­peutics.