• XPOVIO is the First and Only Nuclear Export Inhibitor Approved by the FDA
• XPOVIO is the First and Only Prescription Medicine Approved by the FDA for the Treatment of Patients with Multiple Myeloma whose Disease is Refractory to Proteasome Inhibitors, Immunomodulatory Agents, and an Anti-CD38 Monoclonal Antibody
• Karyopharm to Hold an Investor Conference Call and Webcast at 1:30 PM ET Today

Newton, MA (Press Release) – Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an on­col­ogy-focused pharma­ceu­tical com­pany, today announced that the U.S. Food and Drug Admin­istra­tion (FDA) has approved oral XPOVIOTM (selinexor), a nuclear export inhibitor, in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of adult patients with re­lapsed or 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. This indi­ca­tion is approved under accelerated approval based on response rate. Continued approval for this indi­ca­tion may be contingent upon veri­fi­ca­tion and description of clin­i­cal benefit in a con­firmatory trial. The ongoing, ran­dom­ized Phase 3 BOSTON study eval­u­ating selinexor in com­bi­na­tion with Velcade® (bor­tez­o­mib) and low-dose dexa­meth­a­sone will serve as the con­firmatory trial. The FDA’s Accelerated Approval Program was devel­oped to allow for expedited approval of drugs that treat serious con­di­tions and that fill an unmet medical need.

Karyopharm ex­pec­ts XPOVIO to be­come commercially avail­able in the U.S. on or before July 10, 2019. A Marketing Authorization Application for selinexor is also cur­rently under review by the European Medicines Agency.

“With today’s accelerated approval of XPOVIO by the FDA, patients with heavily pre­treated multiple myeloma will now have a new thera­peutic option to treat their disease,” said Sharon Shacham, PhD, MBA, Founder, Pres­i­dent and Chief Scientific Officer of Karyopharm. “Discovering, devel­op­ing and securing FDA approval for XPOVIO with its novel mech­a­nism of action over the past decade required the dedication of many people, in­clud­ing the patients, care­givers and physicians involved in our clin­i­cal trials, along with the many employees at Karyopharm. We are tremendously grateful for everyone’s con­tri­bu­tions to this im­por­tant mile­stone, and we look for­ward to the next stage in our pursuit of im­prov­ing the lives of patients with cancer.”

“The 25.3% response rate seen in the subgroup of 83 patients in the pivotal Phase 2b STORM study that served as the basis for XPOVIO's accelerated approval is clin­i­cally meaningful and a val­i­dated surrogate marker for clin­i­cal benefit in our patients with ad­vanced refractory disease,” said Sundar Jagannath, MD, Director of the Multiple Myeloma Program, Pro­fessor of Medicine (Hematology and Medical Oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine, and prin­ci­pal investigator of the STORM study.

“Despite recent ad­vances in the treat­ment of multiple myeloma, almost all our patients will develop disease that is resistant to the five most commonly used anti-myeloma drugs we cur­rently have avail­able, and the prognosis for this patient pop­u­la­tion is particularly poor. The accelerated approval of oral XPOVIO marks an im­por­tant ad­vance in the treat­ment paradigm for patients with re­lapsed refractory multiple myeloma, and in my view, is an im­por­tant addi­tion to our thera­peutic armamentarium,” said Dr. Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute.

Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm, commented, “Having worked on novel drugs in myeloma beginning with Velcade in the year 2000, I have been thrilled to see such exciting progress over­all in the field where there are sub­stan­tial in­creases in patients’ duration and quality of life. The accelerated approval of oral XPOVIO targeting XPO1 rep­re­sents the first approval against a new target in myeloma since 2015, and we look for­ward to ad­vanc­ing the further clin­i­cal devel­op­ment of XPOVIO.”

About the Phase 2b STORM Pivotal Trial

The accelerated FDA approval of XPOVIO is based on results from the Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) trial, which was a multi­center, single-arm, open-label study of patients with RRMM. STORM Part 2 in­cluded 122 patients with RRMM who had pre­vi­ously received three or more anti-myeloma treat­ment regi­mens in­clud­ing an alkylating agent, glucocorticoids, bor­tez­o­mib, car­filz­o­mib, lena­lido­mide, poma­lido­mide, and an anti-CD38 mono­clonal anti­body; and whose myeloma was documented to be refractory to glucocorticoids, a pro­te­a­some inhibitor, an immuno­modu­la­tory agent, an anti-CD38 mono­clonal anti­body, and to the last line of ther­apy.

In STORM Part 2, a total of 122 patients were treated with XPOVIO (80 mg) in com­bi­na­tion with dexa­meth­a­sone (20 mg) on Days 1 and 3 of every week. Eighty-three patients had RRMM that was documented to be refractory to bor­tez­o­mib, car­filz­o­mib, lena­lido­mide, poma­lido­mide, and dara­tu­mu­mab. Treatment con­tinued until disease pro­gres­sion, death, or unacceptable toxicity.

The major efficacy out­come measure was over­all response rate (ORR), as assessed by an Independent Review Committee based on the Inter­na­tional Myeloma Work­ing Group (IMWG) Uniform Response Criteria for Multiple Myeloma. The approval of XPOVIO was based upon the efficacy and safety in a prespecified subgroup analysis of the 83 patients whose disease was refractory to bor­tez­o­mib, car­filz­o­mib, lena­lido­mide, poma­lido­mide, and dara­tu­mu­mab, as the benefit-risk ratio appeared to be greater in this more heavily pre­treated pop­u­la­tion than in the over­all trial pop­u­la­tion.

For the STORM Part 2 study’s major efficacy out­come measure, the ORR was 25.3% in the subgroup of 83 patients, which in­cluded one stringent com­plete response, no com­plete responses, four very good partial responses and 16 partial responses. The median time to first response for these patients was 4 weeks and the median duration of response was 3.8 months.

Amongst the 202 patients enrolled in STORM Parts 1 and 2 who were treated with XPOVIO (80 mg) in com­bi­na­tion with dexa­meth­a­sone (20 mg) on days 1 and 3 weekly, the most common adverse reac­tions (incidence ≥20%) were thrombo­cyto­penia, fatigue, nausea, anemia, de­creased appetite, de­creased weight, diarrhea, vomiting, hyponatremia, neu­tro­penia, leu­ko­penia, con­sti­pa­tion, dyspnea, and upper res­pira­tory tract in­fec­tions. 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%.

The full Prescribing Information for XPOVIO will be made avail­able at www.XPOVIO.com.

Conference Call/Webcast at 1:30 PM ET (10:30 AM PT) Today

Karyopharm's man­agement team will host an in­vestor conference call and audio webcast at 1:30 p.m. ET on Wednesday, July 3, 2019 to discuss the FDA’s accelerated approval of XPOVIO.

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 1867439. A live audio webcast of the call will be avail­able under "Events & Presentations" in the Investor section of the Company's website, http://investors.karyopharm.com/events-presentations. An archived webcast will be avail­able on the Company's website approx­i­mately two hours after the event.

About Multiple Myeloma

According to the National Cancer Institute (NCI), multiple myeloma is the second most common cancer of the blood in the U.S. with more than 32,000 new cases each year and over 130,000 patients living with the disease. Despite recent thera­peutic ad­vances, there is cur­rently no cure and most patients’ disease will typically progress fol­low­ing treat­ment with cur­rently avail­able ther­a­pies. According to the NCI, nearly 13,000 deaths due to multiple myeloma are ex­pec­ted in the U.S. in 2019.

About XPOVIOTM (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. In addi­tion to receiving accelerated 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. Selinexor is also being studied in patients with re­lapsed or refractory diffuse large B-cell lym­phoma (DLBCL). In 2018, Karyopharm reported pos­i­tive top-line results from the Phase 2b SADAL study eval­u­ating selinexor in patients with re­lapsed or refractory DLBCL after at least two prior multi-agent ther­a­pies and who are in­eli­gible for trans­plan­ta­tion, in­clud­ing high dose chemo­ther­apy with stem cell rescue. Selinexor has received Fast Track desig­na­tion from the FDA for the patient pop­u­la­tion eval­u­ated in the SADAL study. 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), as a poten­tial back­bone ther­apy in com­bi­na­tion with approved ther­a­pies (STOMP), in liposarcoma (SEAL), in recurrent gliomas (KING) 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.

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 which will be made 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 SINE com­pounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). Karyopharm’s lead com­pound, XPOVIOTM (selinexor), received accelerated approval from the 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 (EMA). 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 our ex­pec­ta­tions relating to XPOVIO for the treat­ment of patients with RRMM, com­mer­cial­iza­tion of XPOVIO or any of our drug can­di­dates, sub­missions to, and the review and poten­tial approval of selinexor by, regu­la­tory author­i­ties, in­clud­ing the antic­i­pated timing of such sub­missions and actions and the poten­tial avail­a­bil­ity of accelerated approval path­ways, and the thera­peutic poten­tial of and poten­tial clin­i­cal devel­op­ment plans for Karyopharm's drug can­di­dates, especially selinexor. 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 regulators will agree that selinexor qualifies for con­di­tional approval in the E.U. as a result of our clin­i­cal data, in­clud­ing the data from the STORM study or accelerated approval in the U.S. based on the SADAL study in patients with re­lapsed or refractory DLBCL, or that any of Karyopharm's drug can­di­dates, in­clud­ing selinexor, will suc­cess­fully com­plete nec­es­sary clin­i­cal devel­op­ment phases or that devel­op­ment of any of Karyopharm's drug can­di­dates will con­tinue. Further, there can be no guar­an­tee that any pos­i­tive devel­op­ments in 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 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; 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 diseases 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 Quarterly Report on Form 10-Q for the quarter ended March 31, 2019, which was filed with the Se­cu­ri­ties and Exchange Com­mis­sion (SEC) on May 9, 2019, 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.