Karyopharm Announces Clinical Trial Collaboration With Bristol Myers Squibb

Karyopharm Therapeutics Inc. recently announced it has entered into a clinical trial collaboration and supply agreement with Bristol-Myers Squibb to evaluate the company’s proprietary investigational cereblon E3 ligase modulator (CELMoD) agent mezigdomide in combination with Karyopharm’s selinexor, an approved first-in-class inhibitor of Exportin 1 (XPO1), plus dexamethasone in patients with relapsed/refractory multiple myeloma.

This trial will evaluate mezigdomide in combination with selinexor doses of either 40 mg or 60 mg plus dexamethasone in patients who have prior exposure to immunomodulatory (IMiD) drug agents , proteasome inhibitors, and anti-CD38 monoclonal antibody treatment. All patients must have received at least two prior lines of therapy, and either have progressed after or are not eligible to receive CAR-T or bispecific antibody treatment.

“This is an important collaboration with Bristol Myers Squibb to explore this novel and entirely oral combination in patients who have progressed following T-cell engaging therapy. This trial will also evaluate mezigdomide-selinexor plus dexamethasone in patients with relapsed/refractory multiple myeloma who need an effective alternative to T-cell therapies, said Richard Paulson, MBA, President and Chief Executive Officer of Karyopharm. “Preclinical studies with selinexor and mezigdomide post T-cell mediated therapies provide a  scientific rationale for this novel combination to potentially prevent/reverse T-cell exhaustion and improve outcomes for more of these patients. We look forward to initiating the trial in the first half of 2024.”

“Despite multiple treatment advances, there is a growing need for new combinations, particularly those that are all-oral, accessible and that have novel mechanisms to help treat patients with relapsed and refractory multiple myeloma,” said Paul Richardson, MD, the RJ Corman Professor of Medicine, Dana Farber Cancer Institute, and senior investigator of the study. “Pre-clinical data suggests the combination of a selective inhibitor of nuclear export (SINE), such as selinexor, with potent cereblon E3 ligase modulators , such as mezigdomide, may spare T-cell function while showing potential activity against resistant myeloma. This particular combination represents an innovative and promising approach to treating relapsed and refractory multiple myeloma with the convenience of an all-oral approach. We look forward to learning more about its potential in triple-class exposed patients, as well as in those who’ve experienced [anti-]BCMA and T-cell directed treatment failure.”

The primary endpoints of this trial are to assess the objective response rate (ORR) and the clinical benefit rate (CBR). Key secondary endpoints include progression-free survival (PFS), overall survival (OS) and duration of response (DOR). In addition, the trial will evaluate dynamic changes in T-cell populations and activity as patients undergo treatment. Under the terms of the agreement with Bristol Myers Squibb, Karyopharm will sponsor the trial as a new arm of Karyopharm’s Phase 1b/2 STOMP trial and Bristol Myers Squibb will supply the study’s clinical drug mezigdomide.

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO in certain countries) has received regulatory approvals in various indications in a growing number of ex-US territories and countries, including but not limited to the EU, the UK, China, South Korea, Canada, Israel, and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS, in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

Cereblon E3 ligase modulators (CELMoD) are a class of oral immunomodulatory therapeutics that are designed to stimulate the immune system and directly kill cancer cells by inducing the degradation of tumor-promoting proteins. Bristol Myers Squibb is investigating a novel CELMoD agent, mezigdomide, for multiple myeloma that was intentionally designed to improve upon the demonstrated efficacy of the IMiD agents, along with manageable tolerability, ease of administration, and the potential to improve patient outcomes. Mezigdomide co-opts cereblon to rapidly induce degradation of target proteins Ikaros and Aiolos, thus inhibiting tumor cell proliferation, promoting tumor cell death, and inducing immune-stimulatory effects.

Karyopharm Therapeutics Inc. is a commercial-stage pharmaceutical company pioneering novel cancer therapies. Since its founding, Karyopharm has been an industry leader in oral Selective Inhibitor of Nuclear Export (SINE) compound technology, which was developed to address a fundamental mechanism of oncogenesis: nuclear export dysregulation. Karyopharm’s lead SINE compound and first-in-class, oral exportin 1 (XPO1) inhibitor, XPOVIO (selinexor), is approved in the US and marketed by the company in three oncology indications and has received regulatory approvals in various indications in a growing number of ex-US territories and countries, including Europe and the UK (as NEXPOVIO) and China. Karyopharm has a focused pipeline targeting multiple high unmet need cancer indications, including in multiple myeloma, endometrial cancer, myelodysplastic neoplasms, and myelofibrosis. For more information, visit www.karyopharm.com.