European Commission Grants Orphan Drug Designation to Selinexor for Myelofibrosis

Reshma Rangwala, MD, PhD

The European Commission (EC) has granted an orphan drug designation to selinexor (Xpovio) for the treatment of patients with myelofibrosis.¹

Selinexor, a first-in-class, oral XPO1 inhibitor, previously received an orphan drug designation for the treatment of myelofibrosis from the FDA in May 2022.

“We are very pleased to receive orphan medicinal product designation from the EC for selinexor for the treatment of myelofibrosis," Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, stated in a press release. “Building on our recent orphan drug designation from the FDA, this recognition continues to reinforce the significant unmet need for a drug with a novel mechanism of action like selinexor for this devastating disease. Our clinical plans remain on track, and we look forward to the continued development of selinexor in myelofibrosis."

Selinexor is under investigation in 3 ongoing clinical trials for patients with myelofibrosis.

A phase 2 trial (NCT04562870) in evaluating selinexor monotherapy vs physician’s choice of therapy in patients with previously treated myelofibrosis.² The trial is enrolling patients with a diagnosis of primary myelofibrosis, post-essential thrombocythemia, or post-polycythemia myelofibrosis, according to the 2016 WHO classification of myeloproliferative neoplasms, who received prior treatment with JAK inhibitors for at least 6 months.

Patients are being randomly assigned to receive selinexor at 80 mg per week in the first two 28-day cycles, followed by 60 mg of selinexor per week in subsequent cycles, or physician’s choice of treatment. The primary end point of the trial is spleen volume reduction of at least 35% from baseline up to week 48. Secondary end points include symptom score reduction, overall survival (OS), overall response rate (ORR), anemia response, and safety.

The phase 2 ESSENTIAL trial (NCT03627403) is also evaluating single-agent selinexor for patients with primary myelofibrosis, post-essential thrombocytosis, or post-polycythemia vera who received prior treatment with ruxolitinib (Jakafi) or any experimental JAK inhibitor.³

Prior to protocol version 7 of the trial, patients were administered 80 mg or 60 mg of selinexor once weekly until disease progression, unacceptable toxicity, or no sign of clinical benefit. Patients enrolled after protocol version 7 will receive 40 mg of selinexor per week.

Change in spleen volume is the primary end point of the trial. Secondary end points are comprised of change in symptom score, ORR, OS, and safety.

Finally, a phase 1/2 trial (NCT04562389) is investigating the combination of selinexor and ruxolitinib in patients with intermediate-1–, intermediate-2–, or high-risk myelofibrosis.⁴

The dose-escalation phase 1a portion of the study will determine the maximum tolerated dose, establish the recommended phase 2 dose (RP2D), and evaluate the safety and preliminary efficacy of the combination in a standard 3+3 trial design. The dose-expansion phase 1b portion of the study will further assess the RP2D for safety and preliminary efficacy.

Phase 2 will randomly assign treatment-naïve patients with myelofibrosis to receive the combination of selinexor and ruxolitinib or ruxolitinib monotherapy.

“Myelofibrosis is a difficult-to-treat and complex disorder of the bone marrow with limited therapeutic options and we are committed to bringing novel treatments to patients through our collaboration with Karyopharm,” Olivia del Puerto, MD, LMS, head of Medical Affairs Oncology at EMEA of Menarini, said. “We are excited about the potential to bring selinexor to myelofibrosis patients in Europe, pending positive study read-outs and regulatory approval.”

In July 2022, the EC approved selinexor in combination with once-weekly bortezomib (Velcade) and low-dose dexamethasone for the treatment of adults with multiple myeloma who have received at least 1 previous therapy.⁵

Additionally, in March 2021, the EC approved selinexor for use in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have previously received at least 4 therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody, and have experienced progressive disease on their last therapy.⁶

References

1. Karyopharm and Menarini Group announce orphan medicinal product designation from the European Commission for selinexor for the treatment of myelofibrosis. News release. Karyopharm Therapeutics, Inc. October 31, 2022. Accessed November 1, 2022. https://bit.ly/3h2hfC3
2. A study to evaluate safety and efficacy of selinexor versus treatment of physician's choice in participants with previously treated myelofibrosis. ClinicalTrials.gov. Updated October 10, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04562870
3. Selinexor in myelofibrosis refractory or intolerant to JAK1/2 inhibitors (ESSENTIAL). ClinicalTrials.gov. Updated May 9, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03627403
4. A study to evaluate safety and efficacy of selinexor in combination with ruxolitinib in participants with myelofibrosis. ClinicalTrials.gov. Updated May 3, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04562389
5. Karyopharm and Menarini Group receive full marketing authorization from the European Commission for Nexpovio (selinexor) for the treatment of patients with multiple myeloma after at least one prior therapy. News release. Karyopharm Therapeutics, Inc. July 21, 2022. Accessed November 1, 2022. https://bit.ly/3PNvWFk
6. Karyopharm receives conditional marketing authorization from the European Commission for NEXPOVIO (selinexor) in combination with dexamethasone for the treatment of adult patients with relapsed and or refractory multiple myeloma. News release. Karyopharm Therapeutics, Inc. March 29, 2021. Accessed November 1, 2022. https://bit.ly/3sz2t6P