Zavabresib Nets FDA Orphan Drug Designation for Myelofibrosis

The FDA has granted orphan drug designation to the BET small molecule inhibitor zavabresib (OPN-2853; formerly PLX2853) for the treatment of patients with myelofibrosis.¹

The regulatory designation was supported by data from the phase 1 PROMise trial (EudraCT 2019-000916-27), which evaluated zavabresib in combination with ruxolitinib (Jakafi) in patients with advanced myelofibrosis who experienced an inadequate response to ruxolitinib alone.² Findings presented at the 2024 ASH Annual Meeting and Exposition demonstrated that the combination was well tolerated across varying dose levels of zavabresib, with the majority of patients completing 8 cycles of treatment with zavabresib and ruxolitinib.

Among evaluable patients (n = 12), the median spleen size reduction was 5 cm (range, 0-10) from baseline to minimum post-baseline spleen size.

“Receiving orphan drug designation for zavabresib in myelofibrosis is a significant regulatory milestone for Opna Bio and highlights the urgent need for new and effective treatment options for patients with this disease,” Reinaldo Diaz, chief executive officer of Opna Bio, stated in a news release.¹ “Our investigator-sponsored clinical trial with zavabresib and ruxolitinib has shown impressive results to date, including durable spleen reduction in patients with advanced myelofibrosis. We believe that selective BET inhibition alongside JAK inhibition offers a promising new therapeutic approach for patients with myelofibrosis. We are further encouraged by recent positive meetings with the FDA to continue to test zavabresib in additional clinical studies.”

What is the mechanism of action of zavabresib, and the rationale of the PROMise trial?

Zavabresib is designed to bind to the BRD domains of BET proteins, leading to downregulation of malignancy signatures such as Myc and BET inhibitor responsive genes such as HEXIM1 and WDR47.² In preclinical models, the addition of zavabresib to ruxolitinib reduced disease burden.

PROMise was a phase 1, multicenter, dose-finding trial that enrolled patients at least 16 years of age with high- or intermediate-2–risk myelofibrosis who were not adequately responding to ruxolitinib alone. Patients needed to be on ruxolitinib for at least 24 weeks, including a stable dose for at least 4 weeks. Persistent splenomegaly extending at least 5 cm below the costal margin was also required.

The study enrolled up to 60 patients across 3 ruxolitinib dosing groups: low dose (5 mg to 20 mg per day), mid dose (25 mg to 45 mg per day), and high dose ( 50 mg per day or higher). Zavabresib was also evaluated at once-daily doses of 20 mg, 40 mg, and 80 mg.

As of the data cutoff for the ASH 2024 data presentation, 16 total patients had been treated at a low dose of ruxolitinib (n = 6), a mid dose (n = 8), and a high dose (n = 2). Patients had a median age of 71 years (range, 66-74) and a median time from diagnosis of 3.8 years (range, 2.3-7.0). Fifty-six percent of patients were male, 56% of patients had primary myelofibrosis, and 82% of patients had a fibrosis grade of MF-3. Among those with secondary myelofibrosis (n = 7), 57% had PET myelofibrosis. Most patients in the overall population (69%) were transfusion independent at baseline.

What additional safety data were reported with zavabresib plus ruxolitinib?

Among the 16-patient population, the most common hematologic adverse effects (AEs) included decreased platelet count/thrombocytopenia (43.8%), anemia (25%), and febrile neutropenia (6.2%). Non-hematologic AEs comprised diarrhea (68.8%), nausea (43.8%), abdominal pain (31.2%), fatigue (31.2%), and other (100%). Bleeding-related AEs included epistaxis (12.5%), hematuria (6.2%), and oral hemorrhage (6.2%).

The most common grade 3 or higher AEs were reduced platelet count (31%) and anemia (12.5%). Furthermore, 3 patients experienced a total of 7 serious AEs. Two dose-limiting toxicities of grade 3 thrombocytopenia and grade 3 elevated liver transaminase levels occurred in the cohort where zavabresib was administered at 40 mg per day. Notably, transformation to leukemia was not observed as a serious AE in any patients. One patient died, with the death deemed related to their disease.

References

1. Opna Bio announces orphan drug designation granted to OPN-2853 (zavabresib) for the treatment of myelofibrosis. News release. Opna Bio. January 21, 2026. Accessed January 21, 2026. https://www.opnabio.com/opna-bio-announces-orphan-drug-designation-granted-to-opn-2853-zavabresib-for-the-treatment-of-myelofibrosis/
2. Mead AJ, Huntly BJP, Psaila B, et al. Interim analysis of PROMise, a clinical study combining the BET inhibitor OPN-2853 with ruxolitinib in patients with advanced myelofibrosis experiencing an inadequate response to ruxolitinib. Blood. 2024;144(suppl 1):3186. doi:10.1182/blood-2024-205105