FDA Grants Orphan Drug Designation to Zavabresib for the Treatment of Myelofibrosis

The FDA has granted orphan drug designation (ODD) to zavabresnib (OPN-2853; Opna Bio) for the treatment of myelofibrosis (MF). The designation highlights the significant unmet need for new therapeutic options in MF, particularly for patients who experience inadequate responses to currently available Janus kinase (JAK) inhibitors.¹

Zavabresib and BET Inhibition in MF

Zavabresib is an orally delivered bromodomain and extra-terminal motif (BET) inhibitor that aims to modulate the epigenetic causes of the disease. BET proteins control the transcription of genes involved in inflammatory response, cell growth, and cell survival, the same processes that are deregulated in MF.² Through the selective inhibition of BET proteins, zavabresib is intended to prevent the expression of harmful genes that lead to disease progression and the increase of symptoms.

Unlike JAK inhibitors, which mainly work by inhibiting cytokine signaling, BET inhibition can potentially target a wide range of transcriptional and inflammatory pathways that are still active even after JAK blockade. Preclinical studies have shown that BET inhibition could reduce pro-inflammatory signaling and the expression of genes involved in fibrosis, providing a mechanistic rationale for investigation in MF.²

Rationale for Combination Therapy With Ruxolitinib

Zavabresib is being evaluated in combination with ruxolitinib (Jakafi; Incyte Corp.), the current standard treatment for patients with intermediate and high-risk MF. Although ruxolitinib works in reducing spleen size and relieving symptoms, its effects usually don't last, and many patients develop cytopenias that limit the dose or loss of response over time.³

BET inhibition combined with JAK inhibition is intended to offer complementary pathway suppression that can deepen and prolong the clinical responses. This strategy reflects a growing emphasis on combination regimens in MF aimed at overcoming limitations of JAK inhibitor monotherapy.²

Clinical Evidence Supporting Zavabresib Development

Emerging clinical data supporting the FDA's ODD of the therapy were derived from an investigator-sponsored trial assessing zavabresib plus ruxolitinib in patients with intermediate-2 or high-risk MF who had not responded adequately to ruxolitinib alone.¹

The PROMise study, which was a phase I, multicenter, dose-finding trial, set out to determine the safety, tolerability, and preliminary efficacy of the combination. The results, which were an interim analysis, were disclosed at the 2024 American Society of Hematology (ASH) Annual Meeting, showing a manageable safety profile at various dose levels and encouraging reductions in spleen size among evaluable patients.⁴

Continuous daily dosing of zavabresib is viable when combined with ruxolitinib, and the study continues to define the recommended phase 2 dose.³ The durable reduction of the spleen that was observed in the early cohorts is a solid rationale for the continuation of clinical investigations of this combination therapy in advanced MF.

Regulatory Significance of ODD

The encouraging clinical activity observed in these early cohorts provided the necessary foundation for the FDA’s ODD designation, a status reserved for therapies targeting rare disease populations with high clinical need. In the U.S., ODD is given to medications meant for patients with rare diseases affecting less than 200,000 individuals.

ODD status confers multiple benefits to the manufacturers, which include tax rebates on expenses of the clinical trials, exemption from FDA application fees, and up to 7 years of market exclusivity after the product gets approved.¹ The goal of these advantages is to motivate the development of pharmaceutical products for rare and serious diseases that are lacking in commercial incentives.

According to Opna Bio, the FDA’s decision reflects both the severity of myelofibrosis and the lack of durable treatment options for patients with advanced disease.¹ The designation may also support accelerated clinical development by facilitating regulatory engagement and enabling broader clinical trial evaluation.

“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,” said Reinaldo Diaz, chief executive officer of Opna Bio. “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.”¹

Implications for Pharmacists and Future Directions

MF is a rare, chronic myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, cytopenias, splenomegaly, and debilitating constitutional symptoms. Although JAK inhibitors such as ruxolitinib have transformed symptom management, many patients develop resistance, intolerance, or disease progression, highlighting the need for novel therapeutic strategies.¹

For pharmacists involved in hematology and oncology care, the development of zavabresib is a therapeutic strategy on the horizon that might help to broaden treatment options for patients with MF who have had inadequate responses to existing treatments. With the increasing use of combination regimens including oral targeted agents, pharmacists will play an essential role in managing drug interactions, monitoring hematologic toxicity, providing adherence support, and educating patients on the changing treatment methods.

Although zavabresib is still an investigational drug, ODD is a major milestone in the journey toward possible regulatory approval. Further clinical trials will be necessary to establish its efficacy and safety as well as to position it within the evolving MF treatment landscape.

REFERENCES

1. Opna Bio announces orphan drug designation granted to OPN-2853 (zavabresib) for the treatment of myelofibrosis. Business Wire. Published January 21, 2026. Accessed January 28, 2026. https://www.businesswire.com/news/home/20260121834497/en/Opna-Bio-Announces-Orphan-Drug-Designation-Granted-to-OPN-2853-Zavabresib-for-the-Treatment-of-Myelofibrosis

2. Zavabresib. Opna Bio. Accessed January 28, 2026. https://www.opnabio.com/programs/zavabresib

3. Clinical trials for Investigation into the combination of PLX2853 with ruxolitinib in patients with intermediate-2 or high risk myelofibrosis not receiving an adequate response with ruxolitinib alone. EU Clinical Trials Register. Accessed January 28, 2026. https://www.clinicaltrialsregister.eu/ctr-search/search?query=Investigation+into+the+combination+of+PLX2853+with+ruxolitinib+in+patients+with+intermediate-2+or+high+risk+myelofibrosis+not+receiving+an+adequate+response+with+ruxolitinib+alone.

4. Mead A, Psaila B, Huntly B, et al. 3186 interim analysis of promise, a clinical study cmbining the BET inhibitor OPN-2853 with ruxolitinib in patients with advanced myelofibrosis experiencing an inadequate response to ruxolitinib. Presented at: 66th American Society of Hematology Annual Meeting and Exposition. December 7-10, 2024. San Diego, CA. Published December 8, 2024. Accessed January 28, 2026. https://ash.confex.com/ash/2024/webprogram/Paper205105.html