FDA Grants Orphan Drug Designation to Rigel's R289 for Myelodysplastic Syndromes

• The FDA has granted Orphan Drug designation to R289 for treating myelodysplastic syndromes (MDS), offering incentives for its development.
• R289, a dual inhibitor of IRAK1 and IRAK4, is currently in a Phase 1b study for lower-risk MDS patients who have relapsed or are refractory to prior treatments.
• The Orphan Drug designation provides Rigel with potential tax credits, exemptions from certain FDA fees, and seven years of market exclusivity upon drug approval.
• R289 had previously received Fast Track designation from the FDA for transfusion-dependent lower-risk MDS, highlighting its potential as a new treatment option.

Rigel Pharmaceuticals' R289, a potent and selective dual inhibitor of IRAK1 and IRAK4, has been granted Orphan Drug designation by the U.S. Food and Drug Administration (FDA) for the treatment of myelodysplastic syndromes (MDS). This designation aims to support the development of R289 for this rare hematologic disorder, which affects fewer than 200,000 people in the U.S. The drug is currently being evaluated in an ongoing Phase 1b study in patients with lower-risk MDS (LR-MDS) who have relapsed or are refractory to prior therapies.

Clinical Development and Significance

The ongoing open-label Phase 1b study is assessing the safety, tolerability, pharmacokinetics, and preliminary activity of R289 in LR-MDS patients who have experienced relapse or are refractory, resistant, intolerant, or have an inadequate response to previous treatments, including erythropoietin, thrombopoietin, luspatercept, or hypomethylating agents. The trial is enrolling patients aged 18 years and older with a definitive diagnosis of MDS with very low, low, or intermediate-1 risk and ≤5% bone marrow myeloblasts. Patients must be blood transfusion dependent and have documented marrow iron stores.

Raul Rodriguez, Rigel's president and chief executive officer, stated, "Receiving Orphan Drug designation for R289 supports the development of this therapeutic candidate for the treatment of MDS and highlights the significant unmet medical need that exists for these patients." He further added that the Orphan Drug and Fast Track designations, along with encouraging initial data from the Phase 1b study, represent significant milestones in advancing R289 as a potential new treatment option.

Mechanism of Action

R289 is a prodrug of R835 and functions as a dual inhibitor of IRAK1 and IRAK4. Preclinical studies have demonstrated its ability to block inflammatory cytokine production in response to toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family signaling. These receptors play a critical role in the innate immune response, and their dysregulation can lead to various inflammatory conditions. Chronic stimulation of these receptor systems is believed to contribute to the pro-inflammatory environment in the bone marrow, which is responsible for persistent cytopenias in lower-risk MDS patients.

Benefits of Orphan Drug Designation

The FDA's Orphan Drug designation provides Rigel with several incentives to support the development of R289. These include tax credits, exemptions from certain FDA fees for clinical trials, and the potential for seven years of market exclusivity in the U.S. following drug approval. This designation is granted to encourage the development of medicines for rare disorders that affect fewer than 200,000 people in the U.S.

Prior FDA Fast Track Designation

In December 2024, R289 was granted Fast Track designation by the FDA for the treatment of patients with previously-treated transfusion dependent lower-risk MDS. This designation is intended to expedite the development and review of drugs that treat serious conditions and fill an unmet medical need.