FDA Grants R289 Orphan Drug Designation in MDS

• The FDA has granted R289 orphan drug designation for treating patients with myelodysplastic syndromes (MDS).
• R289 is a potent and selective dual inhibitor of IRAK1 and IRAK4.
• The agent is currently undergoing evaluation in an ongoing phase 1b study in patients with low-risk MDS.

R289, a potent and selective dual inhibitor of IRAK1 and IRAK4, has been granted orphan drug designation from the FDA for the treatment of patients with MDS.¹

An ongoing, open-label phase 1b study is currently evaluating the agent in patients with MDS. Here, R289’s safety, tolerability, pharmacokinetics, and preliminary activity is being assessed, specifically in patients with LR-MDS who are relapsed or refractory to prior therapies.

"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," said Raul Rodriguez, Rigel's president and chief executive officer, in a press release. "Orphan drug and fast track designations, along with encouraging initial data from our ongoing phase 1b study in patients with lower-risk MDS, represent significant milestones in the advancement of R289 as a potential new treatment option."

R289 is a prodrug of R835 and an IRAK1/4 dual inhibitor. Preclinically, the agent has shown to block inflammatory cytokine production in response to toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family signaling.¹

In December 2024, R289 was granted fast track designation from the FDA in previously-treated transfusion dependent lower-risk MDS.

A close-up of red blood cells flowing through a vein: © catalin - stock.adobe.com

About the Phase 1b Trial

In the open-label, phase 1b study of R289, investigators aim to determine the tolerability and preliminary efficacy of the agent in patients with LR-MDS who are relapsed/refractory, resistant, intolerant, or have inadequate response to prior therapies, including erythropoietin, thrombopoietin, luspatercept, or hypomethylating agents for MDS treatment.²

Enrollment in the trial is open to 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. If marrow iron stain is unavailable, transferrin saturation must be >20% or serum ferritin >100 ng/mL. Further, patients are required to have an ECOG performance status of 0 to 2, adequate organ function and renal function, and those with del(5q) must have failed prior lenalidomide (Revlimid) therapy.

Patients enrolled in the experimental arm will be treated with oral R289 monosodium given once a day. Depending on the specific dose assigned, patients will receive either 250 mg, 500 mg, 750 mg, or 1000 mg of the medication daily.

Safety and tolerability, including incidence of adverse events (AEs), incidence of discontinuation or interruptions of R289 due to AEs, and incidence of dose-limiting toxicities, are the primary end points of the study. Secondary end points consist of pharmacokinetics and the number of patients with red blood cell transfusion independence by week 24, which the study defines as the proportion of patients who achieve 50% or greater reduction in the number of red blood transfusions compared with baseline and 24 or more weeks.

REFERENCES:

1. Rigel announces R289 granted orphan drug designation by the FDA for MDS. News release. Rigel Pharmaceuticals, Inc. January 9, 2025. Accessed January 10, 2025. https://tinyurl.com/yvubuxb5

2. Study of R289 in participants with lower-risk myelodysplastic syndromes (LR MDS). News release. Updated October 10, 2023. Accessed January 10, 2025. https://clinicaltrials.gov/study/NCT05308264