Rigel Shares Early Phase 1b Data on R289 in LR-MDS at 66th ASH Annual Meeting

Rigel Pharmaceuticals, a biotechnology firm based in South San Francisco, has unveiled promising initial data from its ongoing Phase 1b clinical trial involving the investigational oral prodrug R289. This trial is focused on patients with relapsed or refractory lower-risk myelodysplastic syndrome (LR-MDS). Dr. Guillermo Garcia-Manero presented the data at the 66th American Society of Hematology Annual Meeting, highlighting R289 as a potential treatment for this challenging condition.

R289, a prodrug of R835, is a dual inhibitor targeting IRAK1 and IRAK4, crucial proteins involved in inflammatory processes within the body. The drug aims to alleviate the pro-inflammatory environment in the bone marrow, which contributes to persistent cytopenias in LR-MDS patients. Currently, patients with transfusion-dependent LR-MDS have limited therapeutic options, making R289 a promising candidate following its recent Fast Track designation by the FDA.

The Phase 1b study, identified as NCT05308264, is an open-label trial that seeks to evaluate both the safety and preliminary efficacy of R289. As of late October 2024, the study had enrolled 22 elderly patients, all of whom had undergone multiple prior therapies. The median age of participants was 76, and they had received a median of three previous treatments, including hypomethylating agents and luspatercept.

The trial's primary aim is to determine the safety and tolerability of R289, while secondary objectives include assessing its pharmacokinetic profile and initial effectiveness. The interim data suggest that R289 is generally well tolerated among this heavily pretreated patient group. Common side effects included diarrhea, fatigue, chills, nausea, and pruritus, which were mostly mild to moderate. More serious adverse events were less frequent, with anemia, reduced platelet count, pneumonia, and increased alanine aminotransferase levels among the notable Grade 3/4 events. Two patients discontinued treatment due to adverse reactions, one of which was related to the drug.

Efficacy analysis was conducted on 18 participants, all of whom had received at least one dose of R289 and had undergone at least one efficacy assessment. Notably, 40% of evaluable patients who were transfusion-dependent and received R289 doses of 500 mg or more daily showed hematologic responses. Red blood cell transfusion independence (RBC-TI) for eight weeks or longer was achieved in three patients, with two maintaining this independence for over 24 weeks. The median duration of RBC-TI reached 29 weeks. Additionally, one patient on a 500 mg daily dose achieved a minor hematologic improvement, with a 64% reduction in RBC transfusions.

The study also observed that R835 exposure, the active form of R289, increased with higher doses, reaching levels associated with significant cytokine inhibition in some patients. However, no hematologic responses were noted at lower doses of 250 mg daily or twice daily.

Overall, the initial data from Rigel Pharmaceuticals' study of R289 highlights a favorable safety and efficacy profile, suggesting that this investigational drug holds potential as a new treatment option for patients with previously treated transfusion-dependent LR-MDS. The ongoing study seeks to further explore R289's potential to improve outcomes for this patient population.