Novel IRAK1/4 Inhibitor Receives FDA Orphan Drug Designation in MDS

The FDA granted fast track designation to R289 as a therapy for patients with previously treated LR-MDS in December 2024.

The FDA has granted orphan drug designation to R289, an investigational selective dual inhibitor of IRAK1 and IRAK4, for patients with myelodysplastic syndrome (MDS), according to a press release from the developer, Rigel Pharmaceuticals, Inc.¹

Investigators are currently evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of R289 among patients with relapsed/refractory lower-risk MDS (LR-MDS) as part of a phase 1b study (NCT05308264). Findings from the trial were previously presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).²

Among 18 evaluable patients, treatment with R289 produced hematologic responses in 40% (n = 4/10) of those with transfusion dependence after receiving doses of at least 500 mg once daily. Additionally, 3 patients achieved red blood cell (RBC)–transfusion independence for 8 weeks or longer, including 1 patient who received the 500 mg dose and 2 who were treated with the agent at 750 mg. Two patients with high transfusion burden (HTB) had RBC transfusion independence for 24 weeks or longer. Data showed that RBC transfusion independence lasted for a median of 29 weeks (range, 12.7-51.9).

The most common treatment-emergent adverse effects (TEAEs) included diarrhea (27%), fatigue (27%), chills (23%), nausea (23%), and pruritus (23%), which were exclusively grades 1 or 2. Grade 3/4 toxicity included anemia (2.9%), platelet count decreases (2.9%), pneumonia (2.9%), and alanine aminotransferase increases (2.9%). Two patients discontinued study treatment, including 1 who experienced hyperuricemia not associated with R289 and another who had grade 3 drug-related aspartate aminotransferase elevation and grade 4 alanine aminotransferase increase.

“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,” Raul Rodriguez, president and chief executive officer at Rigel, stated in the press release.¹ “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.”

In the open-label phase 1b study, patients received R289 at doses ranging from 250 mg to 1000 mg orally once daily.³

The trial’s primary end point was the safety and tolerability in terms of AEs, dose discontinuations or interruptions due to AEs, and dose-limiting toxicities. Secondary end points included the proportion of patients who achieved a 50% or higher reduction in the number of RBC transfusions compared with baseline and 24 weeks or longer as well as maximum plasma concentration.

Patients 18 years and older with very low, low, or intermediate-1 risk MDS and relapsed/refractory disease were eligible for enrollment on the trial. Other requirements for study entry included having blood transfusion dependence, an ECOG performance status of 0 to 2 at screening, and adequate organ function.

Those with clinically significant anemia following iron, B12, or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding were ineligible for enrollment on the trial.

The FDA granted fast track designation to R289 as a therapy for patients with previously treated LR-MDS in December 2024.⁴

“We are pleased that R289 has been granted fast track designation, which underscores the significant unmet need for patients with transfusion dependent [LR-MDS]. By targeting inflammatory signaling, we believe that R289 has the potential to meaningfully improve the lives of those living with this disease,” Rodriguez said regarding the fast track designation.⁴

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/4pyx8d3c
2. Rigel highlights initial data from ongoing phase 1b study evaluating R289 in LR-MDS at the 66th ASH Annual Meeting and Exposition. News release. Rigel Pharmaceuticals, Inc. December 9, 2024. Accessed January 10, 2025. https://tinyurl.com/4w52rscp
3. Study of R289 in participants with lower-risk myelodysplastic syndromes (LR MDS). ClinicalTrials.gov. Updated October 10, 2023. Accessed January 10, 2025. https://tinyurl.com/3ymx4v59
4. Rigel announces R289 granted fast track designation by the FDA for lower-risk MDS. News release. Rigel Pharmaceuticals, Inc. December 2, 2024. Accessed January 10, 2025. https://tinyurl.com/e9ub2fuh