FDA Grants Fast Track Designation to R289 for Lower-Risk MDS
Following a phase 1b trial, the potent and selective dual inhibitor of IRAK1 and IRAK4 received fast track designation for the treatment of patients with lower-risk myelodysplastic syndrome.
The FDA has granted fast track designation to R289, a potent and selective dual inhibitor of IRAK1 and IRAK4, to treat patients with previously-treated transfusion dependent lower-risk myelodysplastic syndrome (MDS), according to the agent’s manufacturer Rigel Pharmaceuticals.1
“Lower-risk MDS affects a primarily elderly patient population that faces progressive cytopenias, particularly anemia, and treatment options for transfusion-dependent patients are limited,” Lisa Rojkjaer, MD, chief medical officer of Rigel Pharmaceuticals, said in a press release, adding that the agent is being investigated in an ongoing phase 1b study (NCT05308264). “This designation…highlights the potential of R289 to be a new therapeutic option for these patients. We look forward to working closely with the FDA to advance the clinical development of R289.”
The FDA has granted fast track designation to R289 to treat patients with previously-treated transfusion dependent lower-risk myelodysplastic syndrome
The phase 1b trial is an open label, single arm, multicenter study, which includes a 3+3 dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients).2
In the dose escalation phase of the trial, the maximum tolerated dose will be determined using an initial oral dose of 250 mg R289 once daily, progressing to 500 mg once daily with dose limiting toxicity assessed at both doses for 28 days. Patients who do not experience dose limiting toxicities will remain on their respective dose level so long as they demonstrate clinical benefit without toxicity.
In the dose expansion phase, additional patients will be enrolled to receive the maximum tolerated dose previously determined.
Safety and tolerability will serve as the primary end point, and secondary end points include preliminary efficacy and pharmacokinetics of R289. In addition, change from baseline in plasma biomarkers and bone marrow biomarkers will also be assessed.
In preclinical studies, R289 demonstrated its ability to block inflammatory cytokine production in response to toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family signaling. “TLRs and IL-1Rs play a critical role in the innate immune response and dysregulation of these pathways can lead to various inflammatory conditions,” the release stated. “Chronic stimulation of both these receptor systems is thought to cause the pro-inflammatory environment in the bone marrow responsible for persistent cytopenias in lower-risk MDS patients.”
With the aim of addressing an unmet need, Raul Rodriguez, president and CEO of Rigel Pharmaceuticals also noted in the release: “By targeting inflammatory signaling, we believe that R289 has the potential to meaningfully improve the lives of those living with this disease.”
Reference:
1. Rigel Announces R289 Granted Fast Track Designation by the FDA for Lower-Risk MDS. Rigel Pharmaceuticals News Release. Published: December 2, 2024. Accessed: December 2, 2024. https://www.rigel.com/investors/news-events/press-releases/detail/403/rigel-announces-r289-granted-fast-track-designation-by-the.
2. Garcia-Manero G, Silverman LR, Yan L. Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress. Blood. 2023;142(Supplement 1):3247. doi:10.1182/blood-2023-172511.
