Imetelstat (IME, Rytelo; Geron Corporation) is advancing to a pivotal phase 3 trial following encouraging results from the phase 2 IMbark study, which demonstrated the telomerase inhibitor's potential to improve survival and modify disease biology in patients with myelofibrosis who had relapsed or were refractory to Janus kinase (JAK) inhibitor therapy.
The first-in-class telomerase inhibitor received FDA approval in 2024 for adults with low- to intermediate-1 risk myelodysplastic syndrome with transfusion-dependent anemia, based on data showing nearly 40% of patients achieved red blood cell transfusion independence in as little as 8 weeks in the IMerge trial.
Phase 2 Results Demonstrate Clinical Promise
The randomized, single-blind, multicenter IMbark study evaluated imetelstat activity in patients with intermediate-2 or high-risk myelofibrosis who were relapsed or refractory to JAK inhibitors. Patients received imetelstat at 9.4 mg per kg every 3 weeks during the treatment phase.
At week 24, the median overall survival reached 29.9 months, with a median follow-up of 27.4 months. The study revealed clinically meaningful improvements, with 32% of patients achieving at least a 50% reduction in total symptom score and 10% achieving a 35% or greater reduction in spleen volume.
Notably, imetelstat demonstrated disease-modifying activity by reducing variant allele frequency of myelofibrosis driver mutations and improving bone marrow fibrosis. These biological changes correlated with improved survival outcomes, suggesting the drug addresses underlying disease mechanisms rather than merely managing symptoms.
Safety Profile Shows Manageable Toxicities
Safety data from the IMbark trial showed that the most common grade 3 or greater adverse events were cytopenias, including thrombocytopenia, anemia, and neutropenia. However, these events were typically manageable, short-lived, and resolved to grade 2 or less within 4 weeks.
Phase 3 Trial Design and Enrollment Progress
The phase 3 IMpactMF trial (MYF3001; NCT04576156) is comparing imetelstat with best available therapy in approximately 320 patients with intermediate-2 or high-risk myelofibrosis who are relapsed or refractory to JAK inhibitors or ineligible for transplant or further JAK inhibitor therapy.
Participants are randomized in a 2:1 ratio to receive imetelstat at 9.4 mg per kg intravenously every 3 weeks or investigator-chosen best available therapy, which may include agents such as hydroxyurea, interferon, or hypomethylating agents, but excludes JAK inhibitors, stem cell transplant, or splenectomy.
The trial's primary endpoint is overall survival, with secondary endpoints including symptom and spleen response rates at week 24, progression-free survival, clinical responses per modified 2013 IWG-MRT criteria, bone marrow fibrosis reduction, and patient-reported outcomes. Biomarker and mutation analyses are also planned.
As of December 2024, approximately 75% of patients have been enrolled across 172 global sites. An interim analysis is planned for early 2026 once about 35% of participants have died, with the final analysis expected in early 2027.
