In a briefing document for Thursday’s advisory committee meeting, the FDA pointed to efficacy and safety issues with Geron’s New Drug Application for imetelstat in myelodysplastic syndromes.
Pictured: FDA signage outside its office in Washington, DC/iStock, JHVEPhoto
In briefing materials released ahead of a Thursday advisory committee meeting, the FDA expressed skepticism regarding the overall benefit-risk profile of Geron Corporation’s investigational telomerase inhibitor imetelstat, which is being proposed as a treatment for transfusion-dependent anemia in patients with low- to intermediate-risk myelodysplastic syndromes.
While imetelstat met its primary endpoint, the regulator’s reviewers pointed out that the candidate fell short of some crucial secondary outcomes that could be indicative of a disease-modifying effect.
FDA staff noted that imetelstat did not significantly outperform placebo in terms of hematologic improvement in the erythroid lineage, as well as complete and partial remission. Geron’s candidate also did not lead to significantly better overall survival, according to the agency. Patient-reported outcomes, including fatigue and other anemia-related symptoms, likewise did not significantly improve after imetelstat treatment.
The FDA also flagged what it called “residual uncertainties,” such as the low number of patients enrolled in the U.S. Geron’s primary efficacy data “varied greatly” between its U.S. and non-U.S. sites, suggesting that region-specific patient and treatment factors “cannot be ruled out,” the document stated.
In terms of safety, the regulator pointed to a high rate of cytopenias in the imetelstat arm, as well as Grade 3 to4 neutropenia and thrombocytopenia events. A higher proportion of patients treated with imetelstat required platelet transfusions and myeloid growth factors versus placebo, according to the FDA.
“Treatment with imetelstat is associated with risks that might be considered substantial, and it is not clear that the risks of treatment with imetelstat are outweighed by the potential benefit for the intended population,” the briefing document concluded.
Imetelstat is an investigational oligonucleotide therapy that works by binding to the telomerase enzyme and blocking its function, according to Geron’s briefing documents, countering the typically high telomerase activity in cancer cells and leading to cell death, cell cycle arrest and the aging of tumor cells.
Geron filed its New Drug Application (NDA) for imetelstat in June 2023 and the FDA announced its acceptance of the submission in August 2023, noting that it would convene its Oncologic Drugs Advisory Committee as part of its review process.
Imetelstat’s NDA is backed primarily by the Phase II/III MDS3001 study, a two-part, multicenter trial enrolling 178 transfusion-dependent anemia patients with low- to intermediate-risk myelodysplastic syndromes, who were ineligible for or had relapsed after or were refractory to treatment with erythropoiesis-stimulating agents.
MDS3001 met its primary efficacy endpoint demonstrating a “statistically significant and clinically meaningful” improvement in red blood cell transfusion independence at eight weeks versus placebo. Imetelstat also aced key secondary endpoints including transfusion independence at 24 weeks and one year, as well as a sustained increase in hemoglobin levels.
Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
