Advisors to Weigh Imetelstat Benefits, Risks
The FDA Oncology Drugs Advisory Committee (ODAC) will consider on 3/14 whether the benefits of Geron’s imetelstat (proposed trade name Rytelo) in treating some blood cancers outweigh its risks. The company is seeking an indication to treat transfusion-dependent anemia in adults with low-to intermediate-1 risk myelodysplastic syndromes who have failed to respond, have lost response to, or are ineligible for erythropoiesis stimulating agents.
In a briefing document released in advance of the meeting, agency medical reviewers say the NDA was submitted based on a single Phase 3 trial that met its primary endpoint of eight-week red blood cell transfusion independence. The reviewers in the CDER Division of Hematologic Malignancies ask ODAC to discuss whether the magnitude and durability of benefit are sufficient to outweigh the potential risks of imeterlstat considering its safety profile.
“While the Phase 3 study met its primary and key secondary endpoints,” the briefing document says, “questions remain regarding the nature of these effects…. A statistically significant treatment effect was not observed on other secondary endpoints reflective of a disease-modifying effect….In addition, the patient-reported outcomes collected in the study did not reflect an improvement in fatigue or other anemia-related symptoms. There are also residual uncertainties regarding the impact of imetelstat on overall medical resource utilization and the applicability of the trial results to the U.S. population.”
Looking at the safety profile, the reviewers say a high rate of cytopenias was observed in the imetelstat arm of the Phase 3 trial. “It is worth noting that cytopenias occurred regardless of whether a patient responded to imetelstat or not,” the reviewers write. “As most patients do not respond to imetelstat, there is a substantial risk of exposing patients to toxicity with no durable red blood cell-transfusion independence.”
The reviewers conclude that the potential benefits and risks should be weighed in the context of residual uncertainties. For instance, they say, there is residual uncertainty about the optimal dose of imetelstat given the limited dose exploration in the target population and the high rate of dose modifications seen in the study. “This is notable given that dose reductions due to adverse events occurred in 49% of patients in the imetelstat arm versus 7% in the placebo arm,” the document says. “In addition, while the increased risk of cytopenias with imetelstat treatment seems apparent, other risks such as fractures may be increased with imetelstat treatment, though such risks are less well-understood. These uncertainties are due in part to the nature of the development program, which includes only one randomized trial in low-risk myelodysplastic syndromes and limited dose-optimization for this indication.”