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FDA staff appear to have serious doubts about the prospects of imetelstat as a treatment for transfusion-dependent anemia in adults with myelodysplastic syndromes (MDS), according to a released ahead of a meeting of the agency's outside experts.

On Thursday, the FDA will ask its Oncologic Drugs Advisory Committee (ODAC) to vote on whether the benefits of the investigational first-in-class telomerase inhibitor outweigh the risks for patients with lower-risk MDS who failed on erythropoiesis-stimulating agents or are ineligible for this standard treatment.

The main support for any potential approval comes in the form of , a multinational phase III trial that included 178 heavily transfused patients who failed on erythropoiesis-stimulating agents. The primary outcome showed that the group randomized to imetelstat had significantly higher rates of red blood cell (RBC) transfusion independence for at least 8 weeks compared with the group assigned to placebo (39.8% vs 15%, P=0.001).

The trial also met the key secondary endpoint of 24-week transfusion independence (28% vs 3.3%, respectively, P=0.001).

However, while the reviewers acknowledged that the trial met those statistical objectives, they questioned whether that 8-week outcome is meaningful, noting that the "general consensus among MDS experts has been that only a 16-week or longer period of transfusion independence is clinically meaningful."

The briefing document also identified other issues regarding study design and efficacy results.

While imetelstat's developer, Geron, reported a median duration of 51.6 weeks as the longest RBC transfusion-independent interval (versus 13.3 weeks with placebo), this only applied to patients who achieved the primary outcome at 8 weeks, FDA staff pointed out. For the entire study population, these values were just 5 weeks with imetelstat versus 3.9 weeks with placebo.

FDA staff also contended that other secondary endpoints -- including complete or partial remissions, overall survival, and response rates for hematologic improvement in the erythroid lineage -- were "not supportive of a disease-modifying treatment effect."

In the case of overall survival, for instance, the hazard ratio between the imetelstat and placebo arms was 0.98 (95% CI 0.53-1.82) at a median follow-up of at least 28 months.

Moreover, agency reviewers argued that patient-reported outcomes failed to support a treatment effect, and that the 8-week rate of transfusion independence with imetelstat was much lower in the subgroup of U.S. patients, suggesting uncertainty about the applicability of the efficacy results to the U.S. population.

FDA staff also said treatment with imetelstat was associated with risks "that might be considered substantial." For example:

• Incidence of grade 3/4 neutropenia was 71% in the imetelstat arm and 7% in the placebo arm
• Myeloid growth factors were required in 36% and 3% of the two arms, respectively
• Incidence of grade 3/4 thrombocytopenia was 65% and 8%

"As most patients do not respond to imetelstat, there is a substantial risk of exposing patients to toxicity with no durable" RBC transfusion independence, FDA staff observed.

In its , Geron emphasized that MDS3001 met its primary endpoint, argued that the durability of response to imetelstat is clinically meaningful, and that low rates of severe infection and bleeding events in imetelstat-treated patients were similar to the placebo arm, suggesting limited clinical significance of neutropenia and thrombocytopenia.

"There has been a 14-year drought of approvals for MDS treatments between 2006 and 2020," the company pointed out. "There is a need for additional treatments with novel mechanisms of action, that provide alternative options for these underserved patients."

While the FDA is not required to follow the advice of its advisory committees, it typically does.

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