FDA ODAC Votes in Favor of Imetelstat Benefits Vs Risks in Lower-Risk MDS

Neil Vasan, MD, PhD, said that imetelstat may offer "a new therapy for some patients who have no other option depending on their MDS classification" during the ODAC meeting.

The FDA’s Oncologic Advisory Drug Committee (ODAC) cast a 12-to-2 vote in support of the clinical benefit of imetelstat as a treatment for adult patients with transfusion-dependent anemia and low- to intermediate-1 risk myelodysplastic syndrome (MDS) who have progressed on or are ineligible to receive treatment with erythropoiesis-stimulating agents (ESAs).¹

The FDA requested for the ODAC to convene and vote on the question of whether the clinical benefits of imetelstat outweighed its risks in adult patients with transfusion-dependent anemia and low- to intermediate-1 risk MDS who have not responded to or are ineligible for ESAs.

“In my perspective, this trial met its primary end point and offers a new therapy for some patients who have no other option depending on their MDS classification,” Neil Vasan, MD, PhD, a physician-scientist in the Department of Medicine and the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center, said during the meeting while explaining his vote in favor of the drug’s benefits.¹ “I felt that the benefits of improvement in transfusion independence outweighed the risks of cytopenias in a patient population and a blood cancer oncology community that is well versed in these [AEs] and their management.”

Developers originally submitted a new drug application (NDA) for imetelstat as a treatment for those with low- to intermediate-1–risk MDS who are ineligible to receive treatment with ESAs in June 2023.² The FDA subsequently accepted the NDA for imetelstat as a treatment for this population in August 2023.³ Additionally, the regulatory agency assigned a Prescription Drug User Fee Action date of June 16, 2024 for the application.⁴

“Even though the study met its primary outcome, [with] the magnitude of the benefit [of imetelstat] relative to the [AE] profile, I thought the benefits did not outweigh the risks,” stated Mark R. Conaway, PhD, a professor in the Division of Translational Research and Applied Statistics in the Department of Public Health Services at the University of Virginia, who voted against imetelstat during the meeting.¹

Supporting findings for the application in this indication came from the phase 2/3 IMerge trial (NCT02598661). According to findings published in The Lancet, 40.0% (95% CI, 30.9%-49.3%) of those who received imetelstat achieved red blood cell transfusion independence (RBC-TI) for at least 8 weeks compared with 15.0% (95% CI, 7.1%-26.6%) of patients who received placebo (P = .0008).5 The rate of RBC-TI for 8 weeks or more in each respective treatment arm was 45% vs 19% among patients with ring sideroblasts and 32% vs 9% among those without ring sideroblasts.

RBC-TI for at least 24 weeks was reported in 28.0% (95% CI, 20.1%-37.0%) of patients in the imetelstat arm vs 3.0% (95% CI, 0.4%-11.5%) of those in the placebo arm across the overall population (P = .0001). Additionally, the corresponding rates in each respective arm were 33% vs 5% in patients with ring sideroblasts and 20% vs 0% among those without ring sideroblasts.

Grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 91% of patients in the imetelstat arm and 47% of those in the placebo arm. Common high-grade toxicities in each respective arm included neutropenia (68% vs 3%), thrombocytopenia (62% vs 8%), anemia (19% vs 7%), and leukopenia (8% vs 0%).

According to a briefing document from the FDA, questions remained concerning the benefits of imetelstat in this patient population.⁶ A statistically significant effect with the experimental agent was not reported regarding various secondary end points in the IMerge trial; in the imetelstat and placebo arms, respectively, the rate of hematologic improvement (HI-E) was 63.6% vs 51.7%, and the rate of complete response or partial response was 0% vs 0%. Additionally, overall survival did not appear to significantly improve with imetelstat (HR, 0.98; 95% CI, 0.53-1.82), and patient-reported outcomes did not appear to highlight improvements in fatigue or symptoms related to anemia.

Investigators of the double-blind IMerge trial randomly assigned patients 2:1 to receive imetelstat at 7.1 mg/kg (n = 118) or matched placebo (n = 60) intravenously every 4 weeks, with treatment continuing until disease progression, unacceptable toxicity, or withdrawal.

The trial’s primary end point was 8-week RBC-TI. Secondary end points included 24-week RBC-TI, duration of RBC-TI, time to RBC-TI, and safety. The trial included patients 18 years and older with low- to intermediate-1 risk MDS, RBC transfusion dependence requiring 4 or more units over an 8-week period, and ineligibility to receive treatment with ESAs.

References

1. March 14, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live March 14, 2024. Accessed March 14, 2024. https://tinyurl.com/y983ewxj
2. Geron announces submission of new drug application to FDA for first-in-class telomerase inhibitor imetelstat. News release. Geron Corporation. June 20, 2023. Accessed March 14, 2024. https://bit.ly/3CFbD8l
3. Geron announces FDA acceptance of new drug application for imetelstat for the treatment of lower risk MDS. News release. Geron Corporation. August 21, 2023. Accessed March 14, 2024. https://shorturl.at/DOYZ6
4. Geron announces PDUFA date for imetelstat NDA in lower risk MDS. News release. Geron Corporation. August 22, 2023. Accessed March 14, 2024. https://shorturl.at/GMSU6
5. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo- controlled, phase 3 trial. Lancet. Published online December 1, 2023. doi:10.1016/S0140-6736(23)01724-5
6. March 14, 2024 Oncologic Drugs Advisory Committee Meeting. Briefing document. FDA. March 14, 2024. Accessed March 14, 2024. https://tinyurl.com/4478kydr