CHMP Offers Positive Opinion for Imetelstat for Transfusion-Dependent Anemia in Lower-Risk MDS

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of imetelstat (Rytelo) for the treatment of adult patients with transfusion-dependent anemia due to very low–, low- or intermediate-risk myelodysplastic syndromes (MDS) without an isolated deletion 5q cytogenetic abnormality and who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.1

The recommendation was based on data from the phase 3 IMerge trial (NCT02598661). Findings presented at the 2023 ASCO Annual Meeting showed that 39.8% of patients treated with imetelstat (n = 118) achieved transfusion independence for at least 8 consecutive weeks compared with 15.0% of patients given placebo (n = 60; P < .001).2 In the imetelstat arm, 16-week, 24-week, and 1-year transfusion independence was experienced by 31.4%, 28.0%, and 13.6% of patients, respectively. In the placebo arm, these respective rates were 6.7% (P < .001), 3.3% (P < .001), and 1.7% (P = .012).

“The positive CHMP opinion is an important step towards our goal to optimize value and patient access to [imetelstat] in the European Union [EU], where we look forward to the opportunity to make this important new treatment option for [patients with] lower-risk MDS available in select markets. If approved, [imetelstat] would be the first and only telomerase inhibitor available in Europe,” John A. Scarlett, MD, chairman and chief executive officer of Geron, stated in a news release.1 “We are deeply appreciative to the patients, caregivers, advocates and investigators across the EU who contributed to the clinical development of [imetelstat].”

In June 2024, the FDA approved imetelstat for adult patients with low- to intermediate-1–risk MDS and transfusion-dependent anemia requiring 4 or more red blood cell (RBC) units over 8 weeks who have not responded to or have lost response to or are not eligible for erythropoiesis-stimulating agents (ESAs).3 This regulatory decision was also based on data from IMerge.

The double-blind, randomized, placebo-controlled phase 3 study enrolled patients with low- or intermediate-1–risk MDS per International Prognostic Scoring System (IPSS) criteria whose disease was relapsed/refractory to an ESA or who had an erythropoietin level of greater than 500 mU/mL.2 Patients needed to be transfusion dependent, defined as requiring at least 4 units of RBCs every 8 weeks over the course of a 16-week pre-study. Those with tumors harboring deletion 5q or prior exposure to lenalidomide (Revlimid) or hypomethylating agents were not allowed to enroll.

Enrolled patients were randomly assigned 2:1 to receive imetelstat at 7.5 mg/kg once every 4 weeks or placebo. Patients in both arms were allowed to receive best supportive care at investigator discretion. Stratification factors include transfusion burden (4-6 vs >6 RBC units) and IPSS risk category (low vs intermediate-1).

The proportion of patients to achieve transfusion independence for at least 8 consecutive weeks after entering the study served as the trial’s primary end point. Secondary end points included 24-week transfusion independence rate, duration of transfusion independence, hematologic improvement-erythroid (HI-E), and safety. Variant allele frequency changes and patient-reported outcomes served as exploratory end points.

Additional data showed that 83% of patients treated with imetelstat experienced a single continuous transfusion-independence period.

In patients who achieved 8-week transfusion independence, the median duration of transfusion independence was 51.6 weeks (95% CI, 26.9-83.9) in the imetelstat arm vs 13.3% (95% CI, 8.0-24.9) in the placebo arm (HR, 0.23; 95% CI, 0.09-0.57; P < .001). In these responders, the median rise in hemoglobin levels was 3.6 g/dL (range, –0.1 to 13.8) in the imetelstat arm vs 0.8 g/dL (range, –0.2 to 1.7) in the placebo arm. The median hemoglobin peak was 11.3 g/dL (range, 8.0-21.9) and 8.9 g/dL (range, 7.9-9.7), respectively.

HI-E improvement was reported in 42.4% (95% CI, 33.3%-51.8%) of patients in the imetelstat arm vs 13.3% (95% CI, 5.9%-24.6%) of patients in the placebo arm (P < .001).

Regarding safety, adverse effects (AEs) led to dose modification in approximately 75% of patients treated with imetelstat; however, less than 15% of patients in the experimental arm discontinued treatment due to treatment-emergent AEs.

The most common any-grade AEs reported in at least 10% of patients included thrombocytopenia (imetelstat, 75%; placebo, 10%), neutropenia (74%; 7%), anemia (20%; 10%), leukopenia (10%; 2%), asthenia (19%; 14%), COVID-19 (19%; 14%), headache (13%; 5%), diarrhea (12%; 12%), increase alanine aminotransferase levels (12%; 7%), peripheral edema (11%; 14%), hyperbilirubinemia (9%; 10%), pyrexia (8%; 12%), and constipation (8%; 12%).

References

1. Geron announces positive CHMP opinion for Rytelo (imetelstat) for the treatment of adults with transfusion-dependent anemia due to lower-risk MDS. News release. Geron. December 13, 2024. Accessed December 13, 2024. https://ir.geron.com/investors/press-releases/press-release-details/2024/Geron-Announces-Positive-CHMP-Opinion-for-RYTELO-imetelstat-for-the-Treatment-of-Adults-with-Transfusion-Dependent-Anemia-due-to-Lower-Risk-MDS/default.aspx
2. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004
3. FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. June 6, 2024. Accessed December 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent