EMA Validates MAA for Imetelstat for Transfusion-Dependent Anemia in Lower-Risk MDS

The European Medicines Agency (EMA) has validated the marketing authorization application for the use of imetelstat in the treatment of transfusion-dependent anemia in patients with lower-risk myelodysplastic syndrome (MDS).¹

The application is supported by data from the phase 3 IMerge trial (NCT02598661), in which treatment with imetelstat (n = 118) resulted in a red blood cell (RBC) transfusion independence (RBC-TI) rate of 39.8% (95% CI, 30.9%-49.3%) at 8 weeks vs 15.0% (95% CI, 7.1%-26.6%) with placebo (n = 59) in this population (P < .001).² This benefit with imetelstat vs placebo across key subsets, including those without ring sideroblasts (31.8% vs 8.7%l P = .038) and those with a prior RBC transfusion burden of greater than 6 units every 8 weeks (33.9% vs 7.4%; P = .023). The 24-week RBC-TI rates with the agent were 28.0% (95% CI, 20.1%-37.0%) and 3.3% (95% CI, 0.4%-11.5%), respectively (P < .001).

Most patients (83%) who achieved 8-week RBC-TI with imetelstat experienced durable continuous RBC-TI episodes. Those who received imetelstat and achieved RBC-TI at 8 weeks had a significantly longer duration of TI than those given placebo, at 51.6 weeks (95% CI, 26.9-83.9) vs 13.3 weeks (95% CI, 8.0-24.9), respectively (HR, 0.23; 95% CI, 0.09-0.57; P < .001).

A significant improvement in hematologic improvement–erythroid (HI-E) was also observed with imetelstat vs placebo, at rates of 42.4% (95% CI, 33.3%-51.8%) and 13.3% (95% CI, 5.9%-24.6%), respectively (P < .001). Moreover, a significant and sustained increase in hemoglobin was observed in those who received imetelstat vs placebo, at a median rise of 3.6 g/dL (range, -0.1 to 13.8) and 0.8 g/dL (range, -0.2 to 1.7), respectively.

“The EMA validation of the marketing authorization application for imetelstat brings us one step closer to potentially offering this first-in-class therapeutic to lower-risk MDS patients in the European Union suffering from anemia,” John A. Scarlett, MD, chairman and chief executive officer of Geron Corporation, stated in a press release.¹ “Based on the clinical profile of imetelstat to date, we are optimistic about its potential to become a standard of care and address longstanding unmet needs of lower-risk MDS patients.”

The double-blind, placebo-controlled, phase 3 trial enrolled patients with low- or intermediate-1 risk MDS by International Prognostic Scoring System (IPSS) criteria who were relapsed or refractory to erythropoiesis-stimulating agents (ESAs) or had an erythropoietin level of over 500 mU/mL.² Patients also needed to be transfusion dependent, which was defined as requiring at least 4 unites of RBCs every 8 weeks over the 16 weeks before the study. They could not have 5q deletions or have prior exposure to lenalidomide (Revlimid) or hypomethylating agents.

Study participants were randomly assigned 2:1 to receive imetelstat at 7.5 mg/kg every 4 weeks or placebo. Patients were stratified by transfusion burden (4 to 6 units vs over 6 units) and IPSS risk category (low vs intermediate-1).

The primary end point of the trial was RBC-TI at 8 weeks, and important secondary end points included 24-week RBC-TI rates, duration of TI, HI-E rates, and safety. Exploratory end points included variant allele frequency changes and patient-reported outcomes measured by FACIT-Fatigue.

The median age across the investigative and control treatment arms was 72.5 years (range, 39-87), with more than half of patients being male (60% vs 67%). Sixty-two percent of those in both arms had ring sideroblasts by World Health Organization classification. Most patients had low IPSS risk category (68% vs 66%), and the median prior RBC transfusion burden in both arms was 6 (range, 4-33). The median pre-treatment hemoglobin level in the imetelstat arm was 7.9 g/dL (range, 5.3-10.1) vs 7.8 g/dL (range, 6.1-9.2) in the placebo arm. Prior ESA use was noted in 92% and 87% of patients, respectively.

At a data cutoff date of October 13, 2022, the median duration of treatment in the investigative arm was 33.9 weeks vs 28.3 weeks in the placebo arm, with 22.9% vs 23.7% of patients, respectively, still receiving treatment on study. In the imetelstat arm, the most common reason for discontinuation was lack of efficacy (23.7%), followed by an adverse effect (AE; 16.1%), other (16.1%), disease relapse following response on study (14.4%), disease progression (5.9%), and death (0.8%).

Regarding safety, the most common grade 3 or 4 AEs reported in the imetelstat (n = 118) and placebo (n = 59) arms, respectively, were thrombocytopenia (62% vs 8%) and neutropenia (68% vs 3%). Most of these effects occurred during the first 3 treatment cycles, and the median duration of these effects was less than 2 weeks with more than 80% of cases found to be reversible to grade 2 or less within 4 weeks. Additionally, 34.7% vs 3.4% of those in the imetelstat and placebo arms, respectively, received 1 or more doses of a myeloid growth factor.

Nonhematologic toxicities were noted to be generally low grade. Approximately 75% of patients who received imetelstat required dose modifications because of AEs and less than 15% discontinued. Notably, no cases of Hy’s Law or drug-induced liver injury were reported.

In August 2023, the FDA accepted a new drug application seeking the approval of imetelstat for the treatment of transfusion-dependent anemia in patients with lower-risk MDS.³ This application was also based on IMerge data.

References

1. Geron announces EMA validation of marketing authorization application for imetelstat for the treatment of lower risk MDS. News release. Geron Corporation. September 29, 2023. Accessed October 3, 2023. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-EMA-Validation-of-Marketing-Authorization-Application-for-Imetelstat-for-the-Treatment-of-Lower-Risk-MDS/
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. Geron announces FDA acceptance of new drug application for imetelstat for the treatment of lower risk MDS. News release. Geron. August 21, 2023. Accessed October 3, 2023. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-FDA-Acceptance-of-New-Drug-Application-for-Imetelstat-for-the-Treatment-of-Lower-Risk-MDS/default.aspx