The European Commission (EC) has granted marketing authorization for imetelstat (Rytelo) as a monotherapy for adult patients with transfusion-dependent anemia due to very low-, low-, or intermediate-risk myelodysplastic syndrome (MDS) who do not harbor an isolated deletion 5q cytogenetic abnormality and have experienced an unsatisfactory response to or are ineligible for erythropoietin-based therapy (ESAs).
This regulatory decision establishes imetelstat as the first and only telomerase inhibitor approved by the EC. The marketing authorization applies to all 27 member states of the European Union, Iceland, Norway, and Liechtenstein, coming just nine months after the drug received FDA approval in the United States in June 2024.
Pivotal Trial Results Support Approval
The approval was based on compelling data from the phase 3 IMerge trial (NCT02598661). At a median follow-up of 19.5 months in the imetelstat arm (n = 118) and 17.5 months in the placebo arm (n = 60), red blood cell transfusion independence (RBC-TI) for at least 8 consecutive weeks was achieved by 40% of patients receiving imetelstat compared to 15% in the placebo group (P = .0008).
More impressively, the rate of RBC-TI lasting 24 weeks or longer was 28% in the imetelstat arm versus just 3.3% in the placebo arm (P < .001), demonstrating the drug's ability to provide durable transfusion independence.
"I am thrilled that the EC has approved imetelstat in lower-risk MDS. The long-term and durable responses observed in the phase 3 IMerge study reinforce the practice-changing potential of telomerase inhibition as a clinically meaningful and differentiated option for the treatment of lower-risk MDS," said Uwe Platzbecker, MD, chief medical officer at the University Hospital Carl Gustav Carus Dresden in Germany, and co-lead author of the IMerge data published in The Lancet.
Study Design and Patient Population
IMerge was a double-blind, placebo-controlled study that enrolled adult patients with low- or intermediate-1–risk MDS according to the International Prognostic Scoring System (IPSS). Eligible patients were red blood cell transfusion dependent, defined as requiring at least 4 units of RBCs over an 8-week period, and had disease that was either relapsed/refractory to ESAs or were ineligible for ESA therapy.
Patients were randomly assigned 2:1 to receive intravenous imetelstat at a starting dose of 7.5 mg/kg every 4 weeks or placebo. The study's primary endpoint was the 8-week RBC-TI rate, with key secondary endpoints including the 24-week RBC-TI rate, duration of RBC-TI, and hematologic improvement-erythroid (HI-E).
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 was 51.6 weeks in the imetelstat arm compared to just 13.3 weeks in the placebo arm.
Clinical Significance for Patients
"As the first and only treatment of its kind, imetelstat represents an important new option – significantly reducing the need for RBC transfusions for people living with lower-risk MDS who are battling debilitating symptoms like anemia and fatigue," said Joseph Eid, MD, executive vice president of Research and Development at Geron, the drug's manufacturer.
For patients with lower-risk MDS, transfusion dependence significantly impacts quality of life and is associated with increased morbidity and mortality. The ability to achieve transfusion independence represents a meaningful clinical benefit that can improve both survival outcomes and patient well-being.
Safety Profile and Patient Selection Considerations
Imetelstat's safety profile has been well-characterized, with notable adverse effects (AEs) including thrombocytopenia and neutropenia. The most commonly reported grade 3 or higher AEs were neutropenia (69%) and thrombocytopenia (63%), which lasted a median duration of less than 2 weeks. More than 80% of these cases resolved to less than grade 2 within 4 weeks.
Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center, emphasized the importance of patient selection when considering imetelstat therapy.
"Imetelstat can cause significant thrombocytopenia and significant neutropenia, so we start with selecting patients who have some reserve in their platelet counts and their hemoglobin and their neutrophil count," Dr. Yacoub explained. "It is not a drug for everybody; it's a drug for select patients who have otherwise preserved platelets and neutrophils, and then meticulous follow-up for the platelet counts and the neutrophils and supporting patients accordingly."
Non-hematologic adverse events included arthralgia/myalgia, headache, and fatigue, though few were grade 3 or higher. Adverse effects led to dose modification in approximately 75% of patients treated with imetelstat; however, less than 15% of patients discontinued treatment due to treatment-emergent AEs.
Market Impact and Future Directions
The approval of imetelstat adds an important new option to the treatment landscape for lower-risk MDS patients in Europe. As the first telomerase inhibitor approved for this indication, it represents a novel mechanism of action that addresses an unmet need for patients who have limited treatment options after failing or being ineligible for ESA therapy.
John A. Scarlett, MD, chairman and CEO of Geron, stated, "The positive CHMP opinion is an important step towards our goal to optimize value and patient access to imetelstat in the European Union, where we look forward to the opportunity to make this important new treatment option for patients with lower-risk MDS available in select markets."
With both FDA and EC approvals now secured, Geron will focus on commercialization efforts and ensuring patient access to this novel therapy across approved markets.
