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FDA approves first-in-class telomerase inhibitor imetelstat for transfusion-dependent LR-MDS

On June 6, 2024, the U.S. Food and Drug Administration (FDA) approved imetelstat for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) and transfusion-dependent anemia who have not responded to or are ineligible for erythropoiesis-stimulating agents (ESAs).1

Lower-risk MDS (LR-MDS) are a group of hematologic disorders marked by ineffective hematopoiesis, leading to blood cell dysplasia and cytopenias. Patients with transfusion-dependent LR-MDS often become refractory to first-line ESA treatment, presenting an unmet need.2

Imetelstat inhibits telomerase activity, causing telomere shortening and dysfunction in malignant cells, reducing their proliferation and increasing apoptosis.3 The approval was based on positive results from the IMerge trial (NCT02598661), a randomized, double-blind, placebo-controlled study involving 178 patients with MDS who were refractory, resistant, or ineligible for ESAs and had high transfusion dependence. Patients received imetelstat (7.1 mg/kg) or a placebo in 28-day cycles, with a median follow-up of 19.5 months for the imetelstat arm and 17.5 months for the placebo arm.1

The primary endpoint was met, with 39.8% (95% CI: 30.9, 49.3) of patients in the imetelstat arm achieving ≥ 8-week red blood cell transfusion independence (RBC-TI) compared to 15% (95% CI: 7.1, 26.6) in the placebo arm (p-value < 0.001). Additionally, 28% (95% CI: 20.1, 37) of patients in the imetelstat arm achieved ≥ 24-week RBC-TI compared to 3.3% (95% CI: 0.4, 11.5) in the placebo arm.1

Regarding safety, 91% of patients on imetelstat experienced grade 3-4 treatment-emergent adverse events (TEAEs), primarily neutropenia and thrombocytopenia, compared to 47% in the placebo group. No treatment-related deaths occurred.4 Other adverse events (AEs) included fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.1

We spoke with Valeria Santini, MD, University of Florence, Florence, Italy, at the 2023 ASH Annual Meeting and Exposition, who discussed the mechanism of action of imetelstat and results from the IMerge trial. Prof. Santini highlighted that “imetelstat seems to have disease-modifying activity, meaning that responses correlate with a decrease in the variant allele frequency of specific somatic mutations, like TET2, ASXL1, and DNMT3A, which are the most common ones, as well as SF3B1”.

The FDA’s approval of imetelstat represents a pivotal advancement for adults with LR-MDS and transfusion-dependent anemia who have exhausted ESAs. As a first-in-class telomerase inhibitor, imetelstat offers a promising, disease-modifying treatment option, addressing a critical unmet need in this patient population.

References

  1. U.S. Food and Drug Administration. FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. Available here. (Last accessed 13/06/2024).
  2. Mukherjee S, Zimmerman Savill KM, Gajra A, et al. Real-world erythropoiesis-stimulating agent (ESA) treatment patterns and outcomes among U.S. patients with lower-risk myelodysplastic syndromes (LR-MDS). Journal of Clinical Oncology. 2022 Jun 02; 40:19065-19065.
  3. Röth A, Harley CB, Baerlocher GM. Imetelstat (GRN163L)–telomerase-based cancer therapy. Recent Results Cancer Res. 2010;184:221-34.
  4. 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. The Lancet. 2024 Jan 20; 403:249 – 260.

Written by Hannah Elkheir

Edited by Anya Dragojlovic Kerkache