The First Telomerase Inhibitor Receives FDA Approval: Imetelstat (Rytelo)

On June 6, 2024, the US Food and Drug Administration (FDA) approved treatment for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) who have not responded to erythropoiesis-stimulating agents (ESAs), have lost their response, or are ineligible for these agents, and who require transfusions of four or more red blood cell (RBC) units over 8 weeks. The approved medicine is the oligonucleotide telomerase inhibitor imetelstat (Rytelo, Geron Corporation).

Telomeres are structural regions at chromosome ends that protect DNA sequences and maintain genome stability during cell division. Telomeres shorten with each cell division, and this shortening is an important factor in cellular aging and death. Imetelstat is the first telomerase inhibitor approved by the FDA.

What Are MDS and Transfusion-Dependent Anemia?

Myelodysplastic Syndromes (MDS): Myelodysplastic syndromes (MDS) are a group of blood disorders in which the bone marrow's production of healthy blood cells is impaired. This causes symptoms such as anemia (a low red blood cell count), susceptibility to infection (a low white blood cell count) and a tendency to bleed (a low platelet count). Patients with MDS often need blood transfusions to compensate for the shortage of blood cells.

Transfusion-Dependent Anemia Unresponsive to Erythropoiesis-Stimulating Agents (ESA): Erythropoiesis-stimulating agents (ESA) treat anemia by stimulating the bone marrow to produce more red blood cells. However, some patients with MDS do not respond to ESAs or lose their response. Because they cannot produce enough red blood cells, these patients become dependent on ongoing blood transfusions. Transfusion-dependent anemia is a chronic condition that reduces quality of life and requires treatment.

How Does Imetelstat Work?

Imetelstat is an oligonucleotide telomerase inhibitor. Telomerase maintains chromosome ends called telomeres, allowing cells to divide indefinitely. Telomerase activity is increased in some cancers, such as MDS, contributing to uncontrolled cancer-cell proliferation.

Imetelstat binds to the active site of the telomerase enzyme and blocks its function. This inhibition causes telomeres to shorten and eventually stops cell division, preventing cancer cells from growing and multiplying. This mechanism is a targeted approach to cancer treatment and may be effective in diseases such as MDS.

FDA Approval Based on the IMerge Study

Imetelstat's efficacy was evaluated in IMerge, a randomized, double-blind, placebo-controlled, multicenter study involving 178 patients with MDS. Patients were randomized to intravenous infusions of imetelstat at 7.1 mg/kg or placebo in 28-day cycles until disease progression or unacceptable toxicity. Randomization was stratified by previous RBC transfusion burden and International Prognostic Scoring System risk group. All patients received supportive care, including RBC transfusions.

Results

• Follow-Up:

  • Imetelstat group: median follow-up of 19.5 months (range = 1.4–36.2 months)
  • Placebo group: median follow-up of 17.5 months (range = 0.7–34.3 months)

• RBC Transfusion Independence for 8 Weeks:

  • Imetelstat group: 39.8% (95% confidence interval [CI] = 30.9%–49.3%)
  • Placebo group: 15% (95% CI = 7.1%–26.6%)
  • Statistical significance: P < 0.001

• RBC Transfusion Independence for 24 Weeks:

  • Imetelstat group: 28% (95% CI = 20.1%–37%)
  • Placebo group: 3.3% (95% CI = 0.4%–11.5%)
  • Statistical significance: P < 0.001

Adverse Events and Dosing

The most common adverse events (≥ 10%) and laboratory abnormalities occurring more than 5% more often with imetelstat than placebo included thrombocytopenia, leukopenia, neutropenia, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infection and headache.

The recommended imetelstat dose is 7.1 mg/kg, given as a 2-hour intravenous infusion every 4 weeks.

Review and Approval Process

The review used the Assessment Aid, a voluntary submission from the applicant intended to facilitate the FDA's assessment. This product received Orphan Drug designation.

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