FDA Approves Imetelstat for Lower-Risk Myelodysplastic Syndromes With Transfusion-Dependent Anemia


Imetelstat (Rytelo; Geron Corp) is a first-in-class telomerase inhibitor.

The FDA has approved imetelstat (Rytelo; Geron Corp), a first-in-class telomerase inhibitor, for the treatment of adult patients with lower-risk myelodysplastic snyndromes (LR-MDS) with transfusion-dependent anemia who require 4 or more red blood cell units over 8 weeks and who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents (ESAs).1

LR-MDS is a cancer of the blood that often progresses and requires increasingly intense symptom management for anemia and fatigue. Patients with symptomatic LR-MDS frequently become dependent on red blood cell transfusions, although this dependence has been shown to be associated with short- and long-term clinical consequences that reduce quality of life and shorten survival.1

Concept of FDA approved. Food and drugs administration. Quality medcine, assurance, organization.

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Patients with LR-MDS have a high unmet need, particularly those with characteristics pointing to a poorer prognosis. Current options for those failing ESA are limited to select sub-populations, and there is an unmet need for treatments that can provide extended and continuous red blood cell transfusion independence (RBC-TI).1

“With the approval and availability of Rytelo, we believe eligible patients with LR-MDS can potentially experience meaningful clinical benefit, particularly the potential for greater than 24 weeks of freedom from the burden of red blood cell transfusions and symptomatic anemia,” said John A. Scarlett, MD, chairman and chief executive officer of Geron, in a news release. “The approval of Rytelo as the first telomerase inhibitor is a testament to the power of our science and the passion of our people to innovate in the field of blood cancer.”1

As a telomerase inhibitor, imetelstat works by inhibitor telomerase enzymatic activity. Telomeres are protective caps at the end of chromosomes that naturally shorten each time a cell divides. In patients with LR-MDS, abnormal bone marrow cells often express telomerase, which rebuilds those telomeres and allows for uncontrolled cell division.1

The FDA approval is based on results from the IMerge phase 3 clinical trial, which were published in The Lancet. The trial met its primary and key secondary end points, with imetelstat demonstrating significantly higher rates of RBC-TI versus placebo for at least 8 consecutive weeks (imetelstat 39.8% [95% CI, 30.9 to 49.3]; placebo 15% [7.1 to 26.6]; p<0.001) at for at least 24 weeks (imetelstat 28% [95% CI, 20.1 to 37.0]; placebo 3.3% [95% CI, 0.4 to 11.5]; p<0.001). RBC-TI was durable and sustained in the patients treated with imetelstat, with a median RBC-TI duration for 8-week responders of 1 year, and a median RBC-TI duration for 24-week responders of 1.5 years.2

Furthermore, in an exploratory analysis of imetelstat-treated patients who achieved ≥8-week RBC-TI, median increases in hemoglobin were 3.6 g/dL for imetelstat and 0.8 g/dL for placebo. Clinically meaningful efficacy results were observed across key MDS subgroups regardless of ring sideroblast status, baseline transfusion burden, and international prognostic scoring system risk category.2

“For patients with LR-MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of Rytelo potentially practice-changing for us,” said Rami Komrokji, MD, vice chair of the Malignant Hematology Department at Moffitt Cancer Center and an investigator of the pivotal IMerge clinical trial, in the news release. “What is exciting about Rytelo is the totality of the clinical benefit across LR-MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias.”1

According to results of the IMerge trial, the safety profile of imetelstat was well-characterized with manageable and short-lived thrombocytopenia and neutropenia. According to the investigators, these adverse effects are familiar for hematology care teams. The most common grade 3/4 adverse reactions were neutropenia (72%) and thrombocytopenia (65%), which lasted a median duration of less than 2 weeks and resolved to grade 1 or 2 in under 4 weeks for more than 80% of patients. Dose modifications were generally effective at managing cytopenias and the intravenous administration of imetelstat every 4 weeks aligned with the routine blood count monitoring necessary for these patients.2

The most common adverse reactions (≥10% with a difference between arms of >5% compared with placebo), including laboratory abnormalities, were decreased platelets, decreased white blood cells, decreased neutrophils, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infection, and headache. Clinically relevant adverse reactions in more than 5% of patients who received imetelstat included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension.2

“The treatment goal for patients with LR-MDS and anemia is transfusion-independence and before today, this wasn’t possible for many patients,” Komrokji concluded.1


1. Geron Announces FDA Approval of Rytelo (imetelstat), a First-in-Class Telomerase Inhibitor, for the Treatment of Adult Patients with Lower-Risk MDS with Transfusion-Dependent Anemia. News release. Geron Corp. June 6, 2024. Accessed June 7, 2024. https://www.businesswire.com/news/home/20240606850162/en

2. 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, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5

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