SUMMARY: The FDA on June 6, 2024, approved RYTELO® (Imetelstat), an oligonucleotide telomerase inhibitor, for adults with Low- to Intermediate-1 risk Myelodysplastic Syndromes (MDS) with Transfusion-Dependent anemia, requiring four or more red blood cell units over 8 weeks, who have not responded to, or have lost response to, or are ineligible for Erythropoiesis-Stimulating Agents (ESAs).
It is estimated that in the United States approximately 13,000 people are diagnosed with MDS each year. Myelodysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. The majority of individuals diagnosed with MDS are aged 65 years and older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML). The three prognostic factors scored to predict the course of the patients disease include percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia).
Patients with Lower-risk MDS (Revised IPSS-Very Low, Low, or Intermediate risk) often present with symptomatic anemia and these patients are in chronic need for RBC transfusions which in turn can result in iron overload and can have a negative impact on quality of life and Overall Survival. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200 U per liter are less likely to respond to ESAs. Patients with Low Risk (IPSS Low/Int-1) MDS who are RBC Transfusion Dependent, and are Relapsed/Refractory to ESAs, have limited treatment options. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients.
Human telomeres are repetitive DNA sequences present at terminal ends of chromosomes, protecting against premature shortening of chromosome lengths and preventing chromosomal degradation during cell division. Telomerase, a ribonucleoprotein enzyme complex, maintains telomere length by adding telomeric repeats, enabling cancer cells to bypass replicative senescence and achieve immortalization.
Imetelstat is a first-in-class telomerase inhibitor designed to disrupt telomere maintenance in malignant cells. Imetelstat specifically targets the template region of the telomerase RNA component (TERC) and by competitively binding to this template, Imetelstat inhibits telomerase activity, leading to progressive telomere shortening with each cell division. This process triggers cell cycle arrest, senescence, and apoptosis in telomerase-dependent cancer cells, including those in MDS.
The efficacy of Imetelstat was evaluated in IMerge, which is a randomized, double-blind, placebo-controlled multicenter Phase III trial, in which 178 patients with MDS were randomly assigned 2:1 to receive Imetelstat 7.5 mg/kg (N=118) or placebo (N=60), administered as a 2-hour IV infusion, every 4 weeks until disease progression or unacceptable toxicities. Eligibility requirements included patients with ESA-relapsed, ESA-refractory, or ESA-ineligible and non-del(5q) Low Risk-MDS (Low or Intermediate-1 risk disease, as per International Prognostic Scoring System-IPSS criteria), and without previous treatment with Lenalidomide or hypomethylating agents. Randomization was stratified by prior RBC transfusion burden and by IPSS risk group. All patients received supportive care, which included RBC transfusions.
The Primary endpoint was RBC Transfusion Independence (RBC-TI) defined as the proportion of patients achieving at least 8 consecutive weeks or longer without RBC transfusions from the start of treatment until subsequent anti-cancer therapy, if any. Secondary endpoints included the rate of 24-week RBC-TI and Duration of RBC-TI.
The median follow up was 19.5 months in the Imetelstat group and 17.5 months in the placebo group. Imetelstat demonstrated a significant improvement in the Primary endpoint compared to placebo. The rate of RBC-TI of at least 8 weeks was 40% in the Imetelstat group versus 15% in the placebo group (P=0.0008). The rate of 24-week or more RBC-TI was 28% in the Imetelstat group and 3.3% in the placebo group (P<0.001). Responding patients-maintained Transfusion Independence for a median duration of approximately 1 year, indicating durable clinical benefit. The most common grade 3-4 adverse events associated with Imetelstat included neutropenia (68%) and thrombocytopenia (62%). Despite these hematologic toxicities, there were no treatment-related deaths reported during the trial.
In conclusion, Imetelstat represents a promising therapeutic approach in the management of lower-risk MDS, offering a novel mechanism of action through telomerase inhibition. The IMerge trial demonstrated significant clinical benefits, including prolonged periods of RBC Transfusion Independence and disease stabilization, in a patient population with limited treatment options. Ongoing research aims to further elucidate the role of Imetelstat across different subsets of MDS and refine its clinical utility in improving patient outcomes.
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. Platzbecker U, Santini V, Fenaux P, et al. The Lancet. 2024;403:249-260.
