By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration (FDA) has approved a first-in-class telomerase inhibitor for the treatment of myelodysplastic syndrome with transfusion-dependent anemia.
Imetelstat is a 13-mer oligonucleotide that competitively binds to the ribonucleic acid template of human telomerase. It was granted orphan drug designation and distributed by Geron Corporation as Rytelo.1
Indications
Imetelstat is indicated for the treatment of adult patients with low- to intermediate-1 risk myelodysplastic syndrome (MDS) with transfusion-dependent anemia requiring four or more red blood cell units over eight weeks who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents (ESAs).2
Dosage
The recommended dosage is 7.1 mg/kg given as an intravenous infusion over two hours every four weeks.2
Premedication with diphenhydramine and hydrocortisone is recommended 30 minutes prior to imetelstat infusion. Imetelstat is available in 47-mg and 188-mg single-dose vials for reconstitution.
Potential Advantages
Imetelstat provides transfusion independence (≥ 8 weeks) in approximately 40% of patients with low- to intermediate-1 risk MDS who have failed to respond to or have lost response for erythropoiesis-stimulating agents.2,3
Potential Disadvantages
The most common frequent (vs. placebo) grade 3-4 adverse reactions were neutropenia (68% vs. 3%), and thrombocytopenia (62% vs. 8%), with median durations of 1.9 and 1.4 weeks, respectively.3 For most participants, these occur within the first three treatment cycles. Sixteen percent of participants discontinued treatment because of adverse events.3 Based on animal studies, imetelstat may cause embryo-fetal toxicity. Other adverse reactions (> 15%) include arthragia/myalgia, fatigue, and headache.2
Comments
Telomerase is essential to maintaining the length of telomeres within rapidly dividing cells and is upregulated in malignant cells.3 Imetelstat prevents the lengthening and maintenance of telomeres and the induction of apoptotic cell death.2 The efficacy of imetelstat was evaluated in a randomized, double-blind, placebo-controlled trial (IMerg) in subjects (n = 178) with low- to intermediate-1 risk MDS as per the International Prognostic Scoring System (IPSS) criteria.2,4 Eligible participants were
transfusion-dependent (≥ 4 red blood cell units over an eight-week period during the 16 weeks prior to randomization) and relapsed or refractory to (endogenous erythropoietin level > 500 mU/mL) or ineligible for ESAs.
In addition, they had an absolute neutrophil count of ≥ 1.5 x 109/L and a platelet count of ≥ 75 x 109/L. Patients with del(5q) cytogenetic abnormalities or who had received prior treatment with lenalidomide or hypomethylating agents were excluded. Subjects were randomized to imetelstat (n = 118) or placebo (n = 60) arms in 28-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal from the study took place.
The primary efficacy endpoint was the proportion of subjects who were red blood cell-transfusion-independent (RBC-TI) for eight consecutive weeks or longer. Secondary endpoints included rate of 24-week RBC-TI and duration of RBC-TI. About two-thirds of patients were classified as IPSS low-risk and one-third were classified as intermediate-risk MDS. Approximately 90% had prior ESA use.
The median follow-up times were 19.5 months for imetelstat and 17.5 months for placebo. The rate of ≥ 8-week RBC-TI for imetelstat was 39.8% compared to 15.0% for placebo (P < 0.001). Response rates were 40% for both low-risk and intermediate-risk participants in the imetelstat group, compared to 21% and 7%, respectively, for the placebo group. Rates for ≥ 24-week RBC-TI were 28% vs. 3.3%. (P < 0.001). Eighteen percent of participants were transfusion-free for one year or longer (exploratory endpoint), compared to 2% for the placebo groups.3 Reduction of ≥ 50% in bone marrow ring sideroblasts (excess iron in RBCs) relative to baseline was observed with imetelstat, 41% vs. 10%. RBC-TI responders were enriched in these participants. Sixty percent of participants in the imetelstat group showed at least a 50% reduction in telomerase activity in the peripheral blood from baseline, compared to 38% for the placebo group.
Clinical Implications
Myelodysplastic syndrome is a clonal disorder of hematopoietic stem cells characterized by ineffective hematopoiesis and cytopenia.5 More than 100 point somatic mutations have been implicated. The incidence of MDS is estimated to be 4.9 per 100,000 individuals based on data from 2007 through 2011.5 The IPSS or R-IPSS scoring system provides the risk of disease sequela and course of treatment. Some patients may transform to acute myeloid leukemia.
Allogeneic hematopoietic stem cell transplant is the only curative treatment for high-risk MDS. In low-risk MDS patients, those who are asymptomatic can be treated with supportive measures (e.g., intermittent blood/platelet transfusions). An ESA is recommended for those with an erythropoietin level less than 500 mU/mL. Luspatercept, an erythroid maturation agent, may be preferable in ESA-naïve, transfusion-dependent, lower-risk MDS patients with ring sideroblast because of its improved rate of transfusion independence and increase in hemoglobin compared to epoetin alfa.6 Like imetelstat, luspatercept is FDA-approved for those failing an ESA and in ESA refractory/resistant patients. There currently are no published trials comparing imetelstat with luspatercept.
Imetelstat provides an option for patients with low- to intermediate risk MDS naïve to lenalidomide or a hypomethylating agent, who do not have del(5q) cytogenetic abnormality, and in those for whom an ESA no longer is an option to extend transfusion-free period. The cost for imetelstat is approximately $350,000/year.
References
- Tryvio Prescribing Information. Idorsia Pharmaceuticals US Inc. March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217686s000lbl.pdf
- Center for Drug Evaluation and Research. Application number: 217686Orig1s000 integrated review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217686Orig1s000IntegratedR.pdf
- Schlaich MP, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 2022;400:1927-1937.
- Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension 2011;57:1076-1080.
- Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: Detection, evaluation, and management: A scientific statement from the American Heart Association. Hypertension 2018;72:e53-e90.
The U.S. Food and Drug Administration has approved a first-in-class telomerase inhibitor for the treatment of myelodysplastic syndrome with transfusion-dependent anemia.
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