Imetelstat is a first-in-class direct and competitive inhibitor of telomerase activity. Imetelstat specifically targets malignant clones with abnormally high telomerase activity, enabling recovery of effective hematopoiesis. The pivotal Phase III IMerge trial (NCT02598661) results with an October 2022 data cut-off were presented at 2023 American Society of Clinical Oncology (ASCO) Annual Meeting; the top-line results for the same were released in January 2023. Lower-risk Myelodysplastic Syndrome patients who had relapsed after, resistant to, or ineligible for erythropoiesis-stimulating agent (ESA) therapy and transfusion-dependent (requiring at least four units of packed red blood cells (RBCs) during an eight-week period) were included in the trial. The primary objective of the trial was to assess transfusion independence (TI) at 8 weeks, while secondary objectives included evaluating transfusion independence at 24 weeks, the duration of transfusion independence, hematologic improvement in the erythroid system, and safety. Additionally, the investigators examined changes in variant allele frequency (a measure of genetic variations) and patient-reported outcomes as part of the study.
Patients who received imetelstat achieved 8-week RBC TI at a rate of 39.8% compared with 15.0% among patients who received a placebo. 24-week TI was also reached with substantial statistical significance in imetelstat-treated patients (28.0%) compared to placebo (3.3%). In comparison to placebo patients, mean hemoglobin levels increased considerably in imetelstat-treated patients over time. The median rise in hemoglobin for patients who achieved 8-week TI was 3.6 g/dL with imetelstat and 0.8 g/dL for placebo.
Imetelstat-treated individuals also had a statistically significant and clinically relevant decrease in RBC transfusion units when compared to placebo. Using the International Working Group (IWG 2018) HI-E criteria, imetelstat demonstrated a highly statistically significant hematologic improvement-erythroid (HI-E) rate (42.4%) against placebo (13.3%).
The observed safety profile was comparable with previous clinical data, with no new safety signals. Non-hematologic adverse effects (AEs) were mostly minor. The most often reported hematologic AEs were Grade 3-4 thrombocytopenia and neutropenia, which occurred most frequently during Cycles 1-3. Within two weeks, these cytopenias resolved, and over 80% of occurrences were reversible to Grade 2 or below within four weeks. There were no hematologic AEs or cytopenic events that were deadly. Clinical effects from grade 3-4 neutropenia and thrombocytopenia were similar in patients treated with imetelstat and placebo.
Imetelstat-treated individuals had lower variation allele frequency (VAF) of genes frequently mutated in Myelodysplastic Syndrome compared to placebo. Reduced SF3B1 VAF was associated with a larger rise in hemoglobin and a longer TI duration. A higher VAF drop in TET2, DNMT3A, or ASXL1 was similarly linked to a longer TI duration. Such correlations support imetelstat’s disease-modifying potential.
“The IMerge Phase 3 results are especially encouraging because of the significant unmet need in lower risk Myelodysplastic Syndrome patients with symptomatic anemia needing regular red blood cell transfusions, especially with less than half of such patients responding to frontline ESA therapy, and most of those who do respond losing that response in less than two years” – Expert Opinion.
Imetelstat has shown the potential to redefine treatment options for LR-Myelodysplastic Syndrome patients, with robust RBC-TI rates at 8 and 24 week (40%, and 28%), median RBC-TI duration approaching 1 year for 8-week RBC-TI responders, as well as sustained increases in Hgb and HI-E per IWG 2018 (p<0.001 each). These findings backs up Geron's anticipated New Drug Application (NDA) filing to the US Food and Drug Administration (FDA), which is scheduled for June 2023 and could support an imetelstat commercial launch in the United States for lower-risk Myelodysplastic Syndrome in the first half of 2024. This news represents a major breakthrough and an important milestone in offering a viable treatment option for lower-risk Myelodysplastic Syndrome patients.