Initial Results from the QTc Substudy of the IMerge Phase 3 Trial Demonstrate Clinically Meaningful Efficacy, Manageable Safety, and Absence of Proarrhythmic Risk in Patients with Lower-Risk Myelodysplastic Syndromes Who Received Prior Therapies Beyo

Introduction: Imetelstat, a direct and competitive inhibitor of telomerase enzymatic activity, was approved by the United States Food and Drug Administration (FDA) in June 2024 for adult patients (pts) with red blood cell (RBC) transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS) who are relapsed or refractory to or ineligible for erythropoiesis-stimulating agents (ESA) based on the results of the pivotal phase 3 IMerge trial (NCT02598661). IMerge demonstrated a clinically meaningful and statistically significant RBC-transfusion independence (TI) rate for imetelstat versus placebo for the primary endpoint (≥8-wk RBC-TI: 40% vs 15%, respectively; P<.001) and a generally manageable safety profile (Platzbecker U, Santini V, et al. Lancet. 2024). A ventricular repolarization substudy of IMerge was conducted as per FDA guidance. Here, we report the first efficacy and safety results from this substudy. Methods: Adult pts were randomized to receive imetelstat (7.1 mg/kg, equivalent to 7.5 mg/kg imetelstat sodium) or placebo, every 4 wk in 28-d cycles. Placebo recipients could cross over to imetelstat after completing 2 cycles. Efficacy endpoints included ≥8-wk and ≥24-wk RBC-TI rates, hematologic improvement-erythroid (HI-E) by International Working Group (IWG) 2018 criteria, and transfusion reduction and hemoglobin (Hb) changes by IWG 2006 criteria. The proportion of pts with RBC-TI and other binary endpoints were summarized with percentages and 95% 2-sided exact Clopper-Pearson CI. Kaplan-Meier methodology estimated the distribution of duration of RBC-TI. The primary objective of the substudy was to evaluate the concentration-QT relationship by the primary electrocardiogram (ECG) endpoint (change from baseline QTcF using a linear mixed-effects modeling approach). Triplicate ECGs were collected on cycle 1, day 1 (−1, −0.5, and 0 h predose, and at 0.5, 1, 2, 4, 6, and 8 h after the start of infusions). This substudy differed from the IMerge phase 3 trial in its crossover design and by allowing prior lenalidomide and hypomethylating agent (HMA) therapy besides ESAs. Results: The mean age of the QTc substudy population (N=53 [35 imetelstat, 18 placebo]) was 69 y (range, 43-84); 81% were male, 87% had prior ESA use, 98% were non-del(5q), and 43% had prior luspatercept use. At baseline, 55% were receiving >6 U RBC/8 wk and median Hb was 7.6 g/dL. No clinically meaningful effects of imetelstat on cardiac repolarization or other ECG parameters were observed. As of the data cutoff (05/10/2024), 16 placebo recipients crossed over to receive imetelstat. With a median treatment duration of 29.3 wk in the 51 total imetelstat-treated pts (including 35 randomized and 16 crossover pts), 41% (21/51) achieved ≥8-wk RBC-TI; the median (95% CI) duration of RBC-TI among responders was 52.6 wk (40.9-not estimable). Subgroup analyses demonstrated ≥8-wk RBC-TI rates of 30% (7/23) and 50% (14/28) in pts with and without prior luspatercept, 38% (5/13) and 42% (16/38) in pts with and without prior lenalidomide, and 21% (3/14) and 49% (18/37) in pts with and without prior azacitidine or decitabine use, respectively. In the 51 imetelstat-treated pts, ≥24-wk RBC-TI was achieved by 25% (13/51) of pts, HI-E per IWG 2018 response was achieved by 41% (21/51) of pts, 35% (18/51) experienced a Hb increase of ≥1.5 g/dL lasting ≥8 wk per IWG 2006, and 75% (38/51) of pts had a reduction in transfusions by ≥4 U/8 wk per IWG 2006. No new safety signals emerged and in the total imetelstat-treated population, grade 3/4 neutropenia and thrombocytopenia by laboratory evaluation occurred in 65% (33/51) and 49% (25/51) of pts, respectively, of which most cases resolved to grade ≤2 within 4 wk; incidence was similar to the overall phase 3 imetelstat-treated population. As of the data cutoff, progression to acute myeloid leukemia occurred in none of the imetelstat-treated pts versus 1 placebo recipient (before crossover). Conclusions: In this QTc substudy, imetelstat was associated with an absence of proarrhythmic risk, durable RBC-TI, transfusion reduction, clinically meaningful increases in Hb, and safety comparable to the overall population of the pivotal IMerge phase 3 trial. Of note, responses to imetelstat were seen in pts receiving prior treatments including luspatercept, lenalidomide, and HMA. Overall, the results of this IMerge QTc substudy support the use of imetelstat in pts with relapsed/refractory LR-MDS.