Significant and durable transfusion independence was achieved with imetelstat vs placebo in patients with lower-risk myelodysplastic syndromes who were relapsed, refractory, or ineligible for erythropoiesis-stimulating agents, meeting the primary and a key secondary end point of the phase 3 IMerge trial.
John A. Scarlett, MD
Significant and durable transfusion independence (TI) was achieved with imetelstat vs placebo in patients with lower-risk myelodysplastic syndromes (MDS) who were relapsed, refractory, or ineligible for erythropoiesis-stimulating agents (ESAs), meeting the primary and a key secondary end point of the phase 3 IMerge trial (NCT02598661).
Top-line data from the primary analysis of the trial indicated that treatment with imetelstat (n = 118) resulted in a TI rate of 39.8% (95% CI, 30.9%-49.3%) at 8 weeks vs 15.0% (95% CI, 7.1%-26.6%) with placebo (n = 60) in this population (P < .001). The 24-week TI rates in the investigative and placebo arms were 28.0% (95% CI, 20.1%-37.0%) and 3.3% (95% CI, 0.4%-11.5%), respectively (P < .001).
Moreover, the median TI duration achieved with imetelstat was approximately 1 year vs approximately 13 weeks with placebo utilizing Kaplan-Meier estimates, indicating statistically significant durable TI for 8-week TI responders (HR, 0.23). In the 24-week TI responders who received imetelstat, the median TI duration was approximately 1.5 years.
“Today is a great day for lower-risk MDS patients who are living with the burden of transfusions. The results from the IMerge phase 3 study were resoundingly positive, presenting compelling durability of TI, delivering on the promise of imetelstat and telomerase inhibition for these patients,” John A. Scarlett, MD, chairman and chief executive officer of Geron Corporation, stated in a press release.
The double-blind, randomized, placebo-controlled trial enrolled patients with transfusion-dependent MDS who had International Prognostic Scoring System (IPSS)–low and intermediate-1 risk status. Patients were relapsed, refractory, or ineligible for ESA treatment, had not received a prior hypomethylating agent or lenalidomide (Revlimid), and were non-del(5q).
Study participants were randomly assigned 2:1 to receive imetelstat administered intravenously at a starting dose of 7.5 mg/kg every 4 weeks or matching placebo. Treatment was continued until progressive disease, intolerable toxicity, withdrawn consent, or lack of response.
The primary end point of the trial was the percentage of patients without any red blood cell (RBC) transfusions during an 8-week period. A key secondary end point is the percentage of patients without RBC transfusions in a 24-week period.
The cutoff date for the analysis was October 2022. The median time on study and median time on treatment for the imetelstat arm was about 20 months and about 18 months, respectively; for the placebo arm, this was about 8 months and 7 months, respectively.
Additional data showed that transfusion independence was broadly achieved, with a significant improvement in 8-week TI with imetelstat vs placebo (P < .05) across lower-risk MDS subtypes, including World Health Organization (WHO) RS-positive and -negative status, high and very-high transfusion burden, and IPSS low and intermediate-1 risk status.
Specifically, the 8-week TI rates with imetelstat (n = 73) vs placebo (n = 37) in the RS-positive subgroup were 45.2% and 18.9%, respectively (difference, 26.3%; 95% CI, 5.9%-42.2%; P = .016). In the RS-negative subgroup, the 8-week TI rate with imetelstat (n = 44) was 31.8% vs 8.7% with placebo (n = 23; difference, 23.1%; 95% CI, -1.3 to 40.6; P = .038).
In the subgroup of patients with a transfusion burden of 4 to 6 units, the 8-week TI rates achieved with imetelstat (n = 62) and placebo (n = 33) were 45.2% and 21.2%, respectively (difference, 23.9%; 95% CI, 1.9%-41.4%; P = .023). In those with a transfusion burden of more than 6 units, the 8-week TI rates in the investigative (n = 56) and control (n = 27) arms were 33.9% and 7.4%, respectively (difference, 26.5%; 95% CI, 4.7%-41.8%; P = .023).
Moreover, in the subset of patients with an IPSS risk status of low, the 8-week TI rate experienced in the imetelstat arm (n = 80) was 40.0% vs 20.5% in the placebo arm (n = 39; difference, 19.5%; 95% CI, -0.1% to 35.2%; P = .034). In the group of patients with intermediate-1 IPSS risk status, the 8-week TI rates in the investigative (n = 38) and control (n = 21) arms were 39.5% and 4.8%, respectively (difference, 34.7%; 95% CI, 8.8%-52.4%; P = .004).
Additional findings revealed that those who received imetelstat experienced a significant increase in mean hemoglobin levels over time (P < .001) vs those who were given placebo per IWG 2018 criteria for HI-E. Of note, the original trial protocol was finalized in 2015, and as such, IWG 2006 HI-E criteria were used at that time; with those criteria, the difference between the 2 arms was not statistically significant (P = .112).
No new safety signals were observed with imetelstat.
The most frequently experienced non-hematologic treatment-emergent adverse effects (TEAEs) experienced in the imetelstat arm were asthenia, COVID-19, peripheral edema, headache, diarrhea, and increased alanine aminotransferase. Cases of grade 3 liver function test elevations proved to be transient and reversible to a severity level of grade 2 or lower.
The most common grade 3 or 4 hematologic TEAEs experienced in the imetelstat and placebo arms were thrombocytopenia (61.9% vs 8.5%, respectively) and neutropenia (67.8% vs 3.4%). Those who received imetelstat experienced a shorter median duration of thrombocytopenia than those who received placebo, at 1.4 weeks vs 2.0 weeks, respectively; this was also true for neutropenia, with a median of 1.9 weeks vs 2.2 weeks, respectively.
Moreover, those in the imetelstat arm experienced a higher rate of grade 3/4 cytopenia resolution to grade 2 or lower within 4 weeks than those in the placebo arm for thrombocytopenia (86.3% vs 44.4%) and neutropenia (81.0% vs 50.0%).
Based on these data, and other findings from prior clinical trials, Geron Corporation shared plans to submit a new drug application seeking the approval of imetelstat to the FDA in mid-2023, and a marketing authorization application to the European Commission in the second half of 2023.
Geron announces positive top-line results from IMerge phase 3 trial of imetelstat in lower risk MDS. News release. Geron Corporation. January 4, 2023. Accessed January 4, 2023. https://bit.ly/3GjZPKh