Positive results were announced from the phase III IMerge trial (ClinicalTrials.gov identifier NCT02598661) evaluating the first-in-class telomerase inhibitor imetelstat in patients with lower-risk myelodysplastic syndromes (MDS) who are relapsed, refractory, or ineligible for erythropoiesis-stimulating agents. The trial met its primary efficacy endpoint of 8-week transfusion independence and a key secondary endpoint of 24-week transfusion independence, demonstrating a highly statistically significant and clinically meaningful benefit of imetelstat vs placebo and safety results consistent with prior imetelstat clinical trials.
Summary of Top-Line Results
IMerge is a double-blind, randomized (2:1), placebo-controlled clinical trial to evaluate imetelstat therapy in patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk (lower-risk), transfusion-dependent MDS who relapsed after, were refractory to, or were ineligible for treatment with erythropoiesis-stimulating agents; had not received prior treatment with either a hypomethylating agent or lenalidomide; and did not have a 5q deletion.
The top-line efficacy results from the primary analysis of data from IMerge showed a highly statistically significant and clinically meaningful difference between imetelstat and the placebo comparator arm for the primary endpoint of 8-week transfusion independence and key secondary endpoint of 24-week transfusion independence. Among 118 patients treated with imetelstat, at 8 weeks, 39.8% (n = 47) had achieved transfusion independence compared to 15% (n = 9) of the 60 patients treated with placebo; at 24 weeks, 28% (n = 33) of those treated with imetelstat had achieved transfusion independence vs 3.3% (n = 2) of those treated with placebo.
With a clinical data cut-off occurring in October 2022, median time on study and median time on treatment for patients on imetelstat was approximately 20 months and 8 months, respectively, and approximately 18 months and 7 months for placebo, respectively.
Highly statistically significant (P < .001, hazard ratio = 0.23) durable transfusion independence for 8-week transfusion independence responders was achieved, with a median transfusion independence duration approaching 1 year for imetelstat, compared to approximately 13 weeks for placebo, using Kaplan-Meier estimates. The median transfusion independence duration was approximately 1.5 years (80 weeks) for imetelstat 24-week transfusion independence responders.
Statistically significant (P < .05) 8-week transfusion independence was demonstrated with imetelstat vs placebo across lower-risk MDS subtypes, including with and without ring sideroblasts, high and very high transfusion burden, and IPSS low and intermediate-1 risk status, with similar 8-week transfusion independence responses seen for imetelstat within each subtype category.
Additional Data
Mean hemoglobin levels in patients treated with imetelstat increased significantly (P < .001) over time compared to patients receiving placebo. For patients achieving 8-week transfusion independence, median increases in hemoglobin were 3.6 g/dL for the imetelstat arm and 0.8 g/dL for placebo. Patients receiving imetelstat also experienced a statistically significant (P = .042) and clinically meaningful mean reduction in red blood cell transfusion units compared to placebo.
A highly statistically significant (P < .001) hematologic improvement–erythroid rate was achieved for imetelstat (42.4%) vs placebo (13.3%) using the International Working Group (IWG) 2018 criteria for hematologic improvement–erythroid. The original IMerge protocol was finalized in 2015 and applying the IWG 2006 hematologic improvement–erythroid criteria in use at that time, the difference between the imetelstat and placebo patients was not statistically significant (P = .112). The current IWG 2018 hematologic improvement–erythroid criteria places greater emphasis on durability by measuring response for > 16 weeks, rather than > 8 weeks as specified by the IWG 2006 criteria.
Clinical and molecular evidence supporting the potential for MDS disease modification with imetelstat included a 1-year median transfusion independence duration for imetelstat 8-week transfusion independence responders, a median rise of 3.6 g/dL in hemoglobin levels in those same patients and > 50% variant allele frequency decreases in SF3B1, TET2, DNMT3A, and ASXL1 mutations.
Safety Results Consistent
The treatment-emergent adverse events observed in IMerge were consistent with the known safety profile of imetelstat from prior clinical trials, and no new safety signals were found. Overall treatment discontinuation rates were consistent between the imetelstat and placebo groups (77.1% vs. 76.3%, respectively). Treatment discontinuation rates related to lack of efficacy were higher for the placebo group (42.4%) vs imetelstat (23.7%), and lower for adverse events between the placebo and imetelstat groups (0.0% vs. 16.1%, respectively).
The most common nonhematologic treatment-emergent adverse events (≥ 10%) in the imetelstat group included asthenia, COVID-19, peripheral edema, headache, diarrhea, and alanine aminotransferase increase. Grade 3 liver function test elevations reported in the trial were transient and reversible to grade 2 or lower, with no cases of liver test elevations consistent with Hy’s law or drug-induced liver injury observed.
The most frequent hematologic treatment-emergent adverse events were grade 3/4 thrombocytopenia (61.9% imetelstat vs 8.5% placebo) and neutropenia (67.8% imetelstat vs 3.4% placebo). Clinical consequences from cytopenias, such as > grade 3 bleeding events, infections and febrile neutropenia, were similar between the imetelstat and placebo groups. Furthermore, the median duration was shorter for imetelstat for thrombocytopenia (1.4 weeks for imetelstat vs 2.0 weeks for placebo) and for neutropenia (1.9 weeks for imetelstat vs 2.2 weeks for placebo). In addition, resolution of grade 3/4 cytopenias to grade 2 or lower by laboratory assessment within 4 weeks was higher for imetelstat, both for thrombocytopenia (86.3% for imetelstat vs 44.4% for placebo) and neutropenia (81.0% for imetelstat vs 50.0% for placebo).
Uwe Platzbecker, MD
“The IMerge phase III efficacy results illustrate the depth, breadth, and durability of transfusion independence potentially achievable with imetelstat treatment, which could be practice-changing, if approved. These results are especially encouraging, because today we have limited treatment options for [patients with] lower-risk MDS that provide broad and durable transfusion independence,” said Uwe Platzbecker, MD, a principal investigator of IMerge phase III. “With regards to the safety results, cytopenias were manageable and reversible. Importantly for hematologists, who are accustomed to managing cytopenias, clinical consequences were limited and similar to placebo-treated patients. As a once-per-month outpatient intravenous therapy, imetelstat will hopefully become a novel treatment option for [patients with] lower-risk MDS in the near future.”
