CDR132L In Post-MI LV Dysfunction: Phase 2 Trial Results

Key Takeaways

• Neither dose of CDR132L was associated with a significant difference from placebo in the primary remodeling endpoint, and major secondary measures were also similar.
• Plasma miR-132 declined in a dose-dependent pattern, with the largest reduction in the 10 mg/kg group, consistent with circulating target engagement.
• Tolerability was generally similar across groups, and no hepatic, renal, hematologic, or cardiac toxicity signal was reported.

In HF-REVERT, 294 patients were randomized to receive CDR132L or placebo within days of myocardial infarction complicated by left ventricular systolic dysfunction. Investigators tested whether the miR-132 inhibitor could modify early post-infarction remodeling while maintaining acceptable tolerability.

HF-REVERT was an international, multicenter, randomized, double-blind, placebo-controlled phase 2 trial conducted at 54 sites in eight countries. Adults were enrolled 3 to 14 days after spontaneous type 1 myocardial infarction if LVEF was 45% or lower and NT-proBNP was elevated. Patients were assigned 1:1:1 to CDR132L 5 mg/kg, CDR132L 10 mg/kg, or placebo, given as three intravenous doses four weeks apart with standard care. Median age was 61 years, 13% were women, 81% had STEMI, median time to randomization was 11 days, and background therapy was contemporary.

Neither dose differed significantly from placebo for percentage change in LVESVI at 6 months within the hierarchical dose-testing framework. Placebo-adjusted least-squares mean differences were -1.11% for 5 mg/kg and -2.14% for 10 mg/kg, with nominal P values of 0.37 and 0.26. LVEF, NT-proBNP, GLS, and KCCQ likewise showed no significant between-group differences, and absolute LVEF increases were 7.2%, 7.7%, and 8.4%. Missing primary-endpoint data were limited, and sensitivity analyses did not materially alter the interpretation. Overall, efficacy outcomes in the randomized population were neutral.

CDR132L is a locked nucleic acid antisense inhibitor of miR-132, and plasma miR-132 declined in a dose-dependent fashion after treatment. Suppression appeared after the first infusion, persisted through month 12, and was greatest in the 10 mg/kg group. Exploratory subgroup analyses showed numerically more favorable patterns in patients with greater baseline remodeling or higher NT-proBNP, but these findings were hypothesis generating.

CDR132L was generally well tolerated, with no hepatic, renal, hematologic, or cardiac toxicity signals and no clinically significant arrhythmias attributed to treatment. Treatment-emergent adverse events occurred in 44% of placebo recipients, 50% of the 5 mg/kg group, and 54% of the 10 mg/kg group. Serious adverse events were similar across groups, and discontinuations due to treatment-emergent adverse events were 2%, 7%, and 4%, respectively. Six deaths occurred after treatment started, with five in the placebo group and one in the 10 mg/kg group, and no cardiovascular deaths in either CDR132L arm. Infusion-related events were infrequent and usually mild skin reactions.