CDR132L After Myocardial Infarction: Phase 2 Trial Results

Key Takeaways

• No significant between-group difference was seen in 6-month LVESVI, and secondary imaging, biomarker, and patient-reported measures were also similar.
• Plasma miR-132 declined after CDR132L in a dose-related pattern that was evident after the first infusion and remained through month 12.
• Overall tolerability was broadly similar, no organ-specific toxicity pattern was identified, and subgroup trends were described as exploratory only.

In 294 randomized patients enrolled soon after myocardial infarction with reduced LVEF, the HF-REVERT phase 2 trial found no significant improvement in the prespecified 6-month remodeling endpoint. Participants received CDR132L or placebo on top of contemporary care after recent type 1 MI and elevated NT-proBNP. Circulating miR-132 nevertheless declined in a dose-dependent pattern after active treatment, providing a pharmacodynamic signal. The trial paired durable biomarker suppression with no significant difference in the primary imaging outcome.

The multinational HF-REVERT study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 trial conducted at 54 sites in eight countries. It enrolled adults 3 to 14 days after spontaneous type 1 MI with LVEF 45% or lower and elevated NT-proBNP. Patients were assigned 1:1:1 to CDR132L 5 mg/kg, CDR132L 10 mg/kg, or placebo, given as three intravenous infusions 28 days apart with standard care. Randomization was stratified by age group and infarct location, and 280 treated patients formed the modified intention-to-treat population. Median age was 61 years, 81% had STEMI, median LVEF was 36%, and the primary endpoint was percentage change in LVESVI at 6 months.

LVESVI improved modestly in all groups at 6 months, but placebo-adjusted least-squares mean differences were -1.11% for 5 mg/kg and -2.14% for 10 mg/kg, with corresponding P values of 0.37 and 0.26. Other prespecified measures, including LVEF, global longitudinal strain, NT-proBNP, troponin T, and KCCQ scores, also did not differ significantly between groups. Absolute LVEF rose by 7.2% with placebo, 7.7% with 5 mg/kg, and 8.4% with 10 mg/kg. At 6 months, the prespecified remodeling endpoint and related secondary measures were similar across study arms.

Plasma miR-132 fell after treatment in a dose-responsive pattern, with larger suppression at 10 mg/kg that began after the first infusion and persisted through month 12. Circulating miR-132 was treated as a systemic pharmacodynamic biomarker and may not directly reflect myocardial tissue levels. Treatment-emergent adverse events occurred in 44% of placebo patients, 50% of 5 mg/kg patients, and 54% of 10 mg/kg patients. Serious adverse events were similar across groups, most events were mild or moderate, and no hepatic, renal, hematologic, or cardiac toxicity signals were identified. No clinically significant arrhythmias were attributed to treatment, and no organ-specific toxicity pattern emerged in this phase 2 trial.

Exploratory analyses showed numerically favorable trends in patients with more advanced baseline remodeling or higher NT-proBNP, particularly with the 10 mg/kg dose. These subgroup findings were hypothesis generating and were not presented as evidence of efficacy. The trial was not powered for heart failure events or mortality, clinical event counts were low, and nominal P values were not adjusted for multiplicity. About half the cohort had LVESVI in the normal to moderately elevated range at baseline, which may have limited dynamic range for change. HF-REVERT paired durable biomarker suppression with a neutral prespecified remodeling endpoint at 6 months.