VP.59 A single-arm, open-label, multicenter study of tranilast for advanced heart failure in patients with muscular dystrophy

Abstract

The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. Myocytes' damage induces TRPV2 expression on the sarcolemma, which causes calcium influx into the cytoplasm, and triggers degeneration. TRPV2 inhibition was effective in animal models of cardiomyopathy and muscular dystrophy (MD). Our pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Then, we planned a study to evaluate the safety and efficacy of tranilast for heart failure of MD patients. Subjects were MD patients whose serum BNP levels exceeded 100 pg/mL despite receiving standard therapy. Tranilast was administered orally at 100 mg thrice daily. The primary endpoint was the change in log (BNP) (⊿log [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous carvedilol study that resulted in a mean population ⊿log [BNP] of 0.18. TRPV2 expression on the mononuclear cell (MNC) surface, cardiac events, left ventricular fractional shortening (FS), human atrial natriuretic peptide (hANP), creatine kinase, and pinch strength were also assessed. Because of the poor general condition of many patients, among 18 patients included, 13 patients could be treated according to the protocol throughout the 6-month period. There were no serious adverse events related to tranilast except diarrhea, a known adverse effect. TRPV2 expression on the MNC surface was elevated at baseline and reduced after treatment. BNP, hANP, and FS remained stable. In the per-protocol set group, ⊿log [BNP] was -0.2 and significantly lower than that in the null hypothesis. In conclusion, tranilast is safe and effectively inhibits TRPV2 expression, even in MD patients with advanced heart failure. To evaluate the efficacy of tranilast in preventing heart failure, motor impairment, and respiratory failure, we are planning a study for mild MD patients.