Sirolimus and Feline HCM: RAPACAT Trial Evidence Update

TL;DR

The RAPACAT trial demonstrated a statistically significant reduction in maximum left ventricular wall thickness at Day 180 in cats receiving low-dose delayed-release rapamycin versus placebo, with no significant difference in adverse events, providing the first positive randomised controlled data for mTOR inhibition in feline HCM.

What just dropped

• RAPACAT (Rapamycin in Cats) randomised controlled trial: low-dose delayed-release rapamycin significantly reduced maximum left ventricular wall thickness at Day 180 compared to placebo (P=0.01 for the primary endpoint). The treatment was well tolerated, with no significant differences in adverse events between the treatment and placebo arms. (https://pubmed.ncbi.nlm.nih.gov/37495229/)
• A complementary pilot study using cardiac tissue from treated cats documented transcriptomic differences consistent with dose-responsive suppressive effects on myocardial hypertrophy pathways and stimulatory effects on autophagy, providing mechanistic evidence for the mTOR inhibition hypothesis. The study also noted that feline HCM prevalence may be as high as 15%, with little to no established direct therapeutical intervention. (https://pubmed.ncbi.nlm.nih.gov/37893908/)

Context

Feline hypertrophic cardiomyopathy (HCM) is the most common cardiac disease in cats, yet no treatment has been shown to reverse or halt myocardial hypertrophy. Standard-of-care management focuses on managing complications such as congestive heart failure and thromboembolism rather than modifying the underlying structural disease. The mTOR (mechanistic target of rapamycin) pathway has emerged as a mechanistically plausible target: mTOR signalling drives protein synthesis and cell growth including cardiomyocyte hypertrophy, and sirolimus (rapamycin) is a well-characterised mTOR inhibitor used clinically in human medicine.

The RAPACAT trial enrolled cats with confirmed HCM and randomised them to low-dose delayed-release rapamycin or placebo. The primary outcome of maximum LV wall thickness at Day 180 was significantly reduced in the rapamycin group (P=0.01). The drug was well tolerated with no significant increase in adverse events. The transcriptomic pilot study corroborated these findings at a molecular level, showing pathway-level suppression of hypertrophic signalling and upregulation of autophagy, which is consistent with a disease-modifying rather than purely symptomatic effect.

What this changes in Sirolimus for Feline Hypertrophic Cardiomyopathy (https://www.thevoyage.ai/forvets/knowledge/sirolimus-feline-hypertrophic-cardiomyopathy)

The RAPACAT trial and complementary pilot data represent a meaningful step toward a disease-modifying approach to feline HCM, a condition where no approved veterinary treatment currently targets the structural abnormality. However, sirolimus/rapamycin is not authorised for use in cats, and the RAPACAT trial used a specific delayed-release formulation not commercially available as a veterinary product. Veterinary cardiologists considering off-label use should be aware that the clinical population, formulation, and monitoring approach used in RAPACAT may not be replicated in general practice. The ACVIM consensus statement on feline cardiomyopathy remains the current evidence synthesis for clinical decision-making. Longer-term survival data and replication in independent cohorts are needed before this approach becomes practice-changing.

Voyage Clinical Desk: https://www.thevoyage.ai/forvets/ask?context=sirolimus-feline-hypertrophic-cardiomyopathy

References

1. Gouni V et al. 2023. Rapamycin limits myocardial hypertrophy in cats: results of the RAPACAT trial. J Vet Intern Med. PMID 37495229. https://pubmed.ncbi.nlm.nih.gov/37495229/
2. Rivas VN et al. 2023. Transcriptomic and metabolomic responses to rapamycin in feline hypertrophic cardiomyopathy. J Vet Cardiol. PMID 37893908. https://pubmed.ncbi.nlm.nih.gov/37893908/

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