CNT-01

Background: Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare intractable cardiovascular disorder (Orphanet ORPHAcode: 565612) in which defective intracellular lipolysis results in heart failure and coronary artery disease. Myocardial scintigraphy with ¹²³I-β-methyl-p-iodophenylpentadecanoic acid (BMIPP) is useful to evaluate myocardial TG metabolism; its washout rate (WR) reflects myocardial lipolysis. This study reports the effects of CNT-01 (tricaprin), a developing orphan drug to facilitate lipolysis, on BMIPP-WR in patients with TGCV. Methods: An investigator-initiated, multicenter, randomized, double-blind exploratory, trial (Phase IIa) was conducted (UMIN000035403). Seventeen patients with idiopathic TGCV were orally administered 1.5 g/day of CNT-01 or placebo for 8 weeks. Endpoints included delta BMIPP-WR and clinical parameters such as 6-minwalk distance and TGCV severity score. Results: During the protocol, delta BMIPP-WRs were -0.26±3.28 and 7.08±3.28% (95% confidence intervals, -7.36 to 6.84 and -0.01 to 14.18) in the placebo and CNT-01 groups, respectively. The baseline-adjusted difference of delta BMIPP-WR between the two groups was significant (p=0.035) after one patient was excluded from the placebo group because of pseudonormalization of BMIPP-WR related to coronary bypass graft stenosis. Clinical parameters did not show significant changes. Conclusions: This study proved the mechanism of CNT-01 to improve myocardial lipolysis in TGCV, as demonstrated by BMIPP scintigraphy.

Triglyceride deposit cardiomyovasculopathy (TGCV) is a newly identified disease that was discovered in individuals who required cardiac transplantation in Japan in 2008. Defective intracellular lipolysis causes triglyceride (TG) accumulation in the myocardium and coronary artery vascular smooth muscle cells, which results in severe heart failure and coronary artery disease with poor prognosis. A known cause of TGCV is a genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in the intracellular hydrolysis of TG. TGCV is classified into primary TGCV with ATGL mutations and idiopathic TGCV without ATGL mutations. Since its discovery, the Japan TGCV Study Group has attempted to elucidate its pathophysiology, develop diagnostic procedures, and specific treatment. Myocardial scintigraphy with iodine-123-β-methyl iodophenyl-pentadecanoic acid (¹²³I-BMIPP) is a unique imaging modality for evaluating myocardial lipolysis in vivo. The washout rate of ¹²³I-BMIPP is an essential indicator for the diagnosis of TGCV. Along with our efforts to provide awareness of and insights into this disease concept, we found that the cumulative number of clinically diagnosed patients has reached >200 and the cases are distributed throughout Japan. In addition, we successfully completed three investigator-initiated clinical trials of a potential therapeutic agent (CNT-01) for TGCV, which was assigned by the Ministry of Health, Labour, and Welfare, Japan, under the SAKIGAKE Designation System in June 2020. Here, we provide the Diagnostic Criteria 2020 for TGCV in order to further promote this "rare and intractable disease" project.