Background: The treatment landscape of nonalcoholic steatohepatitis (NASH) is changing rapidly; drug safety is key as most patients will need long-term treatment. Cenicriviroc (CVC) is an oral antagonist of C-C chemokine receptors 2/5 in Phase 3 development for NASH. We report cumulative safety data from CVC studies.
Methods: Studies included single- and multi-dose Phase 1 in healthy volunteers and cirrhosis, Phase 2 in NASH and HIV-1, and Phase 3 in progress. Treatment-emergent AEs (TEAEs), lab abnormalities, and causality were assessed.
Results: As of July 2018, >1220 adults received CVC and had available safety data. In Phase 1 studies (N=580), TEAEs in ≥2% of CVC subjects included headache, nasopharyngitis, abdominal pain, nausea, vomiting, diarrhea, contact dermatitis, and somnolence in single-dose studies, and headache and constipation in multi-dose studies, mostly mild or moderate. In Child-Pugh A or B cirrhosis subjects (n=16), CVC dosing for 14 days was well tolerated, with no safety concerns identified. Single-dose administration was well tolerated in subjects with severe hepatic impairment (Child-Pugh C). In Phase 2 studies (N=442), incidence and severity of TEAEs, discontinuation due to TEAEs, and lab abnormalities were similar in CVC vs. comparator; no life-threatening TEAEs (Grade 4) or deaths occurred with CVC. In subjects with NASH and liver fibrosis on CVC for 1 year (n=144), TEAEs in ≥2% of subjects of at least moderate severity (Grade ≥2) were fatigue (2.8%) and diarrhea (2.1%). One serious AE (SAE) [0.3%] was assessed as drug related (Grade 2 arrhythmia). CVC was well tolerated in a 10-day dose-escalation study in HIV-1 (n=44). In HIV patients treated with ≤48 weeks of CVC (n=115), Grade ≥2 TEAEs in ≥2% of subjects were nausea (2.0%). No SAE was assessed as drug related. One CVC subject discontinued due to an AE (Grade 2 depression). To date in Phase 3, no new safety signals have been identified.
Conclusions: CVC was safe in >1200 subjects treated to date, including those with NASH and liver fibrosis, HIV-1, and hepatic impairment.
M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. B. Tan: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal.