PBI 4547 & NAFLD/NASH clinical trials
PBI-4547 is a novel, immunometabolic agent which displays antidiabetic, antihyperlipidemic, anti-inflammatory and anti-fibrotic activity as shown in multiple animal models. PBI-4547 is an orally active small molecule that is a GPR84 antagonist, GPR40 (FFAR1)/GPR120 (FFAR4) agonist, and a partial activator of peroxisome proliferator-activated receptors (PPAR). PBI-4547 treatment significantly improved metabolic regulation of glucose and lipids, and reduced hepatic steatosis, ballooning and overall NAFLD (non-alcoholic fatty liver disease) score in high fat diet (HFD)-fed mice. Fatty acid oxidation and expression of mitochondrial uncoupling proteins were increased by PBI-4547 in the liver. Metabolomic profiling demonstrated that the metabolic dysregulation induced by HFD was abolished by PBI-4547. Preclinical studies suggest that PBI-4547 offers the potential as a novel therapy for NAFLD/NASH, metabolic syndrome and other liver diseases.
NAFLD: NASH and NAFL
Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of hepatic fat, as evidenced by imaging or histologic examination, in the absence of coexisting causes of chronic liver disease or secondary cause of steatosis including drugs, significant alcohol consumption, or inherited or acquired metabolic states. The spectrum of NAFLD encompasses 2 subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Isolated NAFL is characterized by steatosis in at least 5% of hepatocytes, while NASH is defined by a pattern of characteristics including steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.1
NASH, prevalence and incidence:
Nonalcoholic steatohepatitis (NASH) is strongly associated with being overweight or obese and having metabolic syndrome. Metabolic syndrome includes a cluster of conditions occurring together such as, increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. A recent analysis of studies involving more than 8.5 million people from 22 countries showed that more than 80% of patients with nonalcoholic steatohepatitis are overweight or obese, 72% have dyslipidemia, and 44% have received a diagnosis of type 2 diabetes mellitus.2 The prevalence of NAFLD in the US is about 24% to 26%—about 85 million Americans. Up to 20% to 30% of these cases (about 17–25 million Americans) are thought to have NASH. Future projections estimate an exponential rise in NASH expected by 2025, to affect close to 43 million Americans.3 The number of patients awaiting liver transplant due to NASH nearly tripled from 2004 to 2013, and in 2013 NASH became the second leading disease among wait-listed patients for liver transplantation.4 Dynamic Markov modeling predicts that cases of decompensated NASH cirrhosis (i.e., liver failure) will rise by 161%, from about 144,000 to 376,000 cases over the next 15 years.5 These projections predict that NASH will overtake HCV (hepatitis C virus) as the leading cause of chronic liver disease among patients awaiting a liver transplant.
Development stage & clinical trial information:
The current clinical study is designed to assess the safety, tolerability and pharmacokinetics of single ascending doses of PBI-4547 in healthy subjects (ClinicalTrials.gov Identifier: NCT04068259). A total of 40 adult participants will sequentially receive 1 of 5 doses of PBI-4547 or matching placebo, with each cohort of 8 participants randomized in a 3:1 ratio to receive PBI-4547 or matching placebo. The Phase 1 clinical study is being conducted by the CRO, Syneos, at locations in Quebec City and Montreal, QC, Canada.
Nonalcoholic Steatohepatitis (NASH) is a multi-faceted disease including metabolic dysregulation, chronic inflammation and fibrosis. In relevant animal models, PBI-4547 displays activity against each of these aspects of the disease.
PBI-4547 is an investigational drug and its safety and efficacy have not yet been established. For information about the Phase 1 clinical study with PBI-4547: please visit http://www.clinicaltrials.gov
- Lindenmeyer, C McCullough, A. The Natural History of Nonalcoholic Fatty Liver Disease—An Evolving View. Clin Liver Dis 2018;22:11–21.
- Diehl, A Day, C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 2017;377:2063-72.
- Shetty, A Syn, W. Health and Economic Burden of Nonalcoholic Fatty Liver Disease in the United States and Its Impact on Veterans. Federal Practitioner January 2019.
- Wong, R Aguilar, M, et al. Nonalcoholic Steatohepatitis Is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States. Gastroenterology 2015;148:547–555.
- Estes, C Quentin, M, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. Journal of Hepatology 2018;69: 896–904.