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Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial
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Download the PDF here - Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition in the general population with a prevalence ranging from 13% in Africa to 32% in Latin America and the Middle East, which is largely driven by rising rates of obesity and type 2 diabetes (T2D)1. NASH, the progressive form of NAFLD, is characterized by liver fat accumulation coexisting with liver cell injury (hepatocyte ballooning) and hepatic inflammation. NASH leads to fibrosis progression and is a leading cause of cirrhosis, end stage liver disease and liver transplantation. NASH is associated with overweight, obesity, T2D (which are clinical features of the metabolic syndrome) and occurs in a context defined by insulin resistance and adipose tissue dysfunction2. Currently, there are no approved therapies for NASH. Ongoing late-phase clinical trials are designed to test histological improvement, such as resolution of steatohepatitis or fibrosis regression, while long-term outcome trials evaluate whether these histological surrogates will result in less progression to cirrhosis and liver-related morbidity and mortality.
3β-Arachidyl amido cholanoic acid (Aramchol) is an oral, liver-targeted, fatty acid-bile acid conjugate9 that partially inhibits hepatic SCD1 protein expression and reduces liver triglycerides10,11 and fibrosis in animal models of steatohepatitis or fibrosis12,13
Topline phase 3 results were reported in April - there is an Expanded Access policy.
Oct 2021 Nature
Abstract
Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis.
NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively.
The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.
Main
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition in the general population with a prevalence ranging from 13% in Africa to 32% in Latin America and the Middle East, which is largely driven by rising rates of obesity and type 2 diabetes (T2D)1. NASH, the progressive form of NAFLD, is characterized by liver fat accumulation coexisting with liver cell injury (hepatocyte ballooning) and hepatic inflammation. NASH leads to fibrosis progression and is a leading cause of cirrhosis, end stage liver disease and liver transplantation. NASH is associated with overweight, obesity, T2D (which are clinical features of the metabolic syndrome) and occurs in a context defined by insulin resistance and adipose tissue dysfunction2. Currently, there are no approved therapies for NASH. Ongoing late-phase clinical trials are designed to test histological improvement, such as resolution of steatohepatitis or fibrosis regression, while long-term outcome trials evaluate whether these histological surrogates will result in less progression to cirrhosis and liver-related morbidity and mortality.
Patients with NASH have increased de novo lipogenesis; lipotoxic species generated by the increased flux of fatty acids in the liver are a major contributor to hepatic inflammation and liver cell death associated with steatohepatitis3. Several agents in development specifically inhibit key enzymes of lipogenesis such as acetyl coenzyme A (acetyl-CoA) or fatty acid synthase. SCD1 catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids4. In rodents, downregulation of SCD1 reduced body adiposity, increased energy expenditure and upregulated expression of several genes encoding enzymes of fatty acid beta-oxidation in the liver5. Reduction of SCD1 is also known to elevate 5′ adenosine monophosphate-activated protein kinase (AMPK) activity and enhance insulin sensitivity6. In hepatic stellate cells (HSCs), direct SCD1 depletion downregulates their fibrogenic phenotype7. Several small molecule complete SCD1 inhibitors have been discontinued because of skin and lachrymal gland toxicity8.
3β-Arachidyl amido cholanoic acid (Aramchol) is an oral, liver-targeted, fatty acid-bile acid conjugate9 that partially inhibits hepatic SCD1 protein expression and reduces liver triglycerides10,11 and fibrosis in animal models of steatohepatitis or fibrosis12,13. In HSCs, Aramchol downregulates SCD1 and interferes with Wnt signaling to reduce cell proliferation, collagen and fibronectin production and α-smooth muscle actin expression7. Direct SCD1 depletion using small interfering RNA (siRNA) phenocopies the inhibitory effects of Aramchol on HSC fibrogenesis7. In a 12-week phase 2a trial, Aramchol at 300 mg daily markedly reduced liver fat content as measured by magnetic resonance spectroscopy (MRS) versus placebo in a dose-dependent manner14. Aramchol was safe and well tolerated.
The results of the phase 2a study led to the initiation of a global phase 2b study to evaluate the effect of Aramchol for the REsolution of STeatohepatitis (ARREST) in patients with NASH confirmed by liver biopsy. In this article, we report the safety and efficacy results of 52 weeks of treatment with 400 and 600-mg doses of Aramchol in patients with NASH.
Safety and tolerability
Aramchol was safe and well tolerated (Table 4). No deaths occurred during the study (Table 4). Serious AEs were reported in 8.9% (9 out of 101), 9.2% (9 out of 98) and (6 out of 48) 12.5% patients in the 400 mg, 600 mg and placebo arms, respectively. No clustering of event types was noted in the active-treatment arms. The overall incidence of early termination was low and slightly higher in the placebo than the two active-treatment arms (10.9% (11 out of 101), 10.2% (10 out of 98) and 14.6% (7 out of 48) in the 400 mg, 600 mg and placebo arms, respectively). The leading causes for early termination were consent withdrawal and AEs. The incidence of early termination due to AEs was low and similar across study arms (3%, 4.1% and 4.2% of patients in the 400 mg, 600 mg and placebo arms, respectively). AEs were mainly mild and reversible. Headache was the most commonly reported AE in all study arms (13.9%, 15.3% and 12.5% in the 400 mg, 600 mg and placebo arms, respectively). A higher incidence of urinary tract infections (UTIs) was noted in both Aramchol arms, 14.9%, 13.3% and 6.3% in the 400 mg, 600 mg and placebo arms, respectively (P = 0.13 and P = 0.20 for 400 mg and 600 mg versus placebo).
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