Phase 3: Drugs in Development to Fight NASH

GS-4997 – Manufactured by Gilead – GS-4997 acts as an investigational inhibitor of apoptosis signal-regulating kinase 1 (ASK1). The medication is either a 6 or 18 mg one-a-day tablet. It’s Phase 2 results showed anti-fibrotic activity in 72 patients with both NASH and moderate to severe liver fibrosis. The individuals received GS-4997 in isolation or in conjunction with simtuzumab (SIM), an investigational antibody that works against lysol oxidase-like-2 (LOXL2). Some patients only received the SIM alone, via weekly injections of 125 mg. The testing took place over 24 weeks. The drug will now move into Phase 3 testing, and it is has promising prospects of making it to market.

Obeticholic Acid (OCA) – Manufactured by Intercept – OCA has earned Breakthrough Designation from the FDA for NASH patients with liver fibrosis. In 2016, the drug gained FDA approval for treating primary biliary cholangitis under the brand name Ocaliva. The once-daily, orally-administered drug works as a synthetic lipophilic bile acid, specifically chenode oxycholic acid, that binds to the farnesoid X nuclear receptor. When the acid combines with the receptor, it promotes insulin sensitivity and decreases hepatic gluconeogenesis and circulating triglycerides. Reduced hepatic lipid synthesis and boosted peripheral clearance of very low density lipoprotein (VLDL) mediate these positive effects. Moreover, this combination increases the prevalence of hepatic scavenger receptors (SRB1) that accelerate cholesterol transport. When taken together, these effects make the drug attractive for treating NASH.

OCA’s clinical trial for NASH, REGENERATE, will be completed in 2021. This double-blind, placebo-controlled trial will administer 10 or 25 mg OCA tablets or placebos to 2,500 patients and measure the proportion of patients that see liver fibrosis or NASH improvement from the OCA pill versus the placebo. The Phase 2 results for the drug as a NASH treatment had mixed results. Only the highest-dosed group (40 mgs) met the trial’s goal. Safety concerns also exist. Roughly one in four patients in the study suffered from pruritus (itchy skin), with three of the cases being life-threatening. There were also signs that using the drug led to an increase in bad cholesterol. Still, of the three Phase 3 drugs, OCA has advanced the furthest up the FDA pipeline.

Aramchol – Manufactured by Galmed – The FDA has given Aramchol Fast Track status. The once-daily, orally-administered drug works by modifying production and storage of fat and cholesterol by inhibiting sterol-CoA desaturate 1. It operates in two parallel pathways, SCD1 and Reverse Cholesterol Transport, creating synergistic effects. In the SCD1 pathway, Aramchol partially inhibits Stearoyl Coenzyme A Desaturase 1 (SCD1) activity in the liver, leading to reduced fatty acid synthesis. This reduction diminishes liver fat and improves insulin resistance. In the Reverse Cholesterol Transport pathway, Aramchol stimulates the ABCA1 transporter to export cholesterol, leading to a significantly lower blood and body cholesterol count. This drug has been tested in both animals and humans with evidence of the positive outcomes described above.

Currently, scientists are studying Aramchol in a Phase 2B/Phase 3 trial called ARREST. The trial involves 240 patients taking Aramchol over 52 weeks, with a 12 week follow-up period afterward. Results are expected in 2018.

Elafibranor (GFT-505) – Manufactured by Genfit – The FDA has given Elafibranor Fast Track status. The drug is a one-a-day oral medication for treating the underlying symptoms of fibrosis, thus preventing progression to cirrhosis. Elafibranor works as an agonist of the peroxisome proliferator-activated receptor alpha and the peroxisome proliferator-activated receptor gamma. It binds with these receptors to improve insulin sensitivity, glucose homeostasis, and lipid metabolism. This response also reduces inflammation.

The treatment remains in its Phase 3 trial, RESOLVE-IT, which revolves around randomly administering 120mg Elafibranor pills or placebo pills to 2,000 patients and tracking results for each in preventing cirrhosis.