After Synta merger, Madrigal’s NASH drug hits liver fat in midstage test

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Madrigal Pharmaceuticals has seen some positive snapshot data coming out of its phase 2 proof-of-concept fatty liver disease test using an old Roche medication.

Last year the biotech merged with oncology company Synta Pharmaceuticals, coming after Synta ditched a lung cancer study and axed 20% of its staff in 2015. The combined company now has a market cap of more than $500 million as of yesterday (this has since jumped to more than $1 billion today).

The decision to merge with Madrigal (and change its name to Madrigal Pharmaceuticals while moving its corporate headquarters to Philadelphia) pivoted the merger company’s focus away from oncology and saw it move its attention to developing small-molecule drugs in cardiovascular-metabolic diseases and non-alcoholic steatohepatitis (NASH).

Madrigal’s main attraction was its lead NASH compound, MGL-3196, a once-daily pill for fatty liver disease in-licensed from Roche. The drug works as a liver-directed selective thyroid hormone receptor-ß (THR-ß) agonist.

NASH is a form of chronic liver disease caused by a build-up of fat in the liver and is thought to affect around 15 million Americans. If left untreated, it can cause scarring, or fibrosis, in the liver, which can eventually lead to liver failure or cancer.

Some experts predict it could replace alcoholism and viral hepatitis as the leading cause of liver transplants by the next decade, generating a market for NASH-targeted medicines that could reach a whopping $35 billion at its peak. A number of other companies alongside Gilead—including Bristol-Myers Squibb, Allergan, Shire, Genfit and Intercept—are all looking to get into this lucrative market.

Today, Madrigal posted positive data from its med, hitting its primary endpoint in more than 100 U.S. patients with liver biopsy-confirmed NASH after seeing a statistically significant reduction in liver fat compared to a dummy treatment—something that a number of other biopharmas have done in the past year.

RELATED: High-dose Gilead/Nimbus NASH drug hits liver fat

Other secondary endpoints include changes in clinically relevant biomarkers at 12 and 36 weeks, improvement in fibrosis by at least one stage with no worsening of steatohepatitis, and safety and tolerability.

In some of these secondary endpoints, statistically significant improvements “were also seen” and “considered to be potentially clinically relevant in patients with NASH including LDL-C, triglycerides, apolipoprotein B (ApoB), and Lp(a).” Hitting scarring will according to some analysts be a key differentiator for future treatments, alongside hitting liver fat, which can also be reduced via exercise and diet.

The ongoing study remains blinded, the company notes, and that safety, efficacy of NASH resolution by biopsy, and repeat MRI-PDFF “will be assessed at 36 weeks.” Multiple inflammatory and fibrosis serum biomarkers at 12 and 36 weeks “are being and will be assessed,” it added. Results at 36 weeks are expected in the second quarter of 2018, it said in a statement.

The biotech also said the experimental drug was generally well tolerated, and that the three serious adverse effects in the study are “considered unrelated to MGL-3196.”

Rebecca Taub, M.D., CMO and EVP of R&D at Madrigal said: “Results from this study confirm what we have seen in both our preclinical and earlier clinical studies and support our long-standing confidence in the safety and potential therapeutic value of MGL-3196. We fully expect data at 36 weeks to confirm results seen at 12 weeks, and potentially show improvement in NASH on liver biopsy. We look forward to the presentation of the 12-week, phase 2 results to the scientific and clinical community, and further development of MGL-3196 for treatment of patients with NASH.”

Paul Friedman, M.D., CEO of Madrigal (former director at Synta and ex-CEO of Incyte), added: “We are gratified to see clinical results that strongly suggest MGL-3196 has the potential to provide clinically meaningful improvement of NASH by targeting lipotoxicity and inflammation as well as by reduction of cardiovascular risk by lowering atherogenic lipids. These pleiotropic actions, coupled with the excellent safety profile we have seen in this trial, continue to suggest that MGL-3196 has the potential to address the root causes of the underlying disease process in NASH.”

After the merger last spring an investor syndicate, which includes Bay City Capital, Fred Craves—Founder of Bay City Capital—and SQN LLC, committed to invest up to $9 million in Madrigal prior to the closing of the merger, as collateral for the ongoing trials of MGL-3196.

The drug is also targeting a genetic condition which causes very high levels of cholesterol, known as heterozygous and homozygous familial hypercholesterolemia.

The biotech's shares shot up 90% on the news.