NASH is one of the most common reasons for a patients receiving a liver transplant. The condition is a severe form of non-alcoholic fatty liver disease (NAFLD), whereby fat builds up on the liver, potentially leading to liver damage or cirrhosis. And, yet, despite the severity of the disease, there are still no approved NASH treatments in the U.S. or the EU.
But it is not for lack of trying. Many companies over the years have attempted to tackle this disease area – both small biotechs and big pharmas alike. However, many clinical trials fail to make headway.
The most recent blow was dealt to Intercept, as they had their NASH treatment rejected by the Food and Drug Administration (FDA) for the second time.
Intercept sells itself after repeat FDA rejections for NASH treatment
Up until a few months ago, Intercept – a company founded in 2002 to develop and deliver novel medicines for people living with rare liver diseases – was a frontrunner in the race to bring the first ever NASH treatment to market.
Its lead candidate for the disease was Ocaliva (obeticholic acid (OCA)), which is a farnesoid X receptor (FXR) agonist; FXR is a nuclear receptor expressed in the liver and intestine, and is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways.
Ocaliva had already been approved by the FDA in 2016 for treating primary biliary cholangitis (PBC), another liver condition. However, in 2021, the FDA restricted its use due to a risk of serious liver injury, with some patients who took the medication – particularly those with evidence of advanced cirrhosis – developing liver failure, and, in some cases, requiring a liver transplant.
This was a sign of things to come for Ocaliva and Intercept. In June 2020, Intercept received a Complete Response Letter (CRL) regarding its new drug application for OCA as a treatment for NASH. The CRL indicated that, based on the data the FDA had reviewed, the agency determined that the predicted benefit of OCA based on a surrogate histopathologic endpoint remained uncertain, and did not sufficiently outweigh the potential risks to support accelerated approval for the treatment.
The rejection was a disappointment for Intercept, who went on to change its phase 3 analysis to use a central consensus reading of liver biopsy rather than relying on each trial center’s own evaluation.
Then, in what proved to be the final blow for the company, Intercept received another CRL from the FDA in June this year for OCA that once again rejected the treatment. In the announcement, Intercept also said that it would be discontinuing all NASH-related investment, and restructuring the company’s operations to strengthen its focus on rare and serious liver diseases.
The FDA rejection took such a hit on Intercept, that last month it ended up selling itself to Italian pharmaceutical company Alfasigma, in a deal worth around $800 million. According to GlobalData, this acquisition is a reflection of Intercept’s NASH failure, as it ended up with no advanced assets in its pipeline, along with rapidly declining share prices.
Intercept not alone: others have tried and failed
It’s worth noting that Intercept is not alone in its failure to develop an effective NASH treatment. In fact, several giants of the biotech and pharmaceutical industry have made attempts to develop therapies for the disease.
Commenting in an article for GlobalData on the NASH market’s untapped potential, Sravani Meka, senior immunology analyst at GlobalData, said: “The lack of FDA-approved therapies coupled with the emergence of research highlighting the benefits of combination treatments has continued to attract several big pharmaceutical and biotech companies (e.g., as Gilead Sciences, Novo Nordisk, Eli Lilly, and AstraZeneca) to try their hand in developing a successful asset for NASH.”
But even the giants of the industry have not seen much success. For example, AstraZeneca recently cleared its GLP-1/glucagon dual agonist cotadutide from its phase 2 pipeline, which it took into a NASH trial last year, before stopping enrolment after not being able to recruit enough patients. Pfizer also dropped its phase 2 NASH candidate in 2021. And, when Novo Nordisk tried to test semaglutide – a drug now causing a popularity storm in the obesity market due to its efficacy – last year as a NASH treatment in a phase 2 trial, the drug was outperformed by placebo by a wide margin.
A complex disease with a multitude of targets
For such a complex disease, these failures come as no surprise. NASH has been one of the most elusive indications to find a treatment for in the biopharma industry for years. This can be seen in the fact that only 5% (4) of the total number of NASH pipeline assets (84) are currently in phase 3 of development, according to GlobalData.
NASH is so difficult to treat largely due to the lack of validated biomarkers, as well as a lack of understanding of the mechanisms of the disease. This has led to drug developers taking a variety of different approaches to tackling the condition, including targeting metabolic imbalances, inflammation, and fibrosis.
The five main classes of drugs aiming to reach the market for NASH at the moment are: FXR agonists, fibroblast growth factor (FGF) 21 analogs, thyroid hormone receptor-β (THR-β) agonists, glucagon-like peptide 1 (GLP-1) agonists, and PPAR agonists.
As mentioned previously, when talking about Intercept’s Ocaliva, FXR is a nuclear hormone receptor expressed in the liver. FXR agonists are currently among the most popular classes of drug in the field of NASH, and work by correcting the dysregulation of FXR expression, which is a major cause of dysfunction in lipid and bile metabolism in NASH.
But perhaps the most promising class of drugs are THR-β agonists, which target thyroid hormone receptor-β. Activation of this receptor is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. Madrigal Therapeutics’ THR-β agonist, resmetirom, is currently the closest to the NASH treatment approval finishing line.
As well as being developed as monotherapies, several NASH treatments are also being tested as combination therapies. For example, in one of the latest advancements in NASH research, a small phase 2b study showed that a combination therapy of Akero Therapeutics’ efruxifermin (EFX) and GLP-1 drugs – commonly used to treat diabetes and obesity – can reduce liver fat, boosting these drugs’ prospects for the treatment of NASH. EFX is an FGF21 agonist that has been engineered to mimic the biological activity of FGF21, which regulates multiple metabolic pathways and cellular processes.
Madrigal Therapeutics’ THR-β agonist could be first treatment approved for NASH
Following Intercept’s withdrawal from the NASH race, Madrigal Therapeutics now looks the most likely to become the first company to have its NASH treatment approved in both the U.S. and EU.
The company’s phase 3 trial of resmetirom has presented positive data, and the drug has received an FDA breakthrough therapy designation. In the phase 3 MAESTRO-NASH trial, it was found to resolve liver biopsy findings in NASH more often than placebo. While only 10% of placebo patients achieved resolution of inflammation, ballooning, and disease activity, the rate was 26% among patients treated with an 80mg dose of resmetirom, and 30% among patients who received a 100mg dose.
In the co-primary endpoints of the trial, 14% of placebo patients had their liver fibrosis improve by at least one stage, without a worsening of non-alcoholic fatty liver disease activity score (NAS), compared with 24% of patients who took an 80mg daily dose of resmetirom, and 26% of patients on the 100mg dose.
Furthermore, in June, Madrigal presented additional data from the trial, showing that resmetirom achieved both liver histological improvement endpoints that the FDA highlighted as likely to provide clinical benefit for accelerated approval.
In an article in Pharmaceutical Technology, Dr. Rohit Sinha, an associate professor in the Department of Endocrinology at Sanjay Gandhi Postgraduate Institute of Medical Sciences, in Lucknow, India, predicted that the FDA will approve resmetirom within the next several months. If this happens, it will be a historial feat for both Madrigal, and the field of NASH therapeutics.
Patel predicted that this success could also lead to THR-β agonists becoming the main class of drugs in the field in the upcoming years.
NASH market still expected to grow, despite failures
Despite the many failures to develop an effective NASH treatment, it is expected that the NASH market will grow in the next decade or more.
Forecasts show that the NASH treatment market size is anticipated to reach $48.3 billion by the end of 2035, growing at a compound annual growth rate (CAGR) of 18% during this period. In 2022, the industry size of NASH treatment was already over $5.2 billion. If Madrigal’s NASH treatment receives approval in the coming months, then this will almost certainly be the case.
In the previously mentioned article by GlobalData about the NASH market, Sravani commented: “With the slow recovery of the pharma/biotech markets, in addition to the increasing therapeutic potential of combination treatments, it is possible that investments in the pharma/biotech space may continue to see a flat growth rate in the short term. However, it is anticipated that the trend might be reversed with ongoing developments within the NASH pipeline landscape. As the market becomes more saturated, and companies are able to capitalize on clinical trial data, it is likely that late-stage partnering activity will begin to rise.”