Following a negative decision by the US Food and Drug Administration (FDA) for Intercept Pharmaceuticals Ocaliva (obeticholic acid), all eyes are now on the next possible drug to lead the race to market for nonalcoholic steatohepatitis (NASH).
After several failed attempts by pharmaceutical giants such as AstraZeneca and Gilead Sciences to reach the market, a handful of companies are approaching the final stages of clinical development. On June 23, Intercept joined this list after announcing it will close its Ocaliva NASH clinical trials and all NASH-related investments by the end of 2023.
NASH is a severe form of nonalcoholic fatty liver disease (NAFLD), a condition in which fat builds up in the liver, potentially causing liver damage or cirrhosis. The American Liver Foundation estimates that approximately 25% of US adults have NAFLD and 5% of US adults have NASH. However, there have not yet been any successful FDA-approved therapies for the condition despite the growing unmet need.
Up until this point, the main research goal has been to prevent NASH from progressing to cirrhosis, explains Dr. Rohit Sinha, associate professor in the Department of Endocrinology at Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. However, the clinical success of new NASH drugs that target a number of factors influencing disease pathology, such as lipid and biliary metabolism and fibrosis, could provide a departure from the norm.
While the New Jersey-based Intercept initially led the pack, in May 2023, speakers on an FDA advisory committee (AdCom) voted 12 to four against its approval. which was later followed by rejection by the FDA. Jay Patel, a GlobalData analyst specializing in NASH, highlights Intercepts’ recent Phase III results (NCT02548351) in which Ocaliva did not meet the NASH resolution endpoint as a possible reason for the negative result.
GlobalData is the parent company of Pharmaceutical technology.
Another contender is Madrigal Pharmaceuticals’ oral NASH therapy resmetirom. The drug has positive Phase III data from an ongoing study (NCT03900429) and has received a Breakthrough Therapy designation from the FDA. On June 22, Madrigal presented additional data from the study, demonstrating that resmetirom met both endpoints of liver histological improvement that the FDA has identified as likely to provide clinical benefit for accelerated approval. In comparison, the Phase III Ocalivas study failed to meet the key clinical endpoint of resolution of NASH. Patel says these findings indicate that the FDA may be favoring resmetirom over other NASH drugs similar to Ocaliva.
However, despite this, the NASH field has seen a dramatic increase in activity in recent years with increased effort to develop validated biomarkers and improved drug candidates. Dr. Jean-Franois Dufour, principal investigator of several NASH clinical trials, lists five major drug classes aiming to reach market in the current NASH landscape: Farnesoid X receptor (FXR) agonists, fibroblast growth factor (FGF)21, hormone receptor agonists (THR-), glucagon-like peptide 1 (GLP-1) agonists, and PPAR agonists.
These renewed developments in NASH come after other NASH drugs have failed in different ways. In April, AstraZeneca chose to halt its clinical development program for its cotadutide NASH GLP-1RA after reaching Phase II/III trials, and Gileads selonsertib failed in Phase III after the therapy performed worse than to the placebo.
Challenges in drug development
According to GlobalData, there are five therapies in Phase III clinical trials for NASH. Dufour says that one of the major challenges contributing to this scattered landscape is related to the diagnosis of NASH. Clinical trials currently use histology-related endpoints that require repeat biopsies, which complicates study design. It’s very difficult to get the patient to do a liver biopsy, because ultimately even if you see that NASH has progressed or reduced, you don’t have any drug treatment, says Sinha. The lack of validated biomarkers also prevents easy classification of the condition.
New biomarkers are being developed to understand long-term outcomes and measure clinical response. Dufour says this could greatly improve NASH study design and signal an alternative to liver biopsies. For example, Hepion Pharmaceuticals is currently developing non-invasive HepQuant SHUNT tests to evaluate NASH progression. In an email, Robert Foster, CEO of New Jersey-based Hepion Pharmaceuticals, said: “The early stages of the disease (for example, excess liver fat) are, for the most part, asymptomatic. Therefore If a person has fatty liver and is asymptomatic, how would they know to seek treatment?Without a simple diagnosis, this presents a significant challenge.
Hepion used its new functional test in a phase II study of its NASH therapy rencofilstat. The drug reduces NASH fibrosis by inhibiting cyclophilin, a protein that has an important role in fibrosis. Foster said the biotech plans to reinvestigate the therapy using liver biopsies in order to ensure the accuracy of the Phase II results and establish the reliability of the Hepions test. The company aims to complete its Phase IIb rencofilstat NASH trial in early 2025.
Sinha explains that a common reason for NASH drug failure also comes from the massive genetic variation in NASH patients. There are many genetic predispositions, so it’s not one size fits all. Some patients benefit from one class of drugs and some don’t, says Sinha. The stage of the disease can also massively influence the effectiveness of the drugs.
Frederic Cren, CEO of Inventiva Pharma, which is developing a NASH therapy, said: “Given the heterogeneity of the patient population, there is a need for different drugs with different mechanisms of action to meet patients’ needs.
The current NASH pipeline
In May 2016, the FDA approved Ocaliva for the treatment of primary biliary cholangitis (PBC), another liver condition. However, five years later, the agency restricted its use after identifying 25 cases of serious liver injury related to the therapy. The safety of the drugs was the focus of discussion at AdCom discussing their use in NASH, where panelists expressed concerns about side effects such as gallbladder inflammation, bile duct stones and the onset of diabetes.
The question remains how the FDA’s verdict on Intercepts therapy might impact a NASH pipeline filled with FXR agonist monotherapies and combination therapies. FXR agonists correct the dysregulation of FXR expression, which is a major cause of dysfunction in lipid and biliary metabolism in NASH. However, Patel expects the FDA to approve Madrigal’s resmetirom within the next few months. As a result, other THR agonists may benefit from its success. For example, after Madrigal released positive Phase IIb results, the stock price of Viking Therapeutics, another company developing a THR agonist, rose 12% the next day. Patel predicts that THR agonists could become the main focus of the field in the coming years.
Sinha explains that outside of these drugs, GLP-1 agonists are particularly effective due to their specific targeting of insulin resistance, which is a key issue for NASH patients. For example, Novo Nordisk is currently developing its successful diabetes drug Ozempic (semaglutide) in combination with Gilead Sciences’ investigational FXR agonist cilofexor and its acetyl-CoA carboxylase (ACC) inhibitor firsocostat for the treatment of NASH-associated cirrhosis. The combination therapy is currently in a Phase II clinical trial (NCT04971785).
Daix, France-based Inventiva, is addressing NASH with lanifibranor, a peroxisome proliferator-activated receptor (PPAR) agonist. Activation of PPAR causes inhibition of mucosal production of inflammatory cytokines (interleukin-1beta and TNFalpha) and chemokines. Cren says the company expects Phase III results (NCT04849728) to be released in the second half of 2025, which will be used for regulatory submissions.
In terms of coverage after drug approval, long-term outcome data were lacking for both Ocaliva and resmethyrom, according to the US nonprofit Institute for Clinical and Economic Reviews (ICER) assessment. However, resmethyrom was found to be more affordable than Ocaliva and received a placeholder annual price of $19,000 versus $85,000 for Ocaliva. In addition, ICER recommends that payers include NASH drugs in their coverage for obesity medications in the future.
In a statement following the ICER assessment, Dr. David Rind, ICER’s Chief Medical Officer said: “If these drugs receive FDA approval, pending long-term liver and cardiovascular data, patients and physicians will need to balance the risks, burdens and potential benefits of each of these therapies.
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