Intercept’s failure to secure FDA approval for obeticholic acid (OCA) tablets in non-alcoholic steatohepatitis shines a light on safety challenges in the space, experts told BioSpace.
Pictured: a doctor looks at an adominal x-ray/iStock, utah778
The race to the first treatment for non-alcoholic steatohepatitis is packed with contenders—including Madrigal Pharmaceuticals, Hepion Pharmaceuticals and 89Bio—but the recent regulatory failure of Intercept Pharmaceuticals’ obeticholic acid tablets highlights safety concerns in the space.
June saw the end of Intercept’s non-alcoholic steatohepatitis (NASH)-related investments after the FDA rejected obeticholic acid (OCA) tablets, which the company had proposed to treat NASH patients with pre-cirrhotic liver fibrosis. In its Complete Response Letter, the FDA said the drug could not be approved in its current form and would require at least the completion of the Outcomes part of its Phase III trial. The decision came after a panel of experts agreed that the potential benefits of the drug did not outweigh the potential risks.
OCA, marketed as Ocaliva, was first approved in May 2016 for the treatment of primary biliary cholangitis (PBC), a rare, chronic liver disease. Two years after its approval, the FDA added a Black Box warning, advising that dosing at a level higher than what is recommended in the drug’s label—which starts at 5 mg once-per-week and maxes out at 10 mg daily— “can increase the risk for liver decompensation, liver failure and sometimes death,” particularly in patients with severe liver disease.
Previously reported safety data of drugs aid the FDA in its approval decisions. Historically, safety data of OCA indicated a favorable safety profile in patients without severe liver disease in doses of up to 10 mg per day. Intercept’s Phase III trials of OCA in NASH patients showed improvement of fibrosis without worsening of NASH, but at 25 mg.
Anurag Maheshwari, a liver disease specialist at the Melissa L. Posner Institute for Digestive Health & Liver Disease at Mercy Medical Center in Baltimore, said the difference in dosing was a challenge faced by the FDA.
“Given the higher dose, there are lingering concerns about long-term safety, and the efficacy data were not compelling enough to negate the safety concerns,” Maheshwari told BioSpace.
Intercept declined to comment on the FDA’s decision or the OCA program in NASH for this article.
The Safety Conundrum
Drug-induced liver toxicity is the most common reason for the discontinuation of clinical trials and for the withdrawal of an approved drug from the marketplace, according to the FDA.
“Clinical trials typically have a few hundred patients,” Maheshwari said. “When you translate that into a few thousand or a few hundreds of thousands of patients, those numbers of patients who develop liver toxicity can be quite significant.”
The liver is responsible for metabolizing most medications, and bioactive products generated by this process can directly interact with cellular organelles, potentially leading to dysfunction and injury, according to an article published in 2020 in Anaesthesia and Intensive Care Medicine.
Maheshwari said drug-induced liver toxicity is not always recognized in clinical trials, and it is not well-understood why some patients are more predisposed than others to liver damage from drugs.
NASH patients also represent a more challenging population to treat due to comorbid illnesses such as cardiovascular conditions, obesity and type II diabetes, Maheshwari said.
“There are significant medication interactions, and I think that’s going to be another Achilles’ heel for any NASH therapeutic,” he said. If the drug candidate interacts with commonly used anti-diabetic medications or those commonly used for cardiovascular patients, “then that product can’t be utilized on a wide scale for a lot of patients who need it.”
The Race to Safe
Affecting 12% of the U.S. population, NASH is expected to become the country’s leading cause of liver transplantation by 2025, making an effective treatment paramount—and also lucrative. A recent study by The Insight Partners puts the market value for NASH therapeutics at just over $24 billion by 2028.
Treating a chronic liver disease with a potentially lifelong therapy is not an easy feat, said Hank Mansbach, chief medical officer at 89bio.
“Since NASH is likely to require long-term treatment, tolerability and dosage regimen are going to be important to patients,” Mansbach told BioSpace in an email.
The San Francisco–based biopharma is currently conducting clinical trials of pegozafermin in patients with NASH. Mansbach said the drug has demonstrated a favorable safety and tolerability profile, “including no observations of liver toxicity, tremors or hypersensitivity reactions.” Treatment with pegozafarmin resulted in few gastrointestinal side effects, he added. The company intends to meet with the FDA in the second half of 2023 to discuss requirements to advance pegozafermin into a Phase III clinical trial.
Hepion Pharmaceuticals, which is developing rencofilstat for NASH, employs a Data and Safety Monitoring Board (DSMB) made up of an external group of experts, to review unblinded safety data in ongoing clinical trials.
“The DSMB is going to look at any adverse event, whether it’s serious or minor,” Todd Hobbs, chief medical officer at Hepion, told BioSpace.
Hobbs said the DSMB will investigate abnormalities in labs, kidney renal function and hepatic functions. Hepion does not expect these outcomes, “but you never know until you test for it,” he said.
Hepion announced in June that its Phase IIb trial of rencofilstat in NASH passed all key safety milestones and is on track to complete enrollment in the first quarter of 2024. Hobbs said the most-reported adverse event was constipation.
Possibly the most-watched contender in this space, Madrigal Pharmaceuticals completed the rolling submission of its NDA for resmetirom to the FDA last week. The company requested priority review, which, if granted, could place a decision early in 2024.
In December, Madrigal announced that resmetirom hit both its primary endpoint and a key secondary endpoint in the pivotal Phase III MAESTRO-NASH biopsy trial. Madrigal noted in its announcement that the therapeutic was “safe and well-tolerated” at both 80 mg and 100 mg dose levels.
Madrigal declined to comment on the drug’s safety profile when BioSpace reached out for comment.
Ultimately, Maheshwari said that a “magic pill” for NASH may not be on the market any time soon. Instead, he said that lifestyle modifications like weight loss, exercise and improved glucose control combined with a multi-pronged therapeutic approach to treating NASH is more likely in the near term.
Hayley Shasteen is a freelance science writer based in Northeastern Ohio. You can reach her at hayleyshasteen@gmail.com, or follow her on LinkedIn.
