Intercept’s Failure to Launch Successful NASH Program Demonstrates Challenges to Navigating the Healthcare Environment.

The race to find a groundbreaking treatment for non-alcoholic steatohepatitis is heating up, as multiple companies like Madrigal Pharmaceuticals, Hepion Pharmaceuticals, and 89Bio vie to create the first effective remedy. However, Intercept Pharmaceuticals’ recent regulatory failure of obeticholic acid tablets brings a warning about the risks of such treatments.

In June, Intercept’s investment in treatments for non-alcoholic steatohepatitis (NASH) came to a sudden halt after the FDA rejected the company’s proposed obeticholic acid (OCA) tablets to treat patients with pre-cirrhotic liver fibrosis.

The agency’s Complete Response Letter declared the drug could not be approved in its current form without the completion of the Outcomes part of its Phase III trial, agreeing with a panel of experts who found the potential risks outweighing the potential benefits.

In May 2016, Ocaliva was granted approval from the FDA to be used for the treatment of primary biliary cholangitis (PBC), a rare liver disease. However, two years after its release, the FDA warned by adding a Black Box that incorrect dosing, exceeding the recommended dosage of 5mg-10mg per day, could lead to life-threatening scenarios, such as liver decompensation and liver failure. Therefore, medical professionals and patients must exercise extreme caution when using this powerful drug.

Intercept’s Phase III trials of OCA in NASH patients provided encouraging evidence of an improvement in fibrosis without worsening the condition at a dose of 25mg per day – a dose higher than the 10mg per day that previous safety data of the drug had suggested may be suitable for patients without severe liver disease. This data has been instrumental in aiding the FDA in its approval process decisions.

Dr. Anurag Maheshwari, a liver disease specialist at the Melissa L. Posner Institute for Digestive Health & Liver Disease at Mercy Medical Center in Baltimore, has identified an issue faced by the FDA when it comes to dosing: the difference in dosing. With his extensive knowledge and experience in the field, he is seeking to tackle this challenge.

Though the higher dosage had potential benefits, ongoing safety concerns remained, and the lack of convincing support for its efficacy made it unviable. As Maheshwari noted, “the efficacy data were not compelling enough to negate the safety concerns.”

Intercept refused to shed light on the FDA’s choice or its NASH-targeted OCA initiative when approached for comment.

The Safety Conundrum

Drug-induced liver toxicity is a big problem that can’t be ignored, highlighted by the fact that it is the most common cause of clinical trial discontinuation and for the withdrawal of a drug that has gained regulatory approval. This troubling development is well known by the FDA, which is why it is an important factor to consider when assessing the safety of a medication.

Clinical trials are usually limited to a few hundred participants, but when extrapolated to larger scales, the potential implications can be stunning. For example, the number of patients who could develop liver toxicity – something often studied in clinical trials – could easily reach tens of thousands or more. As Dr. Maheshwari states, this is a “significant” issue that needs to be taken seriously.

Clinical trials typically involve only a few hundred patients, so one can only imagine the amount of liver toxicity that would occur when that number climbs to a few thousand or even a few hundred thousand. As highlighted by Dr. Maheshwari, the scope of the issue is truly staggering.

Drug-induced liver toxicity can sometimes go unrecognized in clinical trials, making it difficult to understand why some individuals are more predisposed to drug-induced liver damage than others. By delving into the complexities of this issue, researchers can gain valuable insight into how best to protect those at risk from the dangerous side effects of certain medications.

The intersection of NASH therapeutics and existing medications is a potential challenge that could prove to be an Achilles’ heel. Medication interactions could preclude the wide-scale utilization of NASH drugs for many patients in need, especially those taking anti-diabetic or cardiovascular medications. To avoid this issue, caution must be taken to ensure these drugs can properly coexist.

The Race to Safe

NASH is a growing problem which affects 12% of the US population and, if left unchecked, is set to become the leading cause of liver transplantation in the country by 2025. With such a dire situation, it is no surprise that the global market for NAHS therapeutics has been projected to reach an eye-watering $24 billion by 2028. Clearly, it is paramount that an effective treatment is found to combat this serious condition.

Tackling a chronic liver disease with a long-term treatment regimen is no small feat – and it’s a challenge that Hank Mansbach, Chief Medical Officer at 89bio, is committed to taking on. He and his team are determined to offer individuals with potentially lifelong liver disease more hope and better outcomes.

With the long-term treatment needed for NASH, patients’ well-being is paramount; tolerability and dosage regimens are essential for patient satisfaction and effectiveness of the treatment. According to Dr. Mansbach, this is of the utmost importance.

Mansbach, an executive from a San Francisco-based biopharma, reported surprising yet encouraging results from the clinical trials of the drug pegozafermin. Surprisingly, it had no liver toxicity, tremors, hypersensitivity reactions, or any significant gastrointestinal side effects.

Ready to move further along the road to FDA approval, the company is preparing to meet with the regulatory body in the second half of 2023 to discuss the requirements necessary for its Phase III clinical trial.

Hepion Pharmaceuticals has engaged the expertise of a Data and Safety Monitoring Board (DSMB) – an external group of experts – to review unblinded safety data in their ongoing clinical trials of rencofilstat, a potential breakthrough treatment for NASH.

By bringing in the seasoned professionals of the DSMB, Hepion Pharmaceuticals is committed to developing the drug in a transparent and safe manner, with the utmost respect for patient safety.

The independent Data Safety Monitoring Board (DSMB) is ensuring the safety of trial participants by thoroughly assessing any potential adverse events, no matter how minor. Chief Medical Officer at Hepion, Todd Hobbs, notes that this attention to detail is a paramount priority in any clinical trial.

Hobbs revealed that the Data Safety Monitoring Board (DSMB) is scrupulously examining lab findings, kidney function, and liver function to ensure safety of the trial. Although the team at Hepion Pharmaceuticals hopes for positive outcomes, they understand that the true results lie in the results of the tests.

In June, Hepion revealed that their Phase IIb trial of rencofilstat in NASH had safely cleared all key milestones and was proceeding on track to its forecasted completion date in the first quarter of 2024. As reported by the Chief Medical Officer Mark Hobbs, the most commonly experienced side effect was constipation.

Madrigal Pharmaceuticals made a major milestone last week, submitting its NDA for resmetirom to the FDA with a request for priority review. If the request is granted, the company could hear back from the FDA as early as 2024 – and with so many eyes on the outcome, a decision is eagerly anticipated!

In December, Madrigal announced incredible news—resmetirom had achieved success in its pivotal Phase III MAESTRO-NASH biopsy trial, hitting both its primary and key secondary endpoints. Even more, the therapeutic was found to be safe and well-tolerated at both 80 mg and 100 mg dose levels. This momentous breakthrough marks a major step forward for the development of effective treatments for NASH.

When contacted by BioSpace about the safety profile of the drug, Madrigal remained silent on the matter. No comments were given on the ocassion.

A potent remedy for NASH may still be far from reach, but reliable options exist – through lifestyle modifications like weight loss, exercise and better glucose control combined with a multi-fold therapeutic approach. It’s the way forward to managing NASH!

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