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Can Madrigal Pharmaceutical’s Resmetirom Be a Potential Gamechanger in NASH?

26 Mar Can Madrigal Pharmaceutical’s Resmetirom Be a Potential Gamechanger in NASH?

Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL), a clinical-stage biopharmaceutical company, is developing novel therapeutics that target a specific thyroid hormone receptor pathway in the liver, an approach that has the potential to address the unmet needs in cardiovascular, metabolic and fatty liver diseases.

The Company’s research is focused on unraveling the underlying cause of Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and potentially reduce the risk of cardiovascular morbidity caused by these disorders. Madrigal’s approach is based on thyroid hormone regulation of lipid metabolism by selective activation of thyroid hormone receptor beta (THR)-β.

Resmetirom (MGL-3196), the Company’s lead candidate is a first-in-class, orally administered, small-molecule, liver-directed, thyroid hormone receptor (THR) β-selective agonist that is currently being evaluated in a Phase 3 clinical trial named MAESTRO-NASH, in non-alcoholic steatohepatitis (NASH). The Candidate has demonstrated broad activity, a favorable safety profile and has met its key primary and secondary endpoints such as reduction of liver fat on a sensitive non-invasive imaging test, lowering of multiple atherogenic lipids including LDL-cholesterol and triglycerides, and resolution of NASH on liver biopsy. Resmetirom (MGL-3196), is also being evaluated for the treatment of heterozygous familial hypercholesterolemia (HeFH).

The Company has also initiated MAESTRO-NAFLD-1 (NAFLD: non-alcoholic fatty liver disease), a second phase 3 study with endpoints such as reduction in LDL-cholesterol, triglyceride and liver fat, elevated liver enzymes and fibrosis biomarkers, which will be determined by a magnetic resonance imaging proton density fat fraction (MRI-PDFF).

Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL)

Market Cap: $1.90B; Current Share Price: 118.60 USDChart
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Nonalcoholic Steatohepatitis (NASH) is a form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the buildup of FAT in the liver. This condition is marked by hepatitis, inflammation, cell damage and fat deposits in the liver. These fat deposits can cause fibrosis of the liver, in turn leading to liver cancer or cirrhosis.

According to an estimate only 20 percent of the people suffering from NAFLD have NASH, while the rest only have a simple fatty liver. While nearly 40 percent in the U.S are afflicted with NAFLD, around 3 to 4 percent have NASH. The American Liver foundation estimates that over 100 million people suffer from NAFLD in the U.S alone.

Though the exact cause of the disease is still unknown, NASH often develops from underlying conditions such as obesity and type 2 diabetes, and can affect people of any age. Individuals who have insulin resistance, high triglyceride levels or abnormal cholesterol levels, hypertension and uncontrolled blood glucose are at an increased risk of developing this condition. NASH also increases the chances of developing cardiovascular anomalies and can lead to death from liver-related causes.

The diagnosis usually involves blood tests, use of imaging techniques such as ultrasound, CT scans and MRI, and a liver biopsy. Losing weight through a healthy diet and exercise can help reduce the fat in the liver and is usually the recommended course of action. Currently there are no approved therapies for this condition, with treatment limited to alleviating the symptoms of the condition.

According to a report by Reports and Data, the Global NASH market will be worth over USD 13.38 Billion by 2026. The healthcare costs associated with this disease are likely to reach USD 18 billion by 2030 from USD 5 billion now, if the disease is left untreated.

The Company’s pipeline consists of Resmetirom (MGL-3196) Thyroid Hormone Receptor beta (THR)-β intended for the treatment of non-alcoholic steatohepatitis (NASH) with Fibrosis Stage 2-3 and MGL-3475, a (THR)-β for the treatment of NASH and Hyperlipidemia.

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THR-β selectivity presents a novel approach to treating NASH as it not only enhances the safety profile of Resmetirom but also reduces elevated liver enzymes, making it one of the most promising candidates in development for the treatment of the disease. The Phase 3 trial will be for a period of 52 weeks and enroll 2000 patients. The primary endpoint will be at least a 2-point reduction in NASH Activity Score (NAS) and no progression of fibrosis. The secondary endpoint will be improved by at least one stage and reduction of LDL-cholesterol.

The Company’s long -term goal is to prove the safety and efficacy of Resmetirom in reversing liver disease or preventing progression to cirrhosis and reducing cardiovascular morbidity and mortality.

Madrigal’s MGL-3745 is a THR β-selective agonist that could act as a follow-on compound to MGL-3196.

Upcoming Catalysts

  • Madrigal is targeting the completion of enrollment in its 52-week, serial liver biopsy population for Subpart H approval of MAESTRO-NASH, by the end of Q2,2021.
  • The Company intends to present data from the open label arm of MAESTRO-NAFLD-1 at a major medical conference.
  • Madrigal intends to present topline data from the blinded arms of MAESTRO-NAFLD-1 at the end of 2021.
  • The Company had cash, cash equivalents and marketable securities of $284.1 million, as of December 31, 2020, as compared to $439.0 million at December 31, 2019.

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    Key Takeaways
    The clinical development of potential drug candidates in NASH has been extremely challenging, with many of them failing to show any significant improvement or benefit in larger clinical trials, in spite of demonstrating promising results in pre-clinical or early-clinical development. Most recently, Ocaliva (obeticholic acid), an Farnesoid X receptor (FXR) agonist, being developed by Intercept that showed at least a one-stage improvement in fibrosis but failed to prevent the worsening of fibrosis, failed to win an FDA approval.

    Madrigal Pharmaceuticals is hopeful that its differentiated approach may finally prove to be the breakthrough that the NASH treatment landscape needs.

    Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

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