FDA approved first ever MASH drug

NASH

Steatohepatitis (MASH)

Introduction

Metabolic dysfunction-associated fatty liver disease (MASLD) is the name adopted in 2023 for the disease formerly known as non-alcoholic fatty liver disease (NAFLD). This condition is diagnosed when there is excessive accumulation of fat in the liver (hepatic steatosis) and at least one metabolic risk factor is present. The term MetALD is used when moderate alcohol consumption is also present and to distinguish it from alcoholic liver disease (ALD) when it is the sole cause of steatosis.

The terms NAFL (non-alcoholic fatty liver) and MASH non-alcoholic steatohepatitis (formerly NASH, non-alcoholic steatohepatitis) have been used to describe varying degrees of severity, with the latter indicating the presence of further liver inflammation. NAFL is less dangerous than NASH and usually does not progress to NASH, but this progression may eventually lead to complications such as cirrhosis, liver cancer, liver failure, and cardiovascular disease. It is often caused by diet-related fat accumulation in the liver, leading to inflammation that may later lead to cirrhosis; some patients may even require organ transplants.

How many patients are there?

According to estimates by Frost & Sullivan, there are currently an estimated 115 million NASH hepatitis patients worldwide. In 2030, the number of NASH patients worldwide and in China will reach 486 million and 56 million respectively. The main users are in the United States, Western Europe and Japan. Professional studies show that 12% of Americans and 6% of Europeans have suffered from this disease.

Madrigal projects that 1.5M Americans have been diagnosed with NASH, with obesity and diabetes among the factors driving the disease’s prevalence.

How big is the market?

According to Frost & Sullivan’s forecast, the market capacity of NASH drugs will exceed US$10 billion by 2025, with a compound growth rate of 20.19% from 2016 to 2025.

Research group GlobalData estimates that NASH will become a market worth more than $25 billion by 2026. Moreover, this market will grow by 45% every year starting from the introduction of prescriptions by big pharmaceutical companies.

A new blue ocean for pharma

The number of patients is huge, but treatment drugs are quite scarce. Such an attractive market has attracted the layout of pharmaceutical giants such as Gilead, Novartis, and Merck, but unfortunately they have all failed. There are currently hundreds of NASH drugs under development around the world, targeting nearly 20 targets such as THR-β, FGF21, PPAR and GLP-1.

Difficulties

The reason why NASH treatment drugs are scarce is not only because of the complex pathogenesis of NASH, but also because of the strict clinical endpoint identification by the FDA: pathological evaluation by liver puncture is required, and imaging evaluation and hematological evaluation cannot be used as the primary endpoint for marketing approval.

FDA just approved first NASH drug

Among them, Madrigal’s Resmetirom (will be mentioned later), which has undergone Phase III trials, was approved by the FDA on March 14, 2024, becoming the first new NASH hepatitis drug to be regulatory approved in history (see details below)).

Several well-known drugs

New indications for weight loss drugs

There have been a number of weight loss drug fires that have caused the stock prices of manufacturers to soar, including Eli Lilly (ticker: LLY) and Novo Nordisk (ticker: NOVO), also from Denmark, which have become the European market capitalization due to the development of weight loss drugs Ozempic and Wegovy. The highest company. For this part, please refer to my previous posts for detailed discussions:

The booming development of the weight-loss drug market has made a lot of money for many pharmaceutical companies. The following pharmaceutical companies have used the treatment of NASH hepatitis as a new indication for their new weight-loss drugs. Importantly, these weight loss drugs all use GLP-1.

survodutide from Zealand

Danish pharmaceutical company Zealand Pharm (ticker: ZLDPF) is not far behind. The company announced a trial result on February 26, 2024, which showed that one of its liver disease treatment drugs was effective, stimulating the company’s stock price to rise on February 26, 2024. It soared 36% on the day.

Zealand Pharma and German partner Boehringer Ingelheim (unlisted) stated in an announcement on February 26, 2024 that the phase II trial of the company’s survodutide drug showed that 83% of adult subjects the drug has shown positive results in the treatment of metabolic dysfunction-associated steatohepatitis (NASH).

The company hopes to launch the drug in 2027 or 2028, depending on whether Phase 3 trial results are favorable. Analysts said the trial results showed a “clear victory” for the drug. Preliminary results show that survodutide was effective in treating NASH hepatitis at all doses used in the trial, and treatment with survodutide showed no unexpected safety or tolerability issues, including at the higher dose of 6.0 mg.

The drug survodutide suppresses appetite by mimicking the gut hormone GLP-1 (glucagon-like peptide-1), like other injectable weight-loss drugs, but it also mimics another hormone called glucagon. of intestinal hormones. Survodutide also belongs to the GLP-1 (glucagon-like peptide-1) class of drugs, similar to Novo Nordisk’s Wegovy.

There are currently five Phase III clinical trials underway in overweight or obese people, and the drug has been designated as a fast track development drug by the U.S. Food and Drug Administration (FDA). The trial results show that the drug is safe even at the highest doses.

Novo Nordisk’s semaglutide

Novo Nordisk is conducting a Phase 3 trial of semaglutide, the active ingredient in its Wegovy weight loss injection, against NASH hepatitis, with results expected to be announced in 2028.

According to Novo Nordisk’s announcement, semaglutide showed positive results in the phase 2 clinical trial of NASH. Among the patients in the highest dose semaglutide treatment group, 66.7% of the patients’ NASH symptoms were eliminated.

Eli Lilly’s Mounjaro

Eli Lilly’s weight-loss drug Mounjaro, also known as Zepbound, is also testing its active ingredient in a Phase 2 trial for NASH hepatitis. The drug has a dual mechanism of action, based on two hormones: GLP-1 and GIP (gastric inhibitory peptide). Lilly is currently in the second phase of clinical trials and expects to complete the main study in the first half of 2024.

The results of Mounjaro’s second phase trial showed that the rate of liver fibrosis no longer worsening at a dose of 0.4 mg could reach up to 59%.

Non-weight loss drugs

Akero’s Efruxifermin

In terms of FGF21 analogues, Efruxifermin developed by Akero (ticker: AKRO) is ahead of the curve. It has taken the lead in launching the third phase of trials in December 2023 and is expected to be completed in April 2026. According to the Phase IIb study, both dosage groups of Efruxifermin achieved the primary endpoint and multiple secondary endpoints of improving liver fibrosis, and the liver biopsy data were impressive. The test results show that the proportion of liver fibrosis no longer worsening at the dose of 28 mg can reach up to 63%.

Lanifibranor by Inventiva

Inventiva’s (ticker: IVA) Lanifibranor is an oral PPAR agonist. Trial results show that a dose of 1.2 mg can prevent liver fibrosis from worsening by up to 49%. The Phase III study is expected to be completed in September 2025. If positive clinical data is successfully obtained, an application for accelerated approval from the FDA may be made in the first half of 2026.

Denifanstat by Sagimet

On January 22, 2024, Sagimet (ticker: SGMT) announced that the Phase IIb study of Denifanstat in the treatment of NASH had achieved positive results, and its stock price soared 170%.

Resmetirom by Madrigal

The leader

Resmetirom developed by Madrigal (ticker: MDGL) is a THR-β inhibitor. In December 2022, Madrigal announced that its Phase III trial of Resmetirom in the treatment of NASH was successful.

According to the results of the phase III trial, compared with the placebo group, 26% and 30% of patients who received 80 mg and 100 mg of Resmetirom for 52 weeks achieved remission of NASH symptoms, respectively.

In December 2022, Madrigal’s stock price soared 268% the day after the clinical data of Resmetirom was released.

Has been approved

The U.S. Food and Drug Administration (FDA) has approved Madrigal’s resmetirom on March 14, 2024 as the first drug approved in the United States to treat non-alcoholic steatohepatitis (NASH) liver disease. Its approval marks medical history. a landmark decision.

The once-daily oral thyroid hormone receptor (THR) agonist therapy, branded Rezdiffra, will be available in the United States with a price tag of US$47,000. According to FDA label information, the drug, called REZDIFFRA, will be indicated for adults with NASH and moderate to advanced liver fibrosis.

With the announcement of this bullish news, Madrigal’s stock price surged by 24% immediately after the results.

Viking’s VK2809

Based on THR-β agonists, Viking (ticker: VKTX) announced in May 2023 that the Phase II Voyage study of VK2809 in the treatment of NASH reached the primary endpoint (evaluating changes in liver fat content in patients at week 12) – Liver in the VK2809 group The proportion of patients whose fat content was reduced by at least 30% was as high as 84.9%. Data on liver puncture are expected to be announced in the first half of 2024.

MASH
credit: thelivertransplant.com

I am the author of the original text, the essence of this article was originally published in Smart Magzine, issue of May 2024

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