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The stock price jumped 268%, the results of the phase III clinical trial were positive, and the NASH treatment developed by Madrigal is expected to become the world's first approved therapy

 Last Update: 2022-12-30
 Source: Internet
 Author: User

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On December 19, Eastern time, biopharmaceutical company Madrigal Pharmaceuticals announced that it is developing a drug Resmetirom Phase III trials in the treatment of nonalcoholic steatohepatitis (NASH) have yielded positive results with both primary and key secondary endpoints, which are FDA Considered to be an important indicator
of patient clinical benefit and to support accelerated drug approval.

Its drug candidate Resmetirom Phase III trials in the treatment of nonalcoholic steatohepatitis (NASH) have yielded positive results and both primary and key secondary endpoints have been met

▲Figure | clinical trial results announced by Madrigal Pharmaceuticals (Source: Company official website)

Based on the drug's good efficacy and safety, the company said it plans to release it in 2023 Submit a new drug application in the first half of the year and seek rapid approval
for the drug at the same time.
It is worth noting that if approved, Resmetirom It will be the world's first commercially available non-alcoholic steatohepatitis treatment drug
.

Will be in 2023 Submit a new drug application in the first half of the year and seek rapid approval
for the drug at the same time.
Resmetirom It will be the world's first commercially available non-alcoholic steatohepatitis treatment drug
.

With this announcement, Madrigal Pharmaceuticals' share price has grown significantly, and the company's share price has risen by more than 268% to date At $234.
83, the company's total market capitalization reached $4.
015 billion
.

The company's share price has risen by more than 268%, up to At $234.
83, the company's total market capitalization reached $4.
015 billion
.

▲Figure | Madrigal Pharmaceuticals stock price (Source: Company's official website)

Two endpoints were met, and new drug applications and accelerated approvals are planned for next year

As a relatively common chronic liver disease, nonalcoholic steatohepatitis (Non-alcoholic Steatohepatitis, NASH) refers to the excessive deposition
of fat in the liver in addition to alcohol and other well-defined liver damaging factors.
NASH may occur as a result of environmental, genetic, dietary, and metabolic factors, and histopathological changes include fatty acid accumulation, mitochondrial dysfunction, free radical production, oxygen stress, lipid peroxidation, and endotoxin-mediated cytokine release
.

Globally, there are currently more than 100 million cases of NASH in patients, with 22 million people suffering from NASH in the US alone, including 8 million with severe liver fibrosis NASH
。 Previous studies have found NASH It is an important part of the development of non-alcoholic fatty liver disease (NAFLD) into end-stage liver diseases such as cirrhosis, hepatocellular carcinoma, and liver failure, and about 10%~20% if early intervention is not carried out Simple fatty liver disease will worsen into NASH
.
Statistics show that the probability of developing cirrhosis in patients with NAFLD after 10 to 20 years of follow-up is 0.
6% to 3%, compared with 10-15 in patients with NAASH The probability of developing cirrhosis within the year is as high as 15% to 25%, so early treatment of NASH is particularly important
.

NASH It is an important link in the development of non-alcoholic fatty liver disease (NAFLD) into end-stage liver diseases such as cirrhosis, hepatocellular carcinoma, and liver failure

However, many biopharmaceutical companies, including Gilead, AstraZeneca, and GlaxoSmithKline, have been trying to bring NASH therapeutics to market for years, but no drugs have been approved
to date.

According to the company's official website, the Resmetirom drug is a thyroid hormone receptor developed by Madrigal Pharmaceuticals that targets the liver β (THR-β) oral selective agonist.

Thyroid hormone receptors that target the liver β (THR-β) oral selective agonist.

▲Figure | Mechanism of action of Resmetirom drug (Source: Company official website)

Thyroid hormones play a central role in liver function by activating β receptors in liver cells, such as maintaining serum cholesterol and triglyceride levels
.
THR-β Key to maintaining normal liver function, including regulation of mitochondrial activity (e.
g.
, hepatic lipolysis) and control of normal, healthy mitochondrial levels, where THR-β is found in the liver in NASH Decreased
receptor activity levels.
Therefore, in order to optimize the effectiveness of the THR-β pathway in the treatment of liver disease, it is critical to maintain THR-α receptor activity
.

Madrigal Pharmaceuticals has designed four Phase III clinical trials for Resmetirom, respectively MAESTRO-NASH, MAESTRO-NASH-OUTCOMES, MAESTRO-NAFLD-1, AND MAESTRO-NAFLD-OLE ARE USED TO STUDY THE DRUG Effectiveness and security
of NASH.

Among them, the MAESTRO-NASH trial was conducted in patients with nonalcoholic steatohepatitis (NASH) with non-cirrhosis NASH patients with symptom relief at the same time as 52 Intraweek absence of fibrosis worsening as the primary endpoint of assessment; The MAESTRO-NAFLD-1 trial targeted patients with nonalcoholic fatty liver disease (NAFLD) with safety as the primary endpoint
.

According to the company's official website, MAESTRO-NASH is a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial
.
The study began in March 2019 and recruited a total of 966 people All eligible patients with NASH were randomized to receive Resmetirom 80 mg orally and 100 mg daily Treatment is either with medication or placebo, and patients are evaluated
for liver tissue biopsy at baseline and at 52 weeks of treatment, respectively.

▲Figure | Efficacy analysis of MAESTRO-NASH clinical phase III trial (Source: Company official website)

Data from the trial showed that patients taking both doses of Resmetirom achieved two endpoints compared to placebo: patients had higher NASH The level of symptom relief and improvement in liver fibrosis met the primary endpoint of a decrease in activity score (NAS) in nonalcoholic fatty liver disease, while also achieving a decrease in low-density lipoprotein cholesterol level (LDL) as a key secondary endpoint
.
In addition to this, based on Research data from the MAESTRO-NAFLD-1 clinical trial showed Resmetirom It is safe and well tolerated, and has statistically significant improvements
in key indicators of liver and cardiovascular health.

Patients have higher NASH The level of symptom relief and improvement in liver fibrosis met the primary endpoint of a decrease in activity score (NAS) in nonalcoholic fatty liver disease, while also achieving a decrease in low-density lipoprotein cholesterol level (LDL) as a key secondary endpoint
.

"The results of these pivotal Phase III clinical trials suggest that Resmetirom Drugs have the potential to help patients improve the underlying steatohepatitis that causes the disease and fibrosis associated with cirrhosis and its complications, while top-line data from clinical trials also enhance our understanding of Resmetirom Confidence in
safety and tolerability.
We believe that clinical trials will be the next step for new drug applications and Resmetirom for the treatment of NASH without cirrhosis The accelerated approval with liver fibrosis laid a solid foundation
.
Rebecca, Founder, Chief Medical Officer and President of Research and Development of Madrigal Pharmaceuticals Dr.
Taub said
.

New drug application and Resmetirom for the treatment of NASH without cirrhosis Accelerated with liver fibrosis approved

▲Photo| Dr.
Rebecca Taub, Founder, Chief Medical Officer and President of R&D of Madrigal Pharmaceuticals (Source: Company website)

Rebecca Taub has more than 20 years of experience leading drug development and served as a VIA prior to joining Madrigal Pharmaceuticals, Inc Pharmaceuticals Senior Vice President of Research and Development, Vice President of Metabolic Disease Research at Roche Corporation, and leadership positions
at Bristol-Myers Squibb and DuPont Pharmaceuticals.
In academia, she received her M.
D.
from Yale University School of Medicine and is currently a tenured professor of genetics and medicine at the University of Pennsylvania, an assistant professor at the Joslin Diabetes Center at Harvard Medical School, and an associate researcher
at the Howard Hughes Medical Institute.

Dr.
Paul Friedman, Chairman and CEO of Madrigal Pharmaceuticals, said, "MAESTRO-NASH achieves the FDA With two primary endpoints that predict clinical efficacy, these clear positive Phase III data suggest that our path forward is clear
.
We intend to submit a new drug application in the first half of next year to expedite it The approval of Resmetirom makes this new treatment
available to more patients worldwide.
”

A new drug application was submitted in the first half of next year to expedite it Approval of Resmetirom

"Since there is still no approved treatment, NASH With liver fibrosis represents one of the most pressing unmet needs in healthcare today, and the disease can put patients at risk
of progression to liver failure, liver cancer, the need for liver transplantation, and death.
MAESTRO-NASH Clinical III These unprecedented results from the phase trial mark a major turning point
in the field.
Stephen Harrison, Head of Clinical Research and Visiting Professor of Hepatology at Radcliffe Medical School, University of Oxford The doctor said
.

Drug development for NASH has a long and arduous road

It is reported that Madrigal Pharmaceuticals was established in 2011 Headquartered in Pennsylvania, it is a clinical-stage biopharmaceutical company that develops small molecule drugs that address unmet clinical needs in the cardiovascular and metabolic disease space, and is currently focused on developing new therapeutics
for nonalcoholic steatohepatitis.

According to public information, Madrigal Pharmaceuticals has completed a total of 4 rounds of financing since its inception, with a financing amount of 2.
884 $100 million, the most recent of which was raised in May this year with $250 million invested by Hercules Capital
。 In 2013, Madrigal Pharmaceuticals was listed on NASDAQ under the ticker symbol MDGL.

4 rounds of financing with a financing amount of 2.
884 $250 million in financing

With the announcement of clinical trial results from Madrigal Pharmaceuticals and the skyrocketing stock price, including 89bio, Intercept Pharmaceuticals, Akero Therapeutics and Viking Therapeutics and many other NASH Shares of therapeutic drug developers were also affected
.
In the case of 89bio and Intercept Pharmaceuticals, the shares of both companies fell by 6.
54% and respectively 23.
47%
。

It is worth mentioning that 89bio recently announced its drug candidate Pegozafermin for the treatment of NASH 1b/2a Proof-of-concept study results
.
Data showed that nearly 88% of patients administered weekly or biweekly compared with placebo had a near reduction in liver fat fraction at week 13 30%, the absolute reduction in the amount of fat fraction in the liver is statistically significant, indicating a slowdown in the development of fibrosis of the liver, at the same time, Pegozafermin It also improves hepatic aminotransferases (to assess liver damage), fibrosis, and lipid markers
.
In addition to this, Pegozafermin The drug was well tolerated in this study, and no treatment-related serious adverse events
were observed.

By week 13, nearly 88% of patients had a nearly reduced fraction of liver fat 30%

89bio alleges that Pegozafermin is expected to have become targeted at NASH The potential of the "best-in-class" therapeutics and plans to advance clinical phase III trials
of this drug in patients with severe hypertriglyceridemia in the first half of 2023.

Pegozafermin is expected to have become targeted for NASH The potential of "best-in-class" therapeutic drugs

Pegozafermin is known to be a glycosylated polyethylene glycolated fibroblast growth factor 21 Analogues that can be used to treat severe hypertriglyceridemia (SHTG) and NASH
.
Fibroblast growth factor 21 An endogenous metabolic hormone that regulates energy expenditure and glycolipid metabolism, 89bio is engineered using proprietary glycopolyethylene glycolation technology to extend fibroblast growth factor 21 biological activity and maintain its efficacy
.

Glycosylated fibroblast growth factor 21 Analogues endogenous metabolic hormones that regulate energy expenditure and glycolipid metabolism

▲Figure | Pegozafermin drug mechanism of action (Source: the company's official website)

Not long ago, Intercept Pharmaceuticals developed the NASH treatment Obecholic ACID) in the treatment of NASH clinical III.
Phase II trials have yielded positive results
.
Obeticholic acid is an approved oral drug for the treatment of primary cholangitis, and farnesol X is expressed in the intestine and liver Agonist
of receptor (FXR).

Obecholic acid (Obeticholic ACID) in the treatment of NASH clinical III.
Phase II trials have yielded positive results
.

▲Figure | Intercept Pharmaceuticals company's research pipeline (Source: the company's official website)

Based on the positive results of clinical trials, the company plans to apply for approval of obeticholic acid for the treatment of NASH-induced liver fibrosis, however, eventually by the FDA The company's approval application
was rejected on the grounds that "there is still uncertainty about predicting clinical benefit.
"

An application for approval of obeticholic acid for the treatment of NASH-induced fibrosis is planned

It is for this reason that the investment institutions do not have high expectations for Madrigal Pharmaceuticals and its drug Resmetirom, fortunately in a number of clinical III.
The positive top-line results of the phase phase trial have rekindled investor confidence, and it remains to be seen whether Resmetirom will live up to expectations and become the first approved NASH therapeutical
.

Resources:

References: References:

1.
https://ir.
madrigalpharma.
com/news-releases/news-release-details/madrigal-announces-positive-topline-results-pivotal-phase-3

2.
3.

3.
4.

4.
5.
#bio89-100

5.
#bio89-100

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