NASH is on the verge of a new drug, and the 40-year black hole is finally shining a light

It's coming, it's coming. A cure for NASH, nonalcoholic steatohepatitis, is finally on its way.

On December 19, Madrigal announced that its Phase II NASH drug, Resmetiromi, is on the verge of being marketed. Madrigal jumped 212.13% in the premarket on the news and continued to rise after the opening bell.

A successful phase III drug, why such a big response. The difficulty of developing NASH has something to do with it. There has been no substantial progress in the development of drugs for NASH for more than four decades, since the disease was identified in 1980. What's the challenge with NASH?

The pathogenesis is complex, and drug development is similar to feeling the elephant

Nonalcoholic fatty hepatitis is composed of nonalcoholic fatty liver disease (NonalcoholicFattyLiverDisease, NAFLD) progress to severe chronic liver disease.

According to epidemiological surveys, the prevalence of NAFLD worldwide is about 25%, of which 10% to 30% will eventually develop NASH, which means between 190 million and 580 million NASH patients worldwide.

As a common chronic liver disease, NASH is directly related to the accumulation of fat in the liver, which can lead to chronic liver inflammation and liver cell damage, and can progress to liver fibrosis, cirrhosis, and eventually liver failure or liver cancer.

The pathogenesis of NASH is very complex, and it is believed that it is mainly related to fatty acid accumulation, insulin resistance, abnormal immune signal, inflammatory cells and cell apoptosis, etc. However, the most important pathogenic pathway remains to be determined. For drug companies, therefore, NASH is largely a blind man's game.

At the regulatory level, the drug authorities are strict about the clinical endpoint of NASH. The FDA notes that the reliable diagnosis of NASH and the stage of NASH development can only be determined by histopathological examination of liver biopsy specimens. Because NASH is a diffuse lesion, rapid puncture method can accurately reflect the nature and degree of lesion by extracting a small amount of liver tissue from the liver and observing its morphological changes directly under the microscope. Because a liver biopsy is an invasive procedure, there are some side effects; And some patients are reluctant to have a biopsy. So the requirement certainly made it harder to get NASH approved.

In recent years, clinical trials for NASH drugs have failed frequently.

In April 2019, GileadSciences' NASH drug, selonsertib, an ASK1 inhibitor, failed miserably in phase III trials.

The Phase III trial, called STELLAR 4, enrolled 877 patients with NASH-induced compensatory cirrhosis to compare the effect of 2 doses of selonsertib with placebo on fibrosis.

The results showed that 14.4% of patients in the 48-week 18mg group, 12.5% in the 6mg group, and 12.8% in the placebo group had at least grade 1 fibrosis improvement and missed the preset 48-week clinical endpoint, which sent Gilead's stock down 3.5% in closing trading.

In October 2020, Pfizer announced on its website in the Product Development Pipeline and third quarter report that the Phase I clinical trial of danuglipron(PF-06882961)+PF-06865571 in NASH with hepatic fibrosis had been discontinued. danuglipron will no longer be advanced as a potential treatment for NASH.

Danuglipron is a glucagon-like peptide 1 receptor (GLP-1R) agonist. In addition to danuglipron, Pfizer abandoned another NASH candidate, the ketokinase (KHK) inhibitor PF-06835919, in July 2021.

Aubercholic acid (OCA), an FXR agonist from Intercept, was seen as the most promising drug for NASH. In a Phase III clinical trial, obecholic acid met the end point of improving primary fibrosis. But because of its side effects, the FDA decided that Obocholic acid did not prove that the benefits outweighed the risks and declined to approve the drug for NASH.

Perseverance has led to NASH therapy

Frequent failed clinical trials do not affect the successive pharmaceutical companies, perhaps this is the meaning of innovative drug research and development. Finally, good news from Madrigal offers a glimmer of hope for NASH.

Resmetirom is a liver-targeted thyroid hormone receptor-β (THR-β) agonist being developed by Madrigal.

Thyroid hormone plays an important role in liver function by activating β receptors in liver cells. In humans, it has the activity of reducing low-density lipoprotein (LDL), triglyceride (TG) and liver steatosis.

By promoting the breakdown of fatty acids and stimulating mitochondrial biogenesis, THR-β helps reduce lipotoxicity and improve liver function, thereby reducing liver fat. In the liver of NASH patients, thr-beta receptor activity is reduced, making Thr-beta agonists a potential treatment for NASH.

The Phase III trial of Mastro NASH is a double-blind, randomized, placebo-controlled study with clinical outcomes that fully conform to the gold standard of liver biopsy.

In a 52-week continuous liver biopsy study of more than 950 patients with advanced liver fibrosis (stage F2 and F3) NASH receiving resmetirom, both 80mg and 100mg daily oral doses of resmetirom met the primary endpoint of NASH remission one year after treatment, compared with placebo. A secondary endpoint of lowering LDL cholesterol was also achieved.

Both doses were well tolerated in terms of safety, with the incidence of 80mg, 100mg and placebo SAEs being 11.8%,12.7% and 12.1%, respectively. As it stands, resmetirom is just one step away from hitting the market.

A number of domestic pharmaceutical companies compete for the blue Ocean market

Frost Sullivan reports that the global NASH drug market reached $1.9 billion in 2020 and will grow to $32.2 billion by 2030. Many domestic pharmaceutical companies smell the taste of the blue sea, have entered the game.

Cole's new NASH drug in development, ASC41, a thr-beta agonist, just completed its first Phase II trial in October. The Phase II trial will enroll approximately 180 patients with NASH confirmed by liver biopsy. Enrollment is expected to be completed in the third quarter of 2023.

The advanced NASH drug, TERN-101, a farnisol X receptor (FXR) agonist, is in Phase II trials.

FXR is a nuclear receptor that is heavily expressed in the liver and small intestine. Bile acids are the natural ligand of FXR, and their binding to and activation of FXR are critical for the regulation of cellular pathways that regulate bile acid synthesis, lipid metabolism, inflammation, and fibrosis.

TERN-101 is a highly effective non-bile acid FXR agonist currently under development for the treatment of NASH. The Phase IIa LIFT clinical trial evaluated the safety, tolerability, efficacy, and pharmacokinetics of oral doses of TERN-101 at 5mg, 10mg, and 15mg in 100 presumed non-cirrhotic NASH adults.

The results showed that TERN-101 was generally well tolerated in the LIFT trial, with similar rates of adverse events across treatment groups. All treatment-related adverse events were mild/moderate, and there was no significant dose relationship.

In addition to Geli and Tuozhen, Kylo-0603 of Hegia Biology and ECC4703 of Chengyi Biology have also been reported to the clinic.

Among them, Kylo-0603 of Hekya Biotics is a Galnac-coupled THR-β agonist, which further improves liver targeting.

The ECC4703 is also a THR-β agonist. In preclinical studies, ECC4703 has been shown to have superior efficacy compared to some agonists, and has shown excellent efficacy in animal models of NASH and dyslipidemia.

In addition to THR-β and FXR targets, PPAR, GLP-1 and other targets are also strong competitors of NASH. According to the statistics of Xiangcai Securities, there are a total of 89 new NASH drug research projects in China, most of which are still in the early stage. It remains to be seen who will break through first in the future.