The NASH market is in full swing! At a glance of the latest R&D progress, who will 'reach the top'?

There are about 150 million fatty liver patients in China, and it is increasing, and NASH (non-alcoholic steatohepatitis) is a more serious type of fatty liver.

It is reported that there are 110 million patients with mild fatty liver who can get better through diet and exercise, but tens of millions of patients with moderate to severe NASH cannot recover through this method. And NASH requires lifelong medication, and the market size is large.

It is predicted that within 2030, NASH will surpass hepatitis B and become another killer of human health. The international NASH market is expected to reach $35-40 billion by 2025.

However, the good news is that Madrigal recently disclosed that the positive trial data of the first global phase III clinical study of Resmetirom, a new drug designed to treat NASH, brings new hope to NASH patients and indicates that the development of new drugs in the NASH field is about to usher in a new round of "golden period".

The layout of 6 pharmaceutical companies is at a glance

• Altran Pharma: FXR agonist HPG-1860

Altran's HPG-1860, one of the fastest developed FXR agonists in China. FXR agonist with a highly selective non-bile acid structure.

FXR becomes a key controller of bile acid homeostasis by regulating the expression of genes related to bile acid synthesis. Studies have shown that the expression of FXR is downregulated in the progression of NASH disease, and the role of FXR in inflammation regulation has been widely concerned and studied.

HPG1860 has demonstrated excellent FXR targeted activation properties and good safety in preclinical studies and early clinical trials. However, because FXR activators mainly alter the fat metabolism pathway and have the side effect of increasing blood lipids, they should not be used by patients with cardiovascular disease, even if the market is limited after successful marketing.

• Ascletis Pharmaceutical: FXR agonist ASC40

Ascletis announced that its application for a drug-drug interaction (DDI) study of the FXR agonist ASC42 for the treatment of primary biliary cholangitis (PBC) has been approved by the FDA, which will provide additional support for subsequent phase III clinical trials of ASC42 in China, the United States and the European Union.

However, FXR agonists have been dose-dependent on pruritus and dyslipidemia in different clinical trials, which are the target effects after FXR activation.

Currently, the main challenge is to optimize the structure of FXR agonists and determine the optimal dose, mitigating adverse effects while maintaining definitive improvement in liver histology and clinical efficacy, which is a dilemma to be solved.

• Guangdong Zhongsheng Pharmaceutical: ZSP1601

The company has laid out 6 products in the field of NASH, namely ZSP1601, ZSP0678, ZSYM008 and RCYM001, RAY001 with RAY002 to lay out different targets covering liver fat, inflammation, fibrosis, etc., and has the potential of combined drug pipeline.

Among them, ZSP1601 has completed phase Ib/IIa clinical trials, and the trial has obtained positive results, reaching the main endpoint, supporting ZSP1601 tablets to continue phase IIb clinical trials, and the domestic R&D progress is in the first echelon.

• Shenzhen Junshengtai: HTD1801

The new drugs developed by it are developed simultaneously around the world, and 2 varieties have entered clinical phase II, and have obtained 2 fast-track review channel qualification certifications and 1 orphan drug designation from the US FDA.

• Tern Biologics: FXR agonist TERN101

New therapies mainly for chronic liver diseases such as NASH, liver fibrosis, and hepatocellular carcinoma successfully landed on NASDAQ last year.

TERN-101 is licensed to Eli Lilly. Compared with other FXR agonists, TERN-101 has better tissue specificity, high distribution in the liver, minimizes activation of intestinal pathways, thereby reducing side effects such as itching and adverse lipid changes, and improving drug tolerance.

There are also the SSAO inhibitor TERN-201, the THR-β agonist TERN-501, and a GLP-1R agonist.

• South Korea's LG-Chem VAP-1 inhibitor LR20056

LR20056, which LG Chem has obtained from the domestic drug Ji'ankang, is a new, potent, selective and irreversible half-life-sensitive amine oxidase (SSAO, also known as vascular adhesion protein-1 (VAP-1)) inhibitor, which is intended to be used as an oral treatment drug for nonalcoholic steatohepatitis (NASH) and is undergoing clinical phase I trials in the United States.

NASH drug discovery strategy

At present, NASH targeted drug treatment strategies can be mainly divided into four categories:

The first category targets metabolic targets that improve insulin sensitivity, inhibit different enzymes involved in new fat production, or improve the utilization of fatty acids by mitochondria;

The second category targets inflammatory or cellular damage, inhibits the recruitment of inflammatory cells or blocks inflammatory signaling, reduces oxidation and/or endoplasmic reticulum pressure, or inhibits apoptosis of hepatocytes;

the third category, which regulates the intestinal liver circulation and signaling of bile acids, or the hepatoenteric axis targets that alter the gut microbiota;

The last category, which directly targets the anti-fibrosis target of hepatic stellate cells, reduces the deposition of collagen in the liver and reduces liver fibrosis. Table 1 summarizes the five representative drugs.

Targeting bile acid receptors

Studies have found that bile acids bind to receptors as signaling molecules and play a key role in the initiation, progression, and regression of NAFLD/NASH. In 2015, the interim results of the FLINT trial "Obeticholic acid (OCA) can reduce NAFLD activity score (NAS) and fibrosis "degree" in NASH patients by activating farnesol X receptor (FXR), which attracted industry attention.

The FXR agonist obeticholic acid, although it has met the clinical endpoint set by the FDA in a Phase III clinical study. However, there is still great uncertainty about whether it will be approved for marketing.

The more important question is: Is it worth continuing to develop better FXR small molecule agonists? The answer seems to be yes, but getting rid of side effects like itching may also be wishful thinking on the part of the researchers.

This, combined with other possible hepatotoxicities, limits the dose at which the drug can be used, and its overall efficacy is limited. Phase II clinical data for two FXR agonists, EDP-305 and MET409, have recently been released, but itching remains a big problem.

On September 25, 2019, Enanta Pharmaceuticals released clinical 2a study (ARGON-1) data for another FXR agonist, EDP-305. The study tested two doses (1 mg and 2.5 mg) of EDP-305, and liver enzyme levels decreased by 28 units/L in the high-dose group compared to 15 units/L in the placebo group. The results just above the statistically significant threshold, consistent with the 28 units/liter reduction in OCA clinical tests.

Patients receiving high doses of EDP-305 had a statistically significant reduction in liver fat (MRI-PDFF). Forty-five percent of participants were MRI-PDF responders, i.e. ≥ 30% fat reduction. EDP-305 also demonstrated strong target involvement, such as a decrease in C4 and an increase in FGF-19 and ALP; A strong decrease in GGT was also observed.

Overall, EDP-305 is generally safe, and most treatment-related adverse events (TEAEs) are mild to moderate. The most common (≥5%) include itching (pruritus), gastrointestinal (GI)-related symptoms (nausea, vomiting, diarrhea), headache, and dizziness.

To date, consistent safety profiles have been observed in more than 400 subjects receiving EDP-305 in all studies. As for the tolerability of EDP-305 in this 12-week clinical 2a study, it is not optimistic:

Pruritus was present in approximately 51% of participants in the 2.5 mg dose group, while in less than 10% of participants in the 1 mg arm; Most itching is mild or moderate. Discontinuation rates due to pruritus were 1.8% (1 mg dose) and 20.8% (2.5 mg dose), respectively. In the 2.5 mg dose group, all discontinuation was due to moderate itching.

On August 27, 2020, Metacrine, Inc., based in San Diego, California, USA, released the final positive results of a 12-week randomized, placebo-controlled clinical 1b study of MET409, the company's non-bile acid FXR agonist for the treatment of NASH.

Target PPARs

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors of the nuclear hormone receptor superfamily, including three subtypes: PPARα, PPARγ, and PPARβ/δ. Among them, the activation of PPAR-α can reduce triglyceride levels and participate in the regulation of energy homeostasis, while the activation of PPAR-β/δ enhances fatty acid metabolism.

The PPARgamma agonist pioglitazone promotes fat redistribution and reduces hepatic steatosis, inflammation, and liver fibrosis in addition to improving insulin resistance.

The PPARα and PPARgamma agonist saroglitazar were approved for marketing in India in March 2020 for the treatment of non-cirrhosis NASH, and are the world's first drugs approved for the treatment of NASH, which can not only reduce intrahepatic fat content, reduce liver enzyme levels, but also reduce cardiovascular disease risk factors by regulating glycolipid metabolism, and are suitable for NASH patients with diabetes and hyperlipidemia who cannot be controlled by statins.

Recently, Indian studies reported that saroglitazar (4 mg/day) treatment for 9 months can reduce serum total cholesterol and liver enzyme levels and improve liver stiffness in patients with NAFLD. Clinical studies have shown that the dual agonists elafibranor and the pan-PPAR agonist lanifibranor can reduce blood lipid levels and improve liver histopathology in patients with NAFLD.

However, this target has also been difficult recently: Suzhou Zejing suspended the "ZG0588 preclinical research, clinical research and pharmaceutical research for non-alcoholic steatohepatitis indications" project to emphasize that the efficacy of PPAR agonists in clinical studies for the treatment of NASH is lower than expected, such as May 2020, Genfit announced that its Phase III clinical study of the PPAR agonist elafibranor in the treatment of nonalcoholic fatty liver disease (NASH) failed to meet the pre-set primary endpoint.

Targeting liver-specific thyroid receptors (THRs)

Thyroid hormones regulate many processes of liver triglyceride and cholesterol metabolism, and two subtypes of thyroid receptors, THRα and THRβ, are expressed in most tissues, of which THRβ is the main form expressed in the liver and is more selective.

Resmetirom is the fastest developing THRβ agonist for NASH indications, and at the end of January this year, the aforementioned Madrigal Pharmaceuticals announced that the drug had met the primary endpoint and key secondary endpoint in the Phase III study, and that patients had achieved "significant, clinically relevant" reductions in liver fat and atherogenic lipids with a good safety profile.

Among the products independently developed by domestic companies, the fastest progress is Tern-501 from Topazhen. Phase II clinical trials for monotherapy and in combination with the FXR agonist TERN-101 have been initiated in the United States in March this year.

Targeting GLP-1 receptors

Glucagon-like peptide-1 (GLP-1) receptor agonists, which are incretin analogues, have been widely used in the treatment of type 2 diabetes. There is growing evidence that these drugs improve liver fat content in people with NASH.

The results of a phase II multicenter study of semeglutide in 320 NASH patients showed that the primary endpoints of NASH resolution and no worsening of liver fibrosis were met in all dose groups. In addition, a phase II study of the dual agonist tirp peptide of GIP and GLP-1 receptors confirmed that the drug reduced ALT, K-18, and Pro-C3 markers in patients with NASH.

The domestic company focuses on the research and development of innovative drugs for chronic metabolic diseases, and a number of GLP-1 receptor agonist products are conducting research on NASH indications. Late last year, the company licensed the global development and commercialization rights for a preclinical long-acting GIP receptor agonist program to Sanofi.

Target ACC

GS-0976 (firsocostat) is a direct inhibitor of hepatic acetyl-CoA carboxylase (ACC), cited by Gilead from Nimus. Another such drug under development is Pfizer's ACC1/2 dual inhibitor PF-05221304 (clesacostat).

Both drugs have been conducted in phase II studies for the treatment of NASH in several countries, including China, and preliminary studies have shown positive results, but both have found elevated triglycerides as a major adverse event.

Combination Exploration

The pathogenesis of NASH is complex, and some clinical studies of a single agent have failed to show significant histological improvement, and tolerability issues occur when used at high doses. Therefore, a number of combination studies are currently underway to improve efficacy, alleviate potential tolerability issues, and improve adherence.

Gilead conducted a Phase II study of the combination of the nonsteroidal FXR agonist cilofexor (GS-9674) and the ACC inhibitor firsocostat (GS-0976). Early studies have shown that the combination of drugs can reduce liver fat in patients, but the primary endpoint of improvement in fibrosis was not met in patients with severe liver fibrosis (stages F3 to F4). However, the study met several secondary endpoints, including improvements in NAS scores.

Gilead, in collaboration with Novo Nordisk, launched a IIb study of Novo Nordisk's GLP-1 receptor agonist semaglutide in combination with cilofexor and firsocostat fixed-dose combination tridrug.

In addition, Pfizer and Novartis have also conducted phase II studies of two-drug combinations for NASH in several countries, including China. Pfizer's combination is ACC inhibitor PF-05221304 in combination with DGAT2 inhibitor PF-06865571 (ervogastat), and Novus FXR agonist tropifexor in combination with SGLT1/2 inhibitor LIK066 (licogliflozin). However, given that Novartis has terminated two tropifexor studies, the joint study is also at risk of termination.

brief summary

For new drug development, although the NASH market is huge, it is also a bottomless black hole: there have been many drug development failures, and the list is still growing, many drugs have failed after entering advanced clinical studies.

The road is blocked and long, and the line will come; Keep going, the future can be expected! We look forward to the rapid rise of innovative pharmaceutical companies at home and abroad in the field of NASH.