When will the 10 billion NASH market usher in a new "break"?

MNC has scrambled to lay out NASH drugs, but no company has been successful
so far.

NASH, or nonalcoholic steatohepatitis, is a severe type of nonalcoholic fatty liver disease (NAFLD) characterized by at least 5% steatosis, balloon-like degeneration, and leaflet inflammation, with or without fibrosis
, based on liver biopsy.
Over time, NASH may progress to cirrhosis, end-stage liver disease, or require liver transplantation
.

According to a 2017 article in the journal Nature, NASH has become the second most common cause of liver transplantation in the U.
S.
after chronic hepatitis C and is expected to be the top cause
in 2020.
At present, the global incidence of NAFLD and NASH is rising rapidly, according to statistics, there are more than 100 million NASH patients in the world, and the number of patients is expected to exceed 350 million
in 2030.
NASH pathogenesis is complex, and the main risk factors include obesity, type 2 diabetes, and dyslipidemia and metabolic syndrome
.

The global NASH drug market is growing rapidly in size and is expected to exceed $10 billion
by 2025.
The global NASH drug market grew from $1.
7 billion in 2016 to $1.
9 billion in 2020, with a CAGR of 3.
2%.

It is expected to show a rapid growth trend in the future, reaching $10.
7 billion by 2025 and $32.
2 billion by 2030, with a compound annual growth rate of 41.
8% and 24.
6%
during the period.

Currently, only Zydus Cadila's Sarogliza is approved worldwide for the treatment of NASH
.
The drug, a novel PPAR agonist with the function of regulating both PPARα and PPARγ activity, was approved in India in March 2020 for the treatment of NASH, and the drug was also approved for the treatment of diabetic dyslipidemia that statins cannot control (September 2013) and type 2 diabetes (January 2020).

In addition, more than 200 new drugs have been developed to treat NASH worldwide, of which there are nearly 30 kinds in
China.
These NASH drugs are mainly aimed at metabolic abnormalities, inflammation, and fibrosis, and metabolic products are divided into lipid metabolism, glucose metabolism and bile acid metabolism-related targets
.
Among them drugs to correct abnormal lipid metabolism include acetyl-CoA carboxylase (ACC) inhibitors, stearyl-CoA desaturase-1 (SCD1) inhibitors, fatty acid synthetase (FASN) inhibitors, peroxisome proliferation receptors (PPAR) - α / δ agonists, thyroid hormone β receptors (THRβ) agonists and the like
.
Drugs that affect targets related to glucose metabolism include PPARα/δ agonists, glucagon-like peptide-1 (GLP-1), and the like
.

Drugs similar to bile acid are mainly farnil ester X (FXR) receptor agonists
.
Inhibition of inflammation and apoptosis-related drugs include apoptosis signal-modulating kinase-1 (ASK-1), chemokine receptor (CCR) 2/5, pan-caspase inhibitors and the like
.
Anti-fibrosis preparations mainly include galactolectin-3 (Galectin-3) inhibitors, lysyl oxidase-like molecule-2 (LOXL2) inhibitors, fibroblast growth factor-21 (FGF21) analogues and the like
.

According to statistics, there are currently 26 NASH drugs in the clinical stage in China, one of which is in the clinical stage of clinical stage, one of which is in the clinical stage of Somaglutide; 10 drugs are in clinical phase II, including two Curley pharmaceutical drug candidates, of which ASC40 has completed phase II clinical trial; ZSP1601 of Zhongsheng Pharmaceutical is a drug targeting TNF and has completed Phase I and II.
A clinical trials
.
Microchip Bio's Sipaglita sodium and Dongguang Pharmaceutical's HEC96719 are in clinical phase
II.

According to incomplete statistics, a number of new NASH drugs around the world have made new progress this year:

In January, 89bio announced that its NASH therapy pegozafermin (formerly known as BIO89-100) had achieved positive results
in a Phase 1b/2a proof-of-concept clinical trial.

In February, Axcella Therapeutics' new drug, AXA1125, was granted fast-track qualification by the FDA for the treatment of NASH
accompanied by liver fibrosis.
The drug is a novel multi-targeted oral endogenous metabolic modulator (EMM) designed to address metabolism, inflammation and fibrosis associated
with liver health.

In May, Pfizer combination therapies ervogstat (PF-06865571) and clesacostat (PF-05221304) were granted fast-track qualifications by the FDA for the treatment of NASH
accompanied by liver fibrosis.

In July, Intercept announced that its Obeticholic acid (OCA) had achieved positive results in a new interim analysis of REGENERATE, a key Phase 3 clinical trial: OCA reached the primary endpoint
of the trial in the population of intentional therapy (ITT).

In August and September, Poxel announced positive results
in Phase 2 clinical trial DESTINY-1 for the treatment of NASH with deuterated R-pioglitazone (PXL065).

In September, Akero Therapeutics announced positive data
for a Phase 2b clinical trial of efruxifermin for the treatment of NASH.

In June this year, Novo Nordisk announced at the 2022 European Society for the Study of Liver (EASL) that the Phase 2 clinical trial of semaglutide for the treatment of NASH did not meet the main endpoint
.
The specific data are that only 10.
6% of patients in the smegeglutide treatment group improved liver fibrosis, while NASH did not worsen, compared with 29.
2%
in the placebo group.
In terms of secondary endpoints, 34% of patients in the semeglutide group saw regression of NASH, compared with 20.
8%
in the placebo group.

However, it is not only Novo Nordisk's smegluglutide
that has not progressed well in the field of NASH.
Gilead's selonsertib, Conatus Pharmaceuticals' emricasan and Intercept's Oculva, Genfit's elafibranor, etc.
failed
miserably on NASH indications.
Failure is mainly divided into two categories: no efficacy and side effects
.
For example, there is no improvement of fibrosis such as invalid target Galectin-3 inhibitors and ASK1 inhibitors; Aubeliary bilicylic acid has a fibrotic improvement but has a pronounced itching by-function, PPARδ agonist has interfacial hepatitis
.

In addition, since the beginning of this year, a number of pharmaceutical companies have reached cooperation in the field of NASH, which involves NASH drugs and diagnostics:

In January, Aligos Therapeutics announced the expansion of its ongoing cooperation agreement with Merck to discover and develop oligonucleotide therapies
for NASH.

In April, PathAI and GlaxoSmithKline (GSK) jointly announced that they have entered into a multi-year strategic R&D collaboration that will leverage PathAI's digital pathology technology platform, including its AIM-NASH tool, to accelerate scientific research and drug development projects
in oncology and NASH.

In June, Echosens, a high-tech company that provides diagnostic technologies for liver diseases, and Novo Nordisk jointly announced a partnership to advance the early diagnosis of NASH and increase awareness
of the disease among patients, healthcare providers and other stakeholders.

In September, Chia Tai Tianqing, a subsidiary of China Biologics, signed an agreement with French biotechnology company Inventiva (IVA) to obtain exclusive licensing rights
for the latter's NASH therapeutic drug lanifibranor in Greater China.

As the number of NASH patients increases, the NASH market size will continue to expand, and evaluatePharma predicts that its global drug market size is expected to reach $40 billion
by 2025.
At present, NASH drug research and development is also becoming increasingly hot, many drugs have entered a critical stage, and the types of NASH therapy have become more and more abundant, and RNAi therapy and oligonucleotide therapy
have begun to be involved.
Overall, it is expected that Resmetirom and OCA are expected to make regulatory breakthroughs in the past two years, and it is expected that the NASH market can usher in new choices
at an early date.

Resources:

1.
Southwest Securities Research Report: NASH drugs, the next city in the 10 billion market

2.
Public information such as corporate announcements