Obeid bile acid treatment NASH listing application was rejected after the song ceremony, all life... Who can get the first go?

NASH, a complex metabolic disease, is developing more and more new drugs, but whether it can reach the $10 billion market, there is no drug market can confirm the market capacity, the competitive landscape of different targets is also changing.
's first promising product was delayed According to epidemiological data, the global incidence of alcoholic fatty liver NAFLD is about 25%, about 10-20% of these patients are likely to progress to NASH, the incidence of NASH worldwide is about 1.5% to 6.5%, and China is about 3.5%.
one-third of NASH patients have type 2 diabetes.
NASH global incidence rate of 1.5-6.5% is the closest to the listing of Obecholic acid, on June 29 this year, Intercept announced that Obecholic acid treatment of non-alcoholic fatty hepatitis (NASH) caused by liver fibrosis listing application was rejected by the FDA (full response letter CRL).
For the reasons for this refusal, the FDA considers that the benefits of the interim histological endpoint data remain uncertain, as the REGENRATE trial reached the end point where the end point 1. Liver fibrosis improved by at least 1 level and NASH did not deteriorate, which was statistically significant relative to the placebo group (23.1% vs. 11.9%, p.0002), but did not reach the end point 2. NASH tissue pathology improved (reduced fat accumulation) and the degree of fibrosis did not worsen at the end point, slightly improved relative to the placebo group but not statistically significant.
two endpoints are in 2018, two histological endpoints identified by the FDA to accelerate the development of NASH therapies for critical trials.
So the FDA needs to add more clinical data from Phase III trial REGENRATE, which revealed in Intercept's latest quarterly report to the SEC in October that the FDA has been evaluating Otaliva's potential liver toxicity risk in patients with its approved accopathic disease, primary bile-based bile transulitis (PBC), since May, and has not yet published its findings.
Adverse reactions reported in the WHO Drug Adverse Events Reporting Database, in addition to common adverse reactions to the liver and bile systems listed in the Obe bile acid instruction manual, including bile tube stenosis, acute bileitis, cirrhosis, and obecholic acid, which the FDA concluded in 2018 were due to the use of the wrong dose of obecholic acid in patients. Leading to liver failure compensation and increased risk of liver failure and included in the black box warning, but the valve hypertension, liver and kidney syndrome, autoimmune hepatitis and other adverse events are listed, although not completely related to the PBC disease itself, but the severity and increase in the proportion of risk, is a difficult problem to ignore.
But the current development of FXR exciters will not be abandoned, most of the candidate compounds are basically based on the Obe bile acid structure modification, with a view to enhancing efficacy and reducing adverse events, in the clinical late development of other FXR exciters are Novart's tropifexor, Enanta's EDP-305 and Zhengda Tianqing TQA3526.
new drug on the mechanism of neurofibrobic growth factor has attracted much attention due to two recently published good news drugs, Efruxifermin and aldafermin, which are FGF21 fusion proteins and FGF19 derivatives, respectively.
FGF is a super-family of structurally similar proteins with self-secretion, side secretion and/or endocrine activity.
FGF19 is produced by the intestinal cortectal cells, and bile acid is transported from the gallbladder to the intestines to aid lipid digestion, while activating the physphonol x subject, which is the key intestinal FGF19 regulator.
, FGF19 was found to be damaged in NAFLD, a metabolic imbalance in the liver's bile acid metabolism.
And FGF21 is more widely expressed than FGF19, it is mainly synthesized by the liver to cope with fasting, high-fat low-carbon diet, diabetes and obesity, by regulating insulin sensitivity to maintain normal lipid metabolism, after liver damage, also found that FGF21 can be used as a protective stress response regulator.
FGF19 and FGF21 in the role mechanism of liver disease Efruxifermin Phase II called BALANCED results, 48% (19/40) of patients at 16 weeks by biopsy showed at least one level of fibrosis improvement, and no NASH deterioration, of which 28% of patients received secondary fibrosis improvement.
can determine NASH histological improvements after treatment compared to similar drugs, which is more convincing than imaging.
from a safety point of view, both dose groups of Efruxifermin can lose weight, no LDL increase, blood sugar control and blood lipid abnormalities have improved, which is a good improvement for most patients with combined cardiovascular disease NASH.
the results of aldafermin's Phase II trial also showed considerable improvement in fibrosis relative to the placebo group, but the target-related LDL increased and needed to be controlled with statins.
FGF mechanism drug is currently one of the strongest competitors for NASH treatment, and the only possible deficiency compared to PPAR or FXR agonists today is the need for injectable medication.
Efruxifermin compared to similar FGF21 drugs is the only PPAR agonist that continues to move forward in NASH Peroxidase Proliferative Activator (PPAR) is a nuclear ligand with key regulatory functions in metabolic, inflammatory and fibrous occurrence, and PPAR agonists are also a popular target in NASH new drug development, including Leading may be the first PPAR agonist approved in NASH, Genfit's elafibranor, PPAR alpha/δ double agonist, but its Phase III trial RESOLVE-IT did not show significant improvement relative to the placebo group, and neither result and other metabolically related secondary endpoints showed significant statistically significant improvements.
another PPAR agitant, CymaBay's seladelpar, because the NASH IIb clinical study analysis found "untypical histological results", including interface hepatitis, and bile damage, meaning that seladelpar may not only not reduce liver fat in patients, Instead, it can lead to liver damage, and last year suspended trials at NASH, and this year restarted trials to focus on Obe bile acid-approved adaptation, primary bileitis (PBC), which may now offer better treatment options for PBC patients than the results of Obe bile acid.
Seladelpar compared with the test results of Obe bile acid in PBC and the pan-PPAR agonist Lanifibranor is currently the only forward PPAR agonist in NASH, in phase II trial reached two main endpoints of NASH histology, from the figure below with other types of drugs II, III test results horizontal comparison, the results are still very bright, which may indicate the importance of all PPAR subtypes targeted, especially PPAR-γ.
All kinds of new drugs in the NASH trial main endpoint comparison In addition to the later stages of NASH anti-fibrosis-based drugs to avoid deterioration into the development of drugs for cirrhosis, metabolic drugs currently account for about 1/3 of NASH new drug development, which includes No. Peptides, which have been identified by the FDA as breakthrough therapies, may take longer to prove, although in Phase II trials only reached the end point of 18 months of NASH improvement and no deterioration of fibrosis, the end point of liver fibrosis improvement was not statistically significant, but liver fibrosis achieved by regulating metabolism may take longer to prove.
This is also a difficult point of NASH metabolic drugs, the development of clinical cycle will be relatively long, and for cardiovascular or diabetes and other complications there is no risk of deterioration, but the treatment population will be wider, mild and moderate liver fibrosis patients (F1-2) can use to reduce inflammation and initial fibrosis as the goal of metabolic monotherapy, more serious liver fibrosis patients F3-4 (scapital cirrhosis) can be based on increased anti-hepatic fibrosis drugs.
the domestic NASH clinical research and development progress is fast, there are goliath ASC40, Junsantai HTD1801, the biopic ZSP1601, Tuo TERN-101 and so on in the clinical stage 2, Fujian GuangshengTang GST-HG151, Zhengtianqing TQA3563, Dongsan drug HEC96718 and other clinical stage I.
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