NEJM: Expert comments on the opportunities and challenges of pan-PPAR agonists in the treatment of non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a multifactorial and complex systemic metabolic disease.
It is currently the number one cause of liver cirrhosis and liver transplantation
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NASH has always lacked effective drug treatments, and even the target population of treatment and how to define treatment response are not clear
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The Phase 2 clinical trial of a pan-PPAR agonist published yesterday by the New England Journal of Medicine (NEJM) undoubtedly injects a cardiotonic agent into the field of NASH
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We invited Professor Ma Xiong from Renji Hospital to interpret this study
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Xiao Xiao, Ma Xiong* Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine* Corresponding author Non-alcoholic steatohepatitis (NASH) is a disease caused by adipose tissue insulin resistance, cytokine imbalance and systemic inflammation.
At present, it has become the most important cause of chronic liver disease in the world, and it can progress to liver cirrhosis, hepatocellular carcinoma and the need for liver transplantation
.

NASH is closely related to visceral obesity and metabolic syndrome.
Patients are usually accompanied by extrahepatic diseases, such as obesity, insulin resistance, type 2 diabetes, metabolic syndrome, and cardiovascular disease
.

The NASH treatment options available in clinical practice are very limited
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The current main treatment is life>
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It has been shown that significant weight loss can improve histological indicators
.

But for most patients with NASH, it is difficult to achieve and maintain weight loss
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Previous studies have shown that vitamin E can alleviate hepatocellular edema in patients with NASH, but it cannot reduce liver lobule inflammation, steatosis or fibrosis, and may increase the risk of prostate cancer and all-cause death.
Its clinical application value is limited
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Because of the broad application prospects, NASH drug development has been in the ascendant in recent years, but recently many key phase 2 or phase 3 have failed because they did not reach the primary endpoint
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Obeticholic acid is currently the only NASH treatment drug that has successfully completed Phase 3 clinical trials and entered the US FDA regulatory review
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However, the FDA believes that the expected benefits of obeticholic acid based on histological research endpoints are not yet clear, and that drug-related side effects and potential risks (such as itching, elevated low-density lipoprotein cholesterol) require more long-term research data
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Therefore, despite the urgent medical needs, no drugs have been approved for the treatment of NASH so far
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The focus of NASH new drug development is to improve the three key courses of disease that drive the occurrence and development of the disease: metabolic stress, inflammation, and fibrosis
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PPAR is a type of nuclear receptor with functions of regulating metabolism, inflammation and fibrosis.
As a potential therapeutic target of NASH, it has received wide attention in recent years
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Recently, the PPARα/δ dual agonist elafibranor failed to reach the primary endpoint in the phase 3 clinical study; the PPAR δ agonist seladelpar suspended the phase 2 study due to potential safety issues
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Lanifibranor is the first pan-PPAR agonist that can activate all three subtypes of PPAR α, γ, and δ
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Previous studies have shown that lanifibranor can improve insulin sensitivity and macrophage activation, reduce liver fibrosis and inflammatory gene expression, and its efficacy is higher than single or dual PPAR agonists
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On October 21, 2021, the New England Journal of Medicine (NEJM) published the results of a Phase 2b clinical trial of lanifibranor called NATIVE for the treatment of NASH
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NATIVE is a 24-week, randomized, double-blind, placebo-controlled Phase 2b clinical trial designed to evaluate the efficacy and safety of lanifibranor in the treatment of moderate to severe non-cirrhotic NASH
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A total of 247 patients (42% of them with diabetes) were enrolled in the study, and they were randomly assigned to the lanifibranor 1200 mg, 800 mg or placebo group at a ratio of 1:1:1
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The criteria for enrollment of patients in this trial are: NASH is diagnosed by liver biopsy; SAF-A score is 3 or 4 (SAF-A total score is 4, hepatocyte ballooning is 0~2, liver lobule inflammation is 0~2 Points), indicating the presence of moderate to severe lobulitis and ballooning; fibrosis score <4 points, indicating no cirrhosis
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The primary endpoint of the trial is a decrease of at least 2 points in SAF-A and no progression of liver fibrosis
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Secondary endpoints include reversal of NASH without deterioration of fibrosis, improvement of liver fibrosis without deterioration of NASH, improvement of liver biochemical indicators, metabolic markers, and so on
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After 24 weeks of treatment, 55% of patients in the lanifibranor 1200 mg dose group had a decrease in SAF-A by at least 2 points and no progression of liver fibrosis, compared with 33% in the placebo group.
The difference between the two groups was statistically significant (P=0.
007) )
.

48% of the lanifibranor 800 mg dose group met this standard, but there was no statistically significant difference from the placebo group (P=0.
07)
.

In addition, the treatment group was also better than the placebo group in achieving multiple secondary endpoints
.

In the lanifibranor 1200 mg, 800 mg dose group and placebo group, the proportions of NASH reversal without deterioration of fibrosis were 49%, 39%, and 22%, respectively; the proportions of fibrosis improvement at least grade 1 and no deterioration of NASH were 48, respectively %, 34%, 29%; the proportions of NASH reversal and fibrosis improvement of at least 1 grade are 35%, 25%, and 9% respectively (Figure 1)
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In the lanifibranor treatment group, liver enzyme levels were lower than baseline, and most lipid, inflammation, and fibrosis biomarkers also improved from baseline
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Research results show that lanifibranor can reduce insulin, fasting blood glucose (FPG) and glycosylated hemoglobin (HbA1c) levels in patients with diabetes
.

In addition, the cardiovascular risk factors of patients treated with lanifibranor also improved, their high-density lipoprotein cholesterol (HDL) levels increased, and their serum triglyceride levels decreased
.

Figure 1.
Primary and secondary histological endpoints (N Engl J Med 2021;385:1547-58) lanifibranor showed good tolerability in the trial
.

3 patients (4%) in the lanifibranor 1200 mg group, 4 patients (5%) in the 800 mg group, and 3 patients (4%) in the placebo group withdrew from the study due to adverse events
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Compared with the placebo group, patients in the lanifibranor treatment group were more prone to nausea, diarrhea, peripheral edema, anemia, and weight gain
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A total of 14 patients reported peripheral edema, except for one, the others were mild
.

The hemoglobin level in the lanifibranor treatment group decreased by 5% to 6% from baseline, but recovered after iron supplementation or discontinuation
.

Like other insulin sensitizers, lanifibranor also has the side effects of weight gain
.

The body weight of the 1200 mg dose group increased by an average of 2.
7 kg (3.
1%) from the baseline level, and the body weight of the 800 mg dose group increased by an average of 2.
4 kg (2.
6%) from the baseline level
.

The renal function and bone turnover of the patients in the treatment group were not impaired
.

In summary, this study showed that treatment with lanifibranor 1200 mg daily for 24 weeks reached the primary endpoint of significant reduction in SAF-A and no deterioration of fibrosis and multiple key secondary endpoints
.

Lanifibranor is the first NASH drug candidate to obtain positive results on both histological primary endpoints (Reversal of NASH without deterioration of fibrosis, and improvement of Fibrosis without deterioration of NASH)
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In addition to the liver benefits, lanifibranor may also benefit patients at high risk of adverse cardiovascular outcomes
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The results of the phase 2 trial of lanifibranor, which has good safety and a treatment period of only 6 months, are encouraging, which indicates that lanifibranor has the potential to catch up with obeticholic acid and become another star drug in the field of NASH
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However, most of the patients in the study were white, and the test results were underrepresented for Chinese and other Asian patients
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In order to evaluate the long-term efficacy and its role in other ethnic groups, we also need to wait patiently for the upcoming Phase 3 trial, which will begin with a longer period and a more extensive evaluation of efficacy and safety
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Pan-PPAR Agonist Treatment NASHA Pan-PPAR Agonist in NASH October 21, 2021 Reader: Dr.
Stephen Morrissey, NEJM Executive Editor-in-Chief Expert Introduction Ma Xiong, second-level professor, chief physician, doctoral tutor, National Science Foundation for Outstanding Youth Winner
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Deputy Director of Shanghai Institute of Digestive Diseases, Deputy Director of Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine
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Member of International Autoimmune Hepatitis Working Group (IAIHG), Vice President of Digestive Branch of Chinese Geriatrics Association, Member and Deputy Secretary-General of Hepatology Branch of Chinese Medical Association
.

Undertake 5 general projects of the National Natural Science Foundation of China, 1 key international cooperation project of the National Natural Science Foundation, and 2 key projects of the National Natural Science Foundation
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Serving as a member of the editorial board of Journal of Hepatology, Journal of Autoimmunity and other journals
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He is good at the diagnosis and treatment of difficult hepatobiliary diseases, especially autoimmune liver diseases, and focuses on translational medicine research.
His research interests are mainly in the regulation of the liver immune microenvironment of autoimmune liver diseases
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