Lanifibranor in NASH - a Pan-PPAR Agonist

Lanifibranor is a novel drug from the class of medicines called PPAR (Peroxisome
proliferator-activated receptors) agonists. Lanifibranor regulates the three cardinal processes involved in the pathogenesis of NASH (Non-alcoholic steatohepatitis). These are:

Inflammation
Fibrogenesis, and
Metabolism

Lanifibranor regulates these functions by acting on nuclear receptors. It is a PAN-PPAR agonist and is considered to be more effective than single or dual PPAR agonists.

Currently, the three different PPAR agonists that are being studied in the treatment of various metabolic diseases are:

PPAR alpha,
PPAR gamma, and
PPAR delta

These three PPAR agonists act on different receptors. The Pan-PPAR agonists are drugs that activate all three receptors and hence are considered more effective in reducing the expression of genes involved in inflammation and liver fibrosis.

Different drugs that act on the PPAR receptors are given in the table below:

	Target Peroxisome Proliferator-activated Receptors
Drugs	Alpha	Gamma	Delta
Elafibranor & Lanifibranor	Yes	Yes	Yes
Muraglitazar	Yes	Yes	No
Lobeglitazone	No	Yes	No
Naviglitazar	No	Yes	No
Fibrates (Gemfibrozil, Fenofibrate etc)	Yes	No	No
Thiazolidenediones (Pioglitazone & Rosiglitazone)	No	Yes	No

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Lanifibranor in NASH (Non-alcoholic steatohepatitis):

A recent trial published in the NEJM evaluated the effectiveness of Lanifibranor in the treatment of NASH (Non-alcoholic steatohepatitis) [Ref].

247 patients with moderately severe NASH were enrolled in the study in a 1:1:1 ratio. Patients either receive Linafibranor in a dose of 1200 mg or 800 mg, or a placebo medicine.

The primary outcome was a minimum of two-point reduction in the SAF-A score without worsening fibrosis. More patients in the high-dose Lanifibranor group achieved the primary outcome compared to the placebo.

Primary Outcome	Reduction in 2 points SAF-A score without worsening of fibrosis
Lanifibanor 1200 mg	55%	0.007
Lanifibranor 800 mg	48%	0.07
Placebo	33%

Table:1

Secondary Outcomes:

Outcome	Resolution of NASH without worsening of fibrosis
Lanifibanor 1200 mg	49%	Risk Ratio vs placebo: 2.2
Lanifibranor 800 mg	39%	Risk Ratio vs placebo: 1.7
Placebo	22%

Table 2

Outcome	Improvement in fibrosis of at least 1 stage worsening of NASH
Lanifibanor 1200 mg	48%	Risk Ratio vs placebo: 1.7
Lanifibranor 800 mg	34%	Risk Ratio vs placebo: 1.2
Placebo	29%

Table 3

Outcome	Resolution of NASH plus improvement in fibrosis stage of at least 1
Lanifibanor 1200 mg	35%	Risk Ratio vs placebo: 4
Lanifibranor 800 mg	25%	Risk Ratio vs placebo: 2.6
Placebo	9%

Table 4

Among patients treated with Lanifibranor, weight gain and peripheral edema occurred more frequently compared to placebo. Gastrointestinal side effects were also more common in the treatment group.

The levels of plasma adiponectin were elevated correspondingly to the degree of weight gain. There was also an improvement in the lipid profile.

Patients in the treatment groups had lower triglycerides and high levels of HDL (high-density lipoproteins) compared to the placebo.

Glycated hemoglobin improved by 0.4% each in the treatment group vs 0.1% in the placebo group.

In Conclusion:

Lanifibranor, a Pan-PPAR agonist, when administered in a dose of 1200 mg once daily results in a significant improvement in the active NASH compared to a placebo.

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