Dr. Ahmed 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: Improvement in SAF-A score without worsening fibrosis
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: Resolution of NASH
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: Improvement in Fibrosis
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: Resolution of NASH and Fibrosis
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.
Other new medications being tried in the treatment of NASH, ASH, NAFLD, and Liver Cirrhosis are the incretins or GLP-1 analogs including Ozempic and Mounjaro.
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