Research Article Details
| Article ID: | A01853 |
| PMID: | 34588764 |
| Source: | Drug Des Devel Ther |
| Title: | Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. |
| Abstract: | Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation of fat in liver tissue. Affecting estimated 35 million people globally, NASH is the most common chronic liver condition in Western populations, and with patient numbers growing rapidly, the market for NASH therapy is projected to rise to $27.2 B in 2029. Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. Many have tried and unfortunately failed to find a drug, or drug combination, capable of unravelling the complexities of this metabolic condition. At the time of writing this review, only Zydus Cadila's new drug application for Saroglitazar had been approved (2020) for NASH therapy in India. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Given the complex pathophysiology of NASH, the use of drug combination, different mechanisms of actions and the targeting of each stage of the disease will likely be required. Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come. |
| DOI: | 10.2147/DDDT.S315724 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D321 | Saroglitazar | Chemical drug | DB13115 | PPARA agonist; PPARG agonist | Antidiabetic drug | Approved in India | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D068 | Cenicriviroc | Chemical drug | DB11758 | CCR2 inhibitor; CCR5 inhibitor | Anti-fibrosis | Failed in clinical trials | Details |
| D101 | Dapagliflozin | Chemical drug | DB06292 | SLC5A2 antagonist; SLC5A2 inhibitor | Antidiabetic drug | Under clinical trials | Details |
| D327 | Semaglutide | Chemical drug | DB13928 | GLP1R agonist | Antidiabetic drug | Under clinical trials | Details |
| D200 | Lanifibranor | Chemical drug | DB14801 | PPARD agonist; PPARA agonist; PPARG agonist | Dermatological drug | Advanced in clinical trials | Details |
| D233 | MSDC-0602K | Chemical drug | -- | MPC modulator | Antidiabetic drug | Failed in clinical trials | Details |
| D363 | Tesamorelin | Chemical drug | DB08869 | GHRHR agonist;GHRHR binder | Growth stimulant | Under clinical trials | Details |
| D300 | Resmetirom | Chemical drug | DB12914 | THRB agonist | Anti-fibrosis | Advanced in clinical trials | Details |
| D013 | Aramchol | Chemical drug | DB11860 | SCD-1 | Enhance lipid metabolism | Under clinical trials | Details |
| D083 | CLA | Chemical drug | DB01211 | KCNH2; SLCO1B1; SLCO1B3 | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D028 | Belapectin | Chemical drug | DB15125 | Gelactin-3 inhibitor; LGALS3 inhibitor | Anti-fibrosis | Failed in clinical trials | Details |
| D414 | Efruxifermin | Biological drug | -- | Fibroblast growth factor receptor agonist | anti-fibrotic, improves metabolic status | Under clinical trials | Details |