Research Article Details
| Article ID: | A08933 |
| PMID: | 31931543 |
| Source: | Z Gastroenterol |
| Title: | [What is the (right) target for non-alcoholic fatty liver disease (NAFLD)?] |
| Abstract: | Non-alcoholic fatty liver disease (NAFLD) is of increasing prevalence globally. While lifestyle modifications are recommended, many patients do not succeed to achieve significant and maintained weight loss from lifestyle and as such there is a high unmet need for pharmacotherapy in this group. Comparable to other metabolic diseases including diabetes and dyslipidaemia, a high proportion of patients will likely benefit from permanent pharmacological therapy. Currently there are many compounds with different mechanisms of action in clinical development including metabolic, anti-inflammatory and anti-fibrotic drugs. A number of phase 3 clinical trials are currently ongoing including Elafibranor, a dual PPAR α/δ agonist, Cenicriviroc, a CCR2/CCR5 chemokine antagonist, the nuclear bile acid receptor FXR agonist obeticholic acid, Aramchol, a fatty acid bile acid conjugate that modulates SCD-1, and Resmetrion, a liver-specific THR-β agonist. Further studies with promising pathophysiological mechanisms of action, e. g. the ASK-1 inhibitor Selonsertib or the caspase inhibitor Emricasan have shown negative results. However, some are being further evaluated in combination therapies. The complex pathophysiology of the disease, which combines inflammation, metabolism and fibrosis, has led to the fact that even combinations of several substances are investigated with different modes of action. This review summarizes pivotal clinical trials for patients with NASH in the absence of cirrhosis which are recruiting in the fall of 2019. |
| DOI: | 10.1055/a-1068-3981 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| 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 |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| T13 | Apoptosis Signal-regulating Kinase 1 | ASK1 | inhibitor | Enzyme | Q99683 | M3K5_HUMAN | Details |
| T17 | Farnesoid X-activated receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| T22 | Stearoyl-CoA desaturase | SCD | inhibitor | Enzyme | O00767 | SCD_HUMAN | Details |
| T24 | C-C chemokine receptor type 2 | CCR2 | antagonist | GPCR | P41597 | CCR2_HUMAN | Details |
| T25 | C-C chemokine receptor type 5 | CCR5 | antagonist | GPCR | P51681 | CCR5_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| 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 |
| D326 | Selonsertib | Chemical drug | DB14916 | MAP3K5 inhibitor; ASK1 inhibitor | Anti-oxidative stress; Anticancer agent | Failed in clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D013 | Aramchol | Chemical drug | DB11860 | SCD-1 | Enhance lipid metabolism | Under clinical trials | Details |
| D018 | Aspirin | Chemical drug | DB00945 | AKR1C1 inhibitor; PCNA downregulator | Enhance lipid metabolism | Under clinical trials | Details |
| D119 | Elafibranor | Chemical drug | DB05187 | PPARA; PPARD; PPARG | Anti-inflammatory | Failed in clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D123 | Emricasan | Chemical drug | DB05408 | caspase inhibitor | Anti-inflammatory | Failed in clinical trials | Details |