TABLE 3.
Update of major metabolic targets and potential monotherapy drugs under development for NAFLD/NASH
| Clinical improvements | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Target(s) | Agent | Current phase | Condition | Weight loss | ALT | LFC/steatosis | fibrosis | Sponsor | References |
| FXR | Nidufexor (LMB763)a | Phase 2 (terminated) | NASH | √ | √ | √ | — | Novartis | Chianelli et al247 |
| TERN-101 | Phase 2a | NASH | NA | √ | √ | √ | Terns | Wang et al248 | |
| Cilofexor (GS-9674)a | Phase 2 | NASH | — | — | √ | — | Gilead | Patel et al249 | |
| MET642a | Phase 2 | NASH | NA | NA | √ | NA | Metacrine | — | |
| Px-104 | phase 2 | NAFLD | — | √ | — | TBD | Phenex | Traussnigg et al250 | |
| EDP-297a | Phase 1 | NASH | NA | NA | NA | NA | Enanta | — | |
| EDP-305a | phase 2b | NAFLD | — | √ | √ | — | Enanta | Ratziu et al251 | |
| HPG1860 | Phase 2a | NASH | TBD | √ | TBD | TBD | Hepagene | — | |
| HEC96719 | Phase 2 | NASH | TBD | TBD | TBD | TBD | HEC Pharm | — | |
| Tropifexor (LJN452)a | Phase 2 (terminated) | NASH | √ | √ | √ | — | Novartis | Sanyal et al252 | |
| Vonafexor (EYP001a) | Phase 2 | NASH | √ | √ | √ | √ | Enyo Pharma | Ratziu et al253 | |
| XZP-5610 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Sihuan pharm | — | |
| MET409a | Phase 2 | NASH | √ | — | √ | NA | Metacrine | Harrison et al254 | |
| ASC42 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Ascletis Pharma | — | |
| Obeticholic acid | Phase 3 | NAFLD/NASH with or without T2D | √ | √ | √ | √ | Intercept | Younossi et al255 | |
| iBAT/ASBT/SLC10A2 | Elobixibat (A3309)a | Phase 2 | NAFLD NASH |
NA | — | — | NA | Albireo | — |
| Volixibat (SHP626)a | Phase 2 (terminated) | NASH | NA | — | — | — | Mirum | Newsome et al (2020)256 | |
| SGLT2 | Empagliflozin (Jardiance) | Phase 4 | NAFLD with or without T2D | √ | √ | √ | — | — | Kuchay et al257 Taheri et al258 |
| Ertugliflozin | Phase 4 | NAFLD with T2D | TBD | TBD | TBD | TBD | Getz Pharma | — | |
| Dapagliflozin | Phase 4 | NAFLD with T2D | √ | √ | √ | — | — | Shimizu et al259 Phrueksotsai et al260 | |
| Canagliflozin | Phase 4 | NAFLD with T2D | √ | √ | √ | — | — | Inoue et al261 | |
| SGLT1&2 | Licogliflozin (LIK066) | Phase 2 | NASH | √ | √ | √ | √ | Novartis | Harrison et al262 |
| PPARα | Pemafibrate (K-877) | Phase 2 | NAFLD | — | √ | — | — | Kowa Company | Nakajima et al263 |
| Fenofibrate | Phase 4 | NAFLD | √ | √ | — | — | — | Fernández-Miranda et al264 Oscarsson et al101 | |
| PPARγ | Rosiglitazone | Phase 4 | — | √ | √ | — | — | Ratziu V, et al. (2008)265 | |
| Lobeglitazone | Phase 4 | — | — | √ | √ | — | — | Lee et al266 | |
| Pioglitazone | Phase 4 | NAFLD/NASH with T2D | — | √ | √ | √ | — | Aithal et al267 Cusi et al268 | |
| PXL065 | Phase 2 | NASH | — | — | √ | — | Poxel | Harrison et al269 | |
| PPARδ(PPARβ) | Seladelpar | Phase 2 | NASH | NA | √ | — | NA | CymaBay | — |
| PPARα/δ | Elafibranora | Phase 3 (terminated) | NASH | — | √ | √ | √ | Genfit | Ratziu et al270 |
| PPARα/γ | Saroglitazar | Phase 2 | NAFLD/NASH | — | √ | √ | — | Zydus Therapeutics | Siddiqui et al271 Gawrieh et al272 |
| pan-PPAR | Lanifibranor (IVA337) | Phase 3 | NAFLD/NASH | — | √ | NA | √ | — | Sven et al273 |
| Chiglitazar | Phase 2 | NASH | TBD | TBD | TBD | TBD | Chipscreen Biosciences | — | |
| DPP-4 | Sitagliptin | Phase 4 (terminated) | NAFLD/NASH | — | — | — | — | — | Cui et al274 Joy et al275 |
| Evogliptin | Phase 4 | NAFLD With T2D | — | √ | √ | TBD | Han E, et al. (2022)276 | ||
| GLP-1R | Liraglutide | Phase 4 | NAFLD /NASH | √ | √ | √ | TBD | — | Armstrong et al277 Petit et al278 |
| Semaglutide | Phase 4 | NASH | √ | √ | √ | — | — | Flint et al279 Newsome et al280 | |
| Dulaglutide | Phase 4 | NAFLD/NASH with T2D | √ | — | √ | NA | Kuchay et al281 | ||
| Ecnoglutide (XW003) | Phase 1 | NASH, T2D and obesity | TBD | TBD | TBD | TBD | Sciwind Biosciences | — | |
| Exenatide | Phase 4 | — | √ | √ | √ | √ | — | Shao et al282 Liu et al283 | |
| ECC5004 | Phase 1 | NASH T2D |
TBD | TBD | TBD | TBD | Eccogene | — | |
| GLP-1R& GIPR | VK2735 | Phase 1 | NASH | NA | NA | NA | NA | Viking Therapeutics | — |
| Tirzepatide(LY3298176) | Phase 2 | NASH | √ | √ | √ | NA | Eli Lilly and Company | — | |
| GLP-1R& GCGR | Efinopegdutide | Phase 2a | NASH | TBD | TBD | TBD | TBD | Merck Sharp & Dohme | — |
| Cotadutide (MEDI0382)a | Phase 3 | NASH | — | — | √ | NA | AstraZeneca | — | |
| ALT-801 (Pemvidutide) | Phase 1 | NAFLD with or without T2D | √ | √ | √ | TBD | Altimmune | — | |
| BI 456906 | Phase 2 | NASH | √ | TBD | TBD | TBD | Boehringer Ingelheim | Yazawa et al284 Jungnik et al285 | |
| SAR425899 (Bamadutide) | Phase 2 (withdrawn) | NASH | √ | NA | NA | NA | Sanofi | — | |
| DD01 | Phase 1 | NASH with T2D | TBD | TBD | TBD | TBD | D&D Pharmatech | — | |
| GLP-1R & GIPR & GCGR | Efocipegtrutide (HM15211) | Phase 2b | NASH | TBD | TBD | TBD | TBD | Hanmi | — |
| FGF21 | pegozafermin (BIO89-100) | Phase 2 | NASH | — | √ | √ | TBD | 89bio | Loomba et al286 |
| B1344 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Tasly Biopharma | — | |
| NNC0194 0499 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Novo Nordisk A/S | — | |
| Pegbelfermin (BMS-986036) | Phase 2 | NASH | — | √ | √ | √ | Bristol-Myers Squibb | Sanyal et al287 Brown et al288 | |
| BOS-580 | Phase 2 | NASH | TBD | TBD | TBD | TBD | Boston Pharmaceuticals | — | |
| Efruxifermin (EFX) | Phase 2 | NASH | √ | √ | √ | √ | Akero Therapeutics | Harrison et al289 | |
| GLP-1&FGF21 | HEC88473 | Phase 1 | NASH | TBD | TBD | TBD | TBD | HEC Pharm | — |
| FGFR1&KLB | BFKB8488A | Phase 2 | NASH | √ | √ | √ | TBD | Genentech | Baruch et al290 Wong et al291 |
| MK-3655 (NGM313)a | Phase 2 | NASH | NA | NA | NA | NA | Merck Sharp & Dohme LLC | — | |
| FGF19 | Aldafermin (NGM282)a | Phase 2 | NASH | — | √ | √ | — | NGM Bio | Harrison et al292 |
| GR | miricorilant | Phase 2 (suspended) | NASH | TBD | TBD | TBD | TBD | Corcept Therapeutics | — |
| FASN | Denifanstat (TVB-2640) | Phase 2 | NASH | — | √ | √ | √ | Sagimet Biosciences | Syed-Abdulet al293 Loomba et al294 |
| FT-4101a | Phase 2 (terminated) | NASH | — | NA | √ | NA | Forma Therapeutics | Beysen et al295 | |
| KHK | PF-06835919a | Phase 2 | NAFLD | — | — | √ | NA | Pfizer | Kazierad et al296 Saxena et al297 |
| XZP-6019 | Phase 1 | NAFLD | TBD | TBD | TBD | TBD | Sihuan Pharmaceutical Holdings Group Ltd. | — | |
| DGAT2 | PF-07202954 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Pfizer | — |
| Ervogastat (PF-06865571) | Phase 2 | NASH | NA | NA | √ | NA | Pfizer | — | |
| Pradigstat (LCQ908)a | Phase 2 | NASH | NA | — | √ | NA | Novartis | — | |
| SNP-612a | Phase 2 (terminated) | NASH | NA | NA | NA | NA | Sinew Pharma | — | |
| SNP-610 | Phase 2 | NASH | TBD | TBD | TBD | TBD | Sinew Pharma | — | |
| ION224 | Phase 2 | NASH | TBD | TBD | TBD | TBD | Ionis Pharmaceuticals | — | |
| SCD-1 | Aramchol | Phase 3 (suspended) | NASH | — | √ | √ | — | Galmed Pharmaceuticals | Ratziu et al298 |
| ACC | Clesacostat (PF-05221304)a | Phase 2 | NAFLD NASH |
NA | √ | √ | NA | Pfizer | Bergman et al299 Calle et al300 |
| Firsocostat (GS-0976)a | Phase 2 | NASH | NA | — | √ | √ | Gilead Sciences | Loomba et al301 | |
| MK-4074a | Phase 1 | NAFLD | NA | NA | √ | NA | Merck Sharp & Dohme LLC | Kim et al302 | |
| THR-β | ALG-055009 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Aligos Therapeutics | — |
| Resmetirom (MGL-3196) | Phase 3 | NASH | — | √ | √ | √ | Madrigal Pharmaceuticals | Harrison et al303 Harrison et al304 | |
| ASC41 | Phase 2 | NASH | TBD | TBD | TBD | TBD | Ascletis Pharma | — | |
| TERN-501 | Phase 2 | NASH | TBD | TBD | TBD | TBD | Terns Pharmaceuticals | — | |
| ECC4703 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Eccogene | — | |
| VK2809 | Phase 2 | NASH | TBD | √ | √ | TBD | Viking Therapeutics | — | |
| PNPLA3 | AMG 609 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Amgen | — |
| ALN-PNP | Phase 1 | NASH | TBD | TBD | TBD | TBD | Alnylam | — | |
| AZD2693 | Phase 2 | NASH | TBD | TBD | TBD | TBD | AstraZeneca | — | |
| JNJ-75220795 (ARO-PNPLA3) | Phase 1 | NASH | TBD | TBD | TBD | TBD | Arrowhead | — | |
| ANGPTL3 | Vupanorsen (ISIS 703802)a | Phase 2 | NAFLD with T2D | NA | — | — | NA | Ionis Pharmaceuticals | Gaudet D, et al.305 |
| MPC | MSDC-0602K | Phase 2 | NASH | — | √ | — | — | Cirius Therapeutics | Harrison et al306 |
| MOTS-c | CB4211 | Phase 1 | NASH | — | √ | — | TBD | CohBar | — |
| HTR2A | GM-60106 | Phase 1 | NASH | TBD | TBD | TBD | TBD | JD Bioscience | — |
| GDF15 | NGM395a | Phase 1 | NAFLD | NA | NA | NA | NA | NGM Biopharmaceuticals | — |
| HSD17B13 | ARO-HSD (GSK4532990) | Phase 2 | NASH | — | √ | — | — | Arrowhead Pharmaceuticals (Licensed to GlaxoSmithKline) | Mak et al307 |
| AZD7503 | Phase 1 | NASH | TBD | TBD | TBD | TBD | AstraZeneca | — | |
| ALN-HSD | Phase 2 | NASH | TBD | TBD | TBD | TBD | Alnylam | — | |
| HSD11B1 | RO5093151a | Phase 1 | NASH | √ | √ | √ | NA | Roche | Stefan et al308 |
| miR-103/107 | RG-125 (AZD4076)a | Phase 1 | NAFLD with T2D | NA | NA | NA | NA | AstraZeneca | — |
| RORα | TB-840 | Phase 1 | NASH | TBD | TBD | TBD | TBD | Therasid Bioscience | — |
| CB1 | Namacizumab (RYI-018)a | Phase 1 | NASH | TBD | TBD | TBD | TBD | Bird Rock Bio (Johnson & Johnson) | — |
| Otenabant (CP-945598)a | Phase 1 | NASH | √ | NA | NA | NA | Pfizer | Aronne et al309 | |
| Rimonabanta | Phase 3 (terminated) | NAFLD with or without T2D | NA | NA | NA | NA | Sanofi | — | |
| AMPK | PXL770 | Phase 2 | NASH | — | √ | √ | TBD | Poxel | Cusi et al310 |
| Androgen | Spironolactone | Phase 4 | NAFLD | √ | — | √ | NA | — | Polyzos et al311 |
a
Future development for NAFLD/NASH monotherapy is not pursued.
Abbreviations: ACC, acetyl-CoA carboxylase; ALT, alanine transferase; AMPK, AMP-activated protein kinase; ANGPTL3, angiopoietin like protein 3; CB1, cannabinoid; DPP-4, dipeptidyl peptidase-4; FASN, FGFR1&KLB, β-Klotho/FGFR1c receptor complex; FXR, farnesoid X receptor; GIPR, glucose-dependent insulinotropic polypeptide receptor; GLP-1R, glucagon-like peptide-1 receptor; HSD11B1, 11β-hydroxysteroid dehydrogenase type 1; HSD17B13, hydroxysteroid 17β-dehydrogenase 13; HTR2A, 5-hydroxytryptamine receptor 2A; iBAT, ileal bile acid transporter; LFC, liver fat content; MOTS-c, mitochondrial open-reading frame of the 12 SrRNA type-c; MPC, mitochondrial pyruvate carrier; NA, not available; PNPLA3, patatin-like phospholipase domain–-containing protein 3; PPAR, peroxisome proliferation– activated receptor; PPARG, peroxisome proliferator– activated receptor gamma; SCD-1, stearoyl-CoA desaturase-1; SGLT, sodium-glucose cotransporter; SSPG, steady- state plasma glucose; SWE, shear-wave elastography; TBD, to be determined.