aldafermin (NGM282) / NGM Biopharma - LARVOL DELTA

ALPINE-PSC: A Multi-center Evaluation of Aldafermin in a Randomized, Double-blind, Placebo-controlled Study in Subjects With Primary Sclerosing Cholangitis. (clinicaltrials.gov) - P2/3 | N=0 | Withdrawn | Sponsor: NGM Biopharmaceuticals, Inc | N=300 ➔ 0 | Trial completion date: Dec 2032 ➔ Mar 2025 | Initiation date: May 2025 ➔ Oct 2024 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Dec 2030 ➔ Dec 2024

Enrollment change • Trial completion date • Trial initiation date • Trial primary completion date • Trial withdrawal

Change in cT1 following interventions in metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis (EASL 2025) - "By treatment type, fibroblast growth factor (FGF) analogues (aldafermin; pegozafermin), glucagon-like peptide (GLP)-1 receptor agonists (pemvidutide; tirzepatide) and farnesoid X receptor (FXR) agonists (vonafexor; ocaliva; TERN-101), cT1 had a mean change of -79ms [95% CI: -90, - 68], -68ms [95% CI: -77, -58] and -62ms [95% CI: -74, -49], respectively... Evidence to-date supports a significant treatment-induced reduction in cT1 as compared to minimal changes in the placebo group. Our findings could inform current and future study designs for investigational therapies for liver disease and support monitoring of treatment response in individuals with MASLD in clinical trials and clinical practice."

Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • FGF

Efficacy of pharmacotherapy in improvement of liver fibrosis and steatohepatitis in patients with metabolic dysfunction associated steatotic liver disease (MASLD): a network meta-analysis (EASL 2025) - "Pegozafermin, Lanafibrinor, Obeticholic acid, Resmetirom, Vitamin E and Pioglitazone were significantly better than placebo in achieving  1 stage fibrosis improvement...Efruxifermin, Pegozafermin, Tirzepatide, Semaglutide, Aldafermin, Pioglitazone, Resmetirom and Lanafibrinor were significantly better than placebo in achieving MASH resolution... This study provides an updated relative rank-order of various therapies in terms of their efficacy in fibrosis improvement and MASH resolution. In future, therapies that improve liver fibrosis in patients with MASLD may be combined with therapies which achieve MASH resolution for better treatment response."

Retrospective data • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Bile acids drive fibroblast activation, fibrogenesis, interstitial matrix fibrosis and outcomes in PSC (EASL 2025) - P2 | " Markers of fibroblast activation (nordicPRO-C3 from type III and nordicPRO-C6 from type VI collagen), fibrosis resolution (nordicCTX-III from MMP degraded crosslinked type III collagen), ECM remodeling (type VIII, XVI and XVIII collagen), the ELF score and bile acids were measured in serum from 62 patients with primary sclerosing cholangitis (PSC) at baseline (BL) and after 12 weeks treatment with Aldafermin (FGF-19) )( NCT02704364), and in 167 PSC patients with 4 years transplant free survival... Fibroblast activation and collagen formation is important for outcomes in PSC. These data suggest that bile acids activate fibroblast driving fibrogenesis, and that lowering of bile acids attenuate the fibrotic drive. Lowering fibroblast activity may have positive effects on liver related outcomes in PSC."

Fibrosis • Hepatology • Immunology • Inflammation • FGF19 • KEAP1 • TGFB1

The effect of aldafermin expressing-Escherichia coli Nissle 1917 along with dietary change on visceral adipose tissue in MASLD mouse model. (PubMed, Int J Obes (Lond)) - "These results support the beneficial effects of EcNA, along with dietary change intervention, in obesity-associated MASLD. This microbial therapy could potentially boost the improvements induced by dietary change in eVAT metabolism and its crosstalk with the liver."

Journal • Preclinical • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • BCL6

Efficacy and Safety of Aldafermin for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis. (PubMed, Clin Res Hepatol Gastroenterol) - "In conclusion, Aldafermin improved MASH resolution without worsening fibrosis, enhanced the composite of fibrosis improvement and MASH resolution, reduced hepatic fat fraction by MRI-PDFF, and was safe for treating patients with biopsy-confirmed MASH compared to placebo."

Journal • Retrospective data • Review • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Change in cT1 following interventions in MASLD: A systematic review and meta-analysis (APASL 2025) - "By treatment type, fibroblast growth factor (FGF) analogues (aldafermin; pegozafermin), glucagon-like peptide (GLP)-1 receptor agonists (pemvidutide; tirzepatide) and farnesoid X receptor (FXR) agonists (vonafexor; ocaliva; TERN-101), cT1 had a mean change of -79ms [95% CI: -90, -68], -68ms [95% CI: -77, -58] and -62ms [95% CI: -74, -49], respectively... Evidence to-date supports a significant treatment-induced reduction in cT1 as compared to minimal changes in the placebo group. Our findings could inform current and future study designs for investigational therapies for liver disease and support monitoring of treatment response in individuals with MASLD in clinical trials and clinical practice. Table and Figure:Figure 1.Figure."

Retrospective data • Review • Hepatology • Metabolic Dysfunction-Associated Steatotic Liver Disease • FGF

Study of Aldafermin (NGM282) in Subjects With Compensated Cirrhosis (ALPINE 4) (clinicaltrials.gov) - P2 | N=160 | Completed | Sponsor: NGM Biopharmaceuticals, Inc | Phase classification: P2b ➔ P2

Phase classification • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

Clinical Assessment of Common Medications for Nonalcoholic Fatty Liver Disease: A Systematic Review and Bayesian Network Meta-Analysis. (PubMed, J Evid Based Med) - "Pioglitazone outperformed other western medicines in terms of overall efficacy when treating NAFLD, but Aldafermin and Resmetirom showed superior improvement in liver function. This study provided a certain level of support for the use of specific clinical medications."

Clinical • Journal • Retrospective data • Review • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

ALPINE-PSC: A Multi-center Evaluation of Aldafermin in a Randomized, Double-blind, Placebo-controlled Study in Subjects With Primary Sclerosing Cholangitis. (clinicaltrials.gov) - P2/3 | N=300 | Not yet recruiting | Sponsor: NGM Biopharmaceuticals, Inc | Trial completion date: Dec 2030 ➔ Dec 2032 | Initiation date: Oct 2024 ➔ May 2025 | Trial primary completion date: Dec 2028 ➔ Dec 2030

Trial completion date • Trial initiation date • Trial primary completion date • Hepatology

Efficacy and safety of the FGF19 analog aldafermin for the treatment of nonalcoholic steatohepatitis: a GRADE assessed systematic review and meta-analysis. (PubMed, Ann Med Surg (Lond)) - "Furthermore, significant reductions were noted in absolute AST levels (pooled MD: -13.40, 95% CI: -18.66 to -8.14; P<0.00001) and absolute ALT levels (pooled MD: -19.92, 95% CI: -27.08 to -12.75; P<0.00001), suggesting improved liver function. The meta-analysis indicates that aldafermin, particularly, the 3 mg dose, shows significant efficacy in improving liver histology and biochemical markers in NASH patients compared to placebo, along with a satisfactory safety profile."

Journal • Retrospective data • Review • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • FGF19

Fibroblast Growth Factor Analogues in Metabolic Dysfunction Associated Steatotic Liver Disease: A Network Meta-Analysis (ACG 2024) - "Twelve RCTs comprising 1,420 patients with MASLD were included, involving four FGF agonists: efruxifermin, aldafermin, pegbelfermin, and pegozafermin at various doses. Most significant mean reduction in hepatic fat fraction (HFF) [MD = -67.98, 95% CI [-102.12; -33.84], P 30% [RR=4.68, 95% CI [2.57; 7.97], P1 stage without MASH worsening followed by efruxifermin at 50 mg ( P =0.04)."

Retrospective data • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Novel Coronavirus Disease • FGF

ALPINE-PSC: A Multi-center Evaluation of Aldafermin in a Randomized, Double-blind, Placebo-controlled Study in Subjects With Primary Sclerosing Cholangitis. (clinicaltrials.gov) - P2/3 | N=300 | Recruiting | Sponsor: NGM Biopharmaceuticals, Inc

New P2/3 trial • Hepatology

MASH 2B TRIALS- A SYSTEMATIC REVIEW (AASLD 2024) - "These include PPAR agonists, SGLT-2 inhibitors, GLP-1 inhibitors, and the recently approved Resmetirom...The Harmony trial with efruxifermin showed significant fibrosis improvement, while the Enliven trial with pegozafermin also demonstrated significant fibrosis reduction at higher doses...Alpine 2/3 and Alpine 4 trials with aldafermin showed mixed results, with significant fibrosis improvement only in specific doses. The TANDEM trial, comparing Tropifexor and Cenicriviroc, focused on safety and efficacy, showing ALT, AST, and GGT reductions... RCTs in NASH treatment showed mixed outcomes. Lanifibranor and icosabutate showed promise, especially in T2D patients. FGF21 analogues like efruxifermin improved fibrosis, while FGF19 trials had variable results."

Review • Fatigue • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Pain • Solid Tumor • Type 2 Diabetes Mellitus • FGF19 • FGF21

COMPARATIVE EFFICACY OF PHARMACOLOGIC THERAPIES FOR MASH IN REDUCING LIVER FAT CONTENT: SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (AASLD 2024) - "By comparison of absolute MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were the most efficacious interventions. Efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were the most efficacious interventions for achieving ≥30% decline in MRI-PDFF at 24 weeks...Efruxifermin, aldafermin and pegozafermin were the most efficacious for MRI-PDFF decline at 12 weeks by both the absolute decline and achieving ≥30% decline in MRI-PDFF. At 48 weeks, Cilofexor + firsocostat, selonternib + firsocostat and cilofexor were most efficacious in absolute reduction in MRI-PDFF, while semglutide, tropifexor and tropifexor + cenicriviroc were most efficacious in achieving ≥30% decline in MRI-PDFF... This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat as assessed by MRI-PDFF. These data may help inform the design and..."

Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • FGF21

Genetic heterogeneity of engineered Escherichia coli Nissle 1917 strains during scale-up simulation. (PubMed, Metab Eng) - "Here, the evolution of engineered Escherichia coli Nissle 1917 strains producing Interleukin 2 and Aldafermin were investigated in two strain backgrounds with and without the three error-prone DNA polymerases polB, dinB, and umuDC, which contribute to the mutation rate of the host strain. Whole genome short-read sequencing revealed the genetic instability of the pMUT-based production plasmid after serial passaging for approximately 150 generations using an automated platform for high-throughput microbial evolution in five independent lineages for six distinct strains. While a reduction of the number of mutations of 12%-43% could be observed after the deletion of the error-prone DNA polymerases, the interruption of production-relevant genes could not be prevented, highlighting the need for additional strategies to improve the stability of advanced microbiome therapeutics."

Heterogeneity • Journal • IL2 • POLG2

THE ROLE OF FGF19 IN METABOLIC REGULATION: INSIGHTS FROM PRECLINICAL MODELS TO CLINICAL TRIALS. (PubMed, Am J Physiol Endocrinol Metab) - "Moreover, we provide a comprehensive overview of clinical trials involving a FGF19 analog called aldafermin, emphasizing promising results in diseases such as non-alcoholic steatohepatitis and diabetes. Therefore, we aim to foster a deeper understanding of FGF19 role and encourage further exploration of its clinical applications, thereby advancing the field and offering innovative approaches to address the escalating global health challenge of obesity and related metabolic conditions."

Journal • Preclinical • Review • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • FGF19

NGM Bio Announces $122 Million Series A Financing to Initiate Registrational Trial in Primary Sclerosing Cholangitis and Fund Phase 2 Trial in Hyperemesis Gravidarum (GlobeNewswire) - "NGM Biopharmaceuticals, Inc...announced a $122 million Series A financing led by TCG with participation from a select group of investors. NGM Bio will use the proceeds from the Series A financing to initiate a planned registrational trial of aldafermin, an engineered FGF19 analog, for the treatment of PSC, and to complete a planned Phase 2 trial of NGM120, a GDF15/GFRAL antagonist, for the treatment of HG. Both trials are expected to begin in the fourth quarter of 2024."

Financing • New P2 trial • Metabolic Disorders • Primary Biliary Cholangitis

Comparative efficacy of pharmacologic therapies for MASH in reducing liver fat content: Systematic review and network meta-analysis. (PubMed, Hepatology) - "This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat. These data may help inform the design and sample size calculation of future clinical trials and assist selection of combination therapy."

Journal • Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Fibroblast Growth Factor 19 (FGF19) and its analog Aldafermin synergize with MYC, potently promoting hepatocarcinogenesis. (EACR 2024) - "Conclusion Our study identifies a robust oncogenic synergy between the FGF19/FGF15 hormone and MYC, propelling hepatocarcinogenesis. The retention of oncogenic properties by the FGF19 analogue Aldafermin raises concerns regarding its potential use in patients with compromised, mutation-prone livers."

Gastrointestinal Cancer • Gene Therapies • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor • FGF19 • MYC

FGF-19 analogues for the treatment of metabolic dysfunction-associated steatohepatitis: a systematic review and meta-analysis (EASL-ILC 2024) - "All patients were obese adults and received Aldafermin (also known as NGM282), with daily dosages of 0.3mg, 1mg, 3mg, or 6mg... FGF19 analogues might be a safe and effective treatment option for patients with biopsy-confirmed MASH. However, new large RCTs with long-term follow-up are needed to confirm these findings."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • FGF • FGF19

Efficacy and safety of FGF-analogs for the treatment of MASH: a systematic review and meta-analysis (EASL-ILC 2024) - "The results of our meta-analysis suggest that in patients with MASH, Aldafermin is associated with a decrease of ELF score, liver fat content, and C4. Notably, only Aldafermin 1 mg displayed an increase in MASH resolution with no worsening of fibrosis and no significant side effects compared to placebo. Further studies with larger sample size and extended follow-up are essential for comprehensively assessing the sustained efficacy and safety of the drug."

Retrospective data • Review • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • Pain • Type 2 Diabetes Mellitus • FGF • FGF19 • PRO-C3

Efficacy and Safety of Aldafermin in Non-Alcoholic Steatohepatitis: A systematic review and meta-analysis of randomized controlled trials. (PubMed, Clin Res Hepatol Gastroenterol) - "Aldafermin is a promising well-tolerated therapeutic agent for NASH with evidence supporting its ability to reduce liver fat content, fibrosis serum biomarkers, and liver enzymes. However, its effectiveness in improving histologic fibrosis, while showing numerical trends, still lacks statistical significance. Larger and longer NASH trials are warranted to enhance the robustness of the evidence."

Journal • Retrospective data • Review • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • FGF19

Comparative efficacy of pharmacologic therapies in MASH: Systematic review and meta-analysis (APASL 2024) - "Aldafermin had the highest probability of being ranked as the most effective intervention for MRI-PDFF decline (SUCRA = 89.59), followed by Pegozafermin (SUCRA = 88.99), and Pioglitazone (SUCRA = 61.41) at week 24. For MRI-PDFF response, Aldafermin (SUCRA = 92.61), Efruxifermin (SUCRA = 81.00) and Resmetirom (SUCRA = 55.54) had the highest probability of being ranked the most effective intervention for achieving MRI-PDFF response at week 12. These data provide relative rank-order efficacy of various MASH therapies in terms of improvements in MRI-PDFF."

Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Aldafermin Shown to Reduce ELF Scores in Patients With MASH Cirrhosis (Gastroendonews) - P2b | N=160 | ALPINE 4 (NCT04210245) | Sponsor: NGM Biopharmaceuticals, Inc | "A trial evaluating multiple doses of aldafermin has found it effective and largely well tolerated in patients with compensated cirrhosis due to metabolic dysfunction–associated steatohepatitis....Patients in the 3-mg aldafermin group achieved a statistically significant reduction in ELF scores of 0.5 (P=0.0003) while the 1-mg group’s ELF scores fell by 0.1 (P=0.31)....Looking at progression—participants starting with a lower ELF score and progressing to higher than 11.3—there was again a dose-dependent trend, with less progression in those in the 3-mg group (3%) and more progression in the 1-mg group (10%) and placebo group (18%)....Significant, dose-dependent reductions were seen in ALT, AST, C4 and serum bile acids (P=0.0001). Liver stiffness also showed a relative decrease of 21% in the 3-mg group and 30% in the 1-mg group."

P2b data • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis