zalfermin (NNC0194-0499) / Novo Nordisk - LARVOL DELTA

Efficacy and safety of zalfermin co-administered with semaglutide in participants with fibrosis and cirrhosis due to metabolic dysfunction-associated steatohepatitis: a phase 2, dose-ranging, double-blind, randomised controlled trial. (PubMed, Lancet Gastroenterol Hepatol) - P2 | "In participants with metabolic dysfunction-associated steatohepatitis and clinically significant fibrosis, the combination of zalfermin 30 mg plus semaglutide 2·4 mg did not significantly increase the proportion of participants who had an improvement in liver fibrosis and no worsening of metabolic dysfunction-associated steatohepatitis compared with placebo by week 52. However, a nominally significant treatment effect was observed for semaglutide 2·4 mg versus placebo. Semaglutide might be considered for further clinical assessment as a potential disease-modifying therapy in the F4c population."

Journal • P2 data • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hepatitis C • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

A Study to See the Effect of NNC0194-0499 Alone or in Combination With Semaglutide on Blood Sugar Control in People Living With Type 1 Diabetes (clinicaltrials.gov) - P1 | N=96 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Effects of NNC0194-0499, Cagrilintide, and Semaglutide Alone or in Combinations on Liver Damage and Alcohol Use in People With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=270 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Hepatology

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Long-Acting FGF21 Analog Zalfermin. (PubMed, Clin Transl Sci) - P1 | "Further investigations into multiple ascending doses of zalfermin and treatment duration are warranted to assess the potential treatment of steatohepatitis and cardiometabolic disease. Trial Registration: ClinicalTrials.gov (NCT03015207 and NCT04722653)."

Clinical • Journal • PK/PD data • Cardiovascular • Genetic Disorders • Hepatology • Metabolic Disorders • FGF21

The combination of zalfermin and semaglutide has additive therapeutic effects in a diet-induced obese and biopsy-confirmed mouse model of MASH. (PubMed, PLoS One) - "Combination treatment reduced gene expression markers of fibrosis to a greater degree than monotherapies. In conclusion, combined low-dose zalfermin and semaglutide, as well as high-dose zalfermin, resulted in beneficial effects on body weight and biochemical and histological endpoints, supporting the clinical development of zalfermin as therapy for patients with MASH."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • FGF21

A Study to See the Effect of NNC0194-0499 Alone or in Combination With Semaglutide on Blood Sugar Control in People Living With Type 1 Diabetes (clinicaltrials.gov) - P1 | N=96 | Recruiting | Sponsor: Novo Nordisk A/S

New P1 trial • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Effects of NNC0194-0499, Cagrilintide, and Semaglutide Alone or in Combinations on Liver Damage and Alcohol Use in People With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=270 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

Research Study on Whether a Combination of 2 Medicines (NNC0194 0499 and Semaglutide) Works in People With Non-alcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=698 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

Rational Design of Site-Specific Fatty Acid Derivatives to Extend the Half-Life of Fibroblast Growth Factor 21. (PubMed, Bioconjug Chem) - "Furthermore, these analogues showed superior biological activity in the presence of albumin, outperforming the C-terminal-derived variant zalfermin. This rational design approach not only improves the pharmacokinetic profile of FGF21 but also provides a framework for enhancing the therapeutic potential of other small proteins."

Journal • Metabolic Disorders • FGF21

A Research Study Looking at How a Single Dose of the Study Medicine NNC0194-0499 Behaves in Participants With Reduced Liver Function Compared to Participants With Normal Liver Function (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Hepatology

A Research Study Looking at How the Compound NNC0194-0499 Works With Birth Control Pills in Women Not Able to Bear Children. (clinicaltrials.gov) - P1 | N=34 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed | Trial primary completion date: Aug 2024 ➔ Dec 2024

Trial completion • Trial primary completion date • Hepatology • Long-acting Reversible Contraceptives • Metabolic Dysfunction-Associated Steatohepatitis

Effects of NNC0194-0499, Cagrilintide, and Semaglutide Alone or in Combinations on Liver Damage and Alcohol Use in People With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=240 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Sep 2025 ➔ Jan 2026 | Trial primary completion date: Jun 2025 ➔ Nov 2025

Combination therapy • Trial completion date • Trial primary completion date • Hepatology

A Research Study Looking at How a Single Dose of the Study Medicine NNC0194-0499 Behaves in Participants With Reduced Liver Function Compared to Participants With Normal Liver Function (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Aug 2024 ➔ Jan 2025 | Trial primary completion date: Aug 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Hepatology

Development of Zalfermin, a Long-Acting Proteolytically Stabilized FGF21 Analog. (PubMed, J Med Chem) - "Here, we describe the development of the FGF21 analog zalfermin (NNC0194-0499, 15), intended for once-weekly sc dosing...The fatty diacid binds albumin in a reversible manner, such that the free fraction of zalfermin potently activates the FGF-receptor complex and retains receptor selectivity compared with FGF21, providing strong efficacy on body weight loss in diet-induced obese mice. Zalfermin is currently being clinically evaluated for the treatment of metabolic dysfunction-associated steatohepatitis."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • FGF21

Research Study on Whether a Combination of 2 Medicines (NNC0194 0499 and Semaglutide) Works in People With Non-alcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=672 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Trial primary completion date: May 2024 ➔ Oct 2024

Trial primary completion date • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

Effects of NNC0194-0499, Cagrilintide, and Semaglutide Alone or in Combinations on Liver Damage and Alcohol Use in People With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=240 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Hepatology

Effects of NNC0194-0499, Cagrilintide, and Semaglutide Alone or in Combinations on Liver Damage and Alcohol Use in People With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=240 | Not yet recruiting | Sponsor: Novo Nordisk A/S

Combination therapy • New P2 trial • Hepatology

A Research Study Looking at How a Single Dose of the Study Medicine NNC0194-0499 Behaves in Participants With Reduced Liver Function Compared to Participants With Normal Liver Function (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Apr 2024 ➔ Aug 2024 | Trial primary completion date: Apr 2024 ➔ Aug 2024

Trial completion date • Trial primary completion date • Hepatology

A Research Study Comparing Blood Levels of Medicines NNC0194-0499 and Semaglutide Administered as a Combination Formulation Versus Two Separate Formulations (clinicaltrials.gov) - P1 | N=53 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

A Research Study Looking at How the Compound NNC0194-0499 Works With Birth Control Pills in Women Not Able to Bear Children. (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Novo Nordisk A/S

New P1 trial • Hepatology • Long-acting Reversible Contraceptives • Metabolic Dysfunction-Associated Steatohepatitis

A Research Study Comparing Blood Levels of Medicines NNC0194-0499 and Semaglutide Administered as a Combination Formulation Versus Two Separate Formulations (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Nov 2023 ➔ Feb 2024 | Trial primary completion date: Nov 2023 ➔ Feb 2024

Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis

Research Study on Whether a Combination of 2 Medicines (NNC0194 0499 and Semaglutide) Works in People With Non-alcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=672 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Non-alcoholic Steatohepatitis

A Research Study Looking Into Blood and Urine Levels of the Medicine NNC0194-0499 in the Body and How Well it is Tolerated in Participants With Reduced Kidney Function and Normal Kidney Function (clinicaltrials.gov) - P1 | N=42 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed | Trial completion date: Feb 2024 ➔ Nov 2023 | Trial primary completion date: Feb 2024 ➔ Nov 2023

Trial completion • Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis • Renal Disease

A Research Study Looking Into Blood and Urine Levels of the Medicine NNC0194-0499 in the Body and How Well it is Tolerated in Participants With Reduced Kidney Function and Normal Kidney Function (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Non-alcoholic Steatohepatitis • Renal Disease

A Research Study Looking at How a Single Dose of the Study Medicine NNC0194-0499 Behaves in Participants With Reduced Liver Function Compared to Participants With Normal Liver Function (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology