Semaglutide + Cilofexor/Firsocostat for NASH with Cirrhosis

(WAYFIND Trial)

Recruiting at 247 trial locations

Overseen By Gilead Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gilead Sciences

Must not be taking: Glp-1 receptor agonists

Disqualifiers: Decompensated liver disease, Hepatitis B, Hepatitis C, Alcohol use, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 72 weeks

457 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, if you are on vitamin E or pioglitazone, your dose must be stable for at least 180 days, and if you are on diabetes medications, your dose must be stable for at least 90 days before the liver biopsy.

Is the combination of Semaglutide, Cilofexor, and Firsocostat safe for humans?

The combination of Semaglutide, Cilofexor, and Firsocostat has been studied for safety in patients with non-alcoholic steatohepatitis (NASH), and Semaglutide alone has been found to be generally safe, leading to significant weight loss and improvement in liver conditions. Cilofexor has also been evaluated for safety in NASH patients, and while specific safety data for the combination is limited, these individual components have been studied for safety in humans. ^{1 2 3 4 5}

How is the drug combination of Semaglutide, Cilofexor, and Firsocostat unique for treating NASH with cirrhosis?

This drug combination is unique because it combines semaglutide, which helps with weight loss and liver fat reduction, with cilofexor and firsocostat, which target liver inflammation and fibrosis through different mechanisms. This multi-faceted approach addresses the complex nature of NASH by tackling various aspects of the disease simultaneously. ^{1 2 5 6 7}

What is the purpose of this trial?

This trial is testing a combination of medications to help people with severe liver disease caused by NASH. The treatment includes semaglutide, which helps control blood sugar, and a mix of cilofexor and firsocostat, which reduce liver inflammation and fat. The goal is to see if these drugs can improve liver health and resolve NASH.

Research Team

Gilead Study Director

Principal Investigator

Gilead Sciences

Eligibility Criteria

This trial is for adults with cirrhosis due to Nonalcoholic Steatohepatitis (NASH). Participants must have a certain level of kidney function, blood sugar control, liver enzymes, and blood clotting ability. They need a body mass index (BMI) over 23 at screening and may require a liver biopsy if they haven't had one before.

Inclusion Criteria

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I weigh... pounds.

Your blood's ability to clot is normal, unless you are taking medication to prevent blood clots.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive semaglutide and/or cilofexor/firsocostat for 72 weeks to evaluate fibrosis improvement and NASH resolution

72 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cilofexor/Firsocostat
• Semaglutide

Trial Overview The study tests Semaglutide alone or combined with Cilofexor/Firsocostat in treating NASH-related cirrhosis. It aims to see if these drugs can improve liver fibrosis and resolve NASH symptoms.

Participant Groups

Group I: SEMA + Placebo-To-Match (PTM) CILO/FIR Experimental Treatment 2 Interventions

Participants will receive SEMA 0.24-2.4 mg once weekly (dose escalation every 4 weeks) and PTM CILO/FIR administered once daily for 72 weeks

Group II: SEMA + CILO/FIR FDC Experimental Treatment 2 Interventions

Participants will receive semaglutide (SEMA) 0.24-2.4 mg once weekly (dose escalation every 4 weeks) and fixed-dose combination (FDC) of cilofexor and firsocostat (CILO/FIR 30 mg/20 mg) once daily for 72 weeks

Group III: PTM SEMA + CILO/FIR FDC Experimental Treatment 2 Interventions

PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks

Group IV: PTM SEMA + PTM CILO/FIR Placebo Group 2 Interventions

PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks

Who Is Running the Clinical Trial?

Gilead Sciences

Lead Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Novo Nordisk A/S

Industry Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Findings from Research

In a phase II trial involving 108 patients with non-alcoholic steatohepatitis (NASH), the combination of semaglutide with cilofexor and/or firsocostat was found to be safe and well tolerated, with similar rates of adverse events across treatment groups.

The combination therapies resulted in greater improvements in liver steatosis and liver biochemistry compared to semaglutide alone, suggesting that targeting multiple mechanisms may enhance treatment efficacy for NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. Alkhouri, N., Herring, R., Kabler, H., et al.[2022]

In a phase 2 trial involving 71 patients with NASH-related cirrhosis, semaglutide did not significantly improve liver fibrosis or lead to NASH resolution compared to placebo after 48 weeks.

The safety profile of semaglutide was similar to that of the placebo, with no new safety concerns identified, and common side effects included nausea and diarrhea, but overall liver and kidney function remained stable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Loomba, R., Abdelmalek, MF., Armstrong, MJ., et al.[2023]

In a phase 2 trial involving 140 patients with nonalcoholic steatohepatitis (NASH), cilofexor 100 mg daily for 24 weeks significantly reduced liver fat content by 22.7% compared to a placebo, indicating its efficacy in treating hepatic steatosis.

Cilofexor was generally well-tolerated, although moderate to severe itching was reported more frequently in the 100 mg group (14%) compared to the lower dose and placebo, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Patel, K., Harrison, SA., Elkhashab, M., et al.[2021]

Non-alcoholic fatty liver disease affects about 25% of the global population, with nonalcoholic steatohepatitis (NASH) affecting 1.5% to 6.45%, and patients with NASH face higher risks of serious liver complications.

While there are no FDA-approved drugs specifically for NASH, several agents are currently in large phase 3 trials, and new effective treatments are expected within 2 to 4 years, with a focus on combination therapies and personalized medicine based on patient-specific factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming. Jeong, SW.[2021]

Semaglutide and obeticholic acid (OCA) both show histological improvement in patients with non-alcoholic fatty liver disease (NAFLD), but only semaglutide leads to complete resolution of non-alcoholic steatohepatitis (NASH).

Semaglutide is considered the safer option, promoting significant weight loss and better outcomes for hepatic steatosis, while OCA can improve NASH-associated fibrosis but may cause side effects like dyslipidemia and severe itching, necessitating caution in certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review. Ahmed, NR., Kulkarni, VV., Pokhrel, S., et al.[2022]

In a review of 37 randomized controlled trials involving patients with non-alcoholic fatty liver disease (NAFLD), semaglutide was found to significantly improve liver enzymes and other health markers, showing a therapeutic advantage over other treatments.

Both liraglutide and dapagliflozin also demonstrated beneficial effects on liver health and metabolic parameters, but semaglutide was highlighted as the most effective option based on high certainty evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitor and 4 glucagon-like peptide-1 (GLP-1) receptor agonist drugs in non-alcoholic fatty liver disease: A GRADE-assessed systematic review and network meta-analysis of randomized controlled trials. Gu, Y., Sun, L., Zhang, W., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. [2021]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitor and 4 glucagon-like peptide-1 (GLP-1) receptor agonist drugs in non-alcoholic fatty liver disease: A GRADE-assessed systematic review and network meta-analysis of randomized controlled trials. [2023]