What is the mechanism of action of this treatment?

Semaglutide, a GLP-1 receptor agonist, enhances insulin sensitivity and promotes weight loss, which helps reduce liver fat and inflammation in NAFLD patients. Cilofexor, an FXR agonist, regulates bile acid synthesis and lipid metabolism, reducing liver fat accumulation and fibrosis. Firsocostat, an ACC inhibitor, decreases de novo lipogenesis, thereby lowering liver fat content. These mechanisms are crucial for NAFLD patients as they target the underlying metabolic dysfunctions, potentially reversing liver damage and improving overall liver health.

What side effects are associated with this type of intervention?

Semaglutide, a GLP-1 receptor agonist, commonly causes gastrointestinal side effects such as nausea, vomiting, and diarrhea. Cilofexor, an FXR agonist, may lead to pruritus (itching) and elevated liver enzymes. Firsocostat, an ACC inhibitor, can cause gastrointestinal discomfort and elevated triglycerides. These treatments aim to improve liver function and reduce fibrosis in patients with NAFLD, but their side effects need to be managed carefully.

What prior FDA approvals exist?

As of now, there are no FDA-approved medications specifically for the treatment of Non-alcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH). However, several drugs are under investigation, including Semaglutide, a GLP-1 receptor agonist, which has shown promise in improving liver histology and reducing fibrosis. Cilofexor, an FXR agonist, and Firsocostat, an ACC inhibitor, are also being studied for their potential benefits in treating NASH. These drugs aim to target different pathways involved in the disease process, such as glucose metabolism, lipid metabolism, and inflammation.

What other types of research exist?

Promising novel alternatives for NAFLD treatment in 2024 include obeticholic acid, elafibranor, and liraglutide. Additionally, cenicriviroc and selonsertib, potentially in combination with simtuzumab, are also under investigation and show promise.

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FXR Agonist

Semaglutide + Cilofexor/Firsocostat for NASH with Cirrhosis (WAYFIND Trial)

Phase 2

Waitlist Available

Research Sponsored by Gilead Sciences

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Liver biopsy consistent with cirrhosis (F4) due to NASH in the opinion of the central reader. In participants who have never had a liver biopsy, a screening liver biopsy may be performed

Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m^2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation

Timeline

Screening 3 weeks

Treatment Varies

Follow Up week 72

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include digestive issues like nausea or diarrhea, possible changes in blood sugar levels, allergic reactions, fatigue, and possibly an impact on liver enzyme levels.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My liver biopsy shows I have severe cirrhosis due to NASH.

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My kidney function, measured by eGFR, is at least 30 mL/min/1.73m^2.

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

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You have a body mass index (BMI) of 23 or higher at the time of screening.

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I know my height in inches.

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I weigh... pounds.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ week 72

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~week 72

This trial's timeline: 3 weeks for screening, Varies for treatment, and week 72 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Percentage of Participants Who Achieve ≥ 1-Stage Improvement in Fibrosis According to the NASH Clinical Research Network (CRN) Classification Without Worsening of NASH in Participants Treated With SEMA + CILO/FIR Versus Placebo

Percentage of Participants With NASH Resolution in Participants Treated with SEMA+CILO/FIR Versus Placebo

Secondary study objectives

Percentage of Participants Who Achieve ≥1-Stage Improvement in Fibrosis (According to the NASH CRN Classification) Without Worsening of NASH in Participants Treated With SEMA+CILO/FIR Versus SEMA Alone

Percentage of Participants With NASH Resolution In Participants Treated With SEMA+CILO/FIR Versus CILO/FIR Alone

Trial Design

4Treatment groups

Experimental Treatment

Placebo Group

Group I: SEMA + Placebo-To-Match (PTM) CILO/FIRExperimental Treatment2 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 FDCExperimental Treatment2 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 FDCExperimental Treatment2 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/FIRPlacebo Group2 Interventions

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

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Semaglutide, a GLP-1 receptor agonist, enhances insulin sensitivity and promotes weight loss, which helps reduce liver fat and inflammation in NAFLD patients. Cilofexor, an FXR agonist, regulates bile acid synthesis and lipid metabolism, reducing liver fat accumulation and fibrosis. Firsocostat, an ACC inhibitor, decreases de novo lipogenesis, thereby lowering liver fat content. These mechanisms are crucial for NAFLD patients as they target the underlying metabolic dysfunctions, potentially reversing liver damage and improving overall liver health.

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