Semaglutide + Cilofexor/Firsocostat for NASH with Cirrhosis

(WAYFIND Trial)

No longer recruiting at 261 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of semaglutide (a medication for type 2 diabetes and obesity) and cilofexor/firsocostat (experimental treatments) can improve liver fibrosis and resolve Nonalcoholic Steatohepatitis (NASH) in individuals with cirrhosis due to NASH. Participants will receive different combinations of these drugs, or a placebo, for 72 weeks to observe the effects. The trial targets those diagnosed with cirrhosis from NASH, affecting the liver, who have not experienced severe liver complications like ascites or encephalopathy. Individuals with NASH-related cirrhosis and no history of severe liver issues may be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that semaglutide may improve a liver condition called NASH without worsening liver scarring. In one study, 37% of patients experienced improvement in both NASH and liver scarring. However, some studies suggest it might not aid in scarring but does benefit other health areas, such as heart health.

For the combination of cilofexor and firsocostat, studies indicate it was well-tolerated by patients with liver scarring. After 48 weeks of treatment, patients showed improvements in NASH. Another study found that combining semaglutide with cilofexor/firsocostat was generally well-tolerated in patients with mild-to-moderate liver scarring.

Overall, these treatments appear safe, but they might not work the same for everyone. Always consult a doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for NASH with cirrhosis, which typically include lifestyle changes and medications like vitamin E or pioglitazone, the combination of semaglutide and cilofexor/firsocostat offers a fresh approach. Semaglutide, a GLP-1 receptor agonist, is being used here for its potential to improve liver health by enhancing insulin sensitivity and promoting weight loss. Cilofexor and firsocostat work together to reduce liver fat and inflammation by targeting different pathways in liver metabolism. Researchers are excited about these treatments because they target multiple aspects of the disease, potentially offering more comprehensive benefits than current options.

What evidence suggests that this trial's treatments could be effective for NASH with cirrhosis?

Research shows that semaglutide, one of the treatments in this trial, can help treat non-alcoholic fatty liver disease (NAFLD) and may improve NASH, a liver problem caused by fat buildup and inflammation. One study found that 63% of participants experienced improvement in NASH with semaglutide, and their liver scarring did not worsen. Another study found that semaglutide significantly aided weight loss, which is important for managing NASH.

The combination of cilofexor and firsocostat, another treatment option in this trial, has shown in earlier studies to improve NASH symptoms in patients with liver scarring and cirrhosis after 48 weeks of treatment. This combination was well-tolerated and showed promising results in enhancing liver health. This trial will explore the potential of these treatments, both individually and in combination, for addressing liver issues related to NASH. ^{1 2 3 4 6}

Who Is on the Research Team?

Gilead Study Director

Principal Investigator

Gilead Sciences

Are You a Good Fit for This Trial?

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

I know my height in inches.

I weigh... pounds.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Participants will receive SEMA 3.0 mg/mL, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet, once daily up to 72 weeks.

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

Participants will receive semaglutide (SEMA) 3.0 mg/mL, once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet, once daily up to 72 weeks.

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

Participants will receive PTM SEMA, once weekly and CILO/FIR 30 mg/20 mg FDC tablet, once daily up to 72 weeks.

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

Participants will receive PTM SEMA, once weekly and PTM CILO/FIR FDC tablet, once daily up to 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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33169409/

Combination Therapies Including Cilofexor and Firsocostat for ... Conclusions: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03449446

NCT03449446 | Study to Evaluate the Safety and Efficacy ... Study to evaluate the safety and efficacy of Selonsertib, Firsocostat, Cilofexor, and combinations in participants with bridging fibrosis or compensated ...

3. gileadclinicaltrials.com gileadclinicaltrials.com/study?id=GS-US-454-6075

Study of Semaglutide, and Cilofexor/Firsocostat, Alone ... Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) ( ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0168827822002355

Safety and efficacy of combination therapy with ... Conclusions. In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35439567/

A randomised, open-label phase II trial Conclusions: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated.

6. gilead.com gilead.com/news/news-details/2019/gilead-announces-topline-results-from-phase-2-atlas-study-in-patients-with-bridging-fibrosis-f3-and-compensated-cirrhosis-f4-due-to-nonalcoholic-steatohepatitis-nash

Gilead Announces Topline Results From Phase 2 ATLAS ... Statistically significant improvements in multiple secondary endpoints were observed in patients treated with firsocostat and cilofexor compared ...