Varegacestat for Liver Disease

Not currently recruiting at 1 trial location

Overseen By Thomas Marbury, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Immunome, Inc.

Disqualifiers: Significant emotional problems, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how a new treatment, varegacestat, behaves in individuals with liver issues compared to those with normal liver function. Researchers are examining how the body processes the drug and whether it is safe and well-tolerated. Participants will take a single dose of varegacestat. The trial suits adults with stable liver disease who feel healthy and have a history of liver problems that have not worsened recently. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that varegacestat is likely to be safe for humans?

Research has shown that varegacestat has some safety information derived from studies of a similar drug, nirogacestat. In those studies, about 30% of patients experienced elevated liver enzymes, ALT or AST, which can indicate liver irritation. More serious increases occurred in fewer patients. This suggests that varegacestat might have similar effects, but it's important to note that this trial is in the early stages. Early trials often focus on understanding safety, so not everything is known yet. Prospective participants should consider that this is part of what researchers aim to learn. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about varegacestat for liver disease because it targets the condition in a new way. Unlike standard treatments that often focus on managing symptoms or slowing disease progression, varegacestat works by inhibiting gamma-secretase, an enzyme believed to play a role in liver disease progression. This novel mechanism of action could potentially offer more effective control over the disease process. Additionally, varegacestat is administered as a single oral dose, which may improve patient compliance compared to treatments requiring frequent dosing or invasive administration methods.

What evidence suggests that varegacestat might be an effective treatment for liver disease?

Studies have shown that varegacestat can change MRI results, possibly indicating an effect on disease activity. Early research on other conditions suggests varegacestat could have a noticeable impact. This treatment targets specific pathways in the body involved in disease processes. Although human data on liver disease is limited, early signs suggest potential effectiveness. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults with diabetic liver disease or other forms of liver impairment, as well as healthy individuals. Participants must have varying degrees of liver function from normal to impaired.

Inclusion Criteria

Medically healthy with no clinically significant medical history, physical examination, clinical laboratory profiles, vital signs, and ECGs as deemed by the PI or designee

Has a score on the Child-Pugh scale at screening visit and confirmed at check-in as follows: Mild: ≥5 and ≤6 [Category A]; or Moderate: ≥7 and ≤9 [Category B]; or Severe: ≥10 and ≤15 [Category C].

Medically healthy, apart from HI, with no clinically significant medical history, physical examination, clinical laboratory profiles, vital signs, and ECGs as deemed by the PI or designee

Exclusion Criteria

History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee.

History of any illness that, in the opinion of the PI or designee, might confound the results of the study or pose an additional risk to the participant by their participation in the study.

Participants must not be enrolled in the study, if they meet any of the following criteria:

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single oral dose of varegacestat on study day 1

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Varegacestat

Trial Overview The study is testing varegacestat to see how the drug behaves in the body (pharmacokinetics), and how safe and tolerable it is for people with different levels of liver health.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 1 Intervention

Single oral dose of varegacestat administered on study day 1

Who Is Running the Clinical Trial?

Immunome, Inc.

Lead Sponsor

Trials

7

Recruited

420+

Published Research Related to This Trial

In a study of 38 elderly patients with drug-induced liver injury (DILI), approximately 32.3% of DILI-drug pairs were deemed 'avoidable' using the Liverpool adverse drug reactions avoidability tool (LAAT), indicating potential for prevention strategies.

The findings suggest that a significant portion of DILI cases in this population could be prevented, highlighting the importance of using tools like LAAT for improving patient safety and reducing healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score. Danjuma, MI., Almasri, H., Alshokri, S., et al.[2020]

Drug-induced liver injury (DILI) and herb-induced liver injury are increasingly recognized as significant issues, necessitating careful diagnosis and management, particularly through drug discontinuation and therapy reconciliation.

Post-marketing databases are crucial for detecting DILI risks, highlighting the need for improved pre-clinical testing and ongoing surveillance, with a focus on direct oral anticoagulants and herbal supplements as key areas for future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk. Raschi, E., De Ponti, F.[2020]

Thiazolidinediones, like rosiglitazone and pioglitazone, are safer alternatives to the earlier drug troglitazone, which was withdrawn from the market due to severe liver toxicity; the newer drugs have a much lower risk of liver damage, with rare and usually reversible cases reported.

These newer thiazolidinediones may also help reduce liver fat in patients with non-alcoholic steatohepatitis, potentially protecting against serious liver conditions like cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatotoxicity of thiazolidinediones. Isley, WL.[2019]

A new predictive model using support vector machine (SVM) techniques has been developed to assess the risk of drug-induced liver injury (DILI) based on the physicochemical and structural properties of drug candidates, achieving an average sensitivity and specificity of 70%.

This in silico approach shows promise for early identification of safety alerts in drug development, potentially allowing for better screening of compounds alongside traditional in vitro safety tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A compound attributes-based predictive model for drug induced liver injury in humans. Liu, Y., Gao, H., He, YD.[2020]

The FDA's guidance on evaluating drug-induced liver injury (DILI) is effective for most low-risk populations but presents challenges for patients with existing liver diseases, such as viral hepatitis or cancer.

There is a pressing need for clearer guidelines and consensus on liver safety assessments, particularly regarding stopping rules based on ALT levels, to facilitate the approval and use of new antiviral and cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver safety assessment in special populations (hepatitis B, C, and oncology trials). Kullak-Ublick, GA., Merz, M., Griffel, L., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06841315

NCT06841315 | A Varegacestat Hepatic Impairment Study The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

2. withpower.com withpower.com/trial/phase-1-liver-diseases-1-2025-a8f6e

Varegacestat for Liver Disease This clinical trial is designed to determine the pharmacokinetics, safety and tolerability of varegacestat in people with impaired liver function compared to ...

3. ctv.veeva.com ctv.veeva.com/study/a-phase-1-varegacestat-hepatic-impairment-study

A Varegacestat Hepatic Impairment Study - ClinicalTrials.Veeva This clinical trial is designed to determine the pharmacokinetics, safety and tolerability of varegacestat in people with impaired liver function compared ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.11557

Change in T2-weighted signal intensity, change in tumor ... The RINGSIDE Phase 2 study (NCT04871282) demonstrated arly and continued MRI changes in DTs with varegacestat (AL102) therapy.

5. synapse.patsnap.com synapse.patsnap.com/drug/a1c2961b81954e26949d39a2db9d6e54

Varegacestat - Drug Targets, Indications, Patents The updated findings from the phase III randomized controlled trial (DeFi trial) demonstrated that nirogacestat exerts significant benefits in terms of disease ...

6. onclive.com onclive.com/view/long-term-defi-data-confirm-durable-efficacy-and-consistent-safety-of-nirogacestat-in-desmoid-tumors

Long-Term DeFi Data Confirm Durable Efficacy and ... Among the 69 patients included in the safety population, the median duration of exposure to nirogacestat was 33.6 months (range, 0.3-61.8). The ...

7. merckgroup.com merckgroup.com/en/news/ogsiveo-jco-publication-21-10-2025.html

Merck Announces Publication of Long-Term Efficacy and ... Merck Announces Publication of Long-Term Efficacy and Safety Data from the Phase 3 DeFi Trial of OGSIVEO® (nirogacestat) in Adults with Desmoid ...

8. ogsiveo.com ogsiveo.com/hcp/

OGSIVEO® (nirogacestat) | Official HCP Website Hepatotoxicity: ALT or AST elevations occurred in 30% and 33% of patients, respectively. Grade 3 ALT or AST elevations (>5 x ULN) occurred in 6% and 2.9% of ...

9. springworkstx.gcs-web.com springworkstx.gcs-web.com/news-releases/news-release-details/springworks-therapeutics-announces-long-term-efficacy-and-safety

Press Release Details - SpringWorks Therapeutics SpringWorks Therapeutics Announces Long-Term Efficacy and Safety Data from Phase 3 DeFi Trial of OGSIVEO® (nirogacestat) in Adults with Desmoid ...

10. oncologynewscentral.com oncologynewscentral.com/drugs/monograph/187872-323088/nirogacestat-oral

Nirogacestat: uses, dosing, warnings, adverse events, ... Hepatoxicity can occur in patients treated with nirogacestat. Elevations in ALT or AST occurred in 30 or 33% of patients who received nirogacestat in the ...