Assessment of Vonafexor on Renal Function in Patients with Impaired Renal Function and Suspected Metabolic Associated Steatohepatitis (MASH)

The primary objective of this study is to determine the effect of **vonafexor** on renal function in a population with suspected Metabolic Associated Steatohepatitis (MASH) and mild to moderately reduced Glomerular Filtration Rate (GFR). This is clinically relevant as it aims to assess the potential therapeutic benefits of vonafexor in improving kidney function in patients with impaired renal function, which is a critical aspect of managing MASH and associated comorbidities.

Secondary objectives include:

• To determine the pharmacokinetic (PK) profile of vonafexor at doses of 25 mg and 100 mg once daily (QD).
• To compare the on-treatment with the off-treatment effect of two dose levels of vonafexor on renal function and proteinuria.
• To determine the safety and tolerability profile of two dose levels of vonafexor.

The clinical trial involves a study population comprising **male and female** subjects aged between 18 and 75 years, inclusive. Participants are characterized by **impaired renal function** and suspected metabolic-associated steatohepatitis (MASH), with a focus on those with mild to moderately reduced glomerular filtration rate (GFR). The trial includes individuals who are overweight or obese, with a body mass index (BMI) ranging from 25.0 to 45.0 kg/m², and may include those with type 2 diabetes mellitus, provided their HbA1c is 9.5% or lower. Eligible participants must have an estimated GFR between 30 and 90 mL/min/1.73 m² and exhibit presumed mild to higher liver fibrosis, as indicated by a FIBROTEST score of 0.28 or higher and/or a FIB-4 score of 1.3 or higher. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to assess the effect of **vonafexor** on kidney function in subjects with impaired renal function and suspected metabolic-associated steatohepatitis (MASH). This is a Phase 4, randomized, double-blind, controlled trial. The study will involve the administration of vonafexor, a carboxylic acid FXR agonist, in tablet form, with a maximum daily dose of 100 mg and a total treatment period of 117 days. The trial is expected to commence recruitment on March 22, 2024, and conclude by August 22, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body mass index, and estimated glomerular filtration rate (eGFR). The primary endpoint is the change from baseline of measured glomerular filtration rate (mGFR) using **iohexol** and eGFR at week 16. Secondary endpoints include plasma concentrations of vonafexor at various time points, changes in mGFR and eGFR at specified weeks, and levels of albuminuria and proteinuria.

The trial will include follow-up visits at weeks 4, 8, 12, 16, 20, 24, and 28 to monitor safety and efficacy parameters, including laboratory tests, physical examinations, and electrocardiograms. The end-of-study visit will assess the final outcomes and any adverse events. Participant involvement is expected to last approximately 28 weeks, with conditions for early termination including significant adverse events or withdrawal of consent.

The clinical trial involves the administration of **Vonafexor**, a carboxylic acid FXR agonist, as the primary investigational medication. Vonafexor is provided in tablet form and is administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 11,700 mg over a treatment period of 117 days. The trial also includes a second formulation of Vonafexor, also in tablet form, with a maximum daily dose of 25 mg and a total maximum dose of 2,925 mg over the same treatment period. Both formulations are chemically synthesized and are not pediatric formulations.

**Rosuvastatin Zinc** is included as an auxiliary treatment in the study. It is administered orally in a pharmaceutical form designated as PHF00082MIG. The maximum daily dose is 40 mg, with a total maximum dose of 7,040 mg over a treatment period of 176 days. Rosuvastatin Zinc is a chemically synthesized compound and is not formulated for pediatric use.

**Iohexol** is utilized as a diagnostic agent in the trial. It is administered as a solution for injection, with a maximum daily dose of 3,235 mg and a total maximum dose of 9,705 mg over a treatment period of 3 days. Iohexol is also chemically synthesized and is not a pediatric formulation.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not include any placebo or standard-of-care therapy as a comparator treatment. All medications are administered according to the specified routes and dosages to evaluate the effect of Vonafexor on renal function in subjects with impaired renal function and suspected Metabolic Associated Steatohepatitis (MASH).

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline of **mGFRiohexol** and **eGFRcreat** at week 16. Secondary endpoints include plasma concentrations pre-dose (0h) and post-dose (2h, 5h, and 7h) on Day 1 (week 0) and Day 113 (week 16), which will be modeled against the MASH PopPK expected values. Additionally, changes from baseline in **mGFRiohexol** off treatment at week 24 and **eGFRcreat** on treatment at weeks 4, 8, 12, and off treatment at weeks 20, 24, and 28 will be evaluated. The correlation of **mGFRiohexol** with **eGFRcreat** at baseline, on treatment at week 16, and off treatment at week 24 will also be assessed.

Further secondary endpoints include levels and changes in albuminuria, measured by the Urinary Albumin to Creatinine Ratio (UACR), and proteinuria, measured by the Urinary Protein to Creatinine Ratio (UPCR), in morning urine samples at baseline, on treatment at weeks 4, 8, 12, 16, and off treatment at weeks 20, 24, and 28. Adverse events (AEs) and serious adverse events (SAEs) will be monitored, along with changes from baseline at week 16 in laboratory safety parameters, physical examination, vital signs, and ECGs. These assessments will provide a comprehensive evaluation of the efficacy of the treatment in subjects with impaired renal function and suspected MASH.