Safety and Proof-of-Concept Study of Vonafexor in Patients with Alport Syndrome at Risk of Progression

Trial ID: 2023-509638-20-00
Protocol: EYP001-208
Sponsor: ENYO Pharma

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Diseases & Conditions

Alport's syndrome

Objectives

The primary objective of this study is to assess the **safety** and tolerability of vonafexor, both during and after treatment, in patients with Alport syndrome who are at risk of disease progression. This is clinically relevant as it aims to ensure that vonafexor can be safely administered to this patient population, potentially offering a new therapeutic option for managing a condition that can lead to significant renal impairment.

Secondary objectives include:

Determining the on-treatment and off-treatment effects of three dose levels of vonafexor on **renal function**. This is important for understanding the potential impact of the drug on kidney health, a critical concern in Alport syndrome.
Determining vonafexor **plasma concentrations** levels, which will provide insights into the pharmacokinetics of the drug and help optimize dosing regimens.

Participants

The clinical trial involves a total of **11 participants** diagnosed with **Alport Syndrome**, a genetic condition affecting the kidneys, ears, and eyes. The study population includes both male and female subjects, aged between 18 and 55 years, with the United States allowing a lower age limit of 16 years. Participants were selected based on specific criteria, including a confirmed diagnosis of Alport Syndrome through clinical or genetic means, and an estimated glomerular filtration rate (eGFR) between 30 and 90 ml/min/1.73m². All participants must have increased albuminuria, indicated by a urine albumin-to-creatinine ratio (UACR) of 300 mg/g or higher. The trial excludes vulnerable populations and requires participants to have negative results for hepatitis B, hepatitis C, and HIV. Lifestyle considerations include the requirement for stable treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or Sodium-Glucose Transport Protein 2 inhibitors, if applicable, for at least 60 days prior to the study. Additionally, participants with a history of arterial hypertension must be on a stable anti-hypertensive regimen deemed controlled by the investigator.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and tolerability of **vonafexor** in patients with Alport syndrome who are at risk of disease progression. This is a Phase 2, randomized, double-blind, controlled trial with a fixed dose-escalation approach. The trial is expected to commence on July 15, 2024, and conclude by November 30, 2025, with a maximum treatment period of 24 weeks. Participants will be administered vonafexor orally in tablet form, with a maximum daily dose of 100 mg and a total dose not exceeding 12.3 grams over the study duration.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the **screening** visit, eligibility will be confirmed based on criteria such as age, diagnosis of Alport syndrome, and baseline laboratory values. Participants must have an estimated glomerular filtration rate (eGFR) between 30 and 90 ml/min/1.73m² and increased albuminuria. Follow-up visits will monitor treatment-emergent adverse events (TEAEs), changes in physical examinations, vital signs, laboratory variables, and lipid profiles. The primary endpoint is the number of TEAEs from the first dose until two weeks after the last dose. Secondary endpoints include changes in eGFR and vonafexor plasma concentration levels compared to baseline and expected concentrations based on a population pharmacokinetic model.

Participants are expected to be involved in the study for the entire treatment period, with conditions for early termination including significant adverse events or non-compliance with study protocols. The trial will ensure that all participants provide informed consent, and those of childbearing potential must adhere to strict contraceptive measures throughout the study and for six weeks post-treatment. The trial aims to provide proof-of-concept data on the effects of vonafexor on kidney function in this patient population.

Treatment

The clinical trial involves the administration of **Vonafexor**, an experimental medication, to assess its safety and tolerability in patients at risk of progression of Alport syndrome. **Vonafexor** is provided in the form of a **tablet** and is administered **orally**. The maximum daily dose of **Vonafexor** is 100 mg, with a total maximum dose of 12.3 grams over the course of the treatment period. The treatment duration is set for a maximum of 24 weeks. The active substance in **Vonafexor** is a chemical compound known as 4-chloro-5-(4-((2,6-dichlorophenyl)sulfonyl)-1-piperazinyl)-2-benzofurancarboxylic acid, also referred to by its synonyms, including EYP001A. The medication is not formulated for pediatric use and has been designated as an orphan drug under the designation number EU/3/23/2808.

In addition to the experimental treatment, the study may include the use of standard-of-care therapy as a non-experimental treatment. This may involve the administration of a placebo or comparator treatment to evaluate the efficacy and safety of **Vonafexor**. The administration of these non-experimental treatments will be conducted in accordance with the study protocol to ensure accurate assessment of the experimental medication's effects. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in the clinical trial of Vonafexor for patients with Alport syndrome will be assessed using both primary and secondary endpoints. The primary endpoints include the number of **Treatment-Emergent Adverse Events (TEAE)** from the first dose of treatment until two weeks after the last dose, as well as changes in physical examinations, vital signs, laboratory variables, and lipid profiles during on-treatment and off-treatment periods compared to baseline. Secondary endpoints focus on the change in estimated Glomerular Filtration Rate (eGFR) response at applicable visits during on-treatment and off-treatment periods compared to baseline, and Vonafexor plasma concentration levels at on-treatment applicable visits compared to expected concentrations based on a Vonafexor Population Pharmacokinetic (PK) model.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject signed informed consent and legal representatives signed informed consent as applicable for United States (US) under eighteen patients.
Has negative results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV)
Male and female patients ≥ 18 years (in US accepted lower limit age is ≥ 16 years) and ≤ 55 years.
Has confirmed diagnosis of Alport syndrome: A. Clinical diagnosis (haematuria, family history, hearing loss, ocular change), OR a kidney biopsy showing glomerular basement membrane abnormalities (e.g., significant thinning, thickening, irregularity or lucencies) consistent with AS, AND B. Genetic confirmation of AS (medical history or genotyped during screening)
Has eGFR between ≥ 30 and < 90 ml/min/1.73m2.
Has increased albuminuria criteria i.e. UACR ≥ 300 mg/g
If on an angiotensin converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB), should be on a stable well tolerated treatment during at least the 60 days prior D1.
If on Sodium-Glucose Transport Protein 2 (SGLT2), should be on stable well tolerated treatment with SGLT2 during at least 60 days prior D1.
If patient has a history of arterial hypertension, should be on stable anti-hypertensive therapy for at least 60 days prior to D1 and deemed controlled by the investigator at screening and D1
Sexually active female subjects of childbearing potential and sexually mature male subjects must agree to use two acceptable effective methods of contraception for the entire duration of the study and for at least 6 weeks after last dose.

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Exclusion Criteria

Is pregnant or breastfeeding.
Has participated in any investigational drug study within 60 days prior to D1.
Any clinically significant illness within 30 days before D1 or surgical or medical condition (other than Alport syndrome) that could interfere with the subject's study compliance; confound the study results; impact subject safety.
Any history of active malignancy within the last 1 year before D1 (history of localized basal cell or squamous cell carcinoma and cervical carcinoma in situ that has been excised/appropriately treated or a fully excised malignant lesion with a low probability of recurrence will not be considered exclusionary).
Any other condition or circumstance that, in the opinion of the investigator, may make the subject unlikely to complete the study or comply with study procedures and requirements, or may pose a risk to the subject's safety and well-being.
Has a history of an allergic condition that required the prescription of an emergency epinephrine injection (such as the EpiPen® Auto-Injector).
Any prohibited co-medications as per section 5.2.3 within 30 days prior D1.
Has ALT or AST above near normal (>1.5×ULN) at baseline.
Are at high risk for atherosclerotic cardiovascular disease (ASCVD) risk, with an LDL-C level > 160 mg/dL (4.15 mmol/L) and subjects at intermediate risk for ASCVD risk, with a LDL-C level > 190 mg/dL (4.91 mmol/L) (Lloyd-Jones DM et al., 2019)23.
Has moderate or severe hepatic impairment (Child-Pugh score B or C).
Is taking CYP3A4/5 inhibitors or inducers.