Vonafexor for Alport Syndrome

(ALPESTRIA-1 Trial)

Recruiting at 30 trial locations

Overseen By Isabelle Martin

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Enyo Pharma

Must be taking: ACEi, ARB, SGLT2

Must not be taking: CYP3A4/5 inhibitors

Disqualifiers: Pregnancy, Malignancy, Hepatic impairment, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

20 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you must be on stable doses of ACE inhibitors, ARBs, SGLT2 inhibitors, and anti-hypertensive therapy for at least 60 days before starting. You cannot take CYP3A4/5 inhibitors or inducers, and any prohibited co-medications must be stopped 30 days before starting.

Will I have to stop taking my current medications?

The trial requires that if you are taking certain medications like ACE inhibitors, ARBs, or SGLT2 inhibitors, you should have been on a stable dose for at least 60 days before starting the trial. You cannot take medications that are CYP3A4/5 inhibitors or inducers, and any prohibited medications must be stopped 30 days before starting the trial.

What data supports the idea that the drug Vonafexor for Alport Syndrome is an effective treatment?

The available research does not provide any data on Vonafexor for Alport Syndrome. The studies mentioned focus on other treatments and conditions, such as iloprost for bone marrow oedema and peripheral arterial occlusive disease, and various therapies for venous insufficiency. Therefore, there is no information here to support the effectiveness of Vonafexor for Alport Syndrome. ^{1 2 3 4 5}

What safety data is available for Vonafexor in treating Alport Syndrome?

The provided research does not contain any safety data specifically for Vonafexor (also known as EYP 001, EYP001a, PXL 007) in the treatment of Alport Syndrome. The studies focus on other treatments such as bardoxolone methyl, ramipril, and exon-skipping therapy, but do not mention Vonafexor or its safety profile. ^{6 7 8 9 10}

Is the drug Vonafexor a promising treatment for Alport Syndrome?

The provided research articles do not mention Vonafexor or its potential as a treatment for Alport Syndrome. Therefore, based on the available information, we cannot determine if Vonafexor is a promising treatment for this condition. ^{6 7 9 11 12}

How is the drug Vonafexor different from other treatments for Alport Syndrome?

Vonafexor is a novel treatment option for Alport Syndrome, which currently has no standard treatments. Unlike existing therapies that focus on slowing kidney disease progression, Vonafexor may offer a new mechanism of action, although specific details about its unique properties compared to other treatments are not provided in the available research. ^{6 7 9 11 12}

What is the purpose of this trial?

This study is a proof-of-concept trial of vonafexor safety, its effects on kidney function in subjects with at risk of progression Alport syndrome.

Eligibility Criteria

This trial is for people with Alport syndrome at risk of kidney function decline. Participants must have certain levels of kidney function, no hepatitis B/C or HIV, use contraception if applicable, and be on stable treatments for related conditions. Pregnant individuals or those with recent serious illnesses are excluded.

Inclusion Criteria

My kidney function, measured by eGFR, is between 30 and 90 ml/min.

Has negative results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV)

I am using two effective birth control methods during and 6 weeks after the study.

Exclusion Criteria

Is pregnant or breastfeeding

Is an employee of a site, clinical research organization, vendor, or sponsor involved with this study

I am currently taking medication that affects liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vonafexor at three dose levels for 24 weeks to assess safety, tolerability, and effects on kidney function

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Vonafexor

Trial Overview The study tests the safety and impact of vonafexor on kidney function in Alport syndrome patients. It's a proof-of-concept trial to see how well this drug works and what effects it has on those who might face worsening kidney health.

Participant Groups

Group I: Single arm fixed dose escalation Experimental Treatment 1 Intervention

This is a single arm fixed dose escalation with three dose levels of vonafexor, all QD.

Vonafexor is already approved in European Union, United States for the following indications:

Approved in European Union as Vonafexor for:

• Alport syndrome (Orphan designation)

Approved in United States as Vonafexor for:

• Alport syndrome (Orphan designation)

Who Is Running the Clinical Trial?

Enyo Pharma

Lead Sponsor

Trials

10

Recruited

390+

Findings from Research

A survey of 239 specialists at the American College of Phlebology revealed that 87% use endovenous foam sclerotherapy (EFS) for treating venous disorders, indicating its widespread acceptance in the USA.

The study highlighted variability in how EFS is applied, including differences in indications for use and procedural methods, which suggests a need for standardized national quality improvement guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance of endovenous foam sclerotherapy in the USA. Rathbun, S., Norris, A., Morrison, N., et al.[2016]

Endovenous laser ablation (EVLA) demonstrated a high success rate, with 96% of treated veins showing complete occlusion after three months in a study of 631 patients.

The procedure is considered safe, with only one non-fatal pulmonary embolism reported and no other complications, indicating that EVLA can be effectively performed with proper training and skill acquisition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Introducing endovenous laser therapy ablation to a national health service vascular surgical unit - the Aberdeen experience. Mackenzie, RK., Cassar, K., Brittenden, J., et al.[2016]

In a study of 1070 patients with chronic venous insufficiency, both polidocanol endovenous microfoam (PEM) and endovenous laser ablation (EVLA) effectively eliminated venous reflux in over 92% of cases, demonstrating similar efficacy.

PEM showed a significantly higher healing rate for ulcers in patients with severe symptoms (C6), with 69% healing in less than 1 month, compared to only 5% for EVLA, while both treatments had low rates of serious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of superficial venous insufficiency in a large patient cohort with retrograde administration of ultrasound-guided polidocanol endovenous microfoam versus endovenous laser ablation. Deak, ST.[2022]

In a study involving four uremic patients with severe peripheral arterial occlusive disease (PAOD), intravenous iloprost treatment led to the disappearance of rest pain and increased walking distance after just one week of therapy.

One patient experienced complete regression of necrotic toe lesions, suggesting that iloprost can be an effective treatment for managing severe PAOD in uremic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable clinical effects of iloprost infusion in 4 uremic patients with critical limb ischemia. Bedani, PL., Perini, L., Farinelli, R., et al.[2017]

In a study of 15 patients with bone marrow oedema (BMO) of the knee, treatment with iloprost resulted in significant long-term improvements in knee function and pain, as measured by various scoring systems including the Lysholm Score and WOMAC.

Follow-up MRI after three months showed that 80% of patients experienced complete regression of the bone marrow oedema, supporting the efficacy of iloprost therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Effects of Intravenous Iloprost Therapy in Patients with Bone Marrow Oedema of the Knee Joint. Zippelius, T., Matziolis, G., Perka, C., et al.[2019]

A 12-year-old boy with X-linked dominant Alport syndrome exhibited symptoms such as hematuria, proteinuria, nephrotic syndrome, and hearing loss, alongside a kidney biopsy showing uneven glomerular basement membrane thickness.

Next generation sequencing identified a novel pathogenic variant (c.2632G>A, p.G878R) in the COL4A5 gene, which was inherited from his mother, contributing to the understanding of genetic mutations associated with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical and genetic analysis of a child with X-linked dominant Alport syndrome]. Chang, T., Han, Z., Liu, X., et al.[2023]

In a study involving 157 patients with Alport syndrome, bardoxolone methyl demonstrated significant preservation of kidney function (eGFR) compared to placebo over 100 weeks, indicating its potential efficacy in managing this condition.

While bardoxolone methyl showed benefits in maintaining eGFR, it was associated with more treatment discontinuations due to increases in liver enzymes, highlighting the need for careful monitoring of safety in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Bardoxolone Methyl in Alport Syndrome. Warady, BA., Pergola, PE., Agarwal, R., et al.[2023]

A randomized, placebo-controlled trial involving 66 children with Alport syndrome showed that ramipril therapy was safe, with no significant adverse drug reactions reported over 216.4 patient-years.

While not statistically significant, ramipril appeared to reduce the risk of disease progression by nearly 50%, suggesting it may effectively slow the progression of renal failure in children with Alport syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Gross, O., Tönshoff, B., Weber, LT., et al.[2021]

The study developed an exon-skipping therapy using antisense oligonucleotides (ASOs) for severe male X-linked Alport syndrome (XLAS), targeting mutations in the COL4A5 gene, which is crucial for kidney function.

Results showed that this therapy not only improved the formation of collagen structures essential for kidney health but also significantly prolonged survival in treated mice, indicating its potential as a promising treatment for XLAS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. Yamamura, T., Horinouchi, T., Adachi, T., et al.[2021]

A study of 234 carriers of Alport syndrome revealed that both X-linked and heterozygous autosomal carriers have similar risks for renal issues, including the need for renal replacement therapy and impaired kidney function.

RAAS inhibition was found to significantly delay the onset of end-stage renal failure, highlighting the importance of timely intervention and regular nephrologist follow-ups for affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Temme, J., Peters, F., Lange, K., et al.[2022]

Alport syndrome (AS) is a hereditary kidney disease caused by mutations in type IV collagen genes, leading to kidney failure, and is often underrecognized in patients with chronic kidney disease (CKD).

Current treatments, such as RAAS inhibitors like ramipril, have been shown to delay the progression of kidney disease and are safe for use in children, while novel therapies targeting various pathways are being investigated to further improve outcomes for AS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Therapies for Alport Syndrome. Chavez, E., Rodriguez, J., Drexler, Y., et al.[2022]

A novel variant in the COL4A5 gene (c.3791G>A) was identified in a family with X-linked Alport syndrome, which is linked to the disease and shows a glycine substitution that is considered clinically pathogenic.

The study revealed that the proband's father had negative staining for the a5(IV) chain in the epidermal basement membrane, indicating a significant alteration in collagen structure, and demonstrated the presence of three distinct COL4A5 mRNA transcripts in skin fibroblasts, suggesting variability in gene expression related to the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The First COL4A5 Exon 41A Glycine Substitution in a Family With Alport Syndrome. Wang, F., Zhao, D., Ding, J., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Performance of endovenous foam sclerotherapy in the USA. [2016]

2. England pubmed.ncbi.nlm.nih.gov

Introducing endovenous laser therapy ablation to a national health service vascular surgical unit - the Aberdeen experience. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Treatment of superficial venous insufficiency in a large patient cohort with retrograde administration of ultrasound-guided polidocanol endovenous microfoam versus endovenous laser ablation. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Favorable clinical effects of iloprost infusion in 4 uremic patients with critical limb ischemia. [2017]

5. Czech Republic pubmed.ncbi.nlm.nih.gov

Long-Term Effects of Intravenous Iloprost Therapy in Patients with Bone Marrow Oedema of the Knee Joint. [2019]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical and genetic analysis of a child with X-linked dominant Alport syndrome]. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of Bardoxolone Methyl in Alport Syndrome. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Novel Therapies for Alport Syndrome. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

The First COL4A5 Exon 41A Glycine Substitution in a Family With Alport Syndrome. [2020]