Venglustat for Fabry Disease

(CARAT Trial)

Not currently recruiting at 119 trial locations

Overseen By Trial Transparency email recommended (Toll free for US & Canada)

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sanofi

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Stroke, Heart failure, Seizures, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 3

Duration: 18 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called venglustat for individuals with Fabry disease, a rare genetic disorder that can affect the heart. The goal is to determine if venglustat can reduce heart muscle thickening compared to current treatments. Participants will receive either venglustat or standard treatments like agalsidase or migalastat. It suits adults with Fabry disease who experience heart muscle thickening and may already be on or off treatment. As a Phase 3 trial, this is the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on strong or moderate inducers or inhibitors of cytochrome P450 CYP3A4, you may need to stop them at least 14 days before starting the trial.

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

Research has shown that venglustat was well-tolerated in earlier studies. In one study, adult men with classic Fabry disease took venglustat pills daily for up to 156 weeks. The results indicated that the treatment was generally safe, with no unexpected safety issues. Another study found that even a single dose of venglustat was safe, suggesting it is well-tolerated in the short term as well.

It is important to know that venglustat is still under study and has not been approved by the FDA or other health authorities yet. However, the safety data so far appears promising. Those considering participation in a clinical trial with venglustat can find reassurance in the existing evidence of its safety from earlier research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Venglustat is unique because it targets Fabry disease in a novel way by inhibiting the enzyme glucosylceramide synthase, which is different from the enzyme replacement therapies typically used for this condition. Unlike standard treatments that focus on replacing deficient enzymes in patients, venglustat works at the source by preventing the buildup of harmful substances in cells. Researchers are excited about venglustat because it offers the potential for a more convenient oral treatment option, potentially improving adherence and quality of life for patients who currently rely on regular intravenous infusions.

What evidence suggests that this trial's treatments could be effective for Fabry disease?

Research has shown that venglustat, which participants in this trial may receive, might help reduce organ damage in people with Fabry disease. It works by addressing cellular problems common in this condition. Earlier studies found that venglustat improved symptoms such as nerve and stomach pain. Over three years, adult men with Fabry disease who took venglustat daily experienced benefits. These results suggest that venglustat could effectively treat Fabry disease, particularly in reducing heart-related issues, such as an enlarged heart muscle. ^{1 2 3 4 5}

Who Is on the Research Team?

Clinical Sciences & Operations Clinical Sciences and Operations

Principal Investigator

Sanofi

Are You a Good Fit for This Trial?

Adults aged 18-65 with Fabry disease and heart enlargement (left ventricular hypertrophy) can join this trial. They may be new or existing patients treated with specific enzyme replacement therapies or migalastat. Participants must not be pregnant, breastfeeding, or donating sperm, and should have no severe liver issues, certain infections like HIV/Hepatitis B/C, recent use of strong drugs affecting the liver's drug processing enzymes, major cardiovascular events/surgeries/kidney transplant history, seizures requiring treatment, extreme cardiac fibrosis on MRI scans unrelated to Fabry disease.

Inclusion Criteria

My heart's left ventricle is thickened.

I am currently being treated with or have not received treatment for my condition.

Contraception for male or female participants: not pregnant or breastfeeding; no sperm donating for male participant

Exclusion Criteria

Asymmetric hypertrophy by cardiac MRI at screening if considered by central reader to be not related to Fabry disease

Presence of severe depression as measured by Beck's Depression Inventory (BDI)-II >28 and/or a history of an untreated, unstable major affective disorder within 1 year of the screening visit

I tested positive for COVID-19 recently or was hospitalized due to it in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 month

Treatment

Participants are randomized to receive either venglustat or standard of care therapy for 18 months

18 months

Study visits approximately every 3 to 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 month

Long-term extension

Participants may continue to receive venglustat for up to an additional 45 months

45 months

What Are the Treatments Tested in This Trial?

Interventions

• Agalsidase alfa
• Agalsidase beta (GZ419828)
• Migalastat
• Venglustat (GZ402671)

Trial Overview

The study is testing Venglustat tablets against standard treatments for Fabry disease over an 18-month period to see if they're better at reducing heart enlargement. Patients will visit the clinic every few months and might continue in a long-term extension phase for another 18 months after the initial study.

How Is the Trial Designed?

Group I: Venglustat Experimental Treatment 1 Intervention

Participants will receive venglustat once daily, orally

Group II: Standard of Care Therapy Active Control 3 Interventions

Participants will receive a locally approved Fabry therapy at the standard dose and schedule (in accordance with the locally approved prescribing information)

Who Is Running the Clinical Trial?

Sanofi

Lead Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Genzyme, a Sanofi Company

Lead Sponsor

Trials

528

Recruited

186,000+

David Meeker

Genzyme, a Sanofi Company

Chief Executive Officer since 2011

MD from the University of Vermont Medical School, Advanced Management Program at Harvard Business School

Jean-Paul Kress

Genzyme, a Sanofi Company

Chief Medical Officer since 2015

MD from Faculte Necker-Enfants Malades, Paris

Published Research Related to This Trial

Venglustat effectively inhibits the conversion of ceramide to glucosylceramide, which is crucial for treating Fabry disease by reducing the accumulation of harmful glycosphingolipids, as shown in a 26-week Phase 2a study with 11 adult male patients.

The treatment was generally safe, with most adverse events being mild and unrelated to the drug, and it demonstrated significant reductions in GL-3 inclusions over time, indicating its potential efficacy, although larger studies are needed for confirmation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study. Deegan, PB., Goker-Alpan, O., Geberhiwot, T., et al.[2023]

In a Phase 2 trial involving 11 adults with Gaucher disease type 3, the investigational drug venglustat, when added to standard enzyme replacement therapy, demonstrated acceptable safety and tolerability over one year, with no serious adverse events reported.

Venglustat treatment resulted in significant reductions in glucosylceramide and glucosylsphingosine levels in both plasma and cerebrospinal fluid, suggesting potential efficacy in addressing the biochemical aspects of the disease, although overall neurological function showed signs of deterioration over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial. Schiffmann, R., Cox, TM., Dedieu, JF., et al.[2023]

Miglustat, an oral medication developed for type 1 Gaucher disease, works by inhibiting glucosylceramide glucosyltransferase, which is crucial for managing this genetic disorder.

Approved in the EU in November 2002 and launched in the UK in March 2003, miglustat is also being explored for treating other glycolipid storage disorders, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Miglustat. Oxford GlycoSciences/Actelion. Lachmann, RH.[2016]

Lucerastat, an oral glucosylceramide synthase inhibitor, effectively reduced the accumulation of Gb3 in cultured fibroblasts from 15 Fabry patients, achieving a median reduction of 77% across various GLA mutations.

This treatment offers a promising alternative for all Fabry patients, as it works regardless of their specific genetic mutations, unlike current therapies that are limited to certain amenable mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. Welford, RWD., Mühlemann, A., Garzotti, M., et al.[2022]

Venglustat, a glucosylceramide synthase inhibitor, effectively reduces glucosylceramide levels and has potential therapeutic applications for various diseases, including Gaucher disease and Parkinson's disease, as shown in Phase 1 studies with healthy volunteers.

The drug demonstrated a favorable safety and tolerability profile, with linear pharmacokinetics and consistent absorption regardless of food intake, indicating it can be safely administered in a clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers. Peterschmitt, MJ., Crawford, NPS., Gaemers, SJM., et al.[2022]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05206773

NCT05206773 | A Study to Evaluate the Effect of ...

A Study to Evaluate the Effect of Venglustat Tablets on Neuropathic and Abdominal Pain in Male and Female Participants ≥16 Years of Age With Fabry Disease ( ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S1096719222004322

Assessment over 3 years in adult males with classic Fabry ...

We report the safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy results of oral, once daily treatment with venglustat for 156 weeks in ...

3.

rarediseases.sanofimedical.com

rarediseases.sanofimedical.com/dam/jcr:2871e63d-f7bf-48e1-87a9-eac9ad7bb86e/Venglustat%20PERIDOT%20CARAT%20Clinical%20Trial%20Brochure_MAT-US-2204812_v7.0_Proactive_Expires_11.27.2025.pdf

Venglustat Phase 3 Fabry Disease Clinical Trial Program

Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study. J Inherit Metab.

4.

fabrydiseasenews.com

fabrydiseasenews.com/venglustat-ibiglustat/

Venglustat for Fabry disease

Venglustat is a Fabry disease candidate therapy from Sanofi that aims to slow or prevent organ damage caused by lysosomal dysfunction.

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10299927/

Pharmacokinetics, Safety, and Tolerability of Single-Dose ...

The findings of this study demonstrate that a single oral administration of 15 mg venglustat has a favorable pharmacokinetic profile, comparable ...