Venglustat for Fabry Disease

(CARAT Trial)

Recruiting at 111 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

104 Participants Needed

Trial Summary

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.

How does the drug Venglustat differ from other treatments for Fabry disease?

Venglustat is unique because it is an oral medication that works by inhibiting glucosylceramide synthase, which reduces the production of glycosphingolipids that accumulate in Fabry disease. This approach is different from enzyme replacement therapies that are typically administered intravenously and focus on replacing the deficient enzyme in patients. ^{1 2 3 4 5}

What is the purpose of this trial?

This is an 18-month, multicenter, randomized, active-control, parallel-group Phase 3 study, in which participants will be randomized to venglustat versus standard of care therapy (agalsidase alfa, agalsidase beta, or migalastat) to evaluate the effect of venglustat on left ventricular mass index (LVMI) in adult participants with Fabry disease and left ventricular hypertrophy. * Study visits will take place approximately every 3 to 6 months * Participants who complete the randomized period may continue to the long-term extension (LTE) to receive venglustat for up to additional 45 months with the total study duration up to 5.3 years maximum.

Research Team

Clinical Sciences & Operations Clinical Sciences and Operations

Principal Investigator

Sanofi

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

References

1. United States 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. [2023]

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

Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial. [2023]

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

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Miglustat. Oxford GlycoSciences/Actelion. [2016]

5. England 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. [2022]