Venglustat for Fabry Disease

(PERIDOT Trial)

Not currently recruiting at 114 trial locations

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

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Sanofi

Must not be taking: Cytochrome P450 drugs

Disqualifiers: Cardiovascular disease, Hepatitis, HIV, others

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: 12 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. The goal is to determine if venglustat can reduce pain, particularly in the nerves of the arms and legs or in the stomach, which are common symptoms of Fabry disease. Participants will receive either the actual treatment or a placebo (a pill with no active medicine) for one year, with check-ins every three months. Individuals with Fabry disease who have experienced related symptoms like pain and have not received treatment for at least six months might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you must stop all current medications, but you cannot have started or changed chronic pain treatment within 3 months before joining. Also, you can't use strong or moderate inducers or inhibitors of cytochrome P450 3A within 14 days before joining.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you should not have started or changed any chronic pain treatment within 3 months before joining. Also, you cannot use certain medications that affect liver enzymes within 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 has been tested for safety in people with Fabry disease. In one study, adult men took venglustat daily for about three years, and most did not experience serious side effects. Another study found that a single dose of venglustat was safe and the body handled it predictably.

These results suggest that venglustat is likely safe for humans, at least in the short term. However, it remains under study and has not received FDA approval for treating any condition. This trial aims to gather more safety information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Fabry disease?

Venglustat is unique because it targets Fabry disease by inhibiting glucosylceramide synthase, a different approach from the standard enzyme replacement therapies like agalsidase beta or migalastat. This mechanism aims to reduce the accumulation of harmful substances in the body, which is the root cause of Fabry disease symptoms. Researchers are excited because this novel approach could potentially offer a more effective and convenient daily oral treatment compared to the regular infusions required by current therapies.

What evidence suggests that venglustat might be an effective treatment for Fabry disease?

Research has shown that venglustat, a pill, may help treat Fabry disease by fixing problems in the body's cells. In a past study, men who took venglustat for three years experienced less nerve and stomach pain, along with other symptom improvements. Venglustat addresses the root cause of organ damage in Fabry disease, potentially slowing or stopping further damage. Studies have indicated that the drug was generally well-tolerated by patients, demonstrating a good safety record. In this trial, participants will receive either venglustat or a placebo once daily for 12 months. These findings suggest that venglustat could be a helpful option for managing symptoms in people with Fabry disease. ^{1 2 3 4 5}

Who Is on the Research Team?

Clinical Sciences & Operations

Principal Investigator

Sanofi

Are You a Good Fit for This Trial?

Adults with Fabry disease experiencing neuropathic or abdominal pain can join this trial if they haven't had treatments for Fabry in the last 6 months. They must have a confirmed diagnosis, be at least 18 years old, and agree to use double contraception methods. Exclusions include recent changes in pain meds, certain cardiovascular issues, uncontrolled hypertension, severe liver problems, active infections like COVID-19 within specific timeframes.

Inclusion Criteria

A signed informed consent must be provided prior to any study-related procedures

I am 16 or older with a confirmed diagnosis and symptoms of Fabry disease.

My worst symptom from Fabry disease scores 3 or more on the FD-PRO.

Exclusion Criteria

My blood pressure has been stable and below 150/100 for the past year.

My liver does not work well.

I have a history of liver or bile duct disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive either venglustat or placebo for 12 months to evaluate its effect on neuropathic and abdominal pain

12 months

Study visits approximately every 3 months

Follow-up

Participants are monitored for safety and effectiveness after the double-blind treatment period

4 weeks

Open-label extension

Participants who completed the double-blind period may receive venglustat for up to an additional 12 months, with further treatment until a common study end date

Up to 46 months

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Venglustat (GZ402671)

Trial Overview The study is testing Venglustat tablets against placebo over a year to see if they reduce neuropathic and abdominal pain in adults with Fabry disease. Participants will either get the real drug or a dummy pill without knowing which one. After this 'blind' phase, there's an extra year where everyone gets Venglustat.

How Is the Trial Designed?

Group I: Venglustat Experimental Treatment 1 Intervention

Participant will receive venglustat dose once daily for 12 months

Group II: Placebo Placebo Group 1 Intervention

Participants will receive placebo once daily for 12 months

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

In a study of 151 cystic fibrosis patients with the G551D mutation, ivacaftor treatment led to significant improvements in lung function (FEV1 increased by 6.7%) and body mass index over 6 months, indicating its efficacy as a treatment.

Ivacaftor also reduced sweat chloride levels and improved mucociliary clearance and gastrointestinal function, demonstrating its mechanism of action by enhancing CFTR function and reducing the burden of Pseudomonas aeruginosa infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Rowe, SM., Heltshe, SL., Gonska, T., et al.[2022]

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]

Ivacaftor is the first drug specifically designed to target the underlying cause of cystic fibrosis in patients with the G551D mutation and other rare gating mutations, showing consistent clinical benefits over time.

The drug is well tolerated and is taken orally twice daily, with ongoing trials exploring its effectiveness in combination with other treatments for the more common F508del mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivacaftor for patients with cystic fibrosis. Wainwright, CE.[2016]

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]

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]

In a 5-year study of 35 cystic fibrosis patients with the Gly551Asp mutation, ivacaftor led to an initial improvement in lung function (FEV1) by 9.6% after 6 months, but this benefit declined over time, returning to baseline by 5 years.

Despite the decline in lung function, ivacaftor significantly reduced the need for intravenous antibiotics over the 5 years, highlighting its effectiveness in managing acute symptoms, though maintaining high adherence to the medication is crucial for prolonging its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal effects of ivacaftor and medicine possession ratio in people with the Gly551Asp mutation: a 5-year study. Mitchell, RM., Jones, AM., Stocking, K., et al.[2021]

Efgartigimod was found to be safe and well-tolerated in a phase 2 study involving 24 patients with generalized myasthenia gravis, with no serious adverse events reported.

The treatment led to a significant reduction in pathogenic IgG autoantibodies and resulted in a rapid and long-lasting improvement in disease symptoms for 75% of patients, suggesting its potential as an effective therapy for myasthenia gravis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Howard, JF., Bril, V., Burns, TM., et al.[2020]

In a subgroup of patients with treatment-refractory generalized myasthenia gravis who had previously received chronic intravenous immunoglobulin (IVIg), eculizumab demonstrated sustained clinical improvements over 18 months compared to placebo.

Eculizumab was associated with a lower rate of disease exacerbations and was well tolerated, indicating its efficacy and safety for patients transitioning from IVIg treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to eculizumab in patients with myasthenia gravis recently treated with chronic IVIg: a subgroup analysis of REGAIN and its open-label extension study. Jacob, S., Murai, H., Utsugisawa, K., et al.[2022]

Efgartigimod, a first-in-class neonatal Fc receptor antagonist, received its first approval in the USA in December 2021 for treating generalized myasthenia gravis in adults who are positive for anti-acetylcholine receptor antibodies.

The drug is also being evaluated for other autoimmune diseases and has been approved in Japan for generalized myasthenia gravis patients regardless of antibody status, indicating its potential broad application in autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efgartigimod: First Approval. Heo, YA.[2022]

FTY720 (fingolimod) shows promise as an immunosuppressant with a novel mechanism of action that could lead to fewer side effects, based on preclinical tests in transplantation and autoimmune disease models.

Recent Phase III studies in kidney transplant patients and a Phase II study in multiple sclerosis patients have provided surprising results, indicating that FTY720 may be effective in these settings, warranting further exploration of sphingosine-1 receptor modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current perspectives on FTY720. Martini, S., Peters, H., Böhler, T., et al.[2019]

Lumacaftor-ivacaftor therapy has been shown to improve pulmonary function and reduce exacerbations in cystic fibrosis patients with the Phe-508del mutation, but it may also lead to side effects such as transaminitis and non-congenital cataracts.

The therapy can cause dyspnea in some patients, particularly at the start of treatment, and it has significant drug interaction risks due to lumacaftor's strong induction of CYP3A, which can affect the efficacy of other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Talamo Guevara, M., McColley, SA.[2018]

In a study of 845 cystic fibrosis patients treated with lumacaftor-ivacaftor, those who continued the treatment experienced significant improvements in lung function (ppFEV1 increased by +3.67%) and nutritional status (body mass index increased by +0.73 kg/m2).

However, 18.2% of patients discontinued treatment, primarily due to respiratory and nonrespiratory adverse events, with discontinuation linked to older age and poorer lung function, indicating that while the drug is effective for many, it may pose risks for certain individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis. Burgel, PR., Munck, A., Durieu, I., et al.[2020]

New treatments for multiple sclerosis (MS), including teriflunomide and BG-12, are expected to be approved by the FDA soon, expanding options for patients with relapsing forms of MS.

Fingolimod, the first oral MS treatment, is now commonly used as a first-line therapy, especially for patients who cannot tolerate injections, while natalizumab is being used more widely due to the availability of JC virus antibody testing, allowing safer use in patients without the virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in treating multiple sclerosis: efficacy, risks and place in therapy. Jeffery, DR.[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 ...