Venglustat + Cerezyme for Gaucher Disease

(LEAP Trial)

Recruiting at 17 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Genzyme, a Sanofi Company

Must be taking: Cerezyme

Must not be taking: Corticosteroids, Psoralens, Antipsychotics, others

Disqualifiers: Cancer, Renal insufficiency, Seizures, 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

Compensation: Varies

Number of Visits: 1

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot take certain medications that affect liver enzymes or are known to cause cataracts, and you must avoid grapefruit products. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Imiglucerase for Gaucher Disease?

Imiglucerase is effective in treating Gaucher Disease by improving symptoms like enlarged organs, anemia (low red blood cell count), and bone issues. Studies show it helps reduce spleen size, decreases the need for blood transfusions, and improves heart and lung symptoms in patients with Type 1 Gaucher Disease. ^{1 2 3 4 5}

Is Venglustat + Cerezyme safe for humans?

The safety of Venglustat specifically is not detailed in the provided studies, but related treatments like imiglucerase and velaglucerase alfa for Gaucher disease have been generally well tolerated. Common mild to moderate side effects include headache, joint pain, and cold-like symptoms, with rare serious allergic reactions. ^{3 6 7 8 9}

How is the drug Venglustat + Cerezyme unique for treating Gaucher Disease?

The combination of Venglustat and Cerezyme (imiglucerase) is unique because Venglustat is an investigational oral drug that can penetrate the brain and inhibit glucosylceramide synthase, potentially addressing neurological symptoms of Gaucher Disease type 3, which are not targeted by standard enzyme replacement therapies like imiglucerase alone. ^{1 7 10 11 12}

What is the purpose of this trial?

Part 1: Biomarker evaluation/screening phase Primary Objectives: * Evaluate cerebrospinal fluid (CSF) biomarkers in adult Gaucher disease Type 3 (GD3) participants that distinguish GD3 from adult Gaucher disease Type 1 (GD1) participants * Screen adult GD3 participants who qualify for treatment with venglustat in Parts 2, Part 3, and Part 4 Parts 2 and 3: Combination treatment phases Primary objectives: * Evaluate short-term (Part 2) and long-term (Part 3) safety and tolerability of venglustat in combination with Cerezyme in adult GD3 participants * Evaluate the change in CSF central nervous system (CNS) biomarkers (glucosylceramide \[GL-1\] and lyso-glucosylceramide \[lyso-GL-1\]) from adult GD3 participants receiving venglustat in combination with Cerezyme (Part 2 only) Part 4: Extended treatment phase with monotherapy Primary objectives: • Evaluate safety and tolerability of venglustat monotherapy in adult GD3 participants who have remained systemically stable on venglustat in combination with Cerezyme Parts 2 and 3: Combination treatment phases Secondary Objectives: * Evaluate the pharmacokinetics (PK) of venglustat in adult GD3 participants * Evaluate the efficacy of venglustat in combination with Cerezyme in systemic disease in adult GD3 participants by assessing spleen volume, liver volume, hemoglobin level and platelet count * Evaluate the efficacy of venglustat in combination with Cerezyme on neurological function in adult GD3 participants by assessing Ataxia using the Scale for the Assessment and Rating of Ataxia (SARA) * Evaluate plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants Part 4: Extended treatment phase with monotherapy Secondary objectives: * Evaluate the efficacy of venglustat in systemic disease in adult GD3 participants by assessing spleen volume, liver volume, hemoglobin level and platelet count * Evaluate the efficacy of venglustat on neurological function in adult GD3 participants by assessing Ataxia using the Scale for the Assessment and Rating of Ataxia (SARA) * Evaluate plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants

Research Team

Clinical Sciences & Operations

Principal Investigator

Sanofi

Eligibility Criteria

Adults aged 18+ with Gaucher Disease Type 3 who have been on enzyme replacement therapy for at least 3 years and meet specific health goals can join. They must not be pregnant, agree to use contraception, and avoid grapefruit products. Exclusions include myoclonic seizures, severe kidney issues, hypersensitivity to Cerezyme, or other significant health problems.

Inclusion Criteria

I am willing to use birth control or practice abstinence during and after the study.

My Gaucher disease is under control, meeting all treatment goals.

My seizures are under control with medication that doesn't strongly affect CYP3A.

Exclusion Criteria

I experience sudden, brief muscle jerks.

I need regular blood transfusions to manage my condition.

I do not have any serious health issues other than Gaucher's disease that would stop me from joining.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

45 days

1 visit (in-person)

Biomarker Evaluation

Evaluate cerebrospinal fluid (CSF) biomarkers in adult Gaucher disease Type 3 (GD3) participants

45 days

Combination Treatment

Participants receive venglustat in combination with Cerezyme to evaluate short-term and long-term safety and tolerability

Up to 10 years

Regular visits as per protocol

Extended Treatment with Monotherapy

Evaluate safety and tolerability of venglustat monotherapy in participants who have remained stable

Up to 10 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Imiglucerase
• Venglustat

Trial Overview The trial tests the safety and effects of venglustat in combination with Cerezyme on brain biomarkers in adults with Gaucher Disease Type 3. It includes a screening phase followed by short-term and long-term treatment phases with both drugs, then an extension phase where only venglustat is given.

Participant Groups

Group I: Open label (OL) venglustat Experimental Treatment 2 Interventions

Administered once a day orally for up to approximately 10 years. Participants will continue their usual dose of Cerezyme during Part 1, Part 2 and Part 3. There is no administration of Cerezyme in Part 4 unless administrated as rescue treatment.

Who Is Running the Clinical Trial?

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

In a study involving 211 patients with type 1 Gaucher disease, velaglucerase alfa was found to have a safety profile similar to that of imiglucerase, with only 17.1% of previously treated patients experiencing related adverse events.

The treatment was well-tolerated, with infusion-related adverse events occurring in 13.3% of patients, primarily during the first three infusions, and no significant immune responses observed in treatment-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter open-label treatment protocol (HGT-GCB-058) of velaglucerase alfa enzyme replacement therapy in patients with Gaucher disease type 1: safety and tolerability. Pastores, GM., Rosenbloom, B., Weinreb, N., et al.[2022]

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]

References

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

Imiglucerase and its use for the treatment of Gaucher's disease. [2019]

2. Pakistan pubmed.ncbi.nlm.nih.gov

Imiglucerase treatment in Gaucher's disease. [2016]

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

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease. [2016]

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

Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease. [2016]

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

Individualization of long-term enzyme replacement therapy for Gaucher disease. [2022]

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

A multicenter open-label treatment protocol (HGT-GCB-058) of velaglucerase alfa enzyme replacement therapy in patients with Gaucher disease type 1: safety and tolerability. [2022]

7. France pubmed.ncbi.nlm.nih.gov

Miglustat: new drug. In type 1 Gaucher's disease : a slight benefit after imiglucerase therapy. [2007]

8. Spain pubmed.ncbi.nlm.nih.gov

[Safety of use of velaglucerase in 2 patients with type 1 Gaucher's disease]. [2016]

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

Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. [2021]

10. England pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of velaglucerase alfa replacement therapy for patients with type 1 Gaucher disease. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Switching from imiglucerase to miglustat for the treatment of French patients with Gaucher disease type 1: a case series. [2018]