Venglustat in Combination with Cerezyme in Adult Patients with Gaucher Disease Type 3 with venglustat monotherapy extension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Genzyme Corp.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

18 Sep 2017 → 2 Sep 2025

Decision date (initial)

2023-12-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Genzyme Corp.

External identifiers

EU CT number

2023-508646-18-00

EudraCT number

2014-002550-39

WHO UTN

U1111-1156-4278

ClinicalTrials.gov

NCT02843035

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Therapy, Pharmacodynamic, Pharmacokinetic, Pharmacogenomic, Efficacy, Safety

Part 1: Biomarker evaluation/screening phase
• 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
• 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
• Evaluate safety and tolerability of venglustat monotherapy in adult GD3 participants who have remained systemically stable on venglustat in combination with Cerezyme

Secondary objectives 7

1. Parts 2 and 3 (Combination treatment phases): Evaluate the pharmacokinetics (PK) of venglustat in adult GD3 participants
2. Parts 2 and 3 (Combination treatment phases): 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
3. Parts 2 and 3 (Combination treatment phases): 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 Ratin of Ataxia (SARA)
4. Parts 2 and 3 (Combination treatment phases): Evaluate plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants
5. Part 4 (Extended treatment phase with monotherapy) : Evaluate the efficacy of venglustat in systemic disease in adult GD3 participants by assessing spleen volume, liver volume, hemolobin level and platelet count
6. Part 4 (Extended treatment phase with monotherapy) : 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)
7. Part 4 (Extended treatment phase with monotherapy) : Evaluate plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants

Conditions and MedDRA coding

Gaucher disease type 3

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. -GD1 participant is ≥18 and ≤40 years of age.
2. -GD3 participant is ≥18 years of age.
3. -Participant must provide written informed consent prior to any study-related procedures being performed.
4. -Participant has a clinical diagnosis of Gaucher disease Type 1 (GD1) or Gaucher disease Type 3 (GD3) and documented deficiency of acid beta-glucosidase activity confirming this diagnosis.
5. -Participant has received ERT (Cerezyme or other ERT; as deemed appropriate by local regulations) for at least 3 years prior to enrollment, on a stable dose for at least 6 months and is within the therapeutic goals defined below, and is deemed clinically stable for at least 1 year by the Investigator.
6. -Participant has reached Gaucher disease therapeutic goals defined as all of the following to be eligible for this study: -Hemoglobin level of ≥11.0 g/dL for females and ≥12.0 g/dL for males. -Platelet count ≥100,000/mm3. -Spleen volume <10 multiples of normal (MN), or total splenectomy (provided the splenectomy occurred >3 years prior to randomization). -Liver volume <1.5 MN. -No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to screening.
7. -Participant has maintained GD therapeutic goals defined as all of the following to be eligible for entering Part 4 of this study: -Hemoglobin level of ≥11.0 g/dL for females and ≥12.0 g/dL for males -Platelet count ≥100 000/mm3 -Spleen volume <10 multiples of normal (MN), or total splenectomy -Liver volume <1.5 MN -No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to entering Part 4
8. -Participant, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] at baseline.
9. -If participant has a history of seizures, except for myoclonic seizures, they are well controlled under appropriate medication not identified as a strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A.
10. -Participant is willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit containing products for 72 hours prior to administration of the first dose of venglustat and for the duration of the treatment period.
11. -Oculomotor apraxia characterized by a horizontal saccade abnormality.
12. -Female participants of childbearing potential and male participants must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for the duration of the study and for at least 6 weeks for females and 90 days for males following their last dose of venglustat.

Exclusion criteria 19

1. -Participant has myoclonic seizures.
2. -Participant is pregnant or lactating.
3. -Participant has, according to World Health Organization (WHO) Grading, a cortical cataract > one-quarter of the lens circumference (Grade cortical cataract-2) or a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2). Participants with nuclear cataracts will not be excluded.
4. -Participant requires use of invasive ventilatory support.
5. -Participant requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
6. -Participant is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme treatment to ensure maintenance of Gaucher treatment goals.
7. -Participant is currently receiving potentially cataractogenic medications (corticosteroids, psoralens used in dermatology with ultraviolet light therapy [PUVA], typical antipsychotics, and glaucoma medications) or any medication that may worsen the vision of a participant with cataract (eg, alphaadrenergic glaucoma medications).
8. -Participant has received strong or moderate inducers or inhibitors of CYP3A within 15 days or 5 half-lives from screening, whichever is longer, prior to enrolment in Part 2. This also includes the consumption of grapefruit, grapefruit juice, or grapefruit containing products within 72 hours of starting venglustat administration in Parts 2 and 3.
9. -Participant is scheduled for in-patient hospitalization including elective surgery, during the study.
10. -Participant has had a major organ transplant (e.g., bone marrow or liver).
11. -Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
12. -Participant, in the opinion of the investigator, is unable to adhere to the requirements of the study or unable to undergo study assessments (e.g., contraindications for magnetic resonance imaging).
13. -Participant has had a partial or total splenectomy within 3 years prior to randomization.
14. -Participant is blood transfusion-dependent.
15. -Prior esophageal varices or liver infarction or current liver enzymes (alanine aminotransferase [ALT]/ aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal, unless the participant has a diagnosis of Gilbert Syndrome.
16. -Participant has any clinically significant disease, other than GD, including cardiovascular (congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect), hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia) or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
17. -Participant has renal insufficiency, as defined by an estimated glomerular filtration rate <30 mL/min/1.73m2 at the screening visit.
18. -Participant has received an investigational product within 30 days prior to enrollment.
19. -Participant has a history of cancer, with the exception of basal cell carcinoma.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Number of participants with Treatment Emergent Adverse Events (TEAEs)
2. Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in cerebrospinal fluid (CSF)

Secondary endpoints 16

1. Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in plasma
2. Assessment of plasma pharmacokinetic parameter: Cmax (Part 2)
3. Assessment of plasma pharmacokinetic parameter: Tmax (Part 2)
4. Assessment of plasma pharmacokinetic parameter: AUC 0-24h (Part2)
5. Assessment of plasma pharmacokinetic parameter: Ctrough
6. Assessment of CSF pharmacokinetic parameter: Cmax
7. Assessment of spleen volume
8. Assessment of spleen volume (Part4)
9. Assessment of liver volume
10. Assessment of liver volume (Part 4)
11. Assessment of hemoglobin level
12. Assessment of hemoglobin level (Part 4)
13. Assessment of platelet level
14. Assessment of platelet level (Part 4)
15. Assessment of Ataxia
16. Assessment of Ataxia (Part 4)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Genzyme Corp.

Sponsor organisation

Genzyme Corp.

Address

450 Water Street

City

Cambridge

Postcode

02141-2288

Country

United States

Scientific contact point

Organisation

Genzyme Corp.

Contact name

Clinical Sciences and Operations

Public contact point

Organisation

Genzyme Corp.

Contact name

Clinical Sciences and Operations

Third parties 6

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 40 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications