Patient case: 36-year-old female with Brugada syndrome; genetic feature: SCN5A

Clinical trial: GZ/SAR402671 in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3

Summary: Primary Objective:
  Part 1:
  -  Evaluate central nervous system (CNS) biomarkers in adult Gaucher disease (GD) type 3 (GD3) patients that distinguish GD3 from Gaucher disease type 1 (GD1).
  -  Screen adult GD3 patients who qualify for treatment with GZ/SAR402671 in Part 2.
  Part 2:
  -  Evaluate the safety and tolerability of GZ/SAR402671 in adult GD3 patients.
  -  Evaluate the change in cerebrospinal fluid (CSF) central nervous system (CNS) biomarkers from adult GD3 patients receiving GZ/SAR402671.
  Secondary Objectives:
  -  Evaluate the pharmacokinetics of GZ/SAR402671 in adult GD3 patients.
  -  Explore the efficacy of GZ/SAR402671 in infiltrative lung disease (IDL) in adult GD3 patients.
  -  Explore the efficacy of GZ/SAR402671 in systemic disease in adult GD3 patients.
  -  Explore the efficacy of GZ/SAR402671 in neurological function and on exploratory CSF biomarkers in adult GD3 patients.

Detailed description: The total duration for GD1 patients is 45 days (Part 1), while for GD3 patients, the total duration is up to 168 weeks, including 2 part-treatment of 52 weeks and 104 weeks, respectively.

Eligibility: Inclusion criteria :
  -  The patient must provide written informed consent prior to any study-related procedures being performed.
  -  The patient has a clinical diagnosis of Gaucher Disease Type 1 (GD1) or Gaucher Disease Type 3 (GD3) and documented deficiency of acid beta-glucosidase activity.
  -  The patient has received treatment with enzyme replacement therapy for at least 3 years. For at least 6 months prior to enrollment, the patient has received Cerezyme at a stable monthly dose and must continue at the same monthly dose during the study.
  -  The patient has reached Gaucher disease therapeutic goals defined as all of the following:
  -  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 the last year.
  -  The patient, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] at baseline.
  -  If the patient 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 CYP3A.
  Adult GD1 cohort only:
  -GD1 Patient is ≥18 and ≤40 years of age.
  Adult GD3 cohort only:
  -  GD3 Patient is ≥18 years of age.
  -  The patient 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 GZ/SAR402671 and for the duration of the 156 week treatment period.
  -  Oculomotor apraxia characterized by a horizontal saccade abnormality.
  -  Cerezyme treatment every 2 weeks (minimum dose 30 U/kg every 2 weeks).
  -  Female patients of childbearing potential and male patients 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 study drug.
  Exclusion criteria:
  -  Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
  -  The patient has had a partial or total splenectomy within 3 years prior to randomization.
  -  The patient is blood transfusion-dependent.
  -  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 patient has a diagnosis of Gilbert Syndrome.
  -  Clinically significant congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect.
  -  The patient has any clinically significant disease, other than GD, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (e.g., hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
  -  The patient has received an investigational product within 30 days prior to enrollment.
  -  The patient has a history of cancer, with the exception of basal cell carcinoma.
  -  The patient has myoclonic seizures.
  -  The patient is pregnant or lactating.
  -  The patient 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). Patients with nuclear cataracts will not be excluded.
  -  The patient requires use of invasive ventilatory support.
  -  The patient requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
  -  The patient is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme treatment every 2 weeks.
  -  The patient is currently receiving potentially cataractogenic medications as listed in Section 8.8.2.
  -  The patient has received strong or moderate inducers or inhibitors of Cytochrome p450 Isoform 3A within 30 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 GZ/SAR402671 administration in Parts 2 and 3.
  -  The patient is scheduled for in-patient hospitalization including elective surgery, during the study.
  -  The patient has had a major organ transplant (e.g., bone marrow or liver).
  -  The patient, 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).
  The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Relevance to patient case: not relevant