Mucopolysaccharidosis VI
Conditions
Keywords
MPS VI, Lysosomal disease, Glycoaminoglycans (GAG), Odiparcil
Brief summary
Mucopolysaccharidoses (MPS) are a group of rare inherited disorders characterized by a deficiency of lysosomal enzymes responsible for the normal degradation of glycosaminoglycans (GAGs). Medical need for treatment of MPS is still very high due to the poor penetration of the recombinant enzymes into the blood brain barrier as well as the ocular barriers and into tissues that are poorly vascularized, such as cartilages and bones. Odiparcil is an orally active compound that allows the synthesis of soluble glycosaminoglycans (GAGs), mainly chondroitin sulfate (CS) and dermatane sulfate (DS). The neosynthesized solubles GAGs are then excreted in urine. By diverting endogenous GAG synthesis to the synthesis of soluble odiparcil linked GAGs, odiparcil should decrease the intracellular pool of GAGs and consequently decrease the lysosomal GAG accumulation. The primary objective of the study is to assess the safety and efficacy of two doses of odiparcil in MPS VI patients and to provide evidence to enable the selection of the relevant dose of odiparcil for phase III study. The secondary objective of this study is to characterize the dose response, PK and PD of odiparcil.
Detailed description
Study design: This phase IIa study consists of 2 parts performed sequentially: a preliminary safety assessment followed by the core study with a double-blind, randomized, dose-ranged cohort of patients receiving Enzyme Replacement Therapy (ERT) and an open-label cohort of patients not receiving ERT. Preliminary safety assessment (N=2): open-label, escalating dose (2 doses) study. If acceptable safety profile is achieved, patients will be then included in the open-label arm of the core study. Core study Core study will be conducted on 2 populations in parallel: * A first cohort (N=18): MPS VI patients receiving ERT assigned in 3 arms: * Placebo (N=6) * Odiparcil 500 mg per day (250 mg BID) (N=6) * Odiparcil 1000 mg per day (500 mg BID) (N=6). * A second cohort (N=6): MPS VI patient not receiving ERT (odiparcil 1000 mg per day (500 mg BID)). Study duration: The overall study duration will be 20 months, including the 10-month enrolment period. For each patient, the study duration will be: * Preliminary safety assessment: 6 weeks including a 4-week run-in period followed by 2-week treatment period. Then, patients will go on treatment period in core study. * Core study: 34 weeks including a 4-week run-in period followed by 26-week treatment period and 4-week of follow-up.
Interventions
DRUGOdiparcil
Investigational product: odiparcil 250 mg tablets
OTHERPlacebo
Comparator: placebo tablets similar to odiparcil 250 mg tablets
Sponsors
Inventiva Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo
Intervention model description
Preliminary safety assessment (N=2): an open-label, escalating dose (2 doses) study. Core study: conducted on 2 populations in parallel: * A first cohort (N=18): MPS VI patients receiving ERT assigned in 3 arms: * Placebo (N=6) * Odiparcil 500 mg per day (250 mg BID) (N=6) * Odiparcil 1000 mg per day (500 mg BID) (N=6). * A second cohort (N=6): MPS VI patients not receiving ERT (odiparcil 1000 mg per day (500 mg BID)).
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female gender. 2. Age ≥16 years. 3. Diagnosis of MPS VI, demonstrated by a reduced Arylsulfatase B (ARSB) activity relative to the normal range of the laboratory performing the assay in either white blood cells or fibroblast culture or confirmation of two known disease causing mutations in the ARSB gene. 4. Urine GAG above upper limit of normal (ULN) based on historical data. 5. Willing and able to provide written, dated, signed informed consent, or in the case of subjects age \< 18 years, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures or study assessment. 6. Able to comply with all study procedures. 7. Women with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) must agree to use a highly effective method of birth control during the study and at least 4 weeks after last administration. The following can be considered to be examples of highly effective methods of contraception preferably with low user dependency: * Combined (estrogen and progestogen containing hormonal contraception) associated with inhibition of ovulation (oral, intravaginal, or transdermal) * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable ) * intrauterine device (IUD)1 * intrauterine hormone-releasing system (IUS) 1 * Bilateral tubal occlusion1 * Vasectomised partner1 * Sexual abstinence These methods of contraception must be supplemented with a barrier method (preferably male condom). Women with childbearing potential are required to have a confirmed negative blood pregnancy test before starting medication administration at baseline (V0). Women with childbearing potential agree to repeat blood pregnancy tests at visits in hospital (V2, V4, V7 and V8) and to perform urine pregnancy test before each phone call visit (V3, V5 and V6). Inclusion criteria for ERT treated group: 1\. Patients with MPS Type VI receiving enzyme replacement therapy (Naglazyme) for at least 6 months on the licensed dosage or as per local guidelines. Inclusion criteria for not ERT treated group: Patients with MPS Type VI not receiving enzyme replacement therapy for the following reasons: 1. Patients previously treated with ERT but have discontinued for more than 3 months either due to medical decision or personal choice 2. Patients allergic to ERT therapy 3. Patients that have had a previous hematopoietic stem cell transplant (HSCT) 4. Patients not treated with ERT i.e. treatment naïve
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with modified clinical signs | 26 weeks | Changes in physical examination and vital signs |
| Number of patients with modified biological values | 26 weeks | Change from baseline in laboratory safety tests (coagulation, liver enzymes and crystalluria) 12-lead-ECG and bone biomarkers. |
| Incidence of AEs/SAEs | 26 weeks | Incidence of AEs/SAEs, patient withdrawals from study due to AEs/SAEs, |
| 12-lead ECG | 26 weeks | Change from Baseline in ECG |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Respiratory function | 26 weeks | Change from Baseline in FEV1 |
| Cardiac and vascular function | 26 weeks | Change from Baseline in echocardiogram |
| Audiology assessments | 26 weeks | Change from Baseline in pure tone audiometry |
| Ophthalmology assessments | 26 weeks | Change from Baseline in corneal opacification |
| Quality of life questionnaires | 26 weeks | Change from Baseline in EQ-5D-5L questionnaires. 5 dimensions scored on a 5-point scale will be assessed: mobility, self-care, usual activities, pain/discomfort, anxiety/depression |
| Mobility: 6-minute walk test | 26 weeks | Change from baseline in 6-minute walk test |
| ¨Pharmacodynamics: GAG concentrations | 26 weeks | GAG concentration in leukocytes isolated from peripheral |
| Pharmacodynamics: GAG concentrations | 26 weeks | GAG concentrations in skin |
| ¨Pharmacodynamics: anti-thrombin activity IIa | 26 weeks | Change from Baseline in anti-thrombin activity IIa in plasma |
| ¨Pharmacodynamics: Thrombin Generation Assay (TGA) | 26 weeks | Change from Baseline in TGA in plasma |
| Pharmacokinetics: odiparcil concentration in plasma | 12 hours | Odiparcil concentration in plasma at visit V2 (up to 12 hours post dose). |
| Mobility: 9-hole PEG test | 26 weeks | Change from baseline in 9-hole PEG test |
| Mobility: range of motion of the shoulder | 26 weeks | Change from baseline in range of motion of the shoulder |
| Pain assessment | 26 weeks | Change from Baseline in Brief Pain Inventory (BPI) |
Countries
France, Germany, Portugal, United Kingdom
Outcome results
None listed