A research study to understand benefits and safety of Arimolomol a new drug for patients with Gaucher Disease
- Conditions
- Other sphingolipidosis,
- Registration Number
- CTRI/2017/12/011025
- Lead Sponsor
- Orphazyme AS
- Brief Summary
1. Ahmed et. al. Targeting protein homeostasis in sporadic inclusion body myositis
Abstract: Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, doubleblind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.
2. Cudkowicz et. al. Arimoclomol At Dosages Up To 300 Mg/Day Is Well Tolerated And Safe In Amyotrophic Lateral Sclerosis
Abstract: Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the halflife did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood–brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.
3. Kirkegaard, Thomas, James Gray,David A Priestman et al. 2016: “Heat Shock Protein–Based Therapy as apotential Candidate for Treating the SphingolipidosesAbstract: Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Closed to Recruitment of Participants
- Sex
- All
- Target Recruitment
- 40
- The following are the main inclusion criteria: 1.
- Be able to understand and voluntarily sign informed consent.
- A diagnosis GD, either Type 1 or Type 3, with a glucocerebrosidase enzyme activity 0 to 15% of normal activity.
- Note that the local laboratory test result will be used at inclusion.
- For GD3 at least 1 neurological symptom.
- Age ≥ 4 years and ≤ 60 years at the time of enrolment.
- Plasma or serum chitotriosidase levels > 3000 nmol/mL/h.
- Historical data is acceptable.
- Either naïve to treatment for GD or has not received treatment (investigational or authorized/approved like ERT or SRT, also including procedures such as blood transfusions and splenectomy) for Gaucher disease within 4 months prior to study entry.
- Ability to comply with the protocol-specified procedures/evaluations and scheduled visits; (if platelet counts are < 50000 platelets per microliter of circulating blood lumbar puncture should not be performed).
- Ability to travel to the investigational clinical trial site repeatedly (screening, baseline, 1 month, 3 months, and 6 months, then every 6 months during the extension part) for evaluation and follow-up.
- All sexually active female patients of child-bearing potential (post-menarchal) must use highly effective contraception during the study and until 1 week after the last dose of IMP.
- All sexually active male patients with female partners of child-bearing potential (post-menarchal) must use a condom with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of IMP.
- Recipient of a liver transplant or planned liver transplantation during the course of the study.
- Splenectomy within 4 months of study entry or planned splenectomy during the course of the study.
- Severe liver damage (defined as hepatic laboratory parameters, AST and/or ALT greater than three-times the upper limit of normal for age and gender (central laboratory assessment).
- Severe renal insufficiency, with serum creatinine level greater than 1.5 times the upper limit of normal (ULN) (central laboratory assessment).
- The patient has received any investigational drug within 30 days prior to study entry (Note that investigational drug for GD should not have been taken within the last 4 months prior to enrolment, as per entry criterion no.6).
- The patient is a pregnant and/or lactating female.
- If, in the opinion of the principal investigator, the patient has a clinical condition that is not compatible with the requirements of this protocol; such as confirmed history of serious adverse reaction to sedation or anesthesia (if sedation is necessary for lumbar puncture), uncontrolled severe epileptic seizures and/or severe malnutrition.
- Body weight less than 10 kg.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The primary objective of the study is to evaluate the response in GD biomarkers versus placebo after 6 months of treatment. After 6 months of treatment.
- Secondary Outcome Measures
Name Time Method Secondary objectives include the evaluation of patient safety (after 6 months and long term) as well as long term effects on clinical endpoints and biomarkers during the extension phase. After 6 months of treatment and long-term
Trial Locations
- Locations (8)
All India Institute of Medical Sciences
🇮🇳Delhi, DELHI, India
Christian Medical College and Hospital, Vellore
🇮🇳Vellore, TAMIL NADU, India
Institute of Child Health
🇮🇳Kolkata, WEST BENGAL, India
Jaslok Hospital & Research Centre
🇮🇳Mumbai, MAHARASHTRA, India
KEM Hospital Research Centre
🇮🇳Pune, MAHARASHTRA, India
Maulana Azad Medical College
🇮🇳Delhi, DELHI, India
Seth G. S. Medical College and KEM Hospital
🇮🇳Mumbai, MAHARASHTRA, India
Sir Ganga Ram Hospital
🇮🇳Delhi, DELHI, India
All India Institute of Medical Sciences🇮🇳Delhi, DELHI, IndiaDr Neerja GuptaPrincipal investigator9999995630neerja17aiims@gmail.com