Overview
The goal of this clinical trial is to determine if dimethyl fumarate is effective in treating motor problems in adults with Adrenomyeloneuropathy. The trial will also assess the safety of dimethyl fumarate and explore the molecular mechanisms underlying the disease. The primary questions it aims to answer are:
- Does dimethyl fumarate improve motor problems in participants?
- What medical issues do participants experience while taking dimethyl fumarate? Researchers will compare the effects of dimethyl fumarate to a placebo (a substance that looks like the drug but contains no active ingredients) to evaluate its effectiveness in treating Adrenomyeloneuropathy.
Participants will:
- Take either dimethyl fumarate or a placebo daily for 36 months.
- Visit the clinic at the start of the trial, then at 3 months, 6 months, and every 6 months thereafter for checkups and tests.
Description
Adrenoleukodystrophy (X-ALD) is the most prevalent rare genetic disorder affecting the brain's white matter. It is caused by mutations in the ABCD1 gene, which encodes a transporter involved in the degradation of very long-chain fatty acids (VLCFA). As a result, VLCFA accumulate in tissues and plasma, serving as a pathognomonic biomarker for diagnosis. The disease manifests in two main forms: i) adrenomyeloneuropathy (AMN), characterized by chronic progressive spastic paraplegia due to distal axonopathy, and ii) cerebral ALD (cALD), a rapidly progressing and fatal demyelinating leukodystrophy. Current therapeutic options are inadequate, limited to bone marrow transplants and gene therapy for patients with cerebral inflammation. No treatment is available for AMN, which affects 60% of patients.
We have discovered that excess VLCFA leads to mitochondrial reactive oxygen species (ROS) production and oxidative damage, a major factor driving pathogenesis. More recently, we found that the main endogenous response to oxidative damage (the NRF-2 pathway) is impaired in X-ALD. Preclinical tests with an NRF2 activator, specifically the current treatment for multiple sclerosis, dimethyl fumarate (DMF/Tecfidera), showed promising results. All major molecular and cellular pathogenic mechanisms were restored, including: i) mitochondrial function and biogenesis, ii) redox homeostasis, iii) bioenergetic failure, iv) neuroinflammation, along with axonal damage and clinical signs of the disease such as locomotor disability. Consequently, we obtained an international patent for repurposing DMF for X-ALD (US15/957,601) and Orphan Drug Designation by the EMA in 2020 (EMA/OD/0000010028).
Now we are translating this knowledge into a randomized phase IIb/III double-blind placebo-controlled study over 36 months for 40 AMN patients, to determine if DMF is effective in these patients. For the first 24 months, patients will be divided into two groups (placebo and active treatment) in a ratio of 1:2. A 12-month extension phase will follow, during which all patients will receive treatment. Furthermore, we aim to elucidate the molecular mechanisms driving the disease and dissect the redox-inflammatory effects of DMF using an integrative multi-omics approach, which will involve single-cell RNA sequencing in PBMC, and lipidomics in plasma. The clinical and molecular data from historical national and international AMN and cALD cohorts will be pooled to identify markers of severity and progression. Our goal is to address unmet needs in AMN while generating novel fundamental knowledge that will be useful for this and other common axonopathies.
Eligibility
Inclusion Criteria:
- Men and women of 18 to 65 years old at the time of the inclusion, suffering from AMN
- with
-
- elevated plasma VLCFA
- ABCD1 gene mutation identified
- Clinical signs of AMN with at least pyramidal signs in the lower limbs and
difficulties to walk (EDSS score ≥ 2.0 and ≤ 6.5). EDSS score will also be re-evaluated at M12, M24 and M36.
- Normal brain MRI or brain MRI showing:
- abnormalities that can be observed in AMN patients without cerebral demyelination with a maximum Loes score of 4
- and/or stable (≥ 6 months) cerebral demyelination without gadolinium enhancement with a Loes score ≤ 12
- Appropriate steroid replacement if adrenal insufficiency is present
- Potential childbearing women should use an adequate method of contraception to avoid pregnancy throughout the study to minimize the risk of pregnancy. If oral contraceptives are used, the use of an alternative barrier method is recommended.
- Likely to be able to participate in all scheduled evaluations and complete all required study procedures
- Signed and dated written informed consent to participate in the study in accordance with local regulations
Exclusion Criteria:
- Any progressive neurological disease other than AMN
- Leukopenia below 3.0x109/L, lymphopenia below 0.5x109/L or other pathological results in the complete blood count
- Suspected or confirmed progressive multifocal leukoencephalopathy (PML)
- Severe gastrointestinal disease
- Uncontrolled hepatic, renal or cardiovascular disease, or any evolutive malignancy
- Pregnancy and breast-feeding in woman and potential childbearing woman unable or unwilling to use an acceptable contraceptive method during the study
- Any new medication for AMN initiated less than three months prior to inclusion
- Contra-indications for MRI procedure such as subjects with paramagnetic materials in the body as aneurysm clips, pacemakers, intraocular metal or cochlear implants
- Inclusion in another therapeutic clinical trial for ALD
- Not easily contactable by the investigator in case of emergency or not able to call the investigator