Evaluation of Leriglitazone on Disease Progression in Male Pediatric Patients with Cerebral X-Linked Adrenoleukodystrophy Prior to Hematopoietic Stem Cell Transplantation

Trial ID: 2024-513774-21-00
Protocol: MT-2-02
Sponsor: Minoryx Therapeutics S.L.

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Diseases & Conditions

Adrenoleukodystrophy

Objectives

The primary objective of this study is to evaluate whether **MIN-102** can arrest disease progression in male pediatric patients with **cerebral X-linked adrenoleukodystrophy (CALD)** at week 96. This will be determined through serial clinical and magnetic resonance imaging (MRI) investigations. Arresting disease progression in CALD is clinically significant as it may prevent further neurological decline and improve patient outcomes.

Secondary objectives include:

Determining the effects of MIN-102 treatment on additional clinical and imaging parameters.
Assessing changes in neurological function.
Evaluating the effects of pre-human stem cell transplant (HSCT) MIN-102 treatment on Loes scores, Gadolinium Intensity Score (GIS), overall survival of patients who have not undergone HSCT, and the number of patients meeting HSCT criteria.
Assessing the pharmacokinetics, safety, tolerability, and palatability of MIN-102 in pediatric subjects.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of MIN-102 in the target population.

Participants

The clinical trial involves a total of **5 participants** diagnosed with **Cerebral X-linked Adrenoleukodystrophy (cALD)**. The study population consists exclusively of male subjects, aged between 2 and 12 years, who have been selected based on specific genetic and clinical criteria. Participants were required to have a confirmed diagnosis of X-linked ALD through genetic testing or elevated very long-chain fatty acids (VLCFA) levels, with additional confirmation through family history or genetic testing of a family member. The trial population was selected to include individuals with white matter involvement as determined by cerebral MRI lesions, and a Major Functional Disabilities (MFD) score of 0. Participants were also required to have a baseline Loes score greater than 0 and less than or equal to 10, and a baseline Gadolinium Intensity Score (GIS) of 3 or less. The health status of participants was assessed to ensure no signs or symptoms of adrenal insufficiency, with normal morning cortisol and aldosterone levels, or appropriate steroid replacement if necessary. Glycated hemoglobin (HbA1c) levels were also required to be within the normal range. The trial does not include female subjects, and the population is considered vulnerable due to the pediatric nature of the participants and the severity of the condition being studied.

Plans and Procedures

The clinical trial is designed as an **open-label**, multicenter study aimed at evaluating the effects of **leriglitazone** treatment on disease progression in male pediatric patients with **cerebral X-linked adrenoleukodystrophy (CALD)** prior to human stem cell transplant (HSCT). The primary objective is to determine whether the treatment can arrest disease progression at week 96, assessed through serial clinical and magnetic resonance imaging (MRI) investigations. The trial is expected to run from September 1, 2019, to February 19, 2025, with a maximum treatment period of 240 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic testing, and MRI findings. Follow-up visits will be scheduled to monitor the efficacy and safety of the treatment, with primary and secondary endpoints evaluated at specific intervals. The primary endpoint is the number of patients meeting "arrested disease" criteria at Visit 12. Secondary endpoints include sustained changes in Neurological Function Scale (NFS) scores, changes in Loes MRI severity score, and overall survival of patients who have not undergone HSCT.

The expected length of participant involvement is up to 96 weeks, with conditions for early termination including withdrawal of consent, adverse events, or failure to meet study criteria. Participants must meet specific inclusion criteria, such as a Major Functional Disabilities (MFD) score of 0 and normal glycated hemoglobin (HbA1c) levels. Exclusion criteria are not explicitly detailed in the provided data. The study aims to provide valuable insights into the potential of **leriglitazone** as a treatment option for CALD, contributing to the understanding of its impact on disease progression.

Treatment

The clinical trial involves the administration of the experimental medication **leriglitazone**, which is provided in the form of an **oral suspension**. The pharmaceutical formulation is designed for oral administration, ensuring ease of use in the pediatric population. The maximum daily dose of leriglitazone is 2.6 mg/kg, with a total maximum dose of 10 ml per day. The treatment period is set to a maximum of 240 days. The medication is of chemical origin and is identified by the sponsor product code Min-102. The trial aims to assess the effects of leriglitazone on disease progression in male pediatric patients with cerebral X-linked adrenoleukodystrophy (cALD) prior to human stem cell transplant (HSCT).

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. These treatments are not specified in the provided data but are typically used to ensure comprehensive evaluation of the experimental medication's efficacy and safety. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen and to accurately assess the therapeutic outcomes of leriglitazone.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the number of patients meeting the "arrested disease" criteria at Visit 12. Secondary endpoints include sustained changes from baseline in specific items of the Neurological Function Scale (NFS), such as hearing/auditory processing, aphasia/apraxia, vision impairment, spastic gait, and incontinence. Additionally, changes from baseline in the total NFS score will be evaluated, with "sustained change" defined as consistent scores across specific visits. If this definition is not met, the average of scores from designated visits will be used. Other secondary endpoints include changes from baseline in the Loes MRI severity score and the Gadolinium Intensity Score (GIS), overall survival of patients who have not undergone human stem cell transplant (HSCT), and the number of patients meeting HSCT criteria.

The efficacy parameters will be measured and collected at various timepoints throughout the study, including Visits 6-8 and 11-12, to ensure comprehensive assessment. The trial will utilize serial clinical evaluations and magnetic resonance imaging (MRI) investigations to determine the impact of **leriglitazone** treatment on disease progression in male pediatric patients with cerebral X-linked adrenoleukodystrophy (cALD). The study aims to evaluate whether the treatment can arrest disease progression by week 96. The trial is designed as an open-label, multicenter study, and the efficacy assessments will be conducted in accordance with the trial's protocol to ensure the reliability and validity of the results.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent by parent/legal guardian, or authorized legal representative to participate in the study
Males aged ≥2 and ≤12 years with a diagnosis of X-linked ALD based on genetic testing; or, in absence of genetic testing, elevation of VLCFA and confirmed by family history of X-ALD with clinical symptoms and elevation of VLCFA or by genetic testing of a family member.
White matter involvement as determined by cerebral MRI lesions without Gd enhancement at baseline (Population 1), or with Gd enhancement at baseline (Population 2).
Major Functional Disabilities (MFD) score of 0, as determined by key measures in the Neurological Function Scale (NFS).
Baseline Loes score >0 and ≤10.
Baseline Gadolinium Intensity Score (GIS) ≤3.
No signs or symptoms of adrenal insufficiency and morning cortisol and aldosterone levels within normal laboratory ranges for age, or appropriate steroid replacement if adrenal insufficiency is present. A history of adrenal insufficiency is not exclusionary if the foregoing is currently met.
Glycated hemoglobin (HbA1c) within normal range.

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Exclusion Criteria

Other chronic neurological disease.
Known intolerance to pioglitazone or other thiazolidinediones.
Use of pioglitazone or other thiazolidinediones within the past 6 months prior to screening.
Use of biotin at a daily dose of >50 mg per day within the past 3 months prior to screening.
Current participation in another interventional clinical study or participation in such a study within 6 months prior to screening.
Previous HSCT.
Requirement for a prohibited concomitant medication.
Previous or current history of bladder polyps, bladder cell hyperplasia, or cancer (other than successfully treated basal cell carcinoma).
Chronic or recurrent symptomatic urinary infections (≥2 per year over the past 2 years until Screening [V-1]). (Only applicable in France)
Permanent indwelling urinary catheter or catheter port. (Only applicable in France)
Smoking with 25 cigarettes per day over the past 2 years until Screening (V-1). (Only applicable in France).
Previous or current history of congestive heart failure.
Clinically significant anemia with hemoglobin <10 g/dL.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level >2 times the ULN or total bilirubin >1.5 times the ULN (unless due to Gilbert's syndrome).
Moderate or severe hepatic impairment (groups B and C according to Child-Pugh classification).
eGFR < 90 ml/min or any evidence of renal disease or impairment, including proteinuria or hematuria.
Pulmonary disease or cardiac disease of sufficient severity to limit participation in the study and/or completion of study procedures.
Reduced left-ventricular ejection fraction or other clinically significant cardiac abnormalities on echocardiogram that, in the investigator's opinion, could predispose the subject to volume overload or its attendant consequences.
Hereditary Fructose Intolerance.
History of diabetes, or glycated hemoglobin (HbA1c) levels >6.4% and fasting blood glucose levels ≤ 0.9 times the lower limit of normal and ≥ 1.1 times the upper limit of normal at Screening
A positive result on laboratory tests for hepatitis B surface antigen, hepatitis C antibody or human immunodeficiency virus antibody. (Only applicable in France)
Contraindication to MRI procedure, such as presence of ferromagnetic materials (aneurysm clips, pacemaker, intraocular metal, cochlear implant) in the body.
Conditions that could modify the absorption of the study drug.
Inability or unwillingness of parent/legal guardian or subject to comply with the study procedures.
Inability or unwillingness of parent/legal guardian or subject to resume standard of care at a local center once study is complete or criteria for HSCT is met and treatment available.
Other medical, neurologic, psychiatric, or social condition that, in the opinion of the investigator, is likely to unfavorably alter risk-benefit of study participation, confound interpretation of safety or efficacy results, or interfere with the satisfactory completion of study requirements.