Leriglitazone for Adrenoleukodystrophy

(CALYX Trial)

Recruiting at 13 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: Minoryx Therapeutics, S.L.

Must not be taking: Thiazolidinediones, Honokiol

Disqualifiers: Diabetes, Previous HSCT, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 36 months

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of leriglitazone, a potential treatment for cerebral adrenoleukodystrophy (cALD), a condition affecting the brain. Researchers aim to determine if leriglitazone can manage symptoms and improve life quality for those with cALD. Participants will receive either leriglitazone or a placebo (a non-active substance) to compare results. Men with cALD who have specific brain lesions and do not want or cannot undergo a bone marrow transplant might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking honokiol, pioglitazone, or other thiazolidinediones at least 3 months before joining. If you're on these medications, you'll need to stop them before participating.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that leriglitazone is usually well-tolerated by people with cerebral adrenoleukodystrophy. Studies have found that participants taking leriglitazone experienced fewer new brain lesions, a major concern in this condition. Reports indicate that the treatment is safe, with no serious side effects. However, treatments can affect everyone differently. Discuss with your doctor if considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for adrenoleukodystrophy focus on symptom management or slowing disease progression, often through dietary interventions or bone marrow transplants. But leriglitazone is unique because it targets the underlying issue. It works by activating the PPAR gamma pathway, which helps to reduce inflammation and oxidative stress in the brain. Researchers are excited about leriglitazone because it offers a new way to potentially protect and preserve nerve cells, which could lead to improved outcomes and quality of life for patients with this challenging condition.

What evidence suggests that Leriglitazone might be an effective treatment for adrenoleukodystrophy?

Research shows that leriglitazone, which participants in this trial may receive, may help treat cerebral adrenoleukodystrophy (CALD). In a previous study where participants knew they were receiving the treatment, leriglitazone proved safe and provided significant health benefits. It specifically slowed the worsening of brain-related symptoms in patients. Additionally, early tests with healthy volunteers indicated that leriglitazone could reduce inflammation, an important factor in managing CALD. These findings suggest that leriglitazone could effectively treat this condition. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for adult males with cerebral adrenoleukodystrophy (cALD) who can't or choose not to undergo a bone marrow transplant. Participants should have progressing cALD, a specific brain lesion score, and no major functional disabilities except those common in AMN progression. They must not have diabetes, previous treatments like HSCT or certain drugs within 3 months, and shouldn't be part of another study.

Inclusion Criteria

I do not have major disabilities, except possibly needing a wheelchair or having incontinence.

Your Loes score is between 0.5 and 12 during the screening.

I do not have significant memory or thinking problems that would stop me from participating in the study.

Exclusion Criteria

I have had a bone marrow transplant or gene therapy treatment.

Subject with other medical, neuropsychiatric or social conditions that, in the opinion of the investigator, are likely to adversely affect the risk-benefit of study participation, interfere with study compliance, or confound the study results.

I have been diagnosed with diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Leriglitazone or placebo for up to 36 months

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Leriglitazone
• Placebo

Trial Overview

The trial is testing Leriglitazone's effectiveness and safety against a placebo in treating cALD. Men will randomly receive either the actual drug or an inactive substance to compare outcomes between the two groups.

How Is the Trial Designed?

Group I: Leriglitazone Active Control 1 Intervention

Leriglitazone Treatment

Group II: Placebo Placebo Group 1 Intervention

Placebo

Who Is Running the Clinical Trial?

Minoryx Therapeutics, S.L.

Lead Sponsor

Trials

5

Recruited

240+

Published Research Related to This Trial

In a study comparing patients with hepatic impairment (HI) to healthy controls, lobeglitazone showed similar pharmacokinetic profiles, indicating it can be safely used in patients with mild to moderate HI without needing dose adjustments.

No significant adverse events or tolerability issues were reported, suggesting that lobeglitazone is well-tolerated in individuals with hepatic impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Hepatic Impairment on the Pharmacokinetic Profile and Safety of Lobeglitazone. Park, J., Kim, CO., Oh, ES., et al.[2022]

Lobeglitazone demonstrated sustained safety and efficacy in managing type 2 diabetes over a 52-week period, including an initial 28-week extension study.

The treatment effectively maintained glycemic and lipid control throughout the study duration, indicating its potential as a reliable option for diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 52 weeks: An open-label extension study. Kim, SH., Kim, SG., Kim, DM., et al.[2022]

In a 96-week trial involving 116 adult patients with adrenomyeloneuropathy, leriglitazone did not show a significant difference in improving walking distance compared to placebo, indicating it may not be effective for this specific measure of disease progression.

Despite not meeting the primary endpoint, leriglitazone was well tolerated, with a higher incidence of weight gain and peripheral edema compared to placebo, and notably, serious cases of progressive cerebral adrenoleukodystrophy occurred only in the placebo group, suggesting potential benefits of leriglitazone in preventing this severe complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. Köhler, W., Engelen, M., Eichler, F., et al.[2023]

Leriglitazone, a PPARγ agonist, demonstrated neuroprotective effects in models of X-linked adrenoleukodystrophy (X-ALD) by reducing oxidative stress and improving motor function in mouse models, indicating its potential as a treatment for this severe condition.

In a phase 1 clinical study, leriglitazone showed engagement with the central nervous system and positive changes in inflammatory biomarkers, supporting its efficacy and safety for further development in treating X-ALD and possibly other neuroinflammatory diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy. Rodríguez-Pascau, L., Vilalta, A., Cerrada, M., et al.[2023]

PXL065, a modified version of pioglitazone, shows promise in treating X-linked adrenoleukodystrophy (ALD) by normalizing elevated Very Long Chain Fatty Acids (VLCFA) and improving mitochondrial function in patient-derived cells and mouse models.

Chronic treatment with PXL065 not only reduced VLCFA levels in plasma and brain but also improved neural histology and neurobehavioral performance in mice, suggesting it may offer benefits beyond those of traditional pioglitazone without the associated side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy. Monternier, PA., Singh, J., Parasar, P., et al.[2022]

X-linked adrenoleukodystrophy (X-ALD) is a serious genetic disorder that primarily affects boys under ten, leading to severe neurological symptoms like dementia, and is caused by a defect in a protein that regulates fatty acid transport in peroxisomes.

While treatments like Lorenzo's oil have not been effective for patients with neurological symptoms, bone marrow transplantation is currently the preferred treatment for presymptomatic boys, highlighting the importance of early diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adrenoleukodystrophy--clinical, biochemical and therapeutic aspects]. Skjeldal, OH., Strømme, P., Christensen, E.[2008]

Pioglitazone has been evaluated for safety in over 5,400 subjects, with more than 3,500 receiving the drug, resulting in over 2,500 patient-years of exposure, indicating a robust safety profile.

The trials demonstrated that pioglitazone is well-tolerated both as a standalone treatment and in combination with other diabetes medications, with comprehensive monitoring of adverse events and health metrics throughout the studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of pioglitazone. Hanefeld, M., Belcher, G.[2022]

Lobeglitazone (LGZ) effectively reduces HbA1c levels in people with type 2 diabetes, showing similar efficacy to pioglitazone (PGZ) and sitagliptin, but with a higher incidence of weight gain and edema compared to placebo.

Current evidence does not support LGZ as a superior alternative to PGZ in terms of glycemic control or safety, indicating that more research is needed to determine its long-term benefits and risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Will lobeglitazone rival pioglitazone? A systematic review and critical appraisal. Gangopadhyay, KK., Singh, AK.[2023]

Glyceroltrioleate/glyceroltrierucate (GTO/GTE) therapy effectively normalized plasma fatty acid concentrations in 16 patients with various forms of adrenoleukodystrophy over an average treatment duration of about 19 months, and none of the neurologically asymptomatic patients developed neurological symptoms during this time.

The therapy appears to be most beneficial when started early, as it may prevent the onset of neurological symptoms in asymptomatic boys, while some symptomatic patients experienced clinical deterioration, highlighting the need for careful monitoring and early intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glyceroltrioleate/glyceroltrierucate therapy in 16 patients with X-chromosomal adrenoleukodystrophy/adrenomyeloneuropathy: effect on clinical, biochemical and neurophysiological parameters. Korenke, GC., Hunneman, DH., Kohler, J., et al.[2019]

Edaravone, a free-radical scavenger, was administered intravenously to a patient with adrenoleukodystrophy (ALD) and resulted in a significant decrease in oxidative stress markers in the cerebrospinal fluid and improved neuronal transmission times.

This case represents the first report of edaravone's use in ALD, suggesting it may effectively alleviate symptoms, warranting further formal evaluation of its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New treatment of free-radical scavenger in adrenoleukodystrophy. Kawashima, H., Nishimata, S., Ishii, C., et al.[2018]

In a 26-week study involving 174 patients with type 2 diabetes, aleglitazar at a supratherapeutic dose of 600 μg/day led to a significant decrease in measured glomerular filtration rate (mGFR) compared to pioglitazone, indicating potential renal effects that need to be monitored.

Despite the observed dose-dependent side effects like weight gain and peripheral edema, aleglitazar shows promise as a treatment for cardiovascular risk reduction, particularly at a lower therapeutic dose of 150 μg/day.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of high dose aleglitazar on renal function in patients with type 2 diabetes. Herz, M., Gaspari, F., Perico, N., et al.[2012]

Citations

1.

thelancet.com

thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00197-X/fulltext

Safety and efficacy of leriglitazone in childhood cerebral ...

Safety and efficacy of leriglitazone in childhood cerebral adrenoleukodystrophy (NEXUS): an interim analysis of an open-label, phase 2/3 trial

2.

minoryx.com

minoryx.com/media/leriglitazone_maa_submitted_for_treatment_of_cald_has_been_validated_by_ema/

Leriglitazone Marketing Authorization Application ...

“We believe the new and positive data from Nexus provide compelling evidence for the efficacy of leriglitazone giving hope to patients and their ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11847323/

Safety and efficacy of leriglitazone for preventing disease ...

In a phase 1 trial in healthy male volunteers, leriglitazone decreased plasma proinflammatory biomarker concentrations and increased adiponectin concentrations, ...

4.

minoryx.com

minoryx.com/media/the-lancet-neurology-publishes-results-from-minoryx-therapeutics-phase2-3-advance-clinical-trial-of-leriglitazone-in-x-linked-adrenoleukodystrophy/

The Lancet Neurology publishes results from ...

Leriglitazone was well tolerated, and significant benefit was shown through clinically meaningful myelopathy endpoints and reduced progression of cerebral ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05819866

NCT05819866 | A Clinical Study to Assess the Efficacy and ...

Study Overview. Brief Summary. A Clinical Study to Assess the Efficacy and Safety of Leriglitazone in Adults Male Subjects with Cerebral Adrenoleukodystrophy.

6.

minoryx.com

minoryx.com/media/leriglitazone_has_met_the_primary_endpoint_in_nexus/

Leriglitazone has met the primary endpoint in NEXUS ...

Data from ADVANCE showed that leriglitazone reduces the progression of lesions and the development of progressive cALD in adult patients.