Leriglitazone for Adrenoleukodystrophy

(CALYX Trial)

Recruiting at 12 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

Trial Summary

What is the purpose of this trial?

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

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.

What data supports the effectiveness of the drug Leriglitazone for Adrenoleukodystrophy?

Research shows that Leriglitazone, a drug that targets specific brain pathways, can help reduce inflammation and protect nerve cells in conditions like Adrenoleukodystrophy. In studies with animal models and early human trials, it improved motor function and reduced markers of disease progression, suggesting it may help slow down the disease. ^{1 2 3 4 5}

What safety data exists for Leriglitazone and related treatments?

While specific safety data for Leriglitazone is not provided, related treatments like pioglitazone and lobeglitazone have been studied for safety. Pioglitazone has been evaluated in trials with over 3,500 patients, showing a well-documented safety profile, and lobeglitazone has shown a favorable safety balance in studies, even in patients with mild to moderate liver issues. ^{6 7 8 9 10}

How is the drug leriglitazone unique in treating adrenoleukodystrophy?

Leriglitazone is unique because it is a brain-penetrant drug that specifically targets and modulates pathways involved in neuroinflammation and neurodegeneration, which are key in adrenoleukodystrophy. Unlike other treatments, it acts as a selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, helping to reduce oxidative stress and improve mitochondrial function, potentially slowing disease progression. ^{1 2 3 5 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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 (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]

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]

References

1. England 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Glyceroltrioleate/glyceroltrierucate therapy in 16 patients with X-chromosomal adrenoleukodystrophy/adrenomyeloneuropathy: effect on clinical, biochemical and neurophysiological parameters. [2019]

5. England pubmed.ncbi.nlm.nih.gov

New treatment of free-radical scavenger in adrenoleukodystrophy. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Safety profile of pioglitazone. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of high dose aleglitazar on renal function in patients with type 2 diabetes. [2012]

8. Ireland 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. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Effects of Hepatic Impairment on the Pharmacokinetic Profile and Safety of Lobeglitazone. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Will lobeglitazone rival pioglitazone? A systematic review and critical appraisal. [2023]

11. Norway pubmed.ncbi.nlm.nih.gov

[Adrenoleukodystrophy--clinical, biochemical and therapeutic aspects]. [2008]