IB1001 for Ataxia

Recruiting at 4 trial locations

Overseen By Taylor Fields, MSt

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: IntraBio Inc

Must not be taking: Aminopyridines, Riluzole, Gabapentin, others

Disqualifiers: Chronic diarrhea, Malignancies, Insulin-dependent diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 11

Duration: 6 weeks

39 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multinational, multicenter, open-label, rater-blinded prospective Phase II study which will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the treatment of Ataxia-Telangiectasia (A-T). There are two phases to this study: the Parent Study, and the Extension Phase. The Parent Study evaluates the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the symptomatic treatment of A-T. The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the neuroprotective, disease-modifying treatment of A-T.

Do I have to stop taking my current medications for the trial?

The trial requires a 6-week washout period for certain prohibited medications, including Aminopyridines, N-Acetyl-DL-Leucine, Riluzole, Gabapentin, Varenicline, Chlorzoxazone, Sulfasalazine, and Rosuvastatin. You must stop these medications before starting the trial. Other non-prohibited medications can be continued if they are stable and approved by the investigator.

Will I have to stop taking my current medications?

The trial requires a 6-week period without certain medications before starting, including Aminopyridines, N-Acetyl-DL-Leucine, Riluzole, Gabapentin, Varenicline, Chlorzoxazone, Sulfasalazine, and Rosuvastatin. You can continue other medications if they don't interfere with the study and have been stable for at least 6 weeks.

What data supports the idea that IB1001 for Ataxia is an effective drug?

The available research shows that IB1001, also known as acetyl-DL-leucine, has been observed to improve symptoms in patients with cerebellar ataxia. In one study, 14 out of 18 patients showed improved walking stability after treatment. Another study reported significant improvements in motor functions like walking, speech, and hand movements, as well as an increase in quality of life, without any side effects. These findings suggest that IB1001 could be an effective drug for treating ataxia, although more research is needed to confirm these results. ^{1 2 3 4 5}

What data supports the effectiveness of the drug IB1001 (N-Acetyl-L-Leucine) for treating ataxia?

Research shows that a similar compound, acetyl-DL-leucine, improved walking stability and other motor functions in patients with cerebellar ataxia, suggesting potential benefits for IB1001 in treating ataxia. ^{1 2 3 4 5}

What safety data exists for IB1001 (N-Acetyl-L-Leucine) for Ataxia?

The provided research does not contain specific safety data for IB1001 (N-Acetyl-L-Leucine) for Ataxia. The studies focus on other amino acids like isoleucine, tryptophan, citrulline, lysine, and leucine, but do not address N-Acetyl-L-Leucine or its safety profile in clinical trials for Ataxia. ^{6 7 8 9 10}

Is IB1001 (N-Acetyl-L-Leucine) safe for human use?

There is no specific safety data available for IB1001 (N-Acetyl-L-Leucine) in humans from the provided research articles. ^{6 7 8 9 10}

Is the drug IB1001 a promising treatment for Ataxia?

The information provided does not mention IB1001 or its effects on Ataxia, so we cannot determine if it is a promising treatment based on these articles. ^{11 12 13 14 15}

How is the drug IB1001 different from other treatments for ataxia?

IB1001, also known as N-Acetyl-L-Leucine, is unique because it is a modified amino acid that may offer neuroprotective effects by stabilizing neuronal function, which is different from other treatments that often focus on managing symptoms rather than addressing underlying neuronal stability. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for males and females aged 6 or older diagnosed with Ataxia-Telangiectasia (A-T). Participants must have a specific level of disease severity, weigh at least 15 kg, and be willing to follow study procedures. Women who can bear children must use effective contraception or abstain from sex.

Inclusion Criteria

I have not been sexually active or have used effective birth control for the required time.

Written informed consent signed by the patient and/or their legal representative/parent

I am 6 years or older and have been diagnosed with A-T.

Exclusion Criteria

You have a history of using drugs or alcohol in a way that may cause dependence or harm.

I have chronic diarrhea, unexplained vision loss, cancer, or need insulin for diabetes.

I do not have any symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Initial assessments and baseline measurements are conducted

1 week

1 visit (in-person)

Treatment

Participants receive N-Acetyl-L-Leucine (IB1001) for 6 weeks

6 weeks

3 visits (in-person)

Post-Treatment Washout

Participants undergo a 6-week washout period after treatment

6 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension Phase

Long-term treatment with IB1001 for neuroprotective, disease-modifying effects

25.5 months

6 visits (in-person)

Treatment Details

Interventions

• IB1001

Trial Overview The trial is testing N-Acetyl-L-Leucine (IB1001) in two phases: the Parent Study for symptomatic treatment of A-T, and the Extension Phase for long-term safety and potential disease-modifying effects.

Participant Groups

Group I: Treatment with IB1001 Experimental Treatment 1 Intervention

6-weeks treatment with IB1001 administered orally. Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day). Patients 6-12 years old will receive weight-tiered doses: * Patients aged 6-12 years weighing 15 to \<25 kg will take 2 g per day: 1 g in the morning and 1 g in the evening. * Patients aged 6-12 years weighing 25 to \<35 kg will take 3 g per day: 1 g in the morning, 1 g in the afternoon, and 1 g in the evening. * Patients aged 6-12 years weighing ≥35 kg will take 4 g per day: 2 g in the morning, 1g in the afternoon and 1 g in the evening (as per adults) After the 6-week treatment period, patients will enter a 6-week post-treatment washout period.

Group II: Post-Treatment Washout Active Control 1 Intervention

After the 6-week treatment period, patients will enter a 6-week post-treatment washout period.

Who Is Running the Clinical Trial?

IntraBio Inc

Lead Sponsor

Trials

5

Recruited

220+

Findings from Research

The Scale for the Assessment and Rating of Ataxia (SARA) effectively measures ataxia severity and shows responsiveness to changes in patients, particularly in those with mild to moderate ataxia, as indicated by annualized progression rates across various genotypes.

A novel rank-optimized version of SARA, which excludes certain subitems, can reduce the required sample sizes for clinical trials by 20 to 25%, enhancing its utility in regulatory settings and trial design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients. Traschütz, A., Adarmes-Gómez, AD., Anheim, M., et al.[2023]

The ALCAT trial will evaluate the efficacy and tolerability of acetyl-DL-leucine in improving motor function in 108 patients with cerebellar ataxia, using the Scale for the Assessment and Rating of Ataxia (SARA) as the primary outcome measure.

This multicenter, randomized, double-blind, placebo-controlled trial aims to provide new therapeutic options for cerebellar ataxia, a condition with no proven effective medications, and will also assess quality of life and incidence of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial. Feil, K., Adrion, C., Teufel, J., et al.[2018]

The innovative master protocol and primary outcome assessment for N-acetyl-L-leucine (IB1001) are designed to address the unique challenges of treating ultra-rare neurodegenerative disorders, involving three multinational phase II trials for Niemann-Pick disease type C, GM2 gangliosidoses, and ataxia telangiectasia.

The novel Clinical Impression of Change in Severity (CI-CS) assessment allows for a personalized evaluation of treatment effects, capturing meaningful clinical changes in patients' functional performance, which is crucial for understanding the efficacy of N-acetyl-L-leucine in these rare diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Fields, T., Patterson, M., Bremova-Ertl, T., et al.[2021]

Acetyl-DL-leucine treatment significantly improved walking stability in 14 out of 18 patients with various forms of cerebellar ataxia, as indicated by a reduction in the coefficient of variation of stride time.

Patients also reported better subjective ambulatory scores and improvements in SARA scores, suggesting that Acetyl-DL-leucine may enhance overall mobility and stability in ataxic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series. Schniepp, R., Strupp, M., Wuehr, M., et al.[2020]

In a case series of 13 patients with degenerative cerebellar ataxia, treatment with acetyl-DL-leucine (5 g/day) for one week led to significant improvements in motor function, as measured by the Scale for the Rating and Assessment of Ataxia (SARA), with a notable decrease in scores from 16.1 to 12.8.

Patients also reported enhanced quality of life during treatment, and importantly, no side effects were observed, suggesting a favorable risk-benefit profile for acetyl-DL-leucine in managing ataxic symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. Strupp, M., Teufel, J., Habs, M., et al.[2021]

Broilers fed diets deficient in isoleucine (Ile) showed significantly poorer growth and carcass responses compared to those receiving diets with adequate Ile, indicating the importance of this amino acid for optimal development.

Supplementing diets with isoleucine restored growth and carcass responses to levels comparable to those fed a control diet, suggesting that meeting the recommended dietary needs (6.7-7.1 g/kg for younger broilers and 5.5-6.6 g/kg for older broilers) is crucial for their health and performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary isoleucine responses in male broiler chickens. Kidd, MT., Burnham, DJ., Kerr, BJ.[2019]

The increasing use of amino acids from various sources necessitates thorough safety assessments due to the potential for high intake levels that exceed normal dietary amounts.

Establishing reliable Tolerable Upper Intake Levels (ULs) for amino acids is challenging due to insufficient toxicity studies and lack of clinical data, highlighting the need for comprehensive safety evaluations that include quality specifications and potential interactions with medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline. Oketch-Rabah, HA., Roe, AL., Gurley, BJ., et al.[2023]

A patient with maple syrup urine disease developed symptoms similar to acrodermatitis enteropathica while on a branched-chain amino acid-free formula, highlighting the risks of inadequate amino acid supplementation.

Supplementation with isoleucine led to a rapid clinical improvement, demonstrating the importance of monitoring and providing essential amino acids in patients on specialized diets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease. Giacoia, GP., Berry, GT.[2019]

A systematic review of 71 studies on L-lysine supplementation found that doses up to 6000 mg/day are generally safe, with the most common side effects being mild gastrointestinal issues like nausea and diarrhea.

The analysis showed no significant increase in the risk of gastrointestinal symptoms at higher doses, suggesting that L-lysine can be safely included in diets without major adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of L-lysine oral intake: a systematic review. Hayamizu, K., Oshima, I., Fukuda, Z., et al.[2019]

Leucine supplementation may help prevent age-related muscle loss in elderly individuals, but safety assessments indicate that blood ammonia levels rise above normal at intakes greater than 550 mg/kg/day.

The study suggests that the upper limit for safe leucine intake in healthy elderly men is similar to that of young men, around 500 mg/kg/day, which translates to approximately 35 grams per day for a 70 kg individual.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the safety of leucine supplementation in healthy elderly men. Rasmussen, B., Gilbert, E., Turki, A., et al.[2018]

In a study of Machado-Joseph disease (MJD) using cell models, the nuclear transport receptor KPNB1 was found to interact with both normal and polyQ-expanded ataxin-3, but its modulation did not change the localization of ataxin-3.

Overexpression of KPNB1 led to reduced levels of ataxin-3 and its aggregates, improving cell viability, suggesting that KPNB1 could be a potential therapeutic target for MJD by promoting the degradation of ataxin-3 through a novel mechanism involving the mitochondrial protease CLPP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KPNB1 modulates the Machado-Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP. Abeditashi, M., Weber, JJ., Pereira Sena, P., et al.[2022]

In spinocerebellar ataxia-1 (SCA1), elevated levels of the glial protein S100B are associated with the formation of vacuoles in Purkinje cells, which correlates with disease progression and abnormal cell morphology.

Treatment with the S100B inhibitory peptide TRTK12 not only reversed the protective effects of S100B but also improved motor performance in SCA1 transgenic mice, suggesting that targeting S100B could be a potential therapeutic strategy for mitigating SCA1 pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glial S100B protein modulates mutant ataxin-1 aggregation and toxicity: TRTK12 peptide, a potential candidate for SCA1 therapy. Vig, PJ., Hearst, S., Shao, Q., et al.[2021]

Ataxin-3 (Atx3), the protein mutated in Machado-Joseph Disease (MJD), is actively imported into the nucleus through a specific nuclear localization sequence, indicating its critical role in the disease's pathogenesis.

The study identified that while Atx3 can be exported from the nucleus, its nuclear export activity is enhanced by a specific region in the protein, suggesting that disruptions in this transport process may contribute to the harmful nuclear accumulation of Atx3 aggregates in MJD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nucleocytoplasmic shuttling activity of ataxin-3. Macedo-Ribeiro, S., Cortes, L., Maciel, P., et al.[2021]

The expanded form of ataxin-3 (Q85) leads to significant cell death in yeast models by causing oxidative stress and damaging cell membranes, highlighting its toxic effects in neurodegeneration.

Treatment with guanidine hydrochloride, which inhibits the chaperone Hsp104, can restore cell survival in models expressing toxic ataxin-3 variants, suggesting that targeting protein aggregation may be a potential therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model. Bonanomi, M., Visentin, C., Invernizzi, G., et al.[2020]

The study identified that specific lysine residues, particularly lysine 8 and lysine 85, play crucial roles in stabilizing the ataxin-3 protein and influencing its aggregation, which is important for understanding Machado-Joseph disease.

Lysine-free ataxin-3 exhibited increased toxicity and altered binding to ubiquitin chains, suggesting that modulating these lysine residues could be a potential therapeutic strategy to address the disease's pathophysiology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of specific lysine residues within ataxin-3 for the molecular pathogenesis of Machado-Joseph disease. Pereira Sena, P., Weber, JJ., Bayezit, S., et al.[2023]

References

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

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial. [2018]

3. England pubmed.ncbi.nlm.nih.gov

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. [2021]

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

Dietary isoleucine responses in male broiler chickens. [2019]

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

The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline. [2023]

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

Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease. [2019]

9. Austria pubmed.ncbi.nlm.nih.gov

Safety assessment of L-lysine oral intake: a systematic review. [2019]

10. Austria pubmed.ncbi.nlm.nih.gov

Determination of the safety of leucine supplementation in healthy elderly men. [2018]

11. Switzerland pubmed.ncbi.nlm.nih.gov

KPNB1 modulates the Machado-Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP. [2022]

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

Glial S100B protein modulates mutant ataxin-1 aggregation and toxicity: TRTK12 peptide, a potential candidate for SCA1 therapy. [2021]

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

Nucleocytoplasmic shuttling activity of ataxin-3. [2021]

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

The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model. [2020]

15. Switzerland pubmed.ncbi.nlm.nih.gov

Implications of specific lysine residues within ataxin-3 for the molecular pathogenesis of Machado-Joseph disease. [2023]