Subgroup Analysis by Phenoytpe in a Phase III, Randomized, Placebo-Controlled Crossover Trial with Levacetylleucine (IB1001) for Niemann-Pick Disease Type-C
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
This study aimed to evaluate the efficacy of N-acetyl-L-leucine (levacetylleucine) compared to placebo in Niemann-Pick disease type C (NPC) patient subgroups based on the age of onset of neurological manifestations on the following assessments: the Scale for the Assessment and Rating of Ataxia (SARA), modified Disability Rating Scale (mDRS), Spinocerebellar Ataxia Functional Index (SCAFI), and Clinical Global impression of Improvement Scales (CGI-I).
Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disorder where the age at onset of neurological manifestations significantly correlates to the disease progression and prognosis. In general, patients with neurological onset early in life (early or late infantile stage) have more severe, rapidly progressive forms of the disease than juveniles or adolescents/adults. The IB1001-301 clinical trial was a Phase III, double-blind, randomized, placebo-controlled, crossover trial comparing levacetylleucine with placebo for the treatment of neurological signs and symptoms in NPC after 12 weeks. 60 NPC patients aged 5 to 67 years with a genetically confirmed diagnosis of NPC were enrolled, including patients with early and late infantile, juvenile and adolescent/adult-onset disease forms. The primary SARA endpoint was reduced -1.97 points with levacetylleucine and -0.60 for placebo (p<0.001). Patients treated with levacetylleucine also demonstrated statistically significant improvements in the secondary outcomes compared to placebo.
Methods:
Subgroup analysis was conducted to evaluate the effects of levacetylleucine on the 4 phenotypes of NPC, defined based on the age of neurological manifestation onset.; early infantile (onset <2 years), late infantile (2 - <6 years), juvenile (6 - <15 years), and adult/adolescent (≥ years).
Results:
Subgroup analysis was supportive of the primary endpoint findings in IB1001-301. Across all phenotypes, patients treated with levacetylleucine demonstrated improvements in the SARA compared to placebo: mean difference of -1.94 for early infantile onset patients, -1.61 for late infantile onset patients, -1.48 for juvenile onset patients, and -0.62 for adolescent/adult-onset patients. Levacetylleucine-treated patients also demonstrated consistent functional improvements over placebo across all phenotypes for all secondary outcome measures, supportive of the primary findings. The frequency of adverse events was comparable between subgroups while on levacetylleucine and placebo, and no treatment-related serious adverse events occurred.
Conclusion:
Levacetylleucine demonstrated improvement in neurological manifestations and status over placebo in all phenotypes of NPC (early infantile, late infantile, juvenile, and adolescent/adult-onset) irrespective of the age of onset of neurological manifestations. The clinically meaningful improvement in symptoms was consistent with investigator and caregiver-reported outcome measures regarding functioning and quality of life. Levacetylleucine was safe and well-tolerated, providing a favorable benefit-risk profile for the treatment patients with NPC.
This study aimed to evaluate the efficacy of N-acetyl-L-leucine (levacetylleucine) compared to placebo in Niemann-Pick disease type C (NPC) patient subgroups based on the age of onset of neurological manifestations on the following assessments: the Scale for the Assessment and Rating of Ataxia (SARA), modified Disability Rating Scale (mDRS), Spinocerebellar Ataxia Functional Index (SCAFI), and Clinical Global impression of Improvement Scales (CGI-I).
Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disorder where the age at onset of neurological manifestations significantly correlates to the disease progression and prognosis. In general, patients with neurological onset early in life (early or late infantile stage) have more severe, rapidly progressive forms of the disease than juveniles or adolescents/adults. The IB1001-301 clinical trial was a Phase III, double-blind, randomized, placebo-controlled, crossover trial comparing levacetylleucine with placebo for the treatment of neurological signs and symptoms in NPC after 12 weeks. 60 NPC patients aged 5 to 67 years with a genetically confirmed diagnosis of NPC were enrolled, including patients with early and late infantile, juvenile and adolescent/adult-onset disease forms. The primary SARA endpoint was reduced -1.97 points with levacetylleucine and -0.60 for placebo (p<0.001). Patients treated with levacetylleucine also demonstrated statistically significant improvements in the secondary outcomes compared to placebo.
Methods:
Subgroup analysis was conducted to evaluate the effects of levacetylleucine on the 4 phenotypes of NPC, defined based on the age of neurological manifestation onset.; early infantile (onset <2 years), late infantile (2 - <6 years), juvenile (6 - <15 years), and adult/adolescent (≥ years).
Results:
Subgroup analysis was supportive of the primary endpoint findings in IB1001-301. Across all phenotypes, patients treated with levacetylleucine demonstrated improvements in the SARA compared to placebo: mean difference of -1.94 for early infantile onset patients, -1.61 for late infantile onset patients, -1.48 for juvenile onset patients, and -0.62 for adolescent/adult-onset patients. Levacetylleucine-treated patients also demonstrated consistent functional improvements over placebo across all phenotypes for all secondary outcome measures, supportive of the primary findings. The frequency of adverse events was comparable between subgroups while on levacetylleucine and placebo, and no treatment-related serious adverse events occurred.
Conclusion:
Levacetylleucine demonstrated improvement in neurological manifestations and status over placebo in all phenotypes of NPC (early infantile, late infantile, juvenile, and adolescent/adult-onset) irrespective of the age of onset of neurological manifestations. The clinically meaningful improvement in symptoms was consistent with investigator and caregiver-reported outcome measures regarding functioning and quality of life. Levacetylleucine was safe and well-tolerated, providing a favorable benefit-risk profile for the treatment patients with NPC.