BridgeBio Pharma separately reported positive 12-month data from its phase 2 study of its experimental therapy for patients with limb-girdle muscular dystrophy type 2i and positive updated results from its phase 1/2 experimental gene therapy for Canavan disease.
The company said its affiliate company ML Bio Solutions reported updated 12-month data from the phase 2 study of BBP-418 in patients with limb-girdle muscular dystrophy type 2i (LGMD2i) that continue to support the potential for BBP-418 to reduce muscle damage and preserve motor function for patients over time. The study demonstrated the sustained increase in the ratio of glycosylated-αDG over total αDG, reduction in creatine kinase, improvements in NSAD scores, and improvements in 10MWT velocity observed over a 12-month period.
These updated results were presented in an oral presentation at the 27th International Hybrid Annual Congress of the World Muscle Society in Halifax, Canada.
LGMD2i is a monogenic autosomal recessive disease caused by partial loss of function mutations in the FKRP gene, and these FKRP mutations impair glycosylation of αDG, a protein associated with stabilizing muscle cells. Clinical manifestations typically present as a skeletal myopathy affecting the lower and then upper limbs, which is commonly later accompanied by respiratory muscle and cardiac muscle involvement. Patients who harbor a homozygous genotype typically develop disease manifestations during late childhood with progression to loss of independent ambulation (25 percent), assisted ventilation (5 percent), and cardiomyopathy (10 percent) in adulthood. Patients with heterozygous genotypes have an earlier childhood onset with a more severe clinical course, rapid loss of mobility by 20 years of age, more frequent cardiac involvement (25 percent), and eventual respiratory failure by 30 years of age in nearly all cases.
“LGMD2i dramatically impacts individuals living with the disease, fundamentally robbing people of their independence. As the disease progresses, individuals with LGMD2i lose the ability to function unaided, eventually becoming wheelchair-dependent and requiring ventilation assistance, the timing of which is dependent on the severity of their disease,” said Douglas Sproule, chief medical officer of ML Bio Solutions. “Our phase 2 data show our investigational therapy continues to be well-tolerated and may have the potential to improve or slow clinical decline associated with the disease.”
No treatment-related SAEs or dose limiting toxicities with 12 months of treatment with BBP-418 were reported.
BridgeBio and ML Bio Solutions continue to engage with regulatory agencies and intend to initiate a phase 3 clinical trial in 2023.
Separately, BridgeBio reported promising pharmacodynamic, tolerability, and preliminary functional efficacy data from the first three participants dosed in CANaspire, its phase 1/2 clinical trial of BBP-812, an experimental intravenous, adeno-associated virus serotype 9 gene therapy for the treatment of the ultra-rare and fatal condition Canavan disease.
New data from the third CANaspire participant are consistent with the first two treated children, at three months post treatment, the third participant showed an 89 percent reduction of NAA in cerebrospinal fluid (CSF) and a 45 percent reduction in urine NAA.
In addition, Participant 2 showed a continued decline in urine NAA at Month 6 with an 85 percent decrease compared to pre-treatment.
The company said the consistent reductions in CSF and brain NAA observed to date continue to support the ability of BBP-812 to reach the central nervous system and express active aspartoacylase (ASPA) enzyme.
Most children with Canavan disease are not able to meet developmental milestones, are unable to crawl, walk, sit, or talk, and die at a young age. The disease is caused by an inherited mutation of the ASPA gene that codes for aspartoacylase, a protein that breaks down a compound called N-acetylaspartate (NAA). Deficiency of aspartoacylase activity results in accumulation of NAA, and ultimately results in toxicity to myelin in ways that are not currently well understood. Myelin insulates neuronal axons, and without it, neurons are unable to send and receive messages as they should. The current standard of care for Canavan disease is limited to supportive therapy.
BBP-812 is an investigational AAV9 gene therapy for Canavan disease. Using AAV gene therapy, BridgeBio seeks to deliver functional copies of the ASPA gene throughout the body and into the brain, potentially correcting the disease at its source. Preclinical proof-of-concept results have shown the approach restores survival and normal motor function in Canavan disease models. BBP-812 was granted Fast Track, Rare Pediatric Drug, and Orphan Drug designations by the U.S. Food and Drug Administration. BBP-812 was also granted Orphan Drug Designation by the European Medicines Agency.
“The most critical biomarker, in my mind, is NAA. Reduction in NAA levels, whether in the brain, CSF fluids, or in the urine, may indicate a sign of improvement because the gene missing in Canavan disease directly leads to accumulation of NAA. So, showing that NAA is decreasing is very important,” said Guangping Gao, scientific founder of Aspa Therapeutics, the BridgeBio gene therapy affiliate company developing the gene therapy for Canavan disease.
Photo: Guangping Gao, scientific founder of Aspa Therapeutics
Author: Rare Daily Staff
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