Canavan Disease (Passage Bio)

Dive Brief:BridgeBio Pharma plans to trim its spending on gene therapy research by more than $50 million after early-stage study results for one of its experimental therapies failed to meet the companys threshold for additional investment.Disclosed by BridgeBio Tuesday afternoon, the data showed treatment with the companys BBP-631 therapy led to increased production of a key hormone in people with a condition known as congential adrenal hyperplasia, or CAH. No treatment-related serious side effects were reported.BridgeBio claimed its study showed for the first time that people with CAH can make this hormone, called cortisol and necessary for the bodys response to stressors. But data to date are not yet transformational, said company CEO Neil Kumar, so BridgeBio intends to find a partner for BBP-631s development.Dive Insight:BridgeBio isnt getting out of gene therapy entirely. The company has another experimental treatment for a neuromuscular disease called Canavan.We believe that gene therapies have the potential to fulfill a significant unmet need and are eager to work closely with the FDA and the Canavan community with the goal of bringing our therapy to families living with Canavan disease as fast as possible, said Chief Financial Officer Brian Stephenson in Tuesdays statement.But BridgeBio is taking a step back from the field and, moving forward, will be reserving gene therapy for priority targets that we cannot treat any other way, Stephenson said.The effect is a further focusing of BridgeBios pipeline around a handful of later-stage assets, foremost among them acoramidis, a treatment for transthyretin amyloidosis with cardiomyopathy thats currently under regulatory review in the U.S. The company also has medicines in Phase 3 testing for a rare calcium disorder, a kind of muscular dystrophy and a bone growth disorder.The results for BBP-631 came from the latter half of a Phase 1/2 study that enrolled adults with classic CAH. The study found treatment led to increases in endogenous cortisol production in all patients given higher doses of the therapy. Investigators also reported substantial and durable increases in the product and substrate of the enzyme that makes cortisol. This, BridgeBio said, suggested its therapy had successfully delivered its genetic payload into the body.BBP-631 uses a benign form of an adeno-associated virus to shuttle a functional copy of the gene encoding that enzyme to the adrenal gland. By inducing the body to produce cortisol, BridgeBio hoped to eliminate or substantially reduce the steroid treatments that people with CAH currently use to manage their condition. '

After suffering a blow to its multi-billion dollar liver cancer program with Helsinn Healthcare and LianBio, BridgeBio presented very early but promising data in ultra-rare Canavan disease and updated data in muscular dystrophy. BridgeBio presented data from the first three treated patients in the CANaspire trial studying BBP-812, an intravenous, adeno-associated virus serotype 9 (AAV9) gene therapy. It uses the AAV to deliver functional copies of the ASPA gene throughout the patients’ bodies and brains with the intention of correcting the disease. Canavan disease, a progressive, fatal neurological disorder, is caused by a mutation of the ASPA gene that codes for aspartoacylase. There are currently no approved therapies for the disease. It typically begins in infancy and is the result of an inherited genetic abnormality causing the lack of an essential enzyme. This protein breaks down N-acetylaspartate (NAA). The lack of enzymatic activity results in NAA accumulation, which is toxic to myelin. At month three after dosing, Participant 3 demonstrated an 89% decrease in N-acetylaspartate (NAA) in the cerebrospinal fluid and a 45% decrease in urine NAA. Participant 2 demonstrated a continued drop in urine NAA at Month 6 and an 85% reduction compared to pre-treatment. In June, the company reported data on Participant 1, who had a 77% drop in CSF NAA and a 15% reduction in NAA in brain white matter (myelin) by magnetic resonance spectroscopy (MRS). MRS data isn’t yet available for Participant 2 or 3. “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,” stated Guangping Gao, Ph.D., scientific founder of Aspa Therapeutics, the BridgeBio gene therapy affiliate developing BBP-812. More Data to Support Therapeutic BridgeBio presented the data at the 2022 Child Neurology Society conference. It also presented a poster on the CANinform natural history study. This trial continues to enroll new patients around the world. CANinform is extracting disease-related and motor/developmental data from patient records. It uses two tools to document the presence or absence of Canavan disease key concepts of interest: the Canavan Disease Rating Scale (CDRS), which records signs, symptoms and developmental skills seen in children with the disease, and the CDC Developmental Milestone Checklist, which offers a checklist of expected developmental milestones. The goal of CANinform is “to support the CANaspire gene therapy clinical trial with a control group and clinical endpoint selection.” As of August 19, it had enrolled 48 participants from 16 countries. The company noted the study is “beginning to sharpen our understanding of the most informative and clinically meaningful endpoints for Canavan patients in the CANaspire gene therapy trial." More Positive Data in Muscular Dystrophy BridgeBio also presented 12-month data from a Phase II trial of BBP-418 in Limb-Girdle Muscular Dystrophy Type 2i (LGMD2i) at the 27th International Hybrid Annual Congress of the World Muscle Society. LGMD2i is a single-gene autosomal recessive illness caused by mutations in the FKRP gene, which cause impaired glylcosylation of alpha DG, a protein that helps stabilize muscle cells. The drug targets the molecular defect by supplying excess substrate to the mutated enzyme, which increases the glycosylation of alpha DG in the muscle. With its affiliate company ML Bio Solutions, BridgeBio’s data supports the potential of the therapy to restore glycosylation of alpha DG, while also decreasing damage to muscle and maintaining patients’ motor function. The companies are in talks with regulators with plans to launch a Phase III trial next year. In addition to the trial data, BridgeBio also presented a poster at WMS regarding a novel bioassay to determine the extent of alpha DG glycosylation relative to total alpha DG from muscle biopsies. “We believe this is the first time an increase in alpha DG has been demonstrated in LGMD2i patients as a result of therapy, and that these data are supportive of the therapeutic potential of BBP-418 to treat the disease at its source,” stated Uma Sinha, Ph.D., BridgeBio’s CSO.