BridgeBio Pharma Reports Positive Phase 2 Data for Limb-girdle Muscular Dystrophy Type 2i

BridgeBio Pharma and its affiliate company ML Bio Solutions reported positive data from the phase 2 study of BBP-418 in patients with limb-girdle muscular dystrophy type 2i indicating the potential of BBP-418 to increase glycosylation of αDG and drive functional improvements for patients, as well as reduce creatine kinase, a key marker of muscle breakdown.

Photo: Douglas Sproule, chief medical officer of ML Bio Solutions

The 90- and 180-day data from the phase 2 study also show improvements on walk tests from baseline, which the company believes suggests a potential impact on clinical function and on the rate of disease progression.

BridgeBio is presenting the results at this week’s Muscular Dystrophy Association Annual Meeting in Nashville.

Limb-girdle muscular dystrophy type 2i (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 α-DG, 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 progressive 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. Currently, there are no approved therapeutics to treat the approximately 7,000 LGMD2i patients in the United States and European Union with potentially treatable mutations.

BBP-418 is designed to allow the muscle cell to properly glycosylate αDG, allowing αDG to function normally and potentially resulting in improved muscle strength and function for patients. If the development program is successful, BridgeBio believes BBP-418 could be the first approved therapy for the treatment of patients with LGMD2i.

“To date, people with LGMD2i have no approved disease-modifying treatment options. Many of these patients see their quality of life deteriorate rapidly and lose their functional independence, including their ability to walk,” said Douglas Sproule, chief medical officer of ML Bio Solutions. “Our preliminary trial data holds promise for this unmet patient need as our investigational therapy is shown to be generally well-tolerated and to improve several key markers associated with a patient’s decline.”

The phase 2 trial enrolled 14 participants, including both ambulatory and non-ambulatory patients with LGMD2i. The open-label study is designed to explore the safety and tolerability, feasibility, and usefulness of selected clinical efficacy and pharmacodynamic (PD) assessment of patients with LGMD2i receiving ascending doses of BBP-418 across three cohorts. Based on the data observed after 90 and 180 days of treatment, BridgeBio observed that participants showed an average 0.21 or 43 percent increase in the ratio of glycosylated αDG to total αDG, signifying that the oral therapy has the potential to address both the root cause of LGMD2i and drive functional improvements for patients.

Participants also showed an average of 70 percent reduction in creatine kinase (CK), a key marker of muscle breakdown, after 90 days of treatment and an average 77 percent reduction after 180 days for cohorts 1 and 2. Eleven of 12 participants received at least 50 percent reduction in CK with 75 percent of participants reaching 2x the normal range, suggesting a reduction in muscle breakdown.

All cohorts demonstrated a 3 percent increase in velocity in the 10-meter walk test (10MWT) at day 90 and 180, which is an improvement over the decline in velocity seen in the natural history data where the same patients demonstrated a decline in the 10MWT in the 6-months prior to enrollment in the phase 2 study.

BBP-418 was well-tolerated across a wide range of dose levels with no treatment-related serious adverse events, dose limiting toxicities or discontinuations observed.

BridgeBio plans to engage with regulatory health bodies in 2022 to discuss potential paths to approval and intends to initiate a phase 3 clinical trial in the second half of the year. At MDA 2022, BridgeBio is also presenting phase 1 trial data of BBP-418 in healthy volunteers to support its LGMD2i program. The phase 1 study demonstrated broad tolerability across a wide range of dosing, including doses beyond expected therapeutic range. No dose limiting toxicity was observed.

Author: Rare Daily Staff