BBP-418 in Development to Treat LGMD Type 2I, with Natural History Study to Start Soon

José Lopes, PhD avatar

by José Lopes, PhD |

SRP-9001 gene therapy update

BBP-418, an oral treatment candidate for patients with limb-girdle muscular dystrophy type 2I (LGMD2I), is being developed by ML Bio Solutions, a new subsidiary of BridgeBio Pharma, the company has announced.

BridgeBio intends to start a natural history study by the end of this year to identify which endpoints (goals) and criteria best reflect meaningful clinical outcomes for LGMD2I patients. After completion of this study, the company plans to initiate the clinical program of BBP-418, pending authorization from the U.S. Food and Drug Administration. For information about the study and how to participate, contact Brittney Holmberg by email at [email protected] or call 804-552-0014.

BBP-418 “exemplifies the BridgeBio mission of creating life-altering medicines by pairing well-understood genetically- driven phenotypes with treatments whose mechanisms target the sources of disease,” Uma Sinha, PhD, chief scientific officer at BridgeBio, said in a news release.

“We are thrilled to partner with the foremost experts in the field to explore the translation of these important discoveries into clinical impact for patients who currently lack effective treatment options,” Sinha added.

LGMD2i is caused by mutations in both copies of the FKRP gene. These mutations prevent a natural process in which sugar molecules are added to alpha-dystroglycan protein in cell membranes to enable them to work as shock absorbers. As a result, alpha-dystroglycan is unable to anchor muscle cells to the structural matrix of tissues and protect muscles from mechanical damage and degeneration.

BBP-418, also known as ribitol, is a small molecule intended to bypass the metabolic defect in people with LGMD2I by providing a prodrug — a precursor molecule — that can be transformed inside the body into the missing piece in the sugar backbone of alpha-dystroglycan.

Results from a preclinical study in a mouse model of severe LGMD2I showed that BBP-418 can be absorbed by skeletal and cardiac muscles, which are most affected in this disease. The investigational compound could also raise the levels of both CDP-ribitol and ribitol-5-phosphate, which are two essential components that are missing in people with mutated FKRP.

These mice also showed restored sugar addition to alpha-dystroglycan in skeletal, cardiac, and diaphragm muscles, as well as improvements in respiratory function, physical activity, increased muscle mass, and less fibrosis (scarring).

Based on these results, the researchers anticipate that a 2-gram daily dose of BBP-418 may lead to a greater than six-fold increase in the target molecules, and a minimum 50% reduction in LGMD2I symptoms.

The potential therapy was initially developed by ML Bio Solutions’ scientific co-founder Qi Long Lu, MD, PhD, who is the director of the McColl Lockwood Laboratory for Muscular Dystrophy Research at Atrium Health. This leading healthcare organization will continue supporting the development of the BBP-418 program.

“By combining the scientific leadership of the McColl-Lockwood Laboratory with the rare disease development expertise at BridgeBio, we believe we can accelerate the path to making a safe and effective disease-modifying treatment available to LGMD2i patients as soon as possible,” Luther Lockwood, chairman of the board and president of ML Bio Solutions, said.