BBP‑418

BBP‑418 is an investigational, oral therapy that was designed to supply supraphysiological levels of the substrate used by fukutin‑related protein (FKRP) during glycosylation of alpha‑dystroglycan (αDG). If approved, BBP‑418 has the potential to be the first disease‑modifying oral therapy available for people with limb‑girdle muscular dystrophy type 2I/R9 (LGMD2I/R9).

Group family photo of six people, one of whom is seated in a wheelchair and diagnosed with LGMD2I/R9, all smiling and standing closely together

glycosylation substrate pro‑drug for LGMD2I/R9

The therapeutic hypothesis behind BBP‑418 is that supplying supraphysiological levels of substrate to FKRP can harness the residual activity of the enzyme to glycosylate alpha‑dystroglycan (αDG). Although FKRP does not function at full capacity in people with limb‑girdle muscular dystrophy type 2I/R9 (LGMD2I/R9), some of the enzyme’s function is retained. Harnessing this residual function may help stabilize muscle cells during contraction, with the goal of slowing or stopping further muscle damage.¹

Proposed mechanism of action of BBP‑418 in LGMD2I/R9 muscle tissue

The image shows the process of orally administered BBP-418 (synthesized, pharmaceutical-grade ribitol) contributing to the glycosylation of αDG through the interaction with ISPD and mutant FKRP enzymes. The diagram highlights how the potential partial restoration of αDG glycosylation could help stabilize the muscle cell membrane and restore its ability to repair damage. On the right side, a sequence demonstrates how muscle lengthening contraction leads to a small membrane tear, which is then stabilized and repaired due to the action of BBP-418, restoring muscle membrane integrity.

αDG, alpha‑dystroglycan; CDP, cytidine diphosphate; CTP, cytidine triphosphate; FKRP, fukutin‑related protein; ISPD, isoprenoid synthase domain‑containing protein; LGMD2I/R9, limb‑girdle muscular dystrophy type 2I/R9; P, phosphate; R, ribitol.

The results of BBP‑418 Phase 1 and Phase 2 studies supported the initiation of the FORTIFY Phase 3 registrational study in LGMD2I/R9. BBP‑418 has received rare pediatric disease designation, fast track designation, and orphan drug designation for the treatment of LGMD2I/R9 from the United States Food and Drug Administration and orphan drug designation for LGMD from the European Medicines Agency.

clinical program

FORTIFY (NCT05775848) is a global, randomized, double‑blind, placebo‑controlled Phase 3 registrational study evaluating the safety and efficacy of BBP‑418 in people with LGMD2I/R9. The trial is active in the US, Europe, and Australia. More information about the trial can be found on ClinicalTrials.gov.

References

Cataldi MP, Lu P, Blaeser A, Lu QL. Ribitol restores functionally glycosylated α‑dystroglycan and improves muscle function in dystrophic FKRP‑mutant mice. Nat Commun 2018;9(1):3448.