BridgeBio aces phase 3 rare disease test, clearing path to FDA

BridgeBio has vaulted over the success bar it set for a phase 3 rare disease trial, linking the candidate to significant improvements on biomarker and clinical outcomes to tee up a filing for FDA approval.

The study randomized people with limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9) to receive BBP-418 or placebo. BBP-418 is designed to provide enough of a substrate to counteract problems with the enzyme at the heart of LGMD2I/R9, thereby slowing or stopping muscle damage.

BridgeBio’s trial met all primary and secondary interim analysis endpoints. After three months, the primary endpoint tracked a 1.8-fold increase in glycosylated alpha-dystroglycan (αDG). The molecule, which stabilizes muscle cells, isn’t fully glycosylated in patients with LGMD2I/R9. BridgeBio said highly statistically significant increases in glycosylated αDG were sustained at 12 months.

The result exceeded expectations set by BridgeBio at an investor event in July. Back then, the company named a 5% increase as its base case expectation and a 1.5-fold change as its upside target.

Douglas Sproule, M.D., chief medical officer at BridgeBio’s ML Bio Solutions, said at the July event that the FDA viewed αDG as a surrogate biomarker that could serve as a basis of an accelerated approval proposal. At that time, BridgeBio was planning to seek approval on the basis of significant improvements on biomarkers and positive trends on clinical outcomes. 

The biotech’s phase 3 delivered the hoped-for second biomarker hit, reporting an 82% decline in serum creatine kinase after 12 months. BridgeBio’s base case and upside targets for the muscle damage marker were 40% and 50%, respectively.

The better-than-expected biomarker data translated into improvements in clinical outcomes. In July, ML Bio CEO Christine Siu told investors that the study wasn’t powered to show clinical efficacy after 12 months, adding that statistical significance wasn’t a requirement for accelerated approval. BridgeBio’s goal was to see trends favoring BBP-418 on at least one outcome by the interim analysis.

At 12 months, the biotech reported statistically significant improvements in ambulatory and pulmonary function. Patients completed the 100-meter timed test faster and performed better on a measure of lung function after taking BBP-418 for 12 months.

Evercore ISI analysts said in a note to investors that the results are the "blowout best-case outcome." The results easily beat the analysts' expectations, giving the Evercore ISI team more confidence that BridgeBio is poised to become a multi-product biotech "with each asset representing a blockbuster opportunity." 

BridgeBio’s top-line release lacks safety and tolerability data, only saying that the drug candidate was well tolerated with no new or unexpected safety findings observed. Gastrointestinal adverse events were common in a phase 2 trial of BBP-418. A planned presentation of data could provide clarity on the frequency and persistence of the adverse events in the phase 3 trial. 

The biotech plans to meet with the FDA to discuss the data later this year with a view to filing for approval in the first half of next year. Approval could give BridgeBio a product to supplement growth of its cardiomyopathy drug Attruby. 

In February, BMO Capital Markets analysts forecast peak risk-unadjusted sales of $1.7 billion for BBP-418 and another BridgeBio candidate, encaleret. More recently, the analysts predicted investors’ focus on Attruby would limit the impact of BBP-418 data on BridgeBio’s stock to a 5% to 10% swing.