Phase 1 Study Reveals High Rates of Brain Swelling
A phase 1 study of Prothena’s Alzheimer’s candidate PRX012 has shown higher rates of brain swelling compared to approved therapies, raising challenges for the biotech’s development plans in early symptomatic Alzheimer’s disease.
The ASCENT Program and PRX012
The ASCENT program enrolled 228 participants with early symptomatic Alzheimer’s to test four doses of PRX012, a once-monthly, subcutaneous anti-amyloid beta antibody, against placebo. Like Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, PRX012 is designed to treat the disease by removing amyloid-beta plaques. Its dosing schedule offers potential convenience, with monthly subcutaneous injections rather than intravenous infusions every two to four weeks.
Key Safety Concerns
However, the trial revealed a key safety concern. At the two highest doses, between 38.1% and 41.7% of participants experienced amyloid-related imaging abnormality-edema (ARIA-E), a type of brain swelling linked to anti-amyloid therapies. In comparison, Leqembi was previously associated with a 13% ARIA-E rate, while two Lilly studies reported symptomatic ARIA-E rates of 3% and 6%.
Overall, ARIA rates in the PRX012 study ranged from 16% at the lowest dose to 42% at the highest, versus 7% in the placebo arm. ARIA-E accounted for the highest proportion, ranging from 12% to 42%.
Prothena’s Response and Future Strategy
Prothena acknowledged the data showed PRX012 had “a non-competitive ARIA-E profile.” In its release, the company said the treatment appeared “less appropriate” for early symptomatic Alzheimer’s patients compared to approved antibodies.
The company noted its preclinical amyloid beta transferrin receptor surrogate, PRX012-TfR, has demonstrated in animal studies the potential for higher brain exposure and rapid plaque targeting, while possibly carrying a lower ARIA risk. Prothena said, “Prothena believes this approach may represent an opportunity to significantly lower the risk of ARIA and quickly reduce amyloid plaque with a once-monthly subcutaneous administration.”
Despite the ASCENT results, Prothena reiterated plans to continue advancing PRX012 through “non-dilutive and capital-efficient structures,” and said it would seek partnerships to move both PRX012 and PRX012-TfR forward.
Company Setbacks and Pipeline
The phase 1 readout comes as Prothena continues to face setbacks in its neurodegenerative disease portfolio. In May, the company’s AL amyloidosis therapy birtamimab failed to improve all-cause mortality in a phase 3 trial, leading to its discontinuation. Following that failure, Prothena laid off 63% of its workforce in June as part of a restructuring aimed at focusing on its wholly owned programs.
PRX012 is one of Prothena’s two wholly owned programs, alongside preclinical candidate PRX123. The biotech’s broader pipeline includes collaborations with Bristol Myers Squibb on multiple neurodegenerative programs, with Roche on a Parkinson’s disease therapy, and with Novo Nordisk on an ATTR amyloidosis treatment, the latter two under preparation for phase 3 development by their partners.
