A phase 1 study has linked Prothena’s anti-amyloid beta antibody to a higher rate of brain swelling than rival approved drugs, hindering the biotech’s positioning in early symptomatic Alzheimer’s disease.
The study compared four doses of PRX012, a once-monthly, subcutaneous anti-amyloid beta antibody, against placebo in 228 participants with early symptomatic Alzheimer’s.
Like Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, PRX012 is designed to treat Alzheimer’s by removing amyloid-beta plaques. PRX012’s main advantage is it is given subcutaneously every month rather than intravenously every two to four weeks.
However, the phase 1 data revealed a disadvantage that could render any dosing benefits irrelevant. At the two top doses, 38.1% to 41.7% of patients had amyloid-related imaging abnormality-edema (ARIA-E), a swelling of the brain associated with anti-amyloid beta antibodies.
Eisai and Biogen previously reported (PDF) a 13% rate of ARIA-E in a study of Leqembi. In two Lilly studies, 3% and 6% of patients had (PDF) symptomatic ARIA-E.
PRX012 was associated with higher overall ARIA-E rates than FDA-approved antibodies, making the asset less appropriate for the study population, Prothena said in a release issued after the market closed Aug. 27. The company called the ARIA-E profile in early symptomatic Alzheimer’s “non-competitive.”
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Prothena said its preclinical amyloid beta transferrin receptor antibody surrogate PRX012-TfR may be associated with a significantly lower risk of ARIA. The company has performed initial preclinical studies on the candidate, linking the antibody to substantially increased brain exposure and rapid targeting of plaques in mice.
The question now is whether another company wants to take up the challenge of showing the asset can live up to its early promise. Prothena said early this month that it expected to take PRX012 forward through “non-dilutive and capital efficient structures.”
The biotech reiterated its plans as part of the Wednesday data drop, telling investors it will explore potential partnerships to advance PRX012 and PRX012-TfR.
Prothena outlined its plans for PRX012 in the aftermath of the phase 3 failure of its amyloidosis prospect birtamimab. The biotech responded to the setback by laying off two-thirds of its workforce in June.
