Prothena’s Alzheimer’s Trial Hit by High ARIA-E Rates, Resulting in ‘Non-Competitive’ Profile

Prothena's phase 1 ASCENT trial for its anti-amyloid beta antibody PRX012 in early symptomatic Alzheimer's patients showed significantly higher rates of amyloid-related imaging abnormality-edema (ARIA-E)—brain swelling—than those reported for FDA-approved drugs in the same class1345.

At the two highest doses tested (200 mg and 400 mg), ARIA-E rates ranged from 38.1% to 41.7%, compared to 13% for Eisai/Biogen's Leqembi and 3-6% for Lilly's Kisunla135.

PRX012 achieved a mean amyloid PET reduction to 27.47 centiloids at 400 mg, approaching FDA benchmarks for amyloid clearance, but the elevated ARIA-E rates offset this efficacy benefit34.

The safety profile—specifically the high ARIA-E rates—led Prothena to describe the risk-benefit profile as 'non-competitive' versus current standards, making PRX012 less suitable for the early Alzheimer's population studied1345.

Prothena announced it will seek partnership opportunities to continue developing PRX012 and is shifting focus to a preclinical Aβ-transferrin receptor antibody (PRX123), which may offer lower ARIA risk and be better suited for future development45.

Subcutaneous delivery remains a potential convenience advantage for PRX012, but its safety concerns outweigh this benefit in its current studied population134.

Sources:

1. https://www.fiercebiotech.com/biotech/prothenas-alzheimers-trial-hit-aria-showstopper-resulting-non-competitive-profile

3. https://www.benzinga.com/news/health-care/25/08/47395005/prothena-reports-non-competitive-brain-swelling-rates-in-early-alzheimers-study

4. https://www.biospace.com/press-releases/prothena-provides-update-on-prx012-and-announces-results-from-the-phase-1-ascent-clinical-program

5. https://www.biospace.com/drug-development/prothenas-alzheimers-drug-comes-with-familiar-side-effect-in-phase-i-test