Birtamimab Misses Primary Phase 3 Endpoint for AL Amyloidosis

Birtamimab missed the primary endpoint in the Phase 3 AFFIRM-AL clinical trial for the treatment of AL amyloidosis, resulting in the discontinuation of development and the halt of the open-label extension.1

Announced by Prothena Corporation on May 23, 2025, the company plans to cut operating costs and significantly shrink its workforce, with further details on the matter expected in June.

“This is not the outcome that we expected, and we are surprised and disappointed by these results for patients, their families and caregivers, and for the entire AL amyloidosis community,” said Gene Kinney, PhD, president and chief executive officer of Prothena. “With these results, we believe that the most appropriate action is to discontinue all development of birtamimab.”

An investigational, humanized monoclonal antibody, birtamimab was designed by Prothena to selectively target and clear the amyloid leading to organ dysfunction and failure in individuals with AL amyloidosis. Both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) granted Orphan Drug designation to birtamimab, with the FDA granting further Fast Track Designation.2

The company and the FDA agreed to a Special Protocol Assessment for the AFFIRM-AL clinical trial, confirming the design and planned analysis for the primary endpoint would adequately address the targets required for regulatory submission. The primary endpoint in the Phase 3 AFFIRM-AL clinical trial was the time to all-cause mortality, followed by secondary endpoints consisting of the 6-minute walk test distance and Short Form-36 version 2 Physical Component Score.1

The global, double-blind, placebo-controlled, time-to-event clinical trial enrolled 207 newly diagnosed, treatment-naive patients with Mayo Stage IV AL amyloidosis. Birtamimab was provided to the active arm every 28 days at a dose of 24 mg/kg (maximum dose ≤2500 mg). Patients in both the active and control arms received a bortezomib-containing chemotherapy regimen as standard of care, with allowance of use of daratumumab.

Upon analysis, birtamimab treatment in patients with AL amyloidosis missed the primary endpoint of time to all-cause mortality (hazard ratio [HR], 0.915; P-value = .7680). Neither the 6-minute walk test distance (nominal P-value = .5288) nor the Short Form-36 version 2 Physical Component Score (nominal P-value = .9597) endpoints were met in birtamimab-treated patients.1

Prothena said birtamimab was generally safe and well-tolerated, consistent with its known profile. The company will share next steps after reviewing its options, and plans to release data readouts from its pipeline over the next 18 months.1

“We look forward to initial data from the Phase 1 ASCENT clinical trials on PRX012 in Alzheimer’s disease expected in August, and program updates from our partners at Roche expected mid-year, Novo Nordisk expected in 2H25, and Bristol Myers Squibb expected in 2026,” said Daniel G. Welch, chair of the board of directors of Prothena.1 “The Company and board have begun the work to thoughtfully and expeditiously decrease spend, including but not limited to an expected substantial workforce reduction, and evaluate with its financial advisors business options in the best interest of its shareholders.”

References

1. Prothena announces phase 3 affirm-al clinical trial for Birtamimab in patients with Al Amyloidosis did not meet primary endpoint. Global Press Release & Newswire Distribution Services. May 23, 2025. Accessed May 27, 2025. https://www.businesswire.com/news/home/20250523499173/en/Prothena-Announces-Phase-3-AFFIRM-AL-Clinical-Trial-for-Birtamimab-in-Patients-with-AL-Amyloidosis-Did-Not-Meet-Primary-Endpoint.

2. Palladini G, Liedtke M, Zago W, Dolan P, Kinney GG, Gertz MA. The mechanism of action, pharmacological characteristics, and clinical utility of the amyloid depleter birtamimab for the potential treatment of AL amyloidosis. Leuk Lymphoma. 2024;65(8):1068-1078. doi:10.1080/10428194.2024.2337803