Benzinga | Feb 1, 2021 04:16PM EST

Prothena Reports Confirmatory Phase 3 AFFIRM-AL Study Of Birtamimab For AL Myloidosis: 'Significant survival benefit observed in VITAL study for birtamimab-treated patients with AL amyloidosis at high risk for early mortality'

Prothena Corporation plc (NASDAQ:PRTA) today announced that following further analyses by the Company and multiple in-depth discussions with the U.S. Food and Drug Administration (FDA) regarding the previous analysis of patients categorized as Mayo Stage IV at baseline in the VITAL study, Prothena is advancing birtamimab into the confirmatory Phase 3 AFFIRM-AL study in this category of patients with AL amyloidosis. This registration-enabling study will be conducted with a primary endpoint of all-cause mortality at p<0.10 under a Special Protocol Assessment (SPA) agreement with FDA. Birtamimab is the only investigational therapeutic that has shown a significant survival benefit in Mayo Stage IV patients with AL amyloidosis in a placebo-controlled study, with 74% of birtamimab-treated patients alive at 9 months versus 49% of patients in the control group in VITAL (hazard ratio (HR)=0.413, p=0.025, over 9 months). AFFIRM-AL is expected to initiate mid-2021.

The significant survival benefit observed in VITAL with birtamimab was further supported by evidence of clinical benefit on secondary endpoints, including significant changes observed on both the Short Form-36 version 2 Physical Component Score (SF-36v2 PCS), a measure of quality of life (p=0.026), and 6 Minute Walk Test (6MWT) distance, an assessment of functional capacity (p=0.046).

"Our analysis of the previously disclosed VITAL results revealed a greater than 50% relative risk reduction for all-cause mortality in Mayo Stage IV patients treated with birtamimab," said Gene Kinney, Ph.D., President and Chief Executive Officer of Prothena. "We have extensively reviewed these results during a series of formal and informal interactions with the FDA and are appreciative of the close collaboration that led to this unprecedented SPA agreement for the AFFIRM-AL study. Birtamimab becomes our most advanced late-stage program and now has a defined path forward in this orphan patient population."

Early Mortality in AL Amyloidosis Remains an Urgent Unmet Medical Need

* Recent clinical results for plasma-cell directed therapeutic approaches for AL amyloidosis that target CD38 have demonstrated that daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (DARA-CyBorD) resulted in significantly higher complete hematologic (CR) and organ response rates (best response of hematologic CR: 53% DARA-CyBorD versus 18% CyBorD p<0.0001 and cardiac response rate at 6 months: 42% DARA-CyBorD versus 22% CyBorD p=0.0029).1

* Despite these significant hematologic and organ response rates, results reported to date from the ANDROMEDA study have not demonstrated a survival benefit: ? In the first 6 months: 25 deaths with DARA-CyBorD versus 20 deaths with CyBorD. More than 90% of these deaths were related to underlying AL amyloidosis across both arms.1 ? In the 11.4-month median follow-up period: 27 deaths with DARA-CyBorD versus 29 deaths with CyBorD.2

* An urgent need remains for treatments that improve survival in patients with AL amyloidosis who are at high risk for early mortality.

Confirmatory Phase 3 AFFIRM-AL Study Design

* To be conducted under an SPA agreement with FDA and supported by the significant survival benefit observed in the previous analysis of birtamimab-treated patients categorized as Mayo Stage IV at baseline in the VITAL study (HR=0.413, p=0.025, over 9 months).

* Global, multi-center, double-blind, placebo-controlled, 2:1 randomized, time-to-event study expected to enroll approximately 150 newly diagnosed, treatment na?ve patients with AL amyloidosis categorized as Mayo Stage IV.

* Designed to evaluate the primary endpoint of all-cause mortality with a significance level of p<0.10.

* Includes an interim analysis to be conducted when approximately 50% of the events have occurred, allowing the independent data monitoring committee to recommend either continuing the study or stopping early for overwhelming efficacy.

* Patients will receive 24 mg/kg of birtamimab or placebo by intravenous infusion every 28 days, with all patients receiving concurrent standard of care therapy consisting of a first line bortezomib-containing regimen.

"Birtamimab has a substantial clinical dataset informing its potential as an important therapeutic for patients with AL amyloidosis," stated Isabelle Lousada, Founder and Chief Executive Officer of the Amyloidosis Research Consortium. "The burden of AL amyloidosis on patients and their families remains enormous and I am pleased to see this amyloid-targeting approach advancing into a registration-enabling clinical trial designed to assess patient-relevant endpoints in a subset of patients with an urgent unmet medical need."

Kinney concluded, "We look forward to initiating the AFFIRM-AL study in mid-2021 as one of many milestones ahead. Our team delivered key clinical results across multiple programs in 2020 that further establish Prothena as a leader in addressing diseases caused by protein dysregulation. We look forward to continued execution on multiple milestones in 2021 and beyond to drive sustainable growth. With three late-stage clinical programs including the pivotal AFFIRM-AL study, an internal R&D engine expected to deliver multiple INDs, and significant potential partner payments that add to our strong cash position, we are well positioned to transition to a fully-integrated commercial biotechnology company."

Fast Track and Orphan Drug Designation

* Birtamimab has been granted Fast Track Designation by the FDA for the treatment of Mayo Stage IV patients with AL amyloidosis to reduce the risk of mortality and has been granted Orphan Drug Designation by both the FDA and European Medicines Agency (EMA).