Prothena Announces Confirmatory Phase 3 AFFIRM-AL Study of Birtamimab in Mayo Stage IV Patients with AL Amyloidosis under SPA Agreement with FDA
- Significant survival benefit observed in VITAL study for birtamimab-treated patients with AL amyloidosis at high risk for early mortality (Mayo Stage IV, HR=0.413, p=0.025, over 9 months)
- SPA agreement with FDA to enable registration of birtamimab at unprecedented p≤0.10 for primary endpoint of all-cause mortality in Mayo Stage IV patients with AL amyloidosis
- AFFIRM-AL study of birtamimab expected to initiate mid-2021
- Investor conference call and webcast scheduled
Feb. 2at 8:00am ET, Prothenamanagement will be joined by Morie Gertz, MD, MACP, Division of Hematology, Mayo Distinguished Clinician, Mayo Clinic
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
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 naïve 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
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
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).
Conference Call Details
To access the call via dial-in, please dial (877) 887-5215 (
Special Protocol Assessment
A Special Protocol Assessment (SPA) is a written agreement between a sponsor and the FDA that indicates concurrence between the parties regarding the adequacy and acceptability of specific design elements and planned analysis for a clinical trial intended to form the basis of a licensing application. An SPA does not indicate FDA concurrence on every detail in a particular trial protocol, and final marketing approval depends upon factors including the efficacy and safety results from the trial, the overall safety profile and an evaluation of the risk/benefit ratio for the product candidate as demonstrated across clinical trials.
Birtamimab is an investigational humanized immunoglobulin G1 designed to directly neutralize soluble toxic aggregates and promote clearance of amyloid via phagocytosis. Birtamimab’s depleter mechanism of action broadly targets misfolded kappa and lambda light chain to clear deposited amyloid that causes organ dysfunction and failure in patients with AL amyloidosis. Preclinical research has shown that birtamimab binds to both soluble and insoluble aggregated kappa and lambda immunoglobulin light chain by recognizing an epitope that is exposed at the earliest stages of abnormal light chain misfolding and through aggregation of deposited amyloid involved in AL amyloidosis. In clinical studies, birtamimab was generally safe and well tolerated, and has been evaluated in 302 patients receiving monthly intravenous infusions (including 294 patients who received the recommended 24 mg/kg dose), for an average of approximately 15 months.
Birtamimab was previously evaluated in the Phase 3 VITAL Study, a global multi-center, randomized, double-blind, placebo-controlled clinical study of newly diagnosed, treatment naïve patients with AL amyloidosis and cardiac involvement (N=260). Results from a post hoc analysis of the VITAL study revealed a significant survival benefit favoring birtamimab in a subset of patients categorized as Mayo Stage IV at baseline (n=77), with 74% of birtamimab-treated patients alive at 9 months versus 49% of patients in the control group (hazard ratio of 0.413 (95% CI: 0.191, 0.895; p=0.025, over 9 months). The randomization stratification factors in VITAL were Mayo Stage I-II vs III-IV, renal stage I vs II-III and 6MWD < 300 meters vs ≥ 300 meters.
Significant changes observed on secondary endpoints provided further evidence of clinical benefit in birtamimab-treated Mayo Stage IV patients in VITAL. For SF-36v2 PCS, an assessment of quality of life, the difference in mean change from baseline at 9 months between the birtamimab and control arms of the study was +5 points favoring the birtamimab arm (p=0.026). For 6MWT distance, an assessment of functional capacity, the difference in mean change from baseline at 9 months between the birtamimab and control arms was +27 meters favoring the birtamimab arm (p=0.046).
About AL Amyloidosis
AL amyloidosis is a rare, progressive, and fatal disease where immunoglobulin light chain proteins produced by clonal plasma cells misfold, aggregate, and deposit as amyloid in vital organs. These toxic aggregates and amyloid deposits cause progressive damage and failure of vital organs, including the heart. It is estimated that 200,000 to 400,000 patients globally suffer from this rare disease, with 60,000 to 120,000 patients being categorized as Mayo Stage IV. Patients categorized at diagnosis as Mayo Stage IV have poor outcomes with current standard-of-care that aims to reduce the production of new protein but do not directly target and clear the toxic amyloid that deposits in organs. There are no approved treatments for AL amyloidosis that have demonstrated a survival benefit and there remains an urgent unmet medical need for therapies that improve survival in patients at high risk for early mortality due to amyloid deposition. For more information on AL amyloidosis, please visit the websites of the Amyloidosis Support Groups,
This press release contains forward-looking statements. These statements relate to, among other things, the design, proposed mechanism of action and possible clinical benefits of birtamimab, and its potential as a treatment for Mayo Stage IV patients with AL amyloidosis; the design, expected enrollment and expected timing of the Phase 3 AFFIRM-AL study of birtamimab; the results from post hoc analyses that reveal a potential survival benefit of birtamimab in Mayo Stage IV patients; the continued advancement of our discovery, preclinical and clinical pipeline and the expected milestones in 2021 and beyond; and amounts we might receive under our collaborations with Roche and Bristol-Myers Squibb. These statements are based on estimates, projections and assumptions that may prove not to be accurate, and actual results could differ materially from those anticipated due to known and unknown risks, uncertainties and other factors, including but not limited to the effects on our business of the worldwide COVID-19 pandemic and the risks, uncertainties and other factors described in the “Risk Factors” sections of our Annual Report on Form 10-K filed with the
1Primary Results from the Phase 3 ANDROMEDA Study presented at the
2Full prescribing information for DARZALEX
Source: Prothena Corporation plc