Prothena Receives FDA Fast Track Designation for NEOD001, a Monoclonal Antibody for the Treatment of Patients With AL Amyloidosis
Dec 15 14
Prothena Corporation plc announced that the U.S. Food and Drug Administration granted Fast Track designation to NEOD001, a novel monoclonal antibody for the potential treatment of AL amyloidosis. This is the first investigational immunotherapy specifically targeting the disease-causing protein in AL amyloidosis to receive Fast Track designation. The FDA's Fast Track Drug Development Program is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. An unmet medical need is a condition whose treatment or diagnosis is not addressed adequately by available therapy. The purpose of the Fast Track designation is to make important new drugs available to patients earlier. The Fast Track program also provides a company with the ability to submit sections of the Biologics License Applications (BLA) for review before the company submits the complete BLA. This enables the FDA to review sections of the BLA as they are received, rather than waiting until every section of the application is completed, and also allows for Priority Review, shortening the standard review of the final BLA to six months. A drug program with Fast Track designation permits the company to have early and frequent communications with the FDA in the development and review of the product candidate, potentially to faster drug approval.
Prothena Corporation plc Initiates NEOD001 Global Phase 3 Registrational Trial Based on Positive Results in Ongoing Phase 1/2 Study of NEOD001 in Patients with AL Amyloidosis
Dec 2 14
Prothena Corporation plc announced the initiation of the VITAL Amyloidosis study, an international, multi-center, registrational Phase 3 clinical trial, based on positive results from an ongoing Phase 1/2 clinical study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction. Cardiac and renal biomarker responses in phase 1/2 study: Seven of 14 cardiac-evaluable patients (50.0%) treated with NEOD001 demonstrated a cardiac response, defined as more than 30.0% and 300 pg/mL decrease in levels of NT-proBNP (a validated cardiac biomarker associated with mortality). Cardiac responders, on average, showed more NT-proBNP decline with added monthly NEOD001 infusions. The 50.0% cardiac response rate compares favorably with the expected results of a 26.5% cardiac response rate from historical data in patients treated solely with off-label standard of care (Comenzo, et al., Leukemia. 2012;26:2317-2325). As noted in numerous peer-reviewed publications, increasing levels of NT-proBNP predicts higher mortality rates in patients with AL amyloidosis. Conversely, decreasing levels of NT-proBNP predicts lower mortality rates. In a best response analysis of renal-evaluable patients treated with NEOD001, six of 14 renal-evaluable patients (42.9%) demonstrated a response, defined as a 30.0% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The 42.9% renal response rate compares favorably with the expected results of an approximately 24% renal response rate from historical data in patients treated solely with off-label standard of care (Palladini, et al., Blood. 2014 124: 2325-2332). Increased levels of proteinuria and decreased eGFR predicts faster progression to dialysis where decreased levels of proteinuria and increased eGFR predicts delayed time to dialysis. Mechanism of Action: The clinical results demonstrated to date expand on more than a decade of amyloid research. NEOD001 elicits a rapid response initially, and a deepening response with additional monthly infusions. The results are consistent with the mechanism of action showing that NEOD001 functions in two ways: neutralization of circulating soluble amyloid and clearance of deposited insoluble amyloid within affected organs. The Phase 1/2 data supports that NEOD001 acts as a disease-modifying agent in AL amyloidosis which is distinct from current off-label standard of care therapies that attempt to solely reduce production of immunoglobulin light chain and are associated with adverse events. Safety, Tolerability, Pharmacokinetics and Immunogenicity: Data from the Phase 1/2 study continued to demonstrate that chronic monthly infusions of NEOD001 are safe and well-tolerated in patients with AL amyloidosis and persistent organ dysfunction. A database analysis as of September 30, 2014 showed a total of 27 patients in seven dosing cohorts received 209 infusions, with each patient treated on average for approximately eight months. No hypersensitivity reactions or drug-related serious adverse events were reported and no anti-NEOD001 antibodies were detected. NEOD001 demonstrated excellent pharmacokinetic properties, supporting a dose level of 24 mg/kg on a 28 day cycle. The most frequently reported adverse events (more than 10% of subjects) were fatigue, cough, dyspnea, diarrhea, upper respiratory infection, anemia, headache, hyponatremia, nausea and edema. All adverse events were mild to moderate and no dose limiting toxicities have been observed. As of September 30, 2014, 19 patients continue on therapy (eight patients discontinued). No patient discontinued due to drug-related adverse events. Following selection of 24 mg/kg as the Phase 3 recommended dose, in consultation with their treating physician, 13 out of 14 eligible patients continuing in the dose escalation portion of the Phase 1/2 study have chosen to escalate to 24 mg/kg. Expansion Portion of Phase 1/2 Study: Prothena is now enrolling up to an additional 25 patients, with AL amyloidosis and selected persistent organ dysfunction, in an open-label expansion portion of the Phase 1/2 study. The company plans to enroll 10 patients with cardiac dysfunction, 10 patients with renal dysfunction and five patients with peripheral neuropathy, all of whom will receive 24 mg/kg intravenously every 28 days. The expansion phase will continue to evaluate safety, tolerability, pharmacokinetics and immunogenicity of NEOD001 as well as the specific clinical activity against cardiac, renal and neuropathy biomarkers. The company expects to present results from the NEOD001 expansion portion of the Phase 1/2 study at least once annually at appropriate medical conferences, beginning in 2015. VITAL Phase 3 Registrational Trial Design: The multi-center, randomized, double-blind, placebo-controlled Phase 3 study continues Prothena's commitment to provide disease-modifying therapeutic alternatives for patients suffering from AL amyloidosis. The trial is designed to support global regulatory approvals and to enroll approximately 230 newly-diagnosed, treatment-na ve patients with cardiac dysfunction. Patients will be randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 or placebo via infusion every 28 days, with both arms receiving concurrent standard of care therapy. The composite primary endpoint is event-based, with all-cause mortality or cardiac hospitalizations as qualifying events. Secondary endpoints of the study include evaluation of the cardiac biomarker NT-proBNP, renal biomarker proteinuria, six-minute walk test, and multiple quality of life evaluations including SF-36 and the Kansas City Cardiomyopathy Questionnaire. Prothena designed the study with 90% power to detect as little as 30% change in the event rate between the treatment and placebo groups with a two-sided alpha of 0.05. The trial allows for an interim analysis to assess the primary endpoint for efficacy and futility.