SP051NEOD001 DEMONSTRATES RENAL BIOMARKER RESPONSES IN A PHASE 1/2 STUDY IN PATIENTS WITH IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS AND PERSISTENT RENAL DYSFUNCTION

Abstract

Introduction and Aims: In immunoglobulin light chain (AL) amyloidosis, the accumulation of misfolded light chain (LC) protein (amyloid) results in progressive organ dysfunction. Deposition in the kidney causes nephrotic syndrome and progressive renal failure in 60%-80% of patients, which is associated with morbidity and reduced quality of life. There is no approved treatment for patients with AL amyloidosis. Drugs for multiple myeloma are used off-label to reduce plasma cell LC production but do not directly target deposits underlying multiorgan failure. NEOD001, a novel monoclonal antibody that targets misfolded LC, is proposed to neutralize circulating toxic soluble intermediates and clear insoluble aggregates by inducing phagocytosis. Here we report interim results of a phase 1/2 dose-escalation/expansion study of NEOD001 (NCT01707264; EudraCT2012-002683-27). Method(s): Patients who completed >=1 anti-plasma cell systemic therapy (and did not require another) and had partial hematologic response or better, persistent organ dysfunction, and creatinine clearance >50 mL/min received intravenous NEOD001 every 28 days (q28d). Doses (0.5, 1, 2, 4, 8, 16, 24 mg/kg) were evaluated in a 3+3 study design. Primary objectives determined safety/tolerability and maximum tolerated dose/recommended dose for future studies (RDFS). Secondary/exploratory objectives included pharmacokinetics (PK), immunogenicity, and best organ response based on consensus criteria. Result(s): Among 27 patients (7 cohorts), no infusion/drug-related serious adverse events, discontinuations, dose-limiting toxicities, or antidrug antibodies were observed. Most frequently reported adverse events were fatigue (37.0%), upper respiratory tract infection (25.9%), and cough/dyspnea (18.5% each). The RDFS was 24 mg/kg. PK data supported IV dosing q28d. Of 15 renal-evaluable patients, 60% met criteria for renal response (>=30% reduction in 24-hour urine protein) and 40% had stable disease. Renal response appeared to be independent of the depth of hematologic best response to previous chemotherapy (33.3% partial response, 22.2% very good partial response, 44.4% complete response). Neither albuminuria nor estimated glomerular filtration rate progressed during treatment. Of 14 NT-proBNP-evaluable patients, 57% met criteria for cardiac response (decrease of >30% and > 300 ng/L), and 43% had stable disease. Conclusion(s): Monthly NEOD001 infusions were safe and well tolerated. Organ response rates compare favorably with those of traditional chemotherapy. Antibody therapy may allow for effective management of renal and cardiac AL amyloidosis.