title: First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction.
abstract: OBJECTIVE
  Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264).
  
  
  METHODS
  Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria.
  
  
  RESULTS
  Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease.
  
  
  CONCLUSIONS
  Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA gertz.morie@mayo.edu.
authors: Morie A
authors: MA
authors: Gertz
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Heather
authors: H
authors: Landau
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Raymond L
authors: RL
authors: Comenzo
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: David
authors: D
authors: Seldin
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Brendan
authors: B
authors: Weiss
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Jeffrey
authors: J
authors: Zonder
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Giampaolo
authors: G
authors: Merlini
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Stefan
authors: S
authors: Schönland
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Jackie
authors: J
authors: Walling
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Gene G
authors: GG
authors: Kinney
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Martin
authors: M
authors: Koller
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Dale B
authors: DB
authors: Schenk
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Spencer D
authors: SD
authors: Guthrie
authors: Morie A. Gertz, Mayo Clinic, Rochester, MN; Heather Landau, Memorial Sloan Kettering Cancer Center, New York, NY; Raymond L. Comenzo, Tufts Medical Center; David Seldin, Boston University, Boston, MA; Brendan Weiss, University of Pennsylvania, Philadelphia, PA; Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI; Giampaolo Merlini, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; Stefan Schönland, University of Heidelberg, Heidelberg, Germany; Jackie Walling, JW Consulting, Hillsborough; Gene G. Kinney, Martin Koller, Dale B. Schenk, and Spencer D. Guthrie, Prothena Biosciences, Inc., South San Francisco; and Michaela Liedtke, Stanford University School of Medicine, Stanford, CA.
authors: Michaela
authors: M
authors: Liedtke
mesh_terms: D000328:Adult; D000368:Aged; D000686:Amyloidosis / Q000150:complications / Q000188:drug therapy* / Q000208:ethnology / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003371:Cough / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004417:Dyspnea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology; D012141:Respiratory Tract Infections / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007147:Immunoglobulin Light Chains; C000609646:birtamimab