title: Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.
abstract: Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.
authors.affiliation: Amyloid Research and Treatment Center, Department of Molecular Medicine, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Merlini
authors.affiliation: Amyloidosis Research Consortium, Inc., Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Lousada
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dispenzieri
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Gertz
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Grogan
authors.affiliation: Clinical Cardiovascular Research Laboratory for the Elderly, Columbia University Medical Center, New York, NY, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Maurer
authors.affiliation: Amyloidosis Center, Boston University School of Medicine and Medical Center, Boston, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Sanchorawala
authors.affiliation: Reader in Medicine and Haematology, National Amyloidosis Centre, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Wechalekar
authors.affiliation: Amyloid Research and Treatment Center, Department of Molecular Medicine, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Palladini
authors.affiliation: The John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Comenzo
mesh_terms: D000686:Amyloidosis / Q000175:diagnosis* / Q000401:mortality*; D015415:Biomarkers; D002986:Clinical Trials as Topic; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D007147:Immunoglobulin Light Chains; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain