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.
Highlights
Amyloid light-chain (LC) amyloidosis (AL amyloidosis), a rare, progressive and fatal disease, is the most common form of systemic amyloidosis,[1,2] and it affects an estimated 8–12 per 1 000 000 persons annually.[3,4] Systemic amyloidosis is characterized by the accumulation of abnormal, misfolded protein in various tissue and organs that produce patientspecific clinical manifestations depending on the organ impacted
The data presented here establish that the NT-proBNP response, defined as a decrease in NT-proBNP of 430 % and 4300 ng/l (35.4 pmol/l), predicts clinical outcome and survival and is a validated and qualified surrogate marker of efficacy for interventions for patients with AL amyloidosis
RLC has received consulting fees or honoraria from Takeda Millennium, Karyopharm, and Janssen and research support from Takeda Millennium, Prothena, Janssen, and Teva
Summary
Amyloid light-chain (LC) amyloidosis (AL amyloidosis), a rare, progressive and fatal disease, is the most common form of systemic amyloidosis,[1,2] and it affects an estimated 8–12 per 1 000 000 persons annually.[3,4] Systemic amyloidosis is characterized by the accumulation of abnormal, misfolded protein (amyloid) in various tissue and organs that produce patientspecific clinical manifestations depending on the organ impacted. 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 This consensus is supported by the consistent demonstration of the predictive value of NT-proBNP in all intervention trials to date, which we review here, and is especially striking in light of differences in study design, treatment regimens or combinations of treatment regimens, treatment class, patient population and geographic location. NT-proBNP response predicted a significant survival benefit both in testing (n = 816) and in validation (n = 374) populations treated primarily with MDex, T-based, lenalidomide (L)-based, Bor-based, Dex, MP or ASCT treatments (Figure 3).[11] This international study in 1190 patients failed to show any survival benefit of ⩾ 2-mm reduction in the thickness of the cardiac interventricular septum, which had been used as a criterion for cardiac response.[56].
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