In:
Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. Supplement_1 ( 2023-06-14)
Abstract:
B cell activating factor (BAFF) of the tumor necrosis factor (TNF) family and a proliferation-inducing ligand (APRIL), cytokines which bind and signal through BAFF-R, transmembrane activator and CAML interactor (TACI), and/or B cell maturation antigen (BCMA) on B cells, play overlapping and non-redundant roles in B cell development, proliferation, function, and survival. Therapeutic agents targeting BAFF and/or APRIL have demonstrated promising clinical potential in autoantibody-related glomerulonephritides (GN) such as lupus nephritis (LN), immunoglobulin (Ig) A nephropathy (IgAN), membranous nephropathy, and other B cell-related diseases such as systemic lupus erythematosus (SLE); however, there is still need for more safe and efficacious therapies. Povetacicept (ALPN-303) is an Fc fusion protein of an engineered TACI variant TNFRSF domain (vTD) with enhanced affinity for APRIL and BAFF which mediates more potent inhibitory activity than wild type (WT) TACI-Fc or BAFF- or APRIL-specific antibodies. In preclinical studies, povetacicept demonstrated enhanced pharmacokinetic (PK) and immunomodulatory properties vs. WT TACI-Fc, which may translate to lower and/or less frequent doses in humans. Povetacicept also suppressed autoantibodies, renal IgG deposition, and nephritis in mouse models. Povetacicept may therefore significantly improve clinical outcomes in autoantibody-mediated GNs and other B cell-related diseases. Method In this first-in-human study (NCT05034484), 66 healthy adult volunteers were randomized 4:2 into single ascending dose cohorts of intravenous (IV) or subcutaneous (SC) povetacicept or placebo. Participants were followed to assess safety and PK, circulating Ig, galactose-deficient IgA1 (Gd-IgA1), and circulating leukocyte populations. Results Povetacicept has been well tolerated in all cohorts evaluated as single IV or SC doses of up to 960 mg. Overall, it exhibits dose-related PK and expected pharmacodynamic (PD) effects, including dose-related reductions in serum IgA, IgM, IgG, and Gd-IgA1 (Figure 1), and in circulating antibody-secreting cells (ASC; plasmablasts and plasma cells) (Figure 2). In the same setting, these PD effects appear greater than those reported for WT TACI-Fc molecules and appear to be saturated at doses ≥80 mg. Coverage of free APRIL was maintained for 2-3 weeks with 80 mg and ≥4 weeks with 240 mg, respectively. The most frequent adverse event has been mild headache. To date, there have been no imbalances of infections between placebo and povetacicept groups, no treatment-related reactions other than mild injection site pain, and no adverse trends in safety laboratories. Conclusion To date, povetacicept has demonstrated acceptable safety and tolerability as single IV or SC doses, exhibiting dose-dependent PK and PD that appear to differentiate favorably vs WT TACI-Fc. Based on the magnitude and duration of the observed PD effects, dose regimens of 80-240 mg SC every 4 weeks are anticipated for use in future studies. Overall, the study findings support future clinical development of povetacicept in multiple autoantibody-related GN, as well as other B cell- and/or autoantibody-related diseases such as SLE and autoantibody-associated cytopenias.
Type of Medium:
Online Resource
ISSN:
0931-0509
,
1460-2385
DOI:
10.1093/ndt/gfad063a_4024
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2023
detail.hit.zdb_id:
1465709-0
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