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Background. The cytokine A proliferation-inducing ligand (APRIL) is considered a key driver of the pathogenesis of IgA nephropathy. Sibeprenlimab, a humanized IgG2 monoclonal antibody, selectively binds to and inhibits APRIL.
Methods. In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned adults with biopsy-confirmed IgA nephropathy in a 1:1 ratio to receive either subcutaneous sibeprenlimab at a dose of 400 mg or placebo administered every 4 weeks for 100 weeks. The primary end point for this interim analysis was the 24-hour urinary protein-to-creatinine ratio at 9 months as compared with baseline. The key secondary end point, to be reported at trial completion, is the annualized slope of estimated glomerular filtration rate over 24 months. Other secondary end points included the change in the level of serum immunoglobulin and safety. Exploratory end points included the change in galactose-deficient IgA1 and APRIL concentrations, the spot 24-hour urinary protein-to-creatinine ratio, hematuria, and remission of proteinuria.
Results. A total of 510 patients underwent randomization - 259 to the sibeprenlimab group and 251 to the placebo group. The prespecified interim analysis included the first 320 patients (152 who received sibeprenlimab and 168 who received placebo) who had the opportunity to complete the 9-month evaluation of the 24-hour urinary protein-to-creatinine ratio. At 9 months, a significant reduction in 24-hour urinary protein-to-creatinine ratio was observed with sibeprenlimab (-50.2%) as compared with an increase with placebo (2.1%), corresponding to an adjusted geometric least-squares mean 24-hour urinary protein-to-creatinine ratio that was 51.2% (96.5% confidence interval [CI], 42.9 to 58.2) lower with sibeprenlimab than with placebo (P<0.001). The levels of APRIL and pathogenic galactose-deficient IgA1 at week 48 were reduced from baseline by 95.8% and 67.1%, respectively, with sibeprenlimab. The safety profile appeared to be similar with sibeprenlimab and placebo. No deaths were reported, and the incidence of serious adverse events that occurred during the treatment period was 3.5% with sibeprenlimab and 4.4% with placebo.
Conclusions. Sibeprenlimab resulted in a significant reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Otsuka Pharmaceutical Development and Commercialization. VISIONARY ClinicalTrials.gov number, NCT05248646.).
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Background. IgA nephropathy, the most common primary glomerulopathy worldwide, is a kidney disorder of B-cell origin characterized by mesangial accumulation of IgA-containing immune complexes. In at least 50% of patients, IgA nephropathy leads to kidney failure or death within 10 to 20 years after diagnosis. Atacicept is a native human transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI)-Fc fusion protein that inhibits two key immunoregulatory cytokines - B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) - that are thought to be central to the pathophysiology of IgA nephropathy.
Methods. In this ongoing, phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients with IgA nephropathy in a 1:1 ratio to receive atacicept at a dose of 150 mg once weekly, administered subcutaneously by patients at home, or matching placebo. The primary end point was the percentage change from baseline in the 24-hour urinary protein-to-creatinine ratio at week 36. Safety was also evaluated.
Results. A total of 203 patients were included in the prespecified interim analysis: 106 patients in the atacicept group and 97 in the placebo group. At week 36, the percentage reduction from baseline in the urinary protein-to-creatinine ratio was 45.7% in the atacicept group and 6.8% in the placebo group, with a geometric mean between-group difference of 41.8 percentage points (95% confidence interval, 28.9 to 52.3; P<0.001). Adverse events were observed in 59.3% of the patients in the atacicept group and in 50.0% in the placebo group; most were mild or moderate in severity.
Conclusions. In this prespecified interim analysis, treatment with atacicept resulted in a significantly greater reduction in proteinuria than placebo at week 36 in patients with IgA nephropathy. (Funded by Vera Therapeutics; ORIGIN 3 ClinicalTrials.gov number, NCT04716231.).
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Background. Despite guideline recommendations, evidence for the use of non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy in patients with atrial fibrillation after implantation of a drug-eluting stent remains limited.
Methods. In this multicenter, randomized, open-label, noninferiority trial in South Korea, we assigned patients with atrial fibrillation who had undergone the implantation of a drug-eluting stent at least 1 year earlier in a 1:1 ratio to receive NOAC monotherapy or combination therapy (NOAC plus clopidogrel). The primary end point was net adverse clinical events, a composite of death from any cause, myocardial infarction, stent thrombosis, stroke, systemic embolism, or major bleeding or clinically relevant nonmajor bleeding at 12 months. The noninferiority margin was 3.0 percentage points.
Results. A total of 960 patients underwent randomization: 482 patients to receive monotherapy and 478 to receive combination therapy. The mean age of the patients was 71.1 years, and 21.4% were women. At 12 months, a primary end-point event had occurred in 46 patients (Kaplan-Meier estimate, 9.6%) in the monotherapy group and in 82 patients (Kaplan-Meier estimate, 17.2%) in the combination-therapy group, for an absolute difference of -7.6 percentage points (95.2% confidence interval [CI], -11.9 to -3.3; P<0.001 for noninferiority) and a hazard ratio of 0.54 (95.2% CI, 0.37 to 0.77; P<0.001 for superiority). Major bleeding or clinically relevant nonmajor bleeding occurred in 25 patients (5.2%) in the monotherapy group and in 63 patients (13.2%) in the combination-therapy group (hazard ratio, 0.38; 95% CI, 0.24 to 0.60).
Conclusions. Among patients with atrial fibrillation who had undergone implantation of a drug-eluting stent at least 1 year earlier, NOAC monotherapy was noninferior to combination therapy for net adverse clinical events. (Funded by Cardiovascular Research Center and Samjin Pharmaceutical; ADAPT AF-DES ClinicalTrials.gov number, NCT04250116.).
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Background. Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare prothrombotic complication that occurs after adenoviral vector-based vaccination against coronavirus disease 2019; in rare cases, it can also occur after natural adenovirus infection. VITT is mediated by platelet-activating antibodies against the highly cationic protein platelet factor 4 (PF4). The underlying inciting antigen trigger and immunopathogenesis remain unknown.
Methods. We used antibody proteomics to determine the amino acid sequences of anti-PF4 antibodies from 21 patients with VITT and sequenced the genes encoding the immunoglobulin light-chain hypervariable region from 100 patients with VITT. To identify an adenoviral trigger, we used the antigen-binding fingerprints of anti-PF4 and anti-adenovirus protein antibodies to identify a shared serum clonotype and subsequently used adenovirus protein peptides and recombinant anti-PF4 VITT antibodies to map the mimicking linear epitope.
Results. Genomic and proteomic profiling of VITT antibodies revealed a shared immunoglobulin light-chain allele, IGLV3-21*02 or *03, harboring a critical somatic hypermutation, K31E. Only antibodies purified against adenoviral core protein VII (pVII) contained anti-PF4 species matching the VITT fingerprint; antibodies against intact virions or other adenoviral proteins did not. Cross-reactive IgGs were mapped to a basic linear epitope on pVII. A pathogenic anti-PF4 VITT antibody, back-mutated to germline (K31), lost its prothrombotic activity in vitro and in vivo and preferentially bound pVII, a finding that directly supported the role of the hypermutation in the antigenic shift from adenovirus pVII to PF4.
Conclusions. The results of our study indicate that VITT occurs when, in persons with immunoglobulin light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation develops that affects antibodies that recognize a specific epitope on the adenoviral core protein pVII, which results in misdirection of antibody targeting toward PF4. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00025738; EU Post-Authorization Study Register number, EUPAS45098.).
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