Shortly after posting our last blog on tacicepts, new data was published in the NEJM on the pivotal Phase 3 trial of atacicept. This publication by Lafayette et al. provides results from an IA of the ongoing ORIGIN-3 trial.[1] We updated our table with this new information that centers on reduction of proteinuria, UCPR and hematuria.
The authors do not provide information on the GFR effects of atacicept claiming that this data has to stay blinded until the 2-yr endpoint. This strikes us as strange, because S-creatinine and GFR are measured frequently in every patient enrolled, and interim GFR trends could have been provided without breaking the blind for the final analysis.
The efficacy results are impressive; we learned that pathologic Gd-IgA1 levels, specific autoantibodies and circulating immune complexes were reduced. We don’t know whether these laboratory improvements will ultimately lead to less deposition of Igs in the glomerular mesangium, with corresponding clinical benefit. These lab changes could eventually become early biomarkers of clinical efficacy if confirmed by GFR and possibly kidney biopsy.
Reduction in the concentrations of IgG, IgA and IgM was not of a magnitude to affect immune response against infections; it takes a much greater drop in immunoglobulin levels to become problematic in this regard. This was shown in the tacicept and FcRn inhibitor trials as well. FcRn inhibitors reduce IgG levels by up to 70% and are not associated with a noticeable increase in infections.
The higher frequency of injection site reactions in the atacicept arm, however, was surprising. Unfortunately, the article did not provide much detail except for making a boilerplate statement that most AEs were ‘mild in severity’. We feel this deserves a closer look.
The authors state that the study participants were ‘representative of the general population of patients with IgA nephropathy’. Is that really true? White, Asian and Latino patients were enrolled but almost no Blacks. This is concerning, as a 2023 epidemiology study shows that IgAN is an issue in black patients as well, but here they were underrepresented.[2]
Please check back here periodically as more data become available.
ABBREVIATIONS
APRIL a proliferation-inducing ligand
BAFF B-cell activating factor
CKD chronic kidney disease
eGFR estimated glomerular filtration rate
GdIgA galactose-deficient IgA
IA interim analysis
IgAN immunoglobulin A nephropathy
PBO placebo
UPCR urine protein to creatinine ratio
REFERENCES
[1] Lafayette R. A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy. NEJM DOI: 10.1056/NEJMoa2510198
[2] Kiryluk K. Global Incidence of IgA Nephropathy by Race and Ethnicity: A Systematic Review. KIDNEY360 4: 1112, 2023
