Atacicept Shows Disease-Modifying Potential in IgAN, Linked to Hematuria Resolution

Findings from a post-hoc analysis of the phase 2b ORIGIN study of atacicept in patients with IgA nephropathy (IgAN) are shining light on the dual anti-B-cell activation factor (BAFF)–a proliferation-inducing ligand (APRIL) fusion protein’s impact on hematuria resolution.¹

The new research shows a substantially greater percentage of patients treated with atacicept achieved hematuria resolution at 36 weeks compared with placebo, with improvements observed as early as 4 weeks. Results add to the growing body of evidence supporting atacicept as a potential disease-modifying treatment for IgAN.¹

“Both persistent proteinuria and persistent hematuria have been shown to be independent risk factors for progression of kidney failure, with greater risk of progression in patients with both factors,” Jürgen Floege, MD, head of the division of nephrology and immunology at the University of Aachen in Germany, and colleagues wrote.¹ “It is therefore important to determine the effect of B cell modulators such as atacicept on hematuria.”

Currently, budesonide (Tarpeyo) delayed-release capsules are the only US Food and Drug Administration (FDA)-approved treatment for reducing loss of kidney function in adults with primary IgAN. While budesonide targets mucosal B-cells in the ileum responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1), atacicept targets BAFF and APRIL, both of which have been associated with elevated serum levels of Gd-IgA1, anti–Gd-IgA1 autoantibodies, immune complex formation, and recruitment of inflammatory cells to the glomeruli, all central to IgAN pathogenesis.²

ORIGIN was a randomized, double-blind, placebo-controlled phase 2b study conducted to evaluate the efficacy and safety of atacicept in patients with IgAN and persistent proteinuria who remain at high risk of disease progression despite being on a stable prescribed regimen of renin-angiotensin-aldosterone system inhibitor. It included 116 participants with biopsy-proven IgAN, 24h urine protein >0.75 g/day or urine protein to creatinine ratio (UPCR) >0.75 g/g, and eGFR ≥30 mL/min/1.73m2 despite optimized renin-angiotensin system blockade. Participants were randomly assigned in a 2:2:1:2 ratio to atacicept 150, 75, or 25 mg versus placebo, self-administered by subcutaneous injection once weekly for up to 36 weeks.¹

The study met its primary endpoint with statistically significant UPCR reduction at 24 weeks for atacicept vs placebo. At 36 weeks, atacicept 150 mg achieved statistically significant and clinically meaningful UPCR reduction, eGFR stabilization, and robust reduction of galactose-deficient IgA1 versus placebo, with similar safety to placebo.^1,3

A post-hoc analysis was conducted to evaluate changes in hematuria during treatment with atacicept vs placebo over 36 weeks. Microscopic hematuria was assessed at weeks 2, 4, 12, 24, and 36 via urine dipstick at a centralized lab, and hematuria levels were graded negative/trace, 1+, 2+, or 3+.¹

Participants with hematuria grade of 1+ or higher at baseline were evaluated for improvement or resolution, with improvement defined as a decrease by ≥1 grade and resolution defined as a decrease to negative/trace.¹

In the intent-to-treat population, 15 of 33 (45%) participants who received atacicept 150 mg and 19 of 34 (56%) who received placebo had hematuria ≥ 1+ at baseline. Of these participants, 87% treated with atacicept 150 mg had improved hematuria at 36 weeks compared to 32% on placebo (P = .002). Of note, 80% of those on atacicept 150 mg achieved resolution to negative/trace hematuria versus 5% on placebo (P <.0001).¹

Investigators pointed out patients in the atacicept 150 mg group steadily improved to lower hematuria grades over 36 weeks, with improvement occurring as early as 4 weeks, while the placebo group had no improvement in hematuria over time. Additionally, they noted the majority of participants without hematuria at baseline maintained negative or trace levels at 36 weeks.¹

“These results add to the growing body of evidence supporting atacicept as a potential disease-modifying treatment for IgAN. Atacicept 150 mg is currently being evaluated in a global Phase 3 randomized placebo-controlled trial,” investigators concluded.¹

References:

1. ^{Floege J, Barratt J, Maes B, et al. Impact of atacicept on hematuria in IGA nephropathy: post-hoc analysis of the phase 2b ORIGIN study, Nephrology Dialysis Transplantation, Volume 39, Issue Supplement_1, May 2024, gfae069–0432–123, https://doi.org/10.1093/ndt/gfae069.432}
2. ^{Brooks, A. FDA Awards Full Approval to Budesonide (Tarpeyo) in Treatment of IgA Nephropathy. HCPLive. December 20, 2023. Accessed June 10, 2024. https://www.hcplive.com/view/fda-awards-full-approval-to-budesonide-tarpeyo-in-treatment-of-iga-nephropathy}
3. ^{Campbell, P. 72-Week Phase 2B ORIGIN Data Highlight Potential Benefit of Atacicept in IgA Nephropathy. HCPLive. January 25, 2024. Accessed June 10, 2024. https://www.hcplive.com/view/72-week-phase-2b-origin-data-highlight-potential-benefit-of-atacicept-in-iga-nephropathy}