Jonathan Barratt, MD: Atacicept Could ‘Transform How We Think About Treating IgA Nephropathy’

Findings from a phase 2b trial of atacicept in patients with IgA nephropathy (IgAN) at high risk of disease progression despite being on a renin-angiotensin-aldosterone system inhibitor (RAASi) suggest the dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein may significantly reduce galactose-deficient IgA1 (Gd-IgA1) and stabilize kidney function.¹

Results from the randomized, double-blind, placebo-controlled trial showed a 35% reduction in proteinuria and stabilization of estimated glomerular filtration rate (eGFR) at week 36 following treatment with atacicept in addition to current standard of care, supporting its advancement to the phase 3 ORIGIN 3 study powered to evaluate the benefit of atacicept 150 mg on UPCR and the rate of change in eGFR over 2 years.¹

“Atacicept targets 2 key cytokines that are essential for B cell and plasma cell survival and for the secretion of IgA, and those are BAFF and APRIL,” Jonathan Barratt, MD, Mayer Professor of Renal Medicine at the University of Leicester, explained in an interview with HCPLive. He noted that although the class of drugs is not currently available in IgAN, this pathway looks to be “very exciting” in terms of targeting the pathway that drives the production of pathogenic IgA.

An ongoing, randomized, international, multicenter, double-blind, placebo-controlled, phase 2b trial, ORIGIN enrolled participants from 65 centers in 13 countries to receive blinded treatment with atacicept or placebo, self-administered at home once per week for 36 weeks. For inclusion, participants were required to have biopsy-proven IgAN within 10 years before screening, 24-hour urine protein >0.75 g per day, or urine protein-creatinine ratio (UPCR) >0.75 g/g despite at least 12 weeks on a maximally tolerated, stable dose of RAASi, and eGFR ≥30 ml/min per 1.73 m2.¹

Participants were randomly assigned in a 2:2:1:2 ratio to receive either atacicept 150 (n = 33), 75 (n = 33), or 25 mg (n = 16), or a placebo containing the excipients used in atacicept formulation (n = 34). The primary outcome was the change from baseline in 24-hour UPCR at week 24 in the combined atacicept 150- and 75-mg group compared with placebo. The secondary outcome was the change in UPCR at week 36 in the combined atacicept 150- and 75-mg group as well as in individual atacicept doses versus placebo. Other prespecified endpoints of interest included change in UPCR at week 12, Gd-IgA1 levels, and change in eGFR at weeks 12, 24, and 36.¹

Results showed mean UPCR decreased 31% from baseline in the combined atacicept 150- and 75-mg group compared with 8% in the placebo group, resulting in a 25% reduction versus placebo at 24 weeks (95% CI, 1.74%–43.01%; P = .037). At week 36, mean UPCR decreased by 34% in the combined atacicept 150- and 75-mg group compared with a 2% increase in the placebo group from baseline, resulting in a 35% reduction with atacicept versus placebo (95% CI, 13.03%–51.53%; P = .0042).¹

Mean eGFR increased from baseline by 1% in the combined atacicept 150- and 75-mg group at week 36 compared with an 8% reduction from baseline in the placebo group, resulting in an 11% difference (P = .022), something Barratt noted was a “key” finding, especially through 72 weeks in the open-label extension portion of the trial.^1,2

Additionally, compared with a mean 7% decrease from baseline in Gd-IgA1 with placebo at week 36, a 63% decrease was achieved in the combined atacicept 150- and 75-mg group, resulting in a 60% decrease from baseline with atacicept versus placebo (P <.0001). Atacicept was well tolerated through a median exposure of 36 weeks, with similar proportions of participants with treatment-emergent adverse events between the all-atacicept and placebo groups (73% vs 79%, respectively).¹

“In terms of the data we have available, it is outstanding. But we have to always remember it is a phase 2 study,” Barratt said. “It's not small in the grand scheme of things, but it is a small group of patients compared to a phase 3. But the data is outstanding.”

References:

1. ^{Lafayette R, Barbour S, Israni R, et al. A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy. Kidney Int. Published online March 27, 2024. doi:10.1016/j.kint.2024.03.012}
2. ^{Campbell, P. 72-Week Phase 2B ORIGIN Data Highlight Potential Benefit of Atacicept in IgA Nephropathy. HCPLive. https://www.hcplive.com/view/72-week-phase-2b-origin-data-highlight-potential-benefit-of-atacicept-in-iga-nephropathy}