ORIGIN OLE Data Solidify Atacicept Disease-Modifying Potential for IgA Nephropathy

Jonathan Barratt, PhD
Credit: IgA Nephropathy Foundation

New 96-week data from the open-label extension portion of the ORIGIN trial suggest use of atacicept could slow the rate of kidney decline in patients with IgA nephropathy to a rate similar to physiological aging without kidney disease.

Presented at the American Society of Nephrology’s Kidney Week 2024, results of the trial demonstrate use of atacicept, a dual BAFF/APRIL inhibitor from Vera Therapeutics, was associated with sustained reductions in galactose-deficient IgA1 (Gd-IgA1), hematuria, and urine protein to creatinine ratio (UPCR). According to investigators, data from the trial position atacicept as a disease-modifying therapy and represents an important potential advancement in the future management of IgA nephropathy.¹

“The data is particularly striking in terms of the slowing in the loss of kidney function to a level that we associate with physiological aging,” said principal investigator Jonathan Barratt, PhD, the Mayer Professor of Renal Medicine at the University of Leicester, in an interview with HCPLive. “So, actually, back to almost health for kidneys, and this is in a high-risk group of patients with IgA nephropathy, where, traditionally, we would expect them to lose 5 to 6 mLs of GFR every year. So, really astounding results and something that I certainly didn't think I was going to see in terms of new therapies.”

A 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. At a prespecified interim analysis at 36 weeks, results of the phase 2b ORIGIN trial suggested atacicept 150 mg was associated with a mean placebo-adjusted UPCR reduction of 35% (P=.012) in the study’s intention-to-treat analysis and 43% (P=.003) in a per-protocol analysis.^1,2,3

Following the completion of the 36-week portion of the trial, patients were rolled in an open-label extension portion of the trial where all patients received atacicept 150 mg for an additional 60 weeks. The primary outcomes of interest at the conclusion of the 96-week period were changes in Gd-IgA1, percentage of participants with hematuria, UPCR, and estimated glomerular filtration rate (eGFR).^1,2

In the overall trial, 116 patients underwent randomized and 113 received at least 1 dose of atacicept. Of the 113 patients who received atacicept, 90% completed treatment in the open-label extension period. This cohort had a median age at baseline of 37 (IQR, 18 to 67) years, 59% were male, 45% were Asian, and 52% were White. The cohort’s mean baseline eGFR at baseline was 62 (SD, 28) mL/min/1.73m2 and mean UPCR was 1.8 (SD, 1.3) g/g.^1,2

The 96-week open-label data, which was presented at Kidney Week 2024 and simultaneously published in the Journal of the American Society of Nephrology, demonstrated use of atacicept was associated with sustained reductions across multiple endpoints of interest, including a 66% (SE, 2%) mean reduction in Gd-IgA1 levels, a reduction in percentage of patients with hematuria from baseline (percentage change, 75%; 95% CI, -87% to -59%), and a reduction in UPCR was reduced by 52% (SE, 5%). Investigators highlighted the mean eGFR annualized slope was just -0.6 (SE, 0.5) mL/min/1.73m2 per year.¹

When assessing safety data, investigators found the proportion of patients with a treatment-emergent adverse event during the 60-week open-label extension period (77%) was similar to the rate observed among the atacicept group during the 36-week double-blind period (73%) and to those receiving placebo (82%).¹

“We are one step closer to preventing kidney failure in the lifetime of our patients with IgA nephropathy, which is an amazing turnaround compared to the first 50 years of knowing about this disease, when we couldn't do very much at all other than just watch them just progressively decline in kidney function [and] end up on dialysis,” Barratt explained. “So, a massive turnaround in terms of what we potentially could achieve with the new therapies.”

Atacicept is currently being evaluated in a phase 3 trial named ORIGIN. In September 2024, Vera Therapeutics announced this trial had completed enrollment and the company is on track to announce topline results in Q2 2025.³

For more from our interview with Barratt, check out the video below:

Relevant disclosures of interest for Barratt included Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos NV, GSK, Novartis, and Travere Therapeutics.

References:

1. Barratt J, Barbour S, Brenner RM, et al. Long-Term Results from the ORIGIN Phase 2b Study of Atacicept for the Treatment of IgA Nephropathy (IgAN). Presented at American Society of Nephrology Kidney Week 2024. San Diego, CA. October 23-27, 2024.
2. 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. 2024;105(6):1306-1315. doi: 10.1016/j.kint.2024.03.012
3. Vera Therapeutics. Vera Therapeutics completes enrollment for primary endpoint in Pivotal Phase 3 Origin 3 trial of atacicept in Igan. Vera Therapeutics. September 12, 2024. Accessed October 26, 2024. https://ir.veratx.com/news-releases/news-release-details/vera-therapeutics-completes-enrollment-primary-endpoint-pivotal.