Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy

Abstract

Background: B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell–mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks.

Methods: Participants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated.

Results: There were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received ≥1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean±SEM) in Gd-IgA1 (−66%±2%), percentage of participants with hematuria (−75%; 95% confidence intervals, −87 to −59; in participants with baseline hematuria), and UPCR (−52%±5%). The mean annualized slope of eGFR was −0.6±0.5 ml/min per 1.73 m² through 96 weeks.

Conclusions: Atacicept was also well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks.

Clinical Trial registry name and registration number: Atacicept in Subjects with IgA Nephropathy (ORIGIN 3), NCT04716231.

Figure 1. Screening, treatment, and follow-up through week 96.

*Discontinued to pursue elective surgery (n=1), and discontinued due to positive hepatitis B DNA and adverse event (n=1). †Initiated prohibited medication for concomitant disease (n=1), discontinued due to plan to start prohibited medication for concomitant disease (n=1) and adverse event (n=1). ‡Discontinued due to investigator decision (n=1), pregnancy (n=2), participant withdrawal (n=2), surgery (n=1), serious adverse event of pneumonia in a heavy smoker, resolved (n=1), adverse event of worsening alanine aminotransferase and aspartate aminotransferase (n=1), and medical monitor criteria (n=1). FAS, full analysis set; OLE, open-label extension.

Figure 2. Gd-IgA1 percentage change through 96 weeks percentage changes from baseline were computed using US FDA-endorsed mixed-effects modeling.

Atacicept group includes all participants receiving any atacicept dose at any time point, with baseline defined as the last available measurement before the first dose of atacicept. FDA, US Food and Drug Administration; Gd-IgA1, galactose-deficient IgA1.

Figure 3. Change in percentage of participants with hematuria through 96 weeks among participants with hematuria at baseline (N563).

Percentages represent change from baseline in number of participants with hematuria at each visit (see number of participants with hematuria evaluated at each visit on the lower axis) divided by number with baseline hematuria; microscopic hematuria was evaluated using urine dipstick at a centralized laboratory, and hematuria levels were graded negative/trace, 1+, 2+, or 3+. Atacicept group includes all participants receiving any atacicept dose at any time point, with baseline defined as the last available measurement before the first dose of atacicept. CI, confidence interval.

Figure 4. UPCR percentage change through 96 weeks percentage changes from baseline were computed using US FDA-endorsed mixed-effects modeling, which takes into account the effects of baseline UPCR and implicitly imputes missing data as missing at random.

Atacicept group includes all participants receiving any atacicept dose at any time point, with baseline defined as the last available measurement before the first dose of atacicept. UPCR, urine protein-creatinine ratio.

Figure 5. eGFR change through 96 weeks changes from baseline in eGFR (dashed thin line) are analyzed using mixed-model repeated-measures analysis with change from baseline eGFR as the dependent variable; fixed effects for randomized treatment, baseline value, and visit as independent variables; and participant as a random effect.

Least squares estimation, SEM, and two-tailed 95% CI are estimated from the model directly. eGFR slope (solid thick line) is analyzed using a mixed-effects model with random intercept and random slope, including eGFR as the dependent variable, baseline value and time as independent variables, and participant and time as random effects. Mean slope and SEM are estimated from the model directly. Atacicept group includes all participants receiving any atacicept dose at any time point, with baseline defined as the last available measurement before the first dose of atacicept.