Background The evaluation of abatacept (ABA), a modulator of T-cell costimulation, in lupus nephritis (LN) was supported by favorable preclinical studies in murine LN.
Objectives To compare the efficacy and safety of IV ABA to placebo (PBO) on a background of mycophenolate mofetil (MMF) and steroids in a 12-month Phase II/III multicenter, double-blind, study of patients (pts) with active Class III or IV LN, including exploratory, post-hoc, and subset efficacy analyses.
Methods 298 pts received PBO, ABA 30 mg/kg (30/10), or ABA 10 mg/kg (10/10) in a 1:1:1 ratio on Days 1, 15, 28, 57; thereafter, all ABA pts received 10 mg/kg through Week 48. Prespecified efficacy outcome measures: a) Primary: time to complete response (CR) (CR: eGFR within 10% of preflare/screening; urine protein/creatinine ratio [UPCR] <0.26 g/g; inactive urine: confirmed at 2 consecutive visits); b) CR at Week 52; c) renal improvement (RI) (RI: UPCR <50% of preflare/screening; no worsening of eGFR; inactive urine); d) renal response (RR) (RR: serum creatinine ≤125% of baseline [BL]; UPCR <50% of BL and <3.0 g/g if nephrotic, otherwise <1.0 g/g). Post-hoc efficacy endpoint: CRrev (defined post-hoc to account for renal function misclassifications): eGFR ≥90% of preflare/screening, otherwise same as CR.
Results Time to confirmed CR did not differ between groups (p=0.549 and 0.422 for ABA 10/10 and 30/10 vs PBO). Efficacy at Week 52 is shown (Table). Subset analyses of 122 nephrotic pts (BL UPCR >3.0 g/g) found approximately 20–30% greater reduction in mean UPCR. Safety, assessed as deaths, serious adverse events (SAEs) and serious infections, was similar across groups. AEs were generally mild, self-limited and similar in frequencies across groups, with the exception of Herpes zoster (reported in 2.0%, 11.1%, 8.1% of PBO, ABA 10/10, ABA 30/10, respectively). Post-hoc subset analyses suggested Asian race and early reduction of proteinuria (8–12 weeks) were associated with response (CRrev and RR at Week 52) in all groups.
Conclusions Abatacept and PBO, administered on a background of MMF and steroids to pts with LN, exhibited similar safety profiles, time to confirmed CR, and proportion with CR and RI. Exploratory and post-hoc analyses indicated more complete (CRrev) and renal (RR) responders with abatacept compared to PBO.
Disclosure of Interest R. Furie Grant/Research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, K. Nicholls: None Declared, T. Cheng: None Declared, F. Houssiau: None Declared, R. Burgos-Vargas Grant/Research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, S. Chen: None Declared, J. Hillson Employee of: Bristol-Myers Squibb, S. Meadows-Shropshire Employee of: Bristol-Myers Squibb, M. Kinaszczuk Employee of: Bristol-Myers Squibb, J. Merrill Consultant for: Bristol-Myers Squibb