#2626 Effect of iptacopan discontinuation on proteinuria and complement biomarkers in patients with immunoglobulin A nephropathy (IgAN): a post hoc analysis from a Phase II trial

Abstract Background and Aims Studies have shown involvement of the alternative complement pathway (AP) in glomerular inflammation and tubulointerstitial damage in IgAN. AP inhibition with iptacopan, a potent oral complement factor B inhibitor, demonstrated a significant reduction in proteinuria, leading to its accelerated approval by the US FDA. The effect of iptacopan discontinuation on relevant IgAN characteristics are of clinical interest. Herein, we report proteinuria and AP biomarker data from a Phase II (PhII) study that included an observational period after iptacopan discontinuation, and preliminary data from the ongoing open-label extension study (OLE; NCT04557462), in which iptacopan was reinitiated. Method The PhII randomized, double-blind, placebo (pbo)-controlled study recruited adults with confirmed IgAN and urine protein–creatinine ratio (UPCR) ≥0.8 g/g or urine protein ≥0.75 g/day on stable renin–angiotensin system inhibitors to receive pbo or iptacopan (10, 50, 100 [in Part 2 only] or 200 mg twice daily [bid]) for 90 days in Part 1 or 180 days in Part 2 (Fig. 1). After stopping iptacopan treatment in either part, patients (pts) were followed for a 90-day off-iptacopan phase. Eligible pts could restart iptacopan 200 mg bid in the OLE (time from PhII study end [EoS] to OLE start varied). In this post hoc analysis, data were pooled in the iptacopan dose arms >10 mg bid (which showed effective AP inhibition) to compare the change from baseline (BL) in proteinuria between the on- and off-iptacopan phases. Data from the approved iptacopan dose 200 mg bid arms were also pooled from both parts. OLE data were pooled in all analyses up to Month (M) 12 (cut-off date: 15 August 2023). Mixed models for repeated measures were used to assess UPCR (from first morning void) during the PhII study and OLE. Descriptive analyses were conducted for AP biomarkers (urine soluble C5b-9 [sC5b-9], serum Wieslab and plasma Bb) in pts who received iptacopan 200 mg bid during the PhII study; AP biomarker data were not collected in the OLE. The PhII BL was considered the BL for all analyses. Results PhII data were used from 67 pts (Part 1: n = 23; Part 2: n = 44), 40 of which joined the OLE. In the pooled PhII study cohorts, the relative reduction in UPCR (95% CI) from BL in Part 1 was 30.0% (13.5, 43.4%) at Day (D) 90 (Fig. 2A) and in Part 2 was 35.4% (17.5, 49.5%) at D180 (Fig. 2B). In pts from Part 1 who had a shorter duration of iptacopan treatment relative to pts in Part 2, UPCR returned to BL levels within 30 days of iptacopan discontinuation (Fig. 2A). In pts from Part 2, UPCR remained below BL 30 days after iptacopan discontinuation but was higher compared with the end of treatment (EoT) visit (Fig. 2B). Upon iptacopan reinitiation in the OLE, UPCR decreased again for pts entering from Parts 1 and 2 (Fig. 2A and B). Similar trends were seen in the iptacopan 200 mg bid arms (n = 26); there was a relative reduction in UPCR (95% CI) of 27.0% (10.8, 40.3%) at D90 and 23.2% (−0.8, 41.5%) at EoT (D180). In the first off-iptacopan visit, UPCR increased to near PhII BL values, before decreasing after treatment reinitiation in the OLE. Iptacopan 200 mg bid inhibited the AP in pts pooled from both parts of the PhII trial (n = 26), as shown by a decrease in AP biomarkers (median [interquartile range (IQR)] reduction from BL to D90 in urinary sC5b-9: 97.2% [89.3, 98.4%]; serum Wieslab: 81.4% [72.9, 92.5%]; plasma Bb: 24.5% [13.6, 40.6%]). AP biomarkers increased at the first off-iptacopan visit, with a median (IQR) increase from BL of 18.3% (−77.8, 168.8%) for urinary sC5b-9 and 3.3% (−12.7, 11.2%) for plasma Bb, and a serum Wieslab reduction from BL of only 10.3% (0, 19.7%). Conclusion The data indicate that iptacopan discontinuation leads to quick reactivation of systemic and renal complement to near BL levels. Renal complement reactivation is associated with an increase in proteinuria. Notably, proteinuria decreased again after reinitiation of iptacopan, indicating continued sensitivity to complement inhibition. Limitations of this analysis include the short duration of PhII treatment, low pt numbers, and varying duration and lack of knowledge of other treatments or disease progression between the PhII EoS and the OLE.