Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial

Abstract

Background: IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression.

Methods: In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments.

Results: Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%).

Conclusions: These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

Graphical abstract

Figure 1

Randomization and patient disposition during the double-blind period of the study. ^aAfter treatment discontinuation, the patient was withdrawn from the study because of death from coronavirus disease 2019, which occurred after the double-blind period (>28 days after the last dose of the study drug) and was excluded from the safety reports as prespecified in the statistical analysis plan. No non-serious adverse events led to treatment or study discontinuation.

Figure 2

Change from baseline in 24-hour UPCR and spot UPCR over 32 weeks. (A) Change from baseline in 24-hour UPCR to week 32 in patients treated with cemdisiran compared with placebo. The primary end point was a separate analysis using a mixed-effect model for repeated measures, which showed a placebo-adjusted geometric mean percent change from baseline in 24-hour UPCR at week 32 of –37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) in favor of cemdisiran. (B) Change from baseline in spot UPCR compared with placebo to week 32 in patients treated with cemdisiran compared with placebo (secondary end point). An additional analysis showed that after cemdisiran treatment, placebo-adjusted geometric mean change from baseline in spot UPCR at week 32 was –45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]) (treatment comparison and estimates were analyzed by a similar mixed-effect model for repeated measures as used for the primary end point). CI, confidence interval; UPCR, urine protein-to-creatinine ratio.

Figure 3

Hematuria grade from baseline to week 32 of the double-blind period (secondary end point). ^aHematuria was measured by urine dipstick in the modified intent-to-treat population, using the light reflectance spectroscopy method. Hematuria category indicates reference range from dipstick color change. The percentage of patients in each category at baseline and week 32 was calculated using the total number of evaluable patients in the treatment group as the denominator.

Figure 4

Serum levels of C5 protein and markers of complement activity in the cemdisiran and placebo groups over 32 weeks (exploratory end points). (A) Mean C5 protein levels from baseline to week 32. (B) Percentage change from baseline in serum complement alternative pathway levels. (C) Percentage change from baseline in serum complement classical pathway levels. SD data are shown in all figures (SD values from the mean C5 protein level values for the cemdisiran group [A] are too small to show clearly on the figure from week 4 onward). C5, complement component 5.