C3G: Immunosuppressives have limited efficacy in reducing proteinuria; factor B inhibitor of alternative complement pathway performs well over long term
Presenters: Soumita Bagchi, MD, Nephrology Department, All India Institute of Medical Sciences, New Delhi, India; Carla M. Nester, MD, University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City
Bagchi S, Barwad A, Singh Ge, et al. Clinical and histologic profile of C3 glomerulopathy: a retrospective study. Poster TH-P0504-2022 presented at American Society of Nephrology Kidney Week 2022, November 3, 2022, 10 am.
Nester CM, Eisenberger U, Karras A, et al. 12-month interim analysis of an open-label, non-randomized extension of a phase 2 study to evaluate the long-term efficacy, safety, and tolerability of iptacopan in subjects with C3G. Poster TH-P0505-2022 presented at American Society of Nephrology Kidney Week 2022, November 3, 2022, 10 am.
Summary: Investigators in India found that patients with complement 3 glomerulopathy present young with proteinuria that is rarely responsive to immunotherapy, while a group in Iowa observed promising effects with iptacopan on proteinuria and estimated glomerular filtration rate.
The clinical and histologic picture of complement 3 glomerulopathy (C3G) is evolving. In reviewing the records of a cohort of patients with C3G from All India Institute of Medical Sciences in New Delhi investigators led by Soumita Bagchi, MD, found that patients with C3G present young with significant proteinuria, and that immunosuppression was rarely effective in reducing proteinuria. They presented their data in poster format.
In their analysis of 33 patients who presented with biopsy-proven C3G diagnosed between 2015 and 2020, the median age was 23 years, 69.7% were male, and 51.5% had hypertension.
Median estimated glomerular filtration rate (eGFR) was 49 mL/min/173 m2, median serum albumin level was 2.7 g/dL, and the median urinary protein excretion was 4.3 g/day at presentation. More than half (51.5%) of the cohort had microscopic hematuria and 51.4% had low C3 levels. On histology, 4 patients had dense deposit disease and 29 were diagnosed with C3 glomerulonephritis.
Of the 29 patients who received immunosuppression, 8 were treated with steroids, 20 with mycophenolate mofetil plus steroids, and 1 with cyclophosphamide plus steroids. Only 9 patients achieved a reduction in 24-hour urine protein level with stable eGFR; 5 of these had partial remission, defined as a 50% or greater reduction in 24-hour urine protein with stable eGFR, and 4 had complete remission, defined as a 24-hour urine protein level less than 500 mg/day with stable eGFR.
Only 7 of the 20 patients (35%) who received mycophenolate mofetil achieved remission. During a median follow-up of 29 months, 15 (45.4%) patients had a sustained decline in eGFR greater than 50% or had progressed to end-stage renal failure.
A 12-month interim analysis of an extension of a phase 2 study of iptacopan, presented separately, demonstrated further reduction in proteinuria and improved eGFR beyond the previously reported changes following 12 weeks of treatment in adults with native (cohort A) or recurrent C3G positive kidney transplant (cohort B).
Iptacopan is an investigational highly selective factor B inhibitor of the alternative complement pathway (AP). Following 12 months of treatment in the open-label, nonrandomized extension phase of the study, 53% of the 15 patients in cohort A met the composite renal end point, which consisted of stable/improved eGFR (at least 10% reduction from baseline), a 50% or greater reduction from baseline in urine protein-to-creatinine ratio (UPCR), and a 50% or greater increase from baseline in serum C3, reported Carla M. Nester, MD, University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, and colleagues.
The previously reported 12-week data from the study showed a 45% reduction in proteinuria in patients with native C3G.1 Improvements in kidney function “were associated with substantial inhibition of the alternative complement pathway and normalization of C3 levels in many patients,” the authors wrote.
Of the 27 patients who completed the 12-week study, 26 entered the extension phase with treatment with iptacopan (200 mg twice daily). In cohort A, 16 of 16 patients met the individual serum C3 component of the composite end point by day 21. In this cohort, the 24-hour UPCR was reduced by 57% (P < 0.0001) following 12 months of treatment, and the decline in eGFR was reversed, with an improvement of 1.3 mL/min/1.73 m2/yr (P = 0.0233 for the change in the eGFR slope from pre- to post-treatment). Levels of C3 increased by more than 250% at 12 months in cohort A, and were normalized in 8 of 16 patients in cohort A and 7 of 9 patients in cohort B.
In cohort B, eGFR was stable for 12 months in 9 of 10 patients, and C3 levels increased by 96%.
At 1 year of treatment, biomarkers of AP activity (Wieslib activity and levels of plasma sC5b-9) were inhibited in both cohorts.
Most adverse events were mild or moderate in both cohorts, although a greater proportion of adverse events in cohort B were graded as moderate or severe due to the mandatory immunosuppressive background.
“These results support further evaluation of iptacopan in the ongoing phase 3 APPEAR-3CG trial [in native C3G patients], which is currently recruiting patients, and confirm the efficacy and safety for long-term treatment of C3G with iptacopan,” the authors concluded.
Reference
- Wong E, Nester C, Cavero T, et al. Iptacopan, a novel oral complement alternative pathway factor B inhibitor, significantly reduces urinary protein excretion and C3 deposit scores in native and transplanted kidneys in patients with C3 glomerulopathy. Poster presented at American Society of Nephrology Kidney Week 2021, San Diego, CA, November 4, 2021
Disclosures
Prof. Bagchi has nothing to disclose.
Dr. Nester reports financial relationships with Alexion Pharmaceuticals, Appellis, BioCryst Pharmaceuticals, ChemoCentryx, Kira Pharmaceuticals, Novartis, and Retrophin. Co-authors report financial relationships with several pharmaceutical companies.