KHI Current Project

Endpoints for C3 Glomerulopathy (C3G)

Community Unmet Need

1. C3 Glomerulopathy (C3G) remains an aggressive renal disease with high risk for progression to end stage kidney disease.
2. Recurrence in transplant is common.
3. A precise, systematic description of disease natural history is limited by disease rarity.
4. Current treatment approaches unpredictably affect disease outcome; there are no targeted therapeutics available to patients.
5. Theoretical, targeted therapeutics are emerging; the ability to establish the safety and efficacy of new therapeutics in this space is hindered by the absence of well-defined, validated endpoints.
6. The ultra-rare, nature of C3G makes it an ideal candidate for a global, shared bio-data repository that could be mined to advance both scientific and clinical questions of import.

Project Abstract

C3 glomerulopathy (C3G) is a form of primary kidney disease characterized by the deposition of complement C3 fragments in glomeruli (1). C3G is a rare disease, with an estimated incidence of less than 1:1,000,000. Because it is a relatively recently described entity, however, the incidence of C3G may be higher than is currently appreciated. C3G has one of the worst prognoses of the primary glomerulonephritides. More than 50% of affected patients go to end stage kidney disease (2), and the majority of patients who receive a kidney allograft have recurrence of disease within two years of transplantation (3). C3G frequently affects children. Thus, in spite of its rarity, the disease places an outsized burden on patients, families, and on the healthcare system.

Animal models and molecular studies on well described patients have provided important insights into the pathogenesis of the disease (4-11). C3G is caused by uncontrolled activation of the alternative pathway of complement. The diagnosis of the disease is based on the detection of glomerular C3 deposits in excess of immunoglobulin deposition (at least two orders of magnitude brighter by immunofluorescence microscopy) (12). No disease directed therapeutics are available for this disease. Because uncontrolled complement activation is considered the primary driver of disease, there is a strong rationale for evaluating the efficacy of complement inhibitors as a therapeutic. Multiple complement inhibitory drugs are in clinical development. Several of these agents are being tested in C3G (13, 14).

Clinical trials of these new agents in C3G pose several challenges. First, the natural history of the disease is incompletely understood. Some patients have rapidly progressive disease, whereas other patients show a more gradual progression. Given the variable course of C3G, it is important to identify quantifiable prognostic factors that will allow for prudent patient stratification. In addition, identifying disease specific biomarkers (either clinical or complement related) that accurately define disease activity and risk for progression and therefore both therapeutic need and efficacy will be instrumental in identifying optimal disease targeted therapeutics. The critical nature of understanding these issues and how they may impact clinical trial design is further accentuated by the low prevalence of the disease. Accurately and safely recruiting a rare population can only be done after a robust understanding of the disease. Importantly, the insights gained by an in-depth study of C3G are likely to have a positive impact on the use of complement inhibitory drugs in other forms of glomerulonephritis as well as complement-mediated diseases affecting other organs.

Deliverables

• Manuscript One - Describe the current understanding of the natural history of C3G disease and supported markers of disease.
• Development of a central repository.
• Manuscript Two - Report of Findings of Data Accumulation/ Analysis from Registry and Trial Data.

References

1. Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, et al. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. Journal of medical genetics. 2007;44(3):193-9.
2. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, Traynor C, Flanagan M, Wong L, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clinical journal of the American Society of Nephrology : CJASN. 2014;9(1):46-53.
3. Regunathan-Shenk R, Avasare RS, Ahn W, Canetta PA, Cohen DJ, Appel GB, et al. Kidney Transplantation in C3 Glomerulopathy: A Case Series. Am J Kidney Dis. 2019;73(3):316-23.
4. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, et al. Nat Genet. 2002:424-8.
5. Smith-Jackson K, Yang Y, Denton H, Pappworth IY, Cooke K, Barlow PN, et al. Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice. J Clin Invest. 2019;129(3):1061-75.
6. Marinozzi MC, Chauvet S, Le Quintrec M, Mignotet M, Petitprez F, Legendre C, et al. C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Kidney Int. 2017;92(5):1232-41.