Complement 3 Glomerulopathy (C3G) is an orphan disease which includes C3 glomerulonephritis (C3GN) and the closely related dense deposit disease (DDD), forms of glomerulonephritis. This disease results from abnormal regulation of the alternative complement pathway resulting in unrestrained complement activation. The clinical presentation varies from mild proteinuria to rapid renal deterioration and about half of the individuals with C3G move the End Stage Renal Disease within in 10 years of diagnosis. There are no approved drugs for C3G currently The current treatment recommendations include control of hypertension with angiotensin-converting enzyme (ACE)/angiotensin receptor blocker (ARBs) to empirical use of plasma exchange or infusion. None of these treatments address the dysregulation of the complement system. Hence, there is a significant unmet medical need for novel drugs to treat C3G. Avacopan is an orally active drug that specific inhibitor of the C5a receptor (part of the complement system) and has been shown to be safe and efficacious in Phase 1 and Phase 2 human clinical trials in AAV, and is currently being tested in a Phase 3 AAV trial. More importantly, compelling clinical, laboratory, and kidney biopsy responses have been observed in C3G patients treated with avacopan under a compassionate use protocol. Taken together, these findings provide a strong justification for a human clinical trial to test the safety and efficacy of avacopan as a novel treatment of C3G. This study will enroll 44 patients with C3G at 40 clinical sites in 11 countries. The primary goal of the study is to evaluate the efficacy of avacopan compared to placebo based on histologic changes in kidney biopsies taken before and during treatment. Secondary goals of this study include the evaluation of: 1 The safety of avacopan compared to placebo based on the incidence of adverse events, changes in clinical laboratory measurements, and vital signs; 2 Changes in laboratory parameters of renal disease including estimated glomerular filtration rate (eGFR), proteinuria, and urinary excretion of monocyte chemoattractant protein-1 (MCP- 1) with avacopan compared to placebo; 3 Health-related quality-of-life changes based on Short Form-36 version 2 (SF-36 v2) and EuroQOL-5D-5L (EQ-5D-5L) with avacopan compared to placebo; 4 The pharmacokinetic profile of avacopan in patients with C3G. Additionally, exploratory evaluations studying changes from baseline in markers of alternative complement pathway involvement and other markers of inflammation may be assessed in plasma/serum or urine over the course of the treatment period.
The term ?C3 glomerulopathy? (C3G) includes C3 glomerulonephritis (C3GN) and the closely related dense deposit disease (DDD), forms of glomerulonephritis that result from abnormal regulation of the alternative complement pathway (Smith and Pickering, 2011; Bomback and Appel, 2012; Barbour, 2013; Barbour, 2016; Noris and Remuzzi, 2015), leading to unrestrained complement activation. C3G is characterized by the deposition of complement factors in the glomerulus. A diagnosis of C3G carries serious implications, with a 10 year survival of approximately 50%, particularly in those who fail to respond to initial treatment (Kopel et al, 2016). Although heterogeneous, the pathogenesis of all C3G is believed to be driven by dysregulation of the complement system. C3G is an uncommon disease and there are no large-scale, randomized clinical trials to guide treatment (Kopel et al, 2017). Current treatment includes use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for hypertension control and treatment of hyperlipidemia, if present. For patients with severe disease plasma exchange, immunosuppression, rituximab and in a few cases eculizumab have been used, although there is no consensus on treatment of these patients. A recent Kidney Disease: Improving Global Outcomes? (KDIGO Controversies Conference (Goodship et al, 2016) concluded that ?The development and trial of complement inhibitors as therapeutic interventions for C3G is a high priority?. Currently available treatments have been used with limited success in this disease. Therefore, there is a high unmet medical to develop effective treatments for 3CG. Avacopan (formerly designated CCX168) is an oral small molecule drug candidate that specifically blocks the C5a receptor. Several lines of evidence, including work in pre-clinical models of C3G, and several C3G patients treated with Avacopan under compassionate use protocols have provided mechanistic evidence that Avacopan is a safe and novel therapeutic drug candidate for C3G. Avacopan is also in a Phase 3 trial for ANCA Associated Vasculitis (AAV), a type of autoimmune disease, where it has been shown to be both safe and effective (Bekker, 2016). This grant will facilitate a Phase 2 clinical trial to determine if avacopan is safe and effective when administered in combination with standard of care in patients with C3G.