ChemoCentryx and VFMCRP Provide Topline Results from ACCOLADE Trial of Avacopan in C3 Glomerulopathy Including Improved Estimated Glomerular Filtration Rate (eGFR)
- As in ANCA vasculitis, avacopan demonstrated statistically significant improvement in renal function as measured by eGFR compared to placebo over 26 weeks of blinded treatment
- The change from baseline to Week 26 in C3 Glomerulopathy Histologic Index (C3G HI) for Disease Activity (primary endpoint) was not statistically different between the two treatment groups, while the C3G HI for Disease Chronicity (measuring progression of fibrosis) shows significant benefit for avacopan versus placebo
- Avacopan safe and well tolerated in C3G patients
ChemoCentryxand VFMCRP plan to discuss registration pathway with regulatory agencies in US and EU
- Conference call today at
4:30 pm Eastern Time
Patients in the multi-center ACCOLADE clinical trial were randomized to receive either 30mg of avacopan twice daily (BID) or placebo for 26 weeks in a double-blind manner. The primary endpoint of the study was defined as the change from baseline in the C3G Histologic Index for Disease Activity, as determined by a blinded analysis of kidney biopsies taken at baseline and after 26 weeks of blinded study treatment. Pre-specified secondary endpoints included changes in the estimated Glomerular Filtration Rate (eGFR) (a validated measure of overall renal function), measurement of urinary protein to creatinine ratio (UPCR), measurements of urinary MCP-1 (a marker of kidney inflammation), and the C3G Histologic Index for Disease Chronicity, a biopsy based measure of the progression of renal fibrosis which is a strong predictor for progression to end stage renal disease (ESRD) in C3G. After the initial blinded treatment period, all patients receive avacopan as part of an open label extension for a further 26 weeks. Endpoint determinations from the blinded treatment period (baseline to week 26) are presented.
“The ultra-rare disease, C3 glomerulopathy, is a progressive kidney disorder where a person’s renal function inexorably declines, where we have no approved therapy, and also no clear roadmap on how to get to an approved therapy,” said
“We are pleased with the results of the ACCOLADE study,” said
The primary endpoint of the study was change from baseline to week 26 in the C3G Histologic Index for Disease Activity1, comparing the changes in kidney histology from biopsy sections taken from patients characterized by elevated levels of C5b-9 complement markers in the blood at time of study entry (baseline). Biopsies, taken at baseline and after 26 weeks of treatment showed that the placebo group worsened by 38% on average in the C3G Activity Score while the avacopan group improved by 2% on average. This approximately 40% average difference between the two treatment arms did not constitute statistical significance due to the high patient to patient variability. Comparison of the C3G Activity Score of all C3G subjects (comprising those with both elevated levels of C5b-9 as well as those with normal levels of C5b-9) yielded similar results: the placebo group worsened by 26% on average in the C3G Activity Score, while avacopan therapy resulted in an improvement of 6% on average.
Importantly, those patients who received avacopan experienced significant benefits in terms of kidney function and other parameters compared to those who received placebo. These benefits, assessed as pre-specified secondary endpoints, include:
Slowing of Fibrosis Progression
Avacopan therapy demonstrated evidence for a significant slowing of the progression of fibrosis as assessed by the C3G Histologic Index for Disease Chronicity. The placebo group overall exhibited a 26 percentage point higher change from baseline to Week 26 in the C3G Index for Disease Chronicity than avacopan (58% versus 32%, respectively) representing a worsening in disease chronicity. The mean change from baseline to week 26 was 1.6 for placebo versus 0.8 for avacopan (P<0.05). The avacopan-related lower increase is notable because published literature shows that each 1-unit increase in C3G Histologic Index for Disease Chronicity from baseline increases by 59% (P < 0.001) the risk of doubling of creatinine, progression to chronic kidney disease stage 5, ESRD requiring dialysis or transplantation, or death.1
Improvement in Kidney Function
The avacopan group demonstrated a statistically significant improvement in eGFR from baseline to week 26. Overall, the eGFR in the avacopan group improved 5% on average from baseline while the placebo group worsened by 6% (P = 0.0221). Renal improvement was particularly pronounced for C3G subjects with eGFR of < 60 mL/min/1.73 m2 at baseline, as their eGFR on average increased relative to placebo by nearly 20% after 26 weeks (13% improvement for avacopan versus 6% worsening from baseline for placebo, P = 0.0199). This was equivalent to a mean increase of about 5 mL/min/1.73 m2 on avacopan versus a decrease of 1.4 mL/min/1.73 m2 in the placebo group. Significant improvement in eGFR in a blinded comparative setting over 26 weeks has not been noted in C3G studies prior to this, but the improvement in eGFR with avacopan is reminiscent of a similar improvement seen with avacopan therapy in ANCA–associated vasculitis with renal dysfunction.
Other measures of kidney function include UPCR (proteinuria), where high UPCR is known to be associated with higher risk of ESRD in C3G as well as other renal diseases, and urinary MCP-1 creatinine ratio, a marker of glomerular inflammation.
In the ACCOLADE study, avacopan therapy was associated with a rapid reduction in UPCR (proteinuria). From baseline, a progressive proteinuria drop was seen in the avacopan group: at week 16 there was a 35% mean decrease in UPCR with avacopan versus a 1% decrease in the placebo group (P < 0.05), and at the end of 26 weeks UPCR was reduced by 26% in the avacopan group versus 14% in the placebo group.
Similar reductions were seen in urinary MCP-1 creatinine ratio in the avacopan group versus the placebo group throughout the 26-week treatment period, with the avacopan group consistently exhibiting lower levels of the kidney inflammation marker being shed in the urine.
Avacopan also appeared safe and well-tolerated in patients with C3G.
In the ongoing phase of the study (after the 26 week blinded treatment period), all patients receive avacopan as part of an open label extension for a further 26 weeks, and are followed for an additional 8 weeks without study treatment. Data from the open label and follow up period will be analyzed and presented at a future time.
Based on the data described above, reflecting results of a blinded therapy regimen which resulted in evidence of avacopan’s ability to improve renal function, being well-tolerated in C3G patients to date, and the significant unmet medical need for C3G patients for whom there are no approved therapies to treat renal function decline,
- Bomback AS, et al. C3 glomerulonephritis and dense deposit disease share a similar disease course in a large
United Statescohort of patients with C3 glomerulopathy. Kidney Int. 2018.
Conference Call and Webcast
|Contact and further information:|
+41 79 957 96 73
Head of Investor Relations
+41 58 851 66 90
|Executive Vice President|
|Chief Financial and Administrative Officer|
For more information, please visit viforpharma.com
ChemoCentryx is a biopharmaceutical company developing new medications for inflammatory and autoimmune diseases and cancer. ChemoCentryx targets the chemokine and chemoattractant systems to discover, develop and commercialize orally-administered therapies.
Besides ChemoCentryx’s lead drug candidate, avacopan, ChemoCentryx also has early stage drug candidates that target chemoattractant receptors in other inflammatory and autoimmune diseases and in cancer.
About C3 Glomerulopathy and the ACCOLADE Trial
Complement 3 Glomerulopathy (C3G) is a very rare, potentially progressive kidney disease which can present in patients of all ages, including children. It is diagnosed on kidney biopsy performed because the patient has kidney impairment, hematuria and/or loss of protein into the kidneys. Treatment is challenging and there is no approved drug with proven benefit so patients are at risk of progression to End Stage Renal Disease (ESRD). 30-50% will progress to ESRD within 10 years of diagnosis. The complement system is dysregulated in C3G with various mutations and acquired factors in different patient groups. These can be assessed in specialist centers and may be helpful in understanding treatment approaches and risk of ESRD.
The Phase II ACCOLADE clinical trial randomized patients with C3G to avacopan or placebo. The pre-specified primary endpoint assesses 30 mg BID of avacopan against placebo at 26 weeks of treatment, using the C3G Histologic Index – this is an index assessing acute and chronic damage in the kidney. Pre-specified secondary endpoints include stabilization in disease chronicity, reduction in proteinuria, changes or improvement in renal function and quality of life.
Following the 26-week double-blind treatment period, all patients receive avacopan for a further 26 weeks. Patients are followed for an additional 8 weeks for assessment of safety and efficacy.
Avacopan is an orally-administered small molecule that is a selective inhibitor of the complement C5a receptor C5aR1. By precisely blocking the receptor (the C5aR) for the pro-inflammatory complement system fragment, C5a on destructive inflammatory cells such as blood neutrophils, avacopan arrests the ability of those cells to do damage in response to C5a activation, which is known to be the driver of inflammation. Moreover, avacopan’s selective inhibition of only the C5aR1 leaves the beneficial C5a l pathway through the C5L2 receptor functioning normally.
Source: ChemoCentryx, Inc.