ChemoCentryx reports positive results from Phase II diabetic nephropathy trial of CCX140

The trial met its primary endpoint by demonstrating that treatment with 5 mg of CCX140 given orally once daily added to a standard of care regimen (SOC) of angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor II blocker (ARB) treatment resulted in a statistically significant (p=0.0148) reduction in urinary albumin creatinine ratio (UACR), beyond that achieved with SOC alone.

High UACR is known to predict poor renal outcome. The maximum treatment effect (24 percent reduction) was reached at 12 weeks, and sustained reduction in albuminuria induced by CCX140 relative to SOC alone was observed over the full year, i.e., UACR at each one of the 10 time points over the 52-week treatment period in the patients who received 5 mg CCX140 continuously for 52 weeks, were below those of the SOC alone group.

A dose of 10 mg CCX140 per day did not provide more improvement in albuminuria as compared to the 5 mg dose.

In addition, estimated glomerular filtration rate (eGFR) changes were assessed. Measuring eGFR is important in assessing long-term kidney function (over many months to years), and provides the basis for Phase III clinical trial registration endpoints.

Numerous clinical trials with the current SOC (ACE inhibitors and ARBs) show that these attenuate the slope of decline of eGFR, and that this translates into a beneficial effect on clinical outcome parameters such as time to dialysis, with chronic multi-year treatment.

Treatment with CCX140 improved the eGFR profile. Initial analysis showed that after an acute effect in eGFR in the CCX140 treatment groups in the first 12 weeks, there was a sustained attenuation in the slope of annual decline in eGFR. Such eGFR profiles have been associated with successful long-term clinical benefit in kidney outcomes with approved diabetic nephropathy drugs.

The treatment group receiving 5 mg of CCX140 in addition to SOC showed an attenuated annual slope decline of 1.3 mL/min/1.73 m2, compared to SOC alone group, 2.3 mL/min/1.73 m2. The magnitude of slope improvement seen for CCX140 is consistent with drugs that have been previously approved for diabetic nephropathy.

CCX140 did not affect systemic blood pressure, suggesting that the beneficial effect of CCX140 is mediated locally in the kidney micro-environment, possibly through a beneficial reduction in renal inflammation. CCX140 appeared to be well tolerated with a low overall dropout rate over the 52-week treatment period (10 percent).

No safety issues were observed that would prevent further clinical development of CCX140 in diabetic nephropathy.

"These positive data suggest that treatment with CCX140 may result in clinically meaningful improvements in kidney function when added to standard of care in patients with chronic kidney disease," said Thomas J. Schall, Ph.D., President and Chief Executive Officer, ChemoCentryx.

"Given the positive improvements in albuminuria and eGFR observed in this clinical trial, we believe we have an effective dose of CCX140 to take forward into a Phase III clinical trial in diabetic nephropathy, and that we are well positioned to advance partnering discussions as well as an end of Phase II meeting with the FDA."

"Even with optimal current care, the residual risk in diabetic nephropathy patients for further decrease in renal function is still extremely high," said Prof. Dick de Zeeuw, M.D., Ph.D., in the Department of Clinical Pharmacy and Pharmacology at the University Medical Center in Groningen, The Netherlands.

"The search for new drugs that add to standard of care ACE inhibitor and ARB treatment is therefore of utmost importance. To date, no great successes of new drugs on surrogates like blood pressure, albuminuria, or estimated glomerular filtration rate have been reported. These robust results with CCX140, in this context, are extremely relevant and promising, particularly if translated into preservation of renal function. CCX140 should definitely be tested in a Phase III trial."

The Company plans to present the full results of this clinical trial at upcoming medical meetings.

The objectives of the Phase II study, which took place at more than 90 sites across six European countries, were to determine the safety, tolerability and signs of clinical effect of CCX140 in patients with diabetic nephropathy. CCX140 was studied in a randomized, double-blind, placebo controlled clinical trial in 332 patients with residual albuminuria, despite having received an ACE inhibitor or ARB for at least eight weeks prior to screening for this trial.

The original protocol had a 12-week treatment period that was extended to 52 weeks by protocol amendment. Of the 332 patients enrolled in the study initially, 102 patients were ineligible to re-enroll after the protocol amendment approval due to the length of time off treatment. As such 196 patients participated in the study extension to receive treatment for 52 weeks.

The primary safety objective was evaluation of the safety profile of CCX140 based on the incidence of adverse events. The primary efficacy endpoint was the evaluation of the effect of CCX140 treatment over 52 weeks on first morning urinary albumin:creatinine ratio. Secondary objectives included evaluation of the effect of CCX140 on eGFR and HbA1c.

At baseline, the mean age of the study population was 63 years, the median duration of type 2 diabetes was 14.5 years and the median duration of nephropathy was 3.3 years. The baseline mean urinary ACR for the population overall was 636 mg/g creatinine and baseline mean eGFR was 63 mL/min/1.73 m2. Baseline mean arterial blood pressure was 98 mm Hg.