-- Primary endpoint achieved: CCX168 demonstrates numerical superiority and achieves statistical significance in test for non-inferiority in BVAS response relative to standard of care --
-- Treatment with CCX168 successful in eliminating high-dose oral corticosteroids from current standard-of-care regimen without compromising efficacy --
-- CCX168 treatment resulted in rapid and pronounced improvements in BVAS, albuminuria, and other indicators of renal disease, as well as quality of life assessments --
-- CCX168 appears safe and well tolerated --
-- Company plans to advance CCX168 into Phase III development in AAV in 2016 --
-- Conference call and webcast with topline data presentation today at
The Phase II CLEAR was designed to assess whether high dose chronic steroids used in the standard of care (SOC) regimen in AAV could be sharply reduced or eliminated, without compromising efficacy, by replacement with CCX168, a specific inhibitor of the C5aR. The complement component C5a and its receptor are thought to activate the autoimmune cells that destroy the blood vessels in AAV. Steroid elimination is desirable because steroids are strongly implicated in infections and other serious adverse events resulting in premature death in AAV, as well as long term toxicities, and cumulative organ damage.
The CLEAR trial met its primary endpoint based on the Birmingham Vasculitis Activity Score (BVAS) response at week 12 in patients receiving CCX168, compared to those patients receiving the high dose steroid-containing standard of care. Specifically, all treatment groups receiving CCX168 demonstrated a statistically significant (P=0.005) non-inferior clinical efficacy outcome when compared to SOC. The study contained two CCX168 treated groups: one group which received CCX168 with a low dose of steroid (i.e. one third the steroid in the SOC), in which the BVAS response was 86% at week 12 vs 75% for SOC; P=0.005 for non-inferiority. A separate group received CCX168 in the absence of any steroid; in this group the response was 81% (P=0.02 for non-inferiority). SOC treatment included a placebo to CCX168, and all treatment groups received a standard background immunosuppressant (cyclophosphamide or rituximab) as well. The primary endpoint of BVAS response was prospectively defined as a decrease from baseline of at least 50% in BVAS plus no worsening in any body system. BVAS measures AAV disease activity across all organ systems and is the most widely used and clinically validated outcome measure in AAV clinical trials. The greater the reduction in BVAS score, the greater the disease improvement.
Other beneficial changes were noted, including in pre-specified secondary endpoints:
- CCX168 exhibited a more rapid onset of improvement than SOC treatment, as evidenced by beneficial changes in proteinuria (measured as urinary albumin:creatinine ratio, or UACR); also rapid beneficial reductions from baseline in BVAS, as well as reductions in the levels of MCP-1 (a marker of kidney inflammation) found in the urine;
- Improvements in estimated glomerular filtration rate (eGFR) and hematuria were seen in all three treatment groups, indicating these disease activities did not require high dose chronic steroid administration to be controlled;
- Improvements in "Quality of Life" (as defined by the visual analogue scale of the EuroQOL-5D-5L measurement) were seen in CCX168 treatment groups, but not in the SOC group
Taken together, these results indicate that CCX168, a target-specific complement inhibitor, can replace chronic steroids in the treatment of AAV with at least equal efficacy. CCX168 also appeared safe and well tolerated in the trial. There were no observations that would prevent further clinical development of CCX168. The Company has also recently completed the long-term toxicology program with CCX168. The results provide support for chronic dosing of CCX168 in future clinical trials.
"For my patients with AAV, I would absolutely welcome a safer treatment with a rapid onset of action, retained existing efficacy outcomes, and which also would enable me to eliminate steroids from the current treatment regimen," said
"We are extremely pleased with the CLEAR trial results in 67 patients with AAV, particularly the ability of CCX168 to eliminate the need for chronic steroid administration, thus greatly lessening the harmful side-effects associated with long-term steroid usage. Based on these results, we believe CCX168 could change the treatment paradigm for patients with AAV," said
About the CLEAR Trial and CCX168 in ANCA-Associated Vasculitis
The European CLEAR trial is a 3-step randomized, double-blind, placebo-controlled Phase II trial designed to evaluate the safety and efficacy of CCX168 in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) on background cyclophosphamide or rituximab treatment. Efficacy measurements included global vasculitis disease activity, as measured by Birmingham Vasculitis Activity Score (BVAS), urinary albuminuria as measured by first morning urinary albumin:creatinine ratio, estimated glomerular filtration rate (eGFR) based on serum creatinine, hematuria (based on microscopic RBC count), and urinary MCP-1:creatinine ratio.
Across the three steps of the CLEAR trial, which was conducted in 11 countries in
The Company's CCX168 AAV clinical development program also includes the ongoing North American Phase II CLASSIC trial. The CLASSIC trial is evaluating the safety and efficacy of twice daily, 10 or 30 mg CCX168, for 12 weeks, when added to the full-dose corticosteroid standard of care regimen plus cyclophosphamide or rituximab. Top-line data from the CLASSIC trial are expected in mid 2016.
About ANCA-Associated Vasculitis
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, or AAV, is a type of rare autoimmune inflammation caused by auto-antibodies. AAV encompasses granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis), microscopic polyangiitis (MPA), eosinophilic polyangiitis (formerly Churg-Strauss syndrome) and renal limited vasculitis. By damaging the body's small blood vessels, AAV can affect any organ system, but mostly involves the kidneys, lungs, and ear/nose/throat. This damage is caused by the destructive activity of inflammatory leukocytes in the body, with neutrophils considered to be the terminal effector cell. In AAV, C5a and its receptor, the target of CCX168, are involved in priming and activation of neutrophils, chemoattraction and vascular endothelial adhesion of these neutrophils and other leukocytes, and increased vascular permeability. By blocking the C5aR, CCX168 is thought to reduce vasculitis by reducing neutrophil activation, accumulation, and adhesion, as well as vascular permeability.
AAV affects approximately 40,000 people in
The current standard of care for AAV is associated with significant safety issues. First year mortality is approximately 11 to 18 percent. The single major cause of premature mortality is not disease related adverse events, but rather treatment-induced, including infection that is thought largely to be a consequence of corticosteroid administration. Indeed, the multiple adverse effects of courses of corticosteroid treatment (both initial courses and those that are repeated as a consequence of relapse) are major causes of both short-term and long-term disease and death. Such therapy-related adverse events contribute significantly to patient care costs, as well as to the diminution of quality of life for patients.
CCX168 is an orally-administered complement inhibitor, specifically targeting the C5a receptor (C5aR), which binds the complement fragment C5a. CCX168 is the lead drug candidate in the Company's orphan and rare disease program and is being developed for various autoimmune disorders including
Conference Call and Webcast Information
The Company will host a conference call and webcast today,
Susan M. KanayaSenior Vice President, Finance and Chief Financial Officer [email protected] Media: Denise Powell[email protected] 510.703.9491 Investors: Kimberly Minarovich Burns McClellan212.213.0006 [email protected]