— Treatment with CCX168 successful in achieving clinical efficacy endpoints while eliminating high-dose oral corticosteroids from current standard-of-care regimen, suggesting a new treatment paradigm for ANCA-Associated Vasculitis —
— Separately, utilization of CRISPR-Cas9 to create novel models of complement mediated renal diseases such as aHUS and C3 glomerulopathy highlighted in poster presentation —
MOUNTAIN VIEW, Calif., May 23, 2016 (GLOBE NEWSWIRE) — ChemoCentryx, Inc., (Nasdaq:CCXI), a clinical-stage biopharmaceutical company developing orally-administered therapeutics to treat autoimmune diseases, inflammatory disorders, and cancer, today announced the presentation of positive results from its Phase II CLEAR trial with CCX168 in patients with anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, or AAV, at the 53rd European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Congress, being held May 21-24 in Vienna, Austria. CCX168 is a potent orally-administered small molecule that is a selective inhibitor of the complement C5a receptor, or C5aR, and is the lead drug candidate in the Company’s orphan and rare disease program.
The Phase II CLEAR trial was designed to assess whether high dose chronic steroids (such as prednisone or methylprednisone) currently used in the AAV standard of care (SOC) regimen could be sharply reduced or eliminated, without compromising efficacy, by replacement with CCX168. Chronic high dose steroid administration is associated with significant safety issues, including premature death, in AAV.
The key points highlighted in the presentation include the following:
- The CLEAR trial was successful and met its primary endpoint based on Birmingham Vasculitis Activity Score (BVAS) response at Week 12:
- The proportion of patients with BVAS response at Week 12 was numerically superior and statistically non-inferior in patients receiving CCX168 plus low dose steroids (86%, p=0.002 vs. SOC), and CCX168 plus no steroids (81%, p=0.01 vs. SOC) compared to the high dose steroid containing SOC group (70%);
- The mean percent change from baseline to Week 12 in BVAS was -79% in the CCX168 plus low dose steroid group, -73% in the CCX168 plus no steroid group, compared to -57% in the SOC group;
- A higher proportion of patients receiving CCX168 had early clinical remission at Week 4, sustained through Week 12:
- 29% in the CCX168 plus no steroid group and 14% in the CCX168 plus low dose steroid group, compared to only 5% in the SOC group;
- Statistically significant superior improvement in lowering albuminuria, after only 4 weeks of treatment with CCX168. There was a 47% decrease in albuminuria in patients receiving CCX168 without any steroids (p=0.0006 vs. SOC), and a 40% decrease in patients receiving CCX168 plus low dose steroids (p=0.003 vs. SOC), but an increase of 15% in patients with high dose steroid containing SOC; at Week 12, the change from baseline was -56%, -44%, and -21% in the three groups, respectively;
- Patients receiving CCX168 (especially those who did not receive steroids), compared to the SOC group, showed a significant improvement in health-related quality of life aspects such as physical functioning, mental health, emotional well-being, pain, and vitality as measured by the Short Form-36 version 2 and EuroQOL-5D-5L instruments;
- Patients receiving CCX168 showed less cumulative organ damage, based on the Vasculitis Damage Index (VDI) compared to the SOC group;
- Estimated glomerular filtration rate (eGFR), based on serum creatinine, and hematuria, based on microscopic RBC count, improved similarly with CCX168 compared to control, indicating that steroids are not needed to improve renal function when patients are taking CCX168;
- A marker of renal inflammation, creatinine-corrected urinary MCP-1 excretion, decreased more with CCX168 compared to SOC; and
- CCX168 appeared to be well tolerated in patients with AAV.
“We are pleased to present for the first time at a major medical conference the full data set from the Phase II CLEAR trial, including secondary endpoints that further demonstrate the ability of CCX168 to potentially serve as a replacement for chronic steroids in the treatment of AAV,” said Thomas J. Schall, Ph.D., President and Chief Executive Officer. “The importance of these findings is underscored by the ERA-EDTA’s selection of the presentation as one of the top eight abstracts at the conference. Based on these clinical findings, we continue to prepare for regulatory discussions that we expect will pave the way for Phase III development of CCX168 by the end of this year.
“The data from the CLEAR trial suggest that CCX168 has a rapid onset of action and could potentially replace chronic steroids currently used in the treatment of AAV with the same or better efficacy,” said Dr. David Jayne, Director, Vasculitis and Lupus Clinic, the University of Cambridge, UK and Principal Investigator of the study. “Given the high incidence of morbidity and mortality associated with high dose chronic steroids in this disease setting, CCX168 may offer an important and safer therapeutic option, minimizing or eliminating the use of steroids while potentially improving long-term kidney outcomes in patients with AAV.”
In a separate poster presentation, ChemoCentryx presented details of the creation of a colony of genetically unique mice that are designed to assess the effects of inhibiting the C5aR with CCX168 on diseases characterized by unregulated complement activation, such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). Using CRISPR technology, the Company’s scientists generated mice whose complement system was continuously activated as a consequence of mutating the gene for complement factor H (CFH), an innate down-regulator of complement activation in the body, in mice already genetically altered to express the human C5aR in place of the mouse homolog. In this way, diseases related to CFH dysregulation could be examined in this in vivo system, and the therapeutic benefit of using CCX168 can be evaluated. The mice were examined for signs of spontaneous renal vascular disease, including hematuria, proteinuria and reduced glomerular filtration rate. The data suggest that CFH mutation contributes to renal damage in prototypical complement-mediated kidney diseases such as aHUS and C3G. This unique mouse colony and the singular features it exhibits will now allow for evaluation of inhibition of C5aR by CCX168 in models of important human diseases that prior to this time were intractable to therapeutic assessment.
Presentation information is as follows:
|Phase II CLEAR Data Oral Presentation:|
|Title:||Successful Steroid Replacement in ANCA-Associated Vasculitis with C5a Receptor Inhibitor CCX168 in Phase 2 Randomised Trial (CLEAR) (Abstract No. MO039)|
|Session Title:||Free Communication Session: Glomerulonephritis: clinical and experimental 1|
|Session Date &Time:||Monday, May 23, 2016, 3:15 PM CEST|
|Presenter:||Dr. David Jayne, Director, Vasculitis and Lupus Clinic, the University of Cambridge, UK and Principal Investigator of the CLEAR trial|
|CRISPR C5a Receptor Preclinical Data Poster Presentation:|
|Title:||Creation of Mouse Models of Complement Mediated Renal Disease Using CRISPR-Cas9 to Introduce Known Human Factor H Mutations in Human C5a-Receptor Knock-In Mice (Poster No. SP042)|
|Session Title:||Poster Session: Renal pathology. Experimental and clinical – 1|
|Session Date &Time:||Sunday, May 22, 2016, 9:30 AM CEST|
|Authors:||Chris Li, Linda Ertl, Pirow Bekker, Israel F. Charo, Thomas J. Schall|
A copy of the poster can be obtained by contacting the Company.
About the CLEAR Trial and CCX168 in ANCA-Associated Vasculitis
The European CLEAR trial was 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 Europe, patients received one of three treatment regimens: (1) Placebo + cyclophosphamide or rituximab + full starting dose of prednisone (60 mg), (2) CCX168 30 mg twice daily + cyclophosphamide or rituximab + reduced starting dose of prednisone (20 mg), or (3) CCX168 30 mg twice daily + cyclophosphamide or rituximab + no prednisone. The cyclophosphamide regimen was 15 mg/kg intravenously every two to four weeks. The rituximab regimen was 375 mg/m2 intravenously weekly for four weeks. The primary endpoint compared the two CCX168 treatment groups versus the standard of care control group, based on BVAS response.
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 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 June 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.
AAV represents a severe and often fatal autoimmune disease that is characterized by inflammation that can destroy different organ systems. AAV is the lead indication in the Company’s orphan and rare disease program which has the objective of eliminating chronic high dose steroids, which are associated with significant safety issues including death, from the standard of care (SOC) regimen in AAV and replace steroids with CCX168.
AAV affects approximately 40,000 people in the U.S. (with approximately 4,000 new cases each year) and greater than 75,000 people in Europe (with at least 7,500 new cases each year), and is currently treated with courses of immuno-suppressants (cyclophosphamide or rituximab) combined with high dose steroid administration. Following initial treatment, up to 30 percent of patients relapse within six to 18 months, and approximately half of all patients will relapse within three to five years.
Current SOC 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 infection that is thought largely to be a consequence of steroid administration. Indeed, the multiple adverse effects of courses of steroid 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.
By damaging the body’s small blood vessels, AAV affects many organ systems, mostly the kidneys, eyes, lungs, sinuses and nerves. 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, neutrophils are attracted to sites of vascular destruction as well as activated at those sites by the activity of the complement system product known as C5a and its receptor, C5aR, which is the target of CCX168. By blocking the C5aR, CCX168 is thought to reduce vasculitis by reducing neutrophil activation, accumulation, and adhesion, as well as vascular permeability.
About Complement Mediated Diseases aHUS and C3G
Atypical hemolytic uremic syndrome, or aHUS, an ultra-rare, life threatening disease that causes chronic blood vessel damage, thrombosis or clotting within blood vessels, hemolysis or red blood cell rupture, and sudden, progressive organ failure, such as kidney failure. The disease is caused by genetic defects in factors that control the activation of the complement system. Current treatment options are still quite limited and prognosis and quality of life are extremely poor.
C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. The major features of C3G include high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body. Rapidly progressive forms of C3G usually respond poorly to conventional treatments.
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 ANCA-associated vasculitis (AAV), atypical hemolytic uremic syndrome (aHUS) and immunoglobulin A nephropathy, or IgA nephropathy.
ChemoCentryx, Inc. is a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing orally-administered therapeutics that target the chemokine and chemoattractant systems in order to treat autoimmune diseases, inflammatory disorders and cancer. The chemokine system is a biological network that regulates inflammation via a collection of secreted chemokine molecules, or ligands, and their specific cell surface receptors. Based on its proprietary drug discovery and drug development platform, ChemoCentryx has generated multiple clinical and preclinical-stage programs, each targeting distinct chemokine and chemoattractant receptors with different small molecule compounds. CCX168, a C5aR inhibitor, is in Phase II development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). CCX168 appears to be safe, well tolerated and successful in allowing reduction and elimination of high-dose steroids, part of standard of care for AAV patients, without compromising efficacy or safety in clinical studies to date. CCX168 is also in Phase II studies for the treatment of atypical hemolytic uremic syndrome (aHUS) and immunoglobulin A nephropathy, or IgA nephropathy (IgAN). CCX872, a CCR2 inhibitor, successfully completed Phase I development and is in development for the treatment of non-resectable pancreatic cancer. CCX140, a distinct CCR2 inhibitor, successfully completed a Phase II clinical trial where it was shown to be safe and well tolerated while demonstrating statistically significant improvement in albuminuria in patients with diabetic nephropathy. Other clinical programs include CCX507, a next generation CCR9 inhibitor, which has successfully completed Phase I development, vercirnon (also known as Traficet-EN or CCX282) a specific CCR9 inhibitor for the treatment of inflammatory bowel disease, and CCX354, a CCR1 inhibitor which successfully completed a Phase II clinical trial for the treatment of rheumatoid arthritis. ChemoCentryx also has several programs in advanced preclinical development.
ChemoCentryx cautions that statements included in this press release that are not a description of historical facts are forward-looking statements. Words such as “may,” “could,” “will,” “would,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “intend,” “predict,” “seek,” “contemplate,” “potential,” “continue” or “project” or the negative of these terms or other comparable terminology are intended to identify forward-looking statements. These statements include the Company’s statements regarding whether CCX168 will be shown to be effective in Phase 3 clinical trials in the treatment of AAV and other orphan and rare diseases. The inclusion of forward-looking statements should not be regarded as a representation by ChemoCentryx that any of its plans will be achieved. Actual results may differ from those set forth in this release due to the risks and uncertainties inherent in the ChemoCentryx business and other risks described in the Company’s filings with the Securities and Exchange Commission (“SEC”). Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and ChemoCentryx undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. Further information regarding these and other risks is included under the heading “Risk Factors” in ChemoCentryx’s periodic reports filed with the SEC, including ChemoCentryx’s Annual Report on Form 10-K filed with the SEC March 14, 2016 and its other reports which are available from the SEC’s website (www.sec.gov) and on ChemoCentryx’s website (www.chemocentryx.com) under the heading “Investors.” All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
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