ChemoCentryx is a biopharmaceutical company focused exclusively on discovering, developing and commercializing orally-administered therapeutics to treat autoimmune diseases, inflammatory disorders and cancer.
By altering the cellular microenvironment in diseases of inflammation, autoimmunity, and cancer, we can generate better treatment outcomes. ChemoCentryx specializes in creating orally administered new medicines that inhibit chemo-attractant receptors - the engines of cell migration in disease.
In certain diseases, discrete chemokine or chemo-attractant receptors that play a specific role in the pathology of interest have been identified, and the therapeutic goal is to specifically inhibit that receptor to provide clinical benefit. Accordingly, each of our drug candidates is a small molecule designed to target a specific chemokine or chemo-attractant receptor, thereby blocking the inflammatory response driven by that particular chemokine while leaving the rest of the immune system unaffected.
The ChemoCentryx approach is designed to discover, develop and commercialize therapeutics that we believe provide distinct advantages over currently marketed therapies in our disease areas of focus. These advantages include:
- Improved safety profile.
Our drug candidates are designed to be highly selective to minimize the risk of off-target effects. Unlike several current therapies, which broadly suppress the body's immune system, we believe that our drug candidates, by selectively blocking a given chemokine-chemokine receptor combination, and leaving other chemokine-chemokine receptor interactions unaffected, can potentially bring even aggressive forms of chronic inflammation and autoimmune diseases under control in a safe, effective manner.
- Convenient dosing and improved patient compliance.
Our current drug candidates are designed to be administered orally, providing what we believe to be an important improvement in patient convenience and the potential for improved patient compliance as compared to existing intravenous and subcutaneous treatments with biologics.
- Lower production costs.
Unlike biologic agents, which require complex and expensive cell based systems to produce a given biologic agent, our drug candidates are typically cheaper to manufacture given that small molecules can be synthesized using standard chemistry processes.
ChemoCentryx has five drug candidates in clinical development. All five drug candidates are wholly owned and are being developed independently by us. All of our drug candidates have been internally discovered.
Our four key focus areas are: 1) the complement fragment C5a receptor (C5aR) inhibitor program, led by our unique C5aR inhibitor CCX168; 2) the chemokine receptor CCR2 program and the inhibitors CCX140 and CCX872; 3) the chemokine receptor CCR9 program, with vercirnon and CCX507; and 4) earlier-stage inhibitors of other chemoattractant receptors important in emerging areas of inflammation and immuno-oncology.
CCX168 targets the chemo-attractant C5a receptor, or C5aR, which binds to a biologically activated fragment of the complement protein known as C5a. Chemo-attractant receptors are related to the chemokine receptor family and similarly regulate the migration of certain types of inflammatory cells. The chemokine system is more likely a more recent evolutionary branch of other chemo-attractant systems in the body such as the complement system. The complement system includes the protein C5a, which under certain conditions has pro-inflammatory effects. CCX168 targets the chemo-attractant C5a receptor, or C5aR, which binds to a biologically activated fragment of the complement protein known as C5a.
C5a acting through C5aR is thought to play a pro-inflammatory role in a range of inflammatory and autoimmune diseases such as ANCA associated renal vasculitis, psoriasis, urticarial, age-related macular degeneration, and lupus. CCX168 via blocking C5a binding to C5aR should thus have therapeutic value in treating these diseases. We completed a Phase I clinical trial for CCX168, conducted in Switzerland, which showed that CCX168 was well-tolerated at doses up to 100mg. We completed the first two steps of a three-step Phase II clinical trial in AARV. Data from the first two steps of the C 5aR inhibitor on Leukocytes Exploratory.
A NCA-associated Renal Vasculitis or CLEAR, trial were promising, demonstrating that CCX168 appears to be safe, well-tolerated and successful in allowing both reduction and elimination of high-dose corticosteroids, part of standard of care for AARV patients, without compromising efficacy or safety during a 12-week treatment period. There were no serious unexpected suspected adverse reactions reported by patients taking CCX168. Furthermore, CCX168 treatment showed greater improvements consistently across a number of renal health parameters, including renal remission, albuminuria and the Birmingham Vasculitis Activity Score, or BVAS, compared to standard of care treatment. This clinical trial has been conducted in Belgium, Czech Republic, Germany, Hungary, the Netherlands, Poland, Sweden and the United Kingdom. Under the terms of an alliance with GSK established in August 2006, GSK declined its option to license CCX168. Accordingly, we plan to independently develop CCX168 and expand the clinical development program for CCX168 in AARV.
CCX140 targets the chemokine receptor known as CCR2. CCX140 is a potent and selective inhibitor of CCR2 that is found on subsets of monocytes and macrophages, which are cells of the immune system believed to play an important role in inflammatory processes. Blocking CCR2 is intended to reduce the abnormal monocyte and macrophage driven inflammatory response implicated in renal disease. In addition, it has been shown that levels of CCL2 (also known as MCP-1), the main ligand for CCR2, are elevated in the kidneys of patients with diabetic nephropathy, which is characterized by a persistent and usually progressive decline in renal function. New science has shown that renal cells themselves may express CCR2 under pathological conditions and that this may be responsible for some of the effects of diabetic nephropathy. Current treatments of patients with diabetic nephropathy primarily focus on treatment of the underlying type 2 diabetes and hypertension. Given that the current standard of care does not halt or reverse the progression of diabetic patients with impaired kidney function to end-stage renal disease, we believe that an unmet medical need persists for the treatment of diabetic nephropathy. As a precursor to our clinical trials in patients with diabetic nephropathy, in 2011, we completed a 159-patient randomized Phase II clinical trial, conducted in Australia, the Czech Republic, Germany, Hungary and New Zealand, to assess the safety and tolerability of CCX140 in patients with type 2 diabetes, the most common cause of diabetic nephropathy. CCX140 was safe and well-tolerated in this trial. In addition, CCX140 demonstrated biological activity through a dose-dependent decrease in fasting plasma glucose. The highest dose of 10mg CCX140 administered once-daily also lowered hemoglobin A1c, or HbA1c, with statistical significance compared to placebo over a four-week period.
CCX140 has completed a Phase II clinical development in patients with diabetic nephropathy, also known as diabetic kidney disease. 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 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, a 24 percent reduction in UACR, was reached at 12 weeks, and sustained reduction in albuminuria induced by CCX140 relative to SOC alone was observed over the full year. In addition, estimated glomerular filtration rate (eGFR) changes were assessed. Treatment with CCX140 improved the eGFR profile. 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. 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.
CCX140 appeared to be well tolerated with a low overall dropout rate over the 52-week treatment period. No safety issues were observed that would prevent further clinical development of CCX140 in diabetic nephropathy.
CCX872 is our second generation CCR2 inhibitor. We completed Phase I clinical development in 2014. We plan to commence a Phase Ib multi-center clinical trial in patients with non-resectable pancreatic cancer in 2015. The goal of this study will be to evaluate the safety and efficacy of CCX872 in combination with FOLFIRINOX. In addition to diabetic nephropathy and other renal diseases, CCR2-mediated effects are thought to be involved in the pathology of ischemia-reperfusion injury of organs such as kidney and heart, as well as various metabolic diseases, such as atherosclerosis and cardiovascular disease. These effects may be mediated by a combination of direct activation of CCR2 in the cells of the target tissue and by inducing recruitment of circulating inflammatory cells into the tissue. Inhibition of CCR2 in various animal models has been shown to be beneficial in models of acute kidney injury, post myocardial infarction reperfusion injury, vascular endothelial injury, and hepatosteatosis (fatty liver), among others.
Vercirnon (also known as Traficet-EN or CCX282) targets the chemokine receptor known as CCR9. Vercirnon is our Phase III-ready drug candidate for the treatment of patients with moderate-to-severe Crohn's disease. We completed a Phase II clinical trial of vercirnon for the treatment of patients with moderate-to-severe Crohn's disease, called PROTECT-1. This study was designed to evaluate vercirnon for the induction of clinical response or remission in patients with Crohn's disease as well as to evaluate the utility of vercirnon as maintenance therapy. CCX507 builds on our expertise in the area of CCR9 inhibitors and IBD, with which we have designed a series of novel molecules that we believe represent the second generation of CCR9 inhibitors. CCX507 is selective for CCR9 relative to all other chemokine receptors, orally bioavailable, and has an excellent preclinical safety profile. CCX507 has been designed to interact with the CCR9 receptor in a way that produces molecules with greater potency towards CCR9 than other compounds reported to date. We completed a Phase I clinical trial in 2013 and anticipate completing Phase I clinical development in the first half of 2014 whose results showed that CCX507 is safe and well tolerated in healthy volunteers at all doses tested, and effectively blocked CCR9 on circulating leukocytes. We plan to move the compound forward to Phase II clinical trials, potentially in conjunction with a strategic partner.
We are also advancing several additional independent drug candidates through preclinical development, the most advanced of which target chemokine receptors involved in atopic dermatitis, liver inflammation, psoriasis, RA and cancer. Programs in preclinical development include:
- Anti-inflammatory compounds that target CCR4, a chemokine receptor we believe to be associated with atopic dermatitis, allergic rhinitis and asthma;
- Anti-inflammatory compounds that target CCR6, a chemokine receptor we believe to be associated with psoriasis and RA;
- Anticancer compounds that target CXCR7, a chemokine receptor we believe to be associated with tumor growth; and
- Additional compounds under evaluation targeting a chemokine receptor for indications in liver disease.
A growing body of data suggest that a number of chemokine receptors, including CCR1, CCR2, CCR4, CCR5, CCR6, CXCR2, CXCR4, and CXCR7, may play a diversity of roles in cancer growth, cancer metastasis, cancer angiogenesis, or the composition of the tumor microenvironment. Because of the role of chemokine receptors in cancer cell survival, the combination of chemokine receptor antagonists with traditional chemotoxic agents or with immunotherapy is an alluring strategy since this increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.
ChemoCentryx has developed a suite of proprietary technologies, called the EnabaLink® drug discovery engine, to better understand the chemokine system and to accelerate the identification of small molecule lead compounds that target and inhibit the function of specific chemokine receptors. ChemoCentryx has leveraged the EnabaLink drug discovery engine in our drug candidate programs and continue to apply these powerful research tools in our early stage drug discovery efforts.
We believe that our broad pipeline of oral drug candidates, our ability to advance unique, highly specific compounds into and through clinical development across diverse indications and our proprietary drug discovery technologies provide us with distinct advantages that will enable us to exploit the extensive pharmacologic potential of the chemokine system.
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