Chemokine Receptor Antagonists: ChemoCentryx Is An Aged Red Wine Ripe For Success
- Chemokine biology gained scientific prominence in 1996 when it was discovered that chemokine receptors act as co-receptors for the binding and entry of HIV into target cells.
- 25 years after the initial characterization of chemokine receptors, chemokine receptor antagonists are now used therapeutically to treat HIV/AIDS infection, adult T-cell leukemia/lymphoma and induce hematopoietic stem cells mobilization.
- Chemokines and their receptors are key regulators of leukocyte trafficking and activation to sites of inflammation/injury where they promote interactions between the innate and adaptive immune systems.
- The CDC estimates that >30 million adults in the US have chronic kidney diseases (CKDs) costing$100 billion annually. Their standard steroid therapy has a myriad of side effects.
- No chemokine receptor antagonist(s) has been approved therapeutically for inflammatory diseases. I analyze pioneering clinical data in support of chemokine receptor antagonist, CCX140-B, in a new therapeutic approach to rare CKDs.
Background on Chemokines and their Receptors
Chemokines, chemoattractant cytokines, are a family of small (8 to 15-kDa) structurally related proteins that are one of the most important regulators of leukocyte trafficking and activation (Rollins, Blood, 1997; Baggiolini, Nature, 1998). They control cell migration and cell positioning throughout development, homeostasis, and inflammation and also play a key regulatory role in the biology of non-immune cells important for tumor growth and progression (Sokol & Luster, Cold Spring Harb. Perspect. Biol., 2015). Chemokines exhibit a high degree of conservation between mice and humans. At present, the chemokine superfamily consists of approximately 50 endogenous chemokine ligands and their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, which is made up of 23 members (Bachelerie et. al. Pharmacol. Reviews, 2014). Chemokines and their receptors are structurally subdivided into four subfamilies, XC, C-C, C-X-C, and C-X-X-X-C, based on the position of the first two amino terminal cysteine residues present on the ligand. Thus, CXC chemokine ligands have one amino acid separating first two N-terminal cysteine residues, CC chemokine ligands (CCLs) have two adjoining amino-terminal cysteine residues and CX3CL has three amino acids separating the two initial cysteine residues (Rollins, Blood, 1997). The N-terminal domain in chemokine is important for chemokine receptor recognition since selective deletion or substitution of N-terminal amino acid residues on chemokine produces chemokines with antagonistic effects (Baggiolini & Moser, J. Exp. Med, 1997). The functions of chemokines could be described as being homeostatic or inflammatory (Bachelerie et. al. Pharmacol. Reviews, 2014). Most chemokines are secreted into the extracellular space where they remain soluble or are bound to extracellular matrix components, forming transient or stable concentration gradients, respectively. Chemokines and their gradients are detected by binding to specific chemokine receptors.
Chemokine receptors primarily signal via pertussis toxin-sensitive Gi-type G proteins (Rollins, Blood, 1997; Bachelerie et. al. Pharmacol. Reviews, 2014). It is now well established that there is extensive promiscuity between chemokines and their receptors, whereby a chemokine receptor binds several different chemokines, and a chemokine ligand binds several different receptors. For example, the chemokine CCL2/MCP-1 binds exclusively to CCR2 chemokine receptor but, CCR2 can also bind to the following ligands (CCL5/RANTES, CCL7/MCP-3, CCL8/MCP-2, and CCL13/MCP-4) whereas the chemokine CCL5/RANTES binds CCR1, CCR2, CCR3 and CCR5. This promiscuity within the system has generated the concept of chemokine redundancy. It is also notable that several chemokine receptors can be expressed by a single cell either simultaneously or during different stages of its life. Furthermore, the binding of different chemokines to a given receptor does not necessarily result in the same biological response. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Chemokine receptors can have diverse role in organ systems, be protective in one organ and pro-inflammatory in another. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. The inadvertent or overexpression of chemokines has been implicated in just about every disease process/state with an inflammatory component including autoimmune, glomerular and cardiovascular diseases, IBD, asthma and atherosclerosis (Bachelerie et. al. Pharmacol. Reviews, 2014). For this reason, it is conceivable that therapeutic intervention in the form of chemokine receptors blockade may provide a novel therapeutic approach.
FDA Approved Chemokine Receptor Antagonists
Since 2007 chemokine receptor antagonists have been used therapeutically to treat infectious and oncological ailments including: HIV infection (CCR5 antagonist/Selzentry®/Pfizer-approved 2007), adult T cell leukemia/lymphoma (CCR4 antagonist/Poteligeo®/Kyowa Hakko Kirin-approved in Japan in 2012; pending FDA approval in 2018) and hematopoietic stem cells mobilization (CXCR4 antagonist/Mozobil®/Sanofi-approved 2008). Presently, no chemokine receptor antagonist has been approved for therapy in inflammatory and/or autoimmune diseases. In this article, I highlight novel clinical evidence from ChemoCentryx, a company that is solely focused on chemokine based therapeutics, demonstrating therapeutic efficacy of a C-C chemokine receptor 2 inhibitor in rare and chronic inflammatory kidney diseases.
ChemoCentryx (CCXI) is a $440 million cap biopharma founded by Thomas Schall, PhD, a pioneer of chemokine biology and a world leading expert on chemokine based therapeutics. Dr. Schall has described ChemoCentryx as the only company that is focused exclusively on the discovery, development and commercialization of small molecule therapeutics that target the chemoattractant system. The company’s 2 lead investigational drugs are Avocapan (formerly called CCX168) and CCX140-B. Avocapan is a complement 5a receptor inhibitor in phase 3 clinical trials for the treatment of ANCA Vasculitis and Complement 3 Glomerulopathy (C3G). This article focuses primarily on CCX140-B, a CCR2 chemokine receptor antagonist, which is in late phase development for chronic kidney diseases, Focal Segmental Glomerulosclerosis (FSGS) and Diabetic Nephropathy (DN).
What is FSGS ?
The kidneys are two-bean sized organs with critical biological functions including removal of waste products and excess fluid from the body as urine, regulation of the body's salt, potassium and acid content and they also produce hormones that affect the function of other organs. The production of urine involves highly complex steps of excretion and re-absorption that is necessary to maintain a stable balance of body chemicals. Each kidney contains up to a million functioning units called nephrons and a nephron consists of tiny blood vessels called glomerulus. Glomeruli work like strainers and when blood moves through them, they let waste and extra water pass into the nephrons to make urine. At the same time, they hold back the protein and blood that your body needs.
According to NIDDK/NIH:
many diseases affect kidney function by attacking the glomeruli and when the glomeruli become damaged and cannot do their job, it is called glomerular disease. According to NIDDK/NIH, “damaged glomeruli may cause protein to leak into the urine (albuminuria/proteinuria) and/or interfere with the clearance of waste products by the kidney, so they begin to build up in the blood. In normal blood, protein (albumin) acts like a sponge, drawing extra fluid from the body into the bloodstream, where it remains until the kidneys remove it. But when protein (albumin) leaks into the urine, the blood loses its capacity to absorb extra fluid from the body. Fluid can accumulate outside the circulatory system in the face, hands, feet, or ankles and cause swelling (edema), low blood albumin protein levels, hypercholesterolemia and hypertension collectively called nephrotic syndrome (NS).
Glomerular diseases account for 90% of end stage renal disease (ESRD) in the US costing $100 billion annually with a total of nearly 500,000 patients receiving dialysis treatment and well over 200,000 living with a kidney transplant (US Renal Data System, NIDDK/NIH, 2017). FSGS is a rare, debilitating, chronic glomerular disease with a histologic pattern of injury characterized by scarring (sclerosis) in scattered regions of the kidney, typically limited to one part of the glomerulus and to a minority of glomeruli (less than 50% of all glomeruli affected) in the affected region (Jefferson & Shankland, Adv Chronic Kidney Dis. 2014). NIDDK/NIH and Nephcure Kidney International have both described FSGS as a leading cause of ESRD and represents a condition frequently associated with NS in adults and children in US. In addition, early symptoms of FSGS are similar to other NS conditions and the only way to differentiate FSGS from other NS conditions is to perform a biopsy to confirm the presence of glomerular scarring if the tissue is taken from the affected section of the kidney. Therefore, FSGS is merely a descriptive diagnosis and not a disease entity.
The NIDDK/NIH also states:
untreated FSGS leads to ESRD and most patients with FSGS progress to total kidney failure over 5 to 20 years whereas patients with an aggressive form of FSGS reach total kidney failure in 2 to 3 years, ultimately requiring kidney transplant or renal dialysis.
The US Renal Data System indicates that FSGS affects approximately 80,000 patients in the U.S. and Europe, with 5,500-9,500 new cases each year and is classified as an orphan disease by the FDA. It is more prevalent in adults 45 years and older and males are 1.5 to 2 times more likely to progress to ESRD than females (Kitiyakara, Am. J. Kidney Dis. 2004). FSGS can recur in 30-40% of patients who receive a kidney transplant.
Pathogenesis of FSGS and NS
The etiology of FSGS is still far from being explained, because this disease, often described as a diverse syndrome, seems to be a pathological expression of different types of injury. However, it is known that FSGS develops after podocyte injury or loss from unknown cause (idiopathic kidney disease or primary FGSS) or a known cause (secondary FSGS such as systemic disorder including diabetes, lupus or genetic abnormalities) (Grisham & Chung, Kidney Int. 1975; D’Agati et. al. Am. J. Kidney Dis. 2004). Podocytes are visceral epithelial cells that wrap around capillaries of the glomerulus in the kidney. All glomerular cells including mesangial, endothelial, parietal epithelial, and visceral epithelial cells (podocytes) play an important role in normal glomerular structure and function. Nevertheless, the podocyte is the key organizer of glomerular development and maintenance. Podocytes are terminally differentiated epithelia cells with minimal capacity to regenerate/replicate itself, but novel insights suggest that some replacement is possible as described in the podocyte depletion hypothesis below.
The podocyte depletion hypothesis as described in the article by Jefferson & Shankland (Adv Chronic Kidney Dis. 2014) states
whatever the initial insult to the glomerulus, the outcome depends on whether or not the normal mature podocytes are depleted. On the one hand, if as a result of glomerular injury podocytes are not depleted, then the glomerulus has the capacity to remodel and recover essentially normal structure and function. But, if significant podocyte depletion occurs, then the glomerulus (or that part of the glomerulus) will not recover its normal structure and function and when progressive podocyte depletion is allowed to occur over time, then this will be associated with progressive glomerulosclerosis leading to progressive loss of renal function culminating in ESRD.
Clinically and in murine models, podocytes loss or injury has been associated with FSGS progression for more than 30 years (Haas et. al. Am. J. Kidney Dis. 1995; Lehir et. al. Curr. Opin. Nephrol. Hypertens. 2007; Huber et. al. J. Clin. Inves. 2006; Fogo, Semin Nephrol. 2003; Lemley et. al. Kidney Int. 2002). In addition, podocyte depletion contributes to the progression of DN in type I and type II diabetes mellitus (Pagtalunan et. al. J. Clin. Inves. 1997; Steffes, Kidney Int. 2001; White et. al. Diabetes, 2002). Podocyte loss also correlates closely with the degree of proteinuria, glomerulosclerosis and renal dysfunction in patients with IgA nephropathy (Lemley, Kidney Int. 2002).
Current Standard of Care (SOC)
Currently there are no FDA approved treatments for FSGS. But, clinicians have taken advantage of the pleitropic effects of a diverse array of therapeutic agents originally developed for other clinical indications to treat glomerular diseases including FSGS. The nephrologist may recommend steroids or other immunosuppressive drugs such as calcineurin inhibitor, cyclosporin A (to reduce inflammation and albuminuria/proteinuria), diuretics and low salt diet (to control edema), angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs; to control blood pressure and lower albuminuria/proteinuria), statins (to lower cholesterol levels), healthy diet and exercise. Although, oral steroids is the mainstay therapy for FSGS they carry significant side effects rendering them intolerable to some patients and besides a high percentage of patients with FSGS acquire steroid resistance and do not respond to steroids. Other treatment options such as the immunosuppresant, cyclosporin A, while effective therapeutically in FSGS, is also associated with significant side effects including hypertension, hyperlipidemia, neurotoxicity and new onset diabetes. Despite the renal and cardiovascular protective effects of ARBs blockers and ACE inhibitors in alleviating some symptoms and slowing down damage to kidneys, high renal and cardiovascular risk still persist in these patients due to residual albuminuria/proteinuria (de Zeeuw, et. al. Kidney Int. 2004). For this reason, FSGS is still a leading cause of ESRD. There is a need for innovative therapies that would both quench and reverse the deleterious effects of this disease to reduce the incidence of ESRD. Considering the pathophysiological role of podocytes in glomerular diseases including FSGS, the podocyte is an attractive cell for drug targeting due largely to its presence on the epithelial surface of the glomeruli. In my opinion, an ideal drug candidate for FSGS should promote regression of the disease by positively regulating podocyte density to correct/revert underlying aberrant podocyte injury/loss, edema, glomerular inflammation and scarring, without adverse side effects. Equally important, this putative therapeutic agent must impede residual albuminuria/proteinuria and its ensuing renal and cardiovascular risk.
Pertinent Evidence of CCL2/MCP-1 and CCR2 in DN and FSGS
There is significant evidence that C-C chemokine ligand 2 (CCL2)/Monocyte Chemoattractant Protein-1 (MCP-1), the prototype of the C-C family of chemokines (Rollins, Blood, 1997), contributes to the pathophysiology of diabetes and DN. CCL2/MCP-1 specifically attracts blood monocytes and tissue macrophages to its source, via interaction with CCR2, its sole cell surface G protein-coupled, seven-transmembrane spanning chemokine receptor (Charo et. al, PNAS, 1994). Human renal biopsy studies demonstrated that macrophages accumulate in the glomeruli during glomerular diseases including FSGS and DN, a finding mirrored by murine models. Macrophages mediate immunopathology in both non-renal and renal diseases, and blocking macrophage recruitment can prevent the progression of many types of kidney disease models (Awad et. al. Am J Physiol Renal Physiol. 2011). CCL2/MCP-1 expression has been identified in kidney diseases including DN since data generated from genetic deletion and molecular blocking studies in multiple relevant pre-clinical models of DN provides evidence that CCL2/MCP-1-CCR2 signaling promotes the progression of DN (Seok et al. Nephrol Dial Transplant, 2013; Sayyed, et. al. Kidney Int. 2011; Awad et. al. Am J Physiol Renal Physiol. 2011). Moreover, CCR2 is overexpressed in the glomerular podocytes of patients with DN (Tarabra et al. Diabetes, 2009) and urinary levels of CCL2/MCP-1 are also consistently increased in parallel with proteinuria (Tesh, Am J Physiol Renal Physiol. 2008). DN is a form of glomerular disease that is both systemic and sclerotic-since diabetes itself is a systemic disease, and sclerotic because the specific damage done to the kidneys is associated with scarring. Therefore, the disease profile of DN consistently overlaps with FSGS and early symptoms of FSGS are similar to other NS conditions including DN. Besides, diabetes is a trigger of secondary FSGS. For this reason, the potential clinical efficacy of CCR2 selective antagonist, CCX140-B, was initially validated experimentally in murine models of DN and FSGS as well as in patients with diabetes and DN.
Validation of CCX140-B Safety and Efficacy
CCX140-B is an orally bioavailable, potent, selective, small molecule CCR2 antagonist that inhibits CCR2 and blocks MCP-1-dependent monocyte activation and chemotaxis. CCX140-B is chemically distinct from all other known antagonists of CCR2. Preclinical data showed that CCX140-B selectively inhibits CCR2-mediated migration of monocytes by CCL2/MCP-1 and other CCR2 ligands and does not inhibit migration mediated by other chemokine receptors, even when given at high doses (Sullivan et. al. Am. J. Physiol. Renal Physiol. 2013). CCX140-B has an excellent safety profile without adverse side effects (Hanefeld et al. J. Diabetes Metab. 2012). Data generated in relevant pre-clinical models of obesity-driven type 2 diabetes and DN (Sullivan et. al. Am. J. Physiol. Renal Physiol. 2013) revealed that CCX140-B treatment provides glycemic and renal benefits. Specifically, CCX140-B either prevented albuminuria from worsening or reduced albuminuria outright in transgenic diabetic human CCR2 knockin (hCCR2KI) mice. Remarkably, improvement in renal function coincided with decreases in glomerular hypertrophy and increases in podocyte density. Furthermore, CCX140-B reduced adipose tissue inflammatory macrophage and rapidly improved hyperglycemia and systemic insulin sensitivity. Based on these pre-clinical results, clinical trials were initiated with CCX140-B to validate its safety, tolerability and efficacy in patients with type 2 diabetes and DN. The pilot study, a randomized, double-blind, placebo and active-controlled, Phase 2 clinical trial in 159 subjects assessed the safety and tolerability of CXC140-B in type 2 diabetics over a 28-day period (Hanefeld et al. J. Diabetes Metab. 2012). CCX140-B treatment was well-tolerated with no serious adverse effects or safety concerns in hepatic, renal, metabolic, hematologic, cardiovascular and immunologic systems. No hemodilution was observed over the course of the clinical trial.
It is well established that ACE inhibitors and ARB blockers effectively slow the progression of DN but, residual renal and cardiovascular risks remain problematic in these patients due to residual high albuminuria (de Zeeuw et al. Kidney Int. 2004). Besides, combination therapy involving ACE inhibitors and ARB blockers have been unsuccessful in abolishing the residual renal or cardiovascular risk (Parving et. al. NEJM, 2012; Fried et. al. NEJM, 2013). Consequently, the effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with DN was assessed in a Phase 2b multi-center, randomized double-blind, placebo controlled trial in 332 individuals. Recruited patients were randomly assigned to groups given oral placebo (n=111), 5mg CCX140-B (n=110) or 10mg CCX140-B (n=111) daily for 52 weeks. Patients were on stable diabetes treatment and ACE inhibitors or ARB blockers at a recommended therapeutic dose for at least 8 weeks. The primary efficacy endpoint for this trial was change from baseline in urine albumin to creatinine ratio (UACR) at 52 weeks. CCX140-B had renal protective effects on top of current standard of care, based on the primary efficacy outcome of change in UACR after 52 weeks (–2% [95% CI –11% to 9%] for placebo vs –18% [–26% to –8%] for 5 mg CCX140-B and –11% [–20% to –1%]) for 10 mg CCX140-B. A 5mg dose of the CCX140-B (but not 10mg CCX140-B) produced a significant 16% reduction in albuminuria on top of optimum use of ACE inhibitor or ARB blocker since a –16% difference between 5mg CCX140-B and placebo (one-sided upper 95% confidence limit –5%; p=0·01) and a–10% difference between 10mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0·08) was recorded and no renal events were observed in this study. This effect also persisted for 4 weeks after the drug was stopped. The results of this published proof-of-concept trial (de Zeeuw et al. Lancet Diabetes Endocrinol 2015) highlights CCR2 inhibition as a potential new strategy to limit the progression of diabetic kidney diseases including DN and FSGS. The development of CCX140-B as an add-on therapy for the treatment of DN, FSGS and other NS conditions provides an opportunity to improve on the 20% relative cardiovascular and renal risks decreased benefit seen in clinical trials with ACE inhibitors and ARB blockers (Parving et. al. NEJM, 2012; Fried et. al. NEJM, 2013).
Proposed CCX140-B Mechanism
The exact mechanisms of the renal protective benefits on albuminuria following CCX140-B treatment are unknown. My analysis suggests that several possibilities are worth discussing. Apoptosis is widely regarded as a major mechanism by which podocytes are decreased or lost in the progression of glomerular diseases. All glomerular cells including mesangial, endothelial and podocytes express the CCR2 receptor and they also produce CCL2/MCP-1 during DN and possibly FSGS. CCL2/MCP-1 can induce apoptosis of podocytes (Nam et. al. Apoptosis, 2012). In my opinion, CCL2/MCP-1 secreted by podocytes during FSGS/NS/DN could interact with CCR2-expressive podocytes in an autocrine manner to induce apoptosis-induced cell death (AICD), a process that is attenuated by CCR2 antagonism via CCX140B treatment. This may help explain the decrease or loss of podocytes during DN, FSGS and possibly other NS conditions. Interestingly, a recent presentation by ChemoCentryx at American Society for Nephrology (2017) showed that “CCR2 antagonism reduces proteinuria and glomerular injury in murine models of FSGS via increased density of podocytes. They proposed that CCR2 inhibition involves a unique mechanism of action in the kidney including a novel element of renal cellular protection at the level of the podocyte”. In my opinion, it is also possible that other CCL2/MCP-1-expressing glomerular cells, mesangial and endothelial may act synergistically to promote and induce apoptosis of CCR2-expressing podocyte during glomerular diseases; an effect that is ameliorated by CCX140-B therapy. Additional potential mechanisms for the CCX140-B renal protective benefits may include dampening of renal macrophage infiltration, inflammation/edema and oxidative stress. The questions to be answered in the registration trials is whether reduced albuminuria correlates with increased podocyte density in response to CCR2 antagonism via CCX140-B treatment in patients with FGSG; an effect that could potentially impede and/or reverse the progression of this awful disease.
Registration trial for CCX140-B in FSGS
Given the positive data of CCR2 inhibitor, CCX140-B on DN, ChemoCentryx theorized that “CCX140-B might have the potential to alter and attenuate the relentless decline of renal function in patients with DN and the need for expensive kidney transplant”. ChemoCentryx has indicated that CCX140-B will be developed as add-on therapy for the treatment of FSGS. FSGS is an orphan disease of the kidney for which there is currently no approved treatment option. Based on the last conference call in November 2017, two registration trials are planned to begin 1H/2018 in two different subpopulations of patients with primary FSGS-those with and without NS. Reduced proteinuria was proposed as the registration end point. At the time of writing this article detailed information on the proposed trials had not been released.
Risks and Business
ChemoCentryx has multiple 'shots on goal', one current strategic partnershipbut no approved product and has 2 drugs, Avacopan (formerly CCX168) and CCX140-B, in its pipeline being tested in mid-stage to late-stage studies. Avacopan, a selective inhibitor of the complement C5a receptor, is an orally administered small molecule that is in Phase III development for the treatment of ANCA Vasculitis and C3G. The FDA has granted Avacopan orphan-drug designation for ANCA Vasculitis, C3G and aHUS. The European Commission has granted orphan medicinal product designation for avacopan for the treatment of two forms of ANCA Vasculitis: microscopic polyangiitis and granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), as well as for C3G. Avacopan was also granted access to the EMA PRIority MEdicines (PRIME) initiative, which supports accelerated assessment of investigational therapies addressing unmet medical need. The CCR2 inhibitor, CCX872, is in Phase 1b clinical trial for the treatment of pancreatic cancer and interim results showed positive overall survival. Risks for the company includes risk and unpredictability associated with clinical trials including lack of efficacy in the ongoing large scale phase 3 trials, limited revenues and cash balances with no approved products and potential delays or failure to gain approval by regulatory bodies. ChemoCentryx also has other early stage drug candidates that target chemoattractant receptors in other inflammatory and autoimmune diseases and in cancer in developments. At November, 2017, the company’s cash and cash equivalents amounted to $154.8 million. However, in a recent (Janaury 2018) press release, ChemoCentryx secured additional $100 Million in new capital commitments [$50 million milestone payment from Vifor Fresenius Medical Care Renal Pharma (VFMCRP) and $50 million growth capital financing agreement with Hercules Capital, Inc]. ChemoCentryx is responsible for the discovery and development of avacopan, owns and retains the commercial rights to the drug in the US and China whereas VFMCRP has licensed the rights to commercialize the drug in all other countries. Under the terms of the Kidney Health Alliance with Vifor Pharma, which comprises both avacopan and CCX140, ChemoCentryx has received a total of $155 million in upfront cash and cash commitments and is eligible to receive additional payments upon the achievement of certain development, regulatory and sales -based milestones, as well as tiered double-digit royalties on potential net sales of avacopan and CCX140 in the Vifor licensed territories. The company is on track to complete enrollment for Phase 3 trial of Avacopan in mid-2018 and patient enrollment is ongoing in registration supporting trial for avacopan in the treatment C3G. The company will launch a registration supporting trial for CCX140-B for the treatment of FSGS in 1H/2018.
Aurinia Pharmaceuticals-Voclosporin in FSGS
Voclosporin, a calcineurin inhibitor, is a structural analog of cyclosporin A that has reduced toxicity, enhanced immunosuppressive efficacy and metabolic stability. Voclosporin was developed by Aurinia Pharmaceuticals (AUPH; Vancouver, BC, Canada), a $427 million market cap clinical stage pharmaceutical company focused on the development and commercialization of its lead candidate, Voclosporin, for the treatment of kidney diseases including Lupus Nephritis (LN), FSGS and Minimal Change Disease (MCD). Voclosporin has shown therapeutic efficacy in patients with LN in phase 2b proof-of-concept study where
LN patients receiving Voclosporin in the presence of standard of care Mycophenolate Mofetil (MM) and low dose steroid achieved complete or partial remission and reduced proteinuria relative to placebo control (see articles by fellow SA contributors for detailed information). Voclosporin is currently in Phase 3 trial, AURORA, for LN as an add-on to the standard of care MM and low dose steroid (see articles by fellow SA contributors for detailed information). Of relevance to this article is the report by the company that potential therapeutic effect of Voclosporin in patients with FSGS and MCD will be assessed in a Phase 2b proof of concept trial scheduled to begin 1H/2018. Given that secondary FSGS can be triggered by lupus (as discussed previously), Dr. James Tumlin of Georgia Nephrology Center and an investigator in the AURA and AURORA trials hypothesized that “patients with FSGS may benefit from Voclosporin’s action in reducing proteinuria”. This is a logical hypothesis. In my opinion, there are several questions that a Voclosporin trial in FSGS should address. The 1st question that may need to be asked is whether a potential reduction in proteinuria in FSGS patients by Voclosporin will be associated with a reduction in the progression of FSGS. Regardless of the drug regimen, the ultimate objective is to prevent/delay/reverse the progression of renal damage associated with FSGS thereby avoiding ERSD and dialysis. The 2nd question is whether any therapeutic benefits seen with Voclosporin can be adequately measured by change in albuminuria/proteinuria and will Voclosporin regulate podocyte phenotype? Irrespective of the intent when they were developed, currently available non-FDA approved treatment modalities including steroids and cyclosporin A, which affirm their place among recommended drug regimens for FSGS actively regulate the survival, differentiation, structural regulation, and cell signaling of podocytes to provide renal protection (Meliambro et. al. J. Nephrol. Ther. 2013; Schönenberger et. al. Nephrol Dial Transplant, 2011). However, their documented side effects and resistance are very problematic and intolerable to some patients. The 3rd and final question is whether Voclosporin if administered as add-on in the presence of ACE inhibitors or ARB blockers, could further attenuate renal and cardiovascular risks due to the residual albuminuria/proteinuria. I do believe that any FDA-approved therap(ies) that is specific for FSGS and other NS conditions would be an improvement over current therapies and a major breakthrough for these patients.
“It always seems impossible until it’s done”-Nelson Mandela
Chemokines and their receptors “gained fame when they were found to act as co-receptor for HIV/AIDS infection. Two decades after their initial characterization, the first chemokine receptor antagonist was approved for therapy in 2007 and other antagonists have been subsequently approved for different ailments (as discussed previously). Despite the inadvertent or overexpression of chemokines in just about every disease process with an inflammatory component, there has been numerous setbacks in the clinical setting to employ chemokine receptor inhibitors or antagonists as therapeutics in inflammatory diseases. ChemoCentryx is the only company that is solely focused on discovery of small molecule therapeutics that target the chemoattractant system. This is not totally surprising given that ChemoCentryx was founded by Dr. Thomas Schall, a pioneer of chemokine biology. From a personal perspective as a graduate student of chemokine biology in mid 1990s, I found my PhD study and thesis to be scientifically and intellectually very rewarding. So rewarding, that both my post-doctoral training and independent career as a Principal Investigator have focused on chemokine biology. In writing this article, I reminisce on my humble beginnings into the chemokine biology field and understand Dr. Schall’s passion about the “science underlying the chemoattractant network and the opportunity it holds to provide better medicines for better lives”. CCX140-B, a CCR2 inhibitor by ChemoCentryx, could be the first chemokine receptor therapeutic for inflammatory diseases, specifically for FSGS, a rare debilitating chronic inflammatory kidney disease with unmet need and no approved FDA therapy. As we await the beginning of registration trials for CCX140-B therapy in FSGS patients, I expect key data readouts for Avocapan in the next 12 months that could create a lot of value for shareholders and anticipate that ChemoCentryx may be ready to pop open the aged red wine sooner rather than later.
As always, my articles are meant to facilitate your understanding. Please implement due diligence and invest wisely.
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Analyst’s Disclosure: I am/we are long CCXI, AUPH. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
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