Orphan and Rare Diseases

While orphan and rare diseases affect thousands of people, many of these people are not well served by today’s standards of care. Oftentimes approaches to their conditions are not targeted enough, so in some cases treatments may make patients more ill than they would be without them. In other cases, short-term results often give way to an eventual worsening of the patient’s condition overall. Through our focus on the chemoattractant network, we strive to create more targeted and more effective therapies for patients who previously thought they did not have many options.
In our orphan and rare disease program, our lead drug candidate is CCX168 (avacopan). This is a small molecule that targets the chemoattractant receptor known as C5aR, and is being developed for inflammatory and autoimmune diseases. CCX168 blocks the activity of complement C5a, a component of the complement system and the natural ligand for C5aR.

The complement system is a group of proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation and remove debris from cells and tissues. The complement system must be carefully regulated so it targets only unwanted materials and does not attack the body’s healthy cells.

Our most advanced orphan and rare disease clinical program is in patients with ANCA associated vasculitis (AAV). In May 2016, Vifor Pharma licensed the rights to commercialize CCX168 for orphan and rare renal diseases, in certain geographies outside the U.S. The regional agreement is part of a larger ChemoCentryx-Vifor Pharma kidney health alliance that also includes CCX140, our orally-administered inhibitor of the chemokine receptor known as CCR2.

We also have clinical trials of avacopan that are ongoing in atypical Hemolytic Uremic Syndrome (aHUS). Additionally, through a Special Needs protocol, we have treated one patient with C3 Glomerulopathy (C3G) and we intend to initiate a clinical endpoint study in C3G in the first half of 2017. AAV, C3G and aHUS are all rare diseases that are characterized by inflammation that often affects the kidneys.

What are orphan and rare diseases? A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population. Most rare diseases are genetic, and thus are present throughout a person’s life, even if symptoms do not immediately appear. An orphan disease is further defined in the United States as a condition that affects fewer than 200,000 people nationwide. We have been granted orphan drug designation for CCX168 for granulomatosis with polyangiitis or Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome (which are all forms of AAV) and atypical Hemolytic Uremic Syndrome (aHUS).
ANCA Associated Vasculitis (AAV)

We are currently evaluating avacopan (CCX168) in a Phase III clinical trial in patients with AAV. In 2016, we successfully completed, and reported positive clinical data from two Phase II clinical trials with avacopan in patients with AAV, known as the CLEAR and CLASSIC trials.

The CLEAR trial was a three-part, Phase II study to determine if CCX168 treatment would allow for the elimination or reduction of high-dose corticosteroids, without compromising efficacy or safety. 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 chronic high dose steroid-containing standard of care. Specifically, all treatment groups receiving CCX168 demonstrated a numerically superior and statistically significant non-inferior clinical efficacy outcome when compared to the chronic high dose steroid standard of care. Part of the current standard of care for AAV, chronic administration of high dose corticosteroids, is associated with numerous and severe side-effects, including pre-disposition to serious infections. In addition, the individual patient data from the CLEAR trial also showed that BVAS response and BVAS remission (BVAS score going to zero) was rapid and sustained in the CCX168 treatment groups.

Whereas the CLEAR trial focused on efficacy outcomes, the CLASSIC trial was intended to confirm that CCX168 would not engender additional safety concerns in patients with AAV. In the CLASSIC safety trial, patients received CCX168 in addition to the full chronic high dose steroid standard of care. The CLASSIC safety trial successfully met its objectives. The addition of CCX168 to standard of care therapy did not add safety concerns beyond those seen with standard of care alone.

Complement 3 Glomerulopathy (C3G)
Through a Special Needs protocol (similar to the compassionate use protocols in the United States), we have treated a C3G renal transplant recipient patient with avacopan. Prior to being treated with avacopan, this patient had deteriorating kidney function and received previous treatment with a wide spectrum of immunosuppressant drugs– all of which had failed to prevent disease recurrence or progression.

This patient has now been on avacopan treatment for over a year. After one month of treatment, the patient’s renal function, based on estimated glomerular filtration rate (eGFR) stabilized. Sequential kidney biopsies taken after the patient had been on avacopan for 2 and 7 months showed continued improvement in kidney histology based on a decrease in glomerular endocapillary proliferation and a marked reduction in the number of glomerular inflammatory macrophages, as compared to the pre-treatment biopsy.

We plan to initiate a clinical endpoint study with avacopan in patients with C3G in the first half of 2017.

Atypical Hemolytic Uremic Syndrome (aHUS)
We have an ongoing Phase II proof-of-concept clinical trial with CCX168 in patients with atypical Hemolytic Uremic Syndrome (aHUS) who are on dialysis. The primary efficacy objective of the trial is to evaluate whether treatment with CCX168 may reduce thrombosis (blood clot) formation in chronic dialysis patients with aHUS. This clinical trial continues to enroll patients and we plan to provide an update on this study in late 2016.

ANCA Associated Vasculitis (AAV)
ANCA Associated Vasculitis (AAV) is a rare, severe, and often fatal autoimmune disease that is caused by autoantibodies called anti-neutrophil cytoplasmic antibodies and is characterized by inflammation that can affect many different organ systems, and commonly involves the kidneys.
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C3 Glomerulopathy (C3G)
C3G disease is an ultra-rare disease of the kidney that is characterized by deposition of the protein known as C3 in the glomeruli, or filtration units of the kidney, thus causing renal damage.
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Atypical Hemolytic Uremic Syndrome (aHUS)
Atypical Hemolytic Uremic Syndrome (aHUS) is a genetic, chronic, rare disease that is caused by the formation of blood clots within blood vessels, or thrombosis, throughout the body.
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Focal Segmental Glomerulosclerosis (FSGS)
FSGS is a rare form of chronic disease kidney that affects approximately 80,000 patients in the U.S. and Europe, with 5,500-9,500 new cases each year. FSGS attacks the kidney’s filtering units (glomeruli) causing serious scarring which leads to permanent kidney damage.
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ANCA Associated Vasculitis (AAV)
ANCA Associated Vasculitis (AAV) is a rare, severe, and often fatal autoimmune disease that is caused by autoantibodies called anti-neutrophil cytoplasmic antibodies and is characterized by inflammation that can affect many different organ systems, and commonly involves the kidneys.

Complement C5a, acting through its receptor C5aR, is thought to play a pro-inflammatory role in AAV. Autoantibodies lead to the activation and increased adhesiveness of neutrophils to the walls of small blood vessels in different tissues and organs of the body. These accumulating adhering neutrophils initiate an inflammatory cascade in the small blood vessels by secreting pro-inflammatory cytokines and chemoattractants. Activation of the complement pathway occurs with production of complement 5a (C5a), one of the most potent pro-inflammatory mediators of the complement system. C5a, through binding to its receptor C5aR, induces expression of adhesion molecules and chemotactic migration of neutrophils, eosinophils, basophils and monocytes.

C3 Glomerulopathy (C3G)
C3G disease is an ultra-rare disease of the kidney that is characterized by deposition of the protein known as C3 in the glomeruli, or filtration units of the kidney, thus causing renal damage. While the disease name refers to complement 3, it is well known that the C5a receptor pathway, which is further downstream of C3 in the complement cascade and the target of avacopan, is an essential part of the disease causing pathology. Hence, C3 is a marker of the downstream effects of C5aR.

Atypical Hemolytic Uremic Syndrome (aHUS)
Atypical Hemolytic Uremic Syndrome (aHUS), often results from a combination of environmental and genetic factors. The genes associated with aHUS provide instructions for making proteins involved in a part of the body’s immune response known as the complement system. This system is a group of proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues. The complement system must be carefully regulated so it targets only unwanted materials and does not attack the body’s healthy cells. The regulatory proteins associated with aHUS protect healthy cells by preventing activation of the complement system when it is not needed.

Mutations in the genes associated with regulatory proteins of complement activation lead to uncontrolled activation of the complement system, including an abundance of complement C5a. By acting on cells that express the C5a receptor, such as neutrophils, the overactive complement system attacks cells that line blood vessels in the kidneys and other organs, causing inflammation and blood clots, which leads to the impairment of blood flow. These abnormalities lead to kidney damage and, in many cases, kidney failure and end stage renal disease (ESRD).

Immunoglobulin A (IgA) Nephropathy (IgAN)
Our bodies are equipped with elegant systems to ward off infections. One of these is the complement system in which proteins enhance or complement the ability of our white blood cells to combat foreign invaders, such as infection causing bacteria. One of the key components of the complement system is the protein known as Complement 5a (C5a), and it works by activating a receptor on cells called the C5a receptor (C5aR).

In certain disease states the complement system is sometimes abnormally overactive, and this leads to attacks upon our own bodies, or auto-immunity. Immunoglobulin A (IgA) nephropathy (IgAN), is one of these autoimmune diseases in which auto-antibodies are inappropriately made, deposited in the kidney, and activate the complement system. The end result is marked impairment of the kidney to filter the blood of toxins and waste. Consequently, this can ultimately lead to kidney failure and dialysis.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. David R.W. Jayne, Annette N. Bruchfeld, Lorraine Harper, Matthias Schaier, Michael C. Venning, Patrick Hamilton, Volker Burst, Franziska Grundmann, Michel Jadoul, István Szombati, Vladimír Tesar, Mårten Segelmark, Antonia Potarca,| Thomas J. Schall, and Pirow Bekker, for the CLEAR Study Group. Published in the Journal of the American Society of Nephrology, April 2017.

Orally Administered Complement 5a Receptor Inhibitor CCX168 Shows Ex Vivo Anti-Thrombogenic Activity in a Phase 2 Study in End-Stage Renal Disease Patients with Atypical Hemolytic Uremic Syndrome (ACCESS Study). Valentina Portalupi, Miriam Galbusera, Piero Luigi Ruggenenti, Nadia Rubis, Sara Gastoldi, Serena Bettoni, Pirow Bekker, Thomas J. Schall, Marina Noris and Giuseppe Remuzzi. Presented at the American Society of Nephrology (ASN) Kidney Week 2016 Annual Meeting.

Rapid Onset of Action of Orally Administered C5aR Inhibitor CCX168 in Randomized Clinical Trial in ANCA-Associated Vasculitis (CLEAR) David R.W. Jayne, Annette Bruchfeld, Lorraine Harper, Matthias Schaier, Patrick Hamilton, Volker Rolf Burst, Franziska Grundmann, Michel Y. Jadoul, Istvan Szombati, Vladimir Tesar, Antonia Potarca, Thomas J. Schall and Pirow Bekker. Presented at the American Society of Nephrology (ASN) Kidney Week 2016 Annual Meeting.

A Randomized Clinical Trial of CCX168, an Orally Administered C5aR Inhibitor for Treatment of Patients with ANCA-Associated Vasculitis. Peter Merkel, John Niles, Richard Jimenez, Brad Rovin, Robert Spiera, Andrew Bomback, Christian Pagnoux, Antonia Potarca, Thomas J. Schall and Pirow Bekker. Presented at the 2016 American College of Rheumatology (ACR) Annual Meeting.

Successful Steroid Replacement in ANCA-Associated Vasculitis with C5a Receptor Inhibitor CCX168 in Phase 2 Randomised Trial (CLEAR). David Jayne, Annette Bruchfeld, Lorraine Harper, Matthias Schaier, Michael Venning, Patrick Hamilton, Volker Burst, Franziska Grundman, Michel Jadoul, Istvan Szombati, Vladimir Tesar, Mårten Segelmark, Antonia Potarca, Thomas J. Schall and Pirow Bekker. Presented at the 53rd European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress, May 2016.

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. Chris Li, Linda Ertl, Pirow Bekker, Israel Charo, Thomas Schall. Presented at the 53rd European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress, May 2016.

Orally Administered Complement 5a Receptor Inhibitor CCX168 Development in Atypical Hemolytic Uremic Syndrome. Miriam Galbusera, Sara Gastoldi, Valentina Portalupi, Elena Mondo, Pirow Bekker, Thomas J. Schall, MarinaNoris, GiuseppeRemuzzi. Presented at the American Society of Nephrology Annual Kidney Week Meeting, 2015.

Inhibition of the C5a Receptor by CCX168 Markedly Reduces the Thrombogenic Potential of Serum from Patients with atypical Hemolytic Uremic Syndrome: Evidence for C5a-Dependent Activation of the Complement System.  Sara Gastoldi, Israel F. Charo, Daniel Dairaghi, Pirow Bekker, Thomas J. Schall, Ariela Benigni, Marina Noris, Giuseppe Remuzzi and Miriam Galbusera.  Presented at the ERA-EDTA Meeting, 2015.

C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN
Hong Xiao, Daniel J. Dairaghi, Jay P. Powers, Linda S. Ertl, Trageen Baumgart, Yu Wang, Lisa C. Seitz, Mark E.T. Penfold, Lin Gao, Peiqi Hu, Bao Lu, Norma P. Gerard, Craig Gerard, Thomas J. Schall, Juan C. Jaen, Ronald J. Falk, and J. Charles Jennette. J Am Soc Nephrol 25: 225–231, 2014. doi: 10.1681/ASN.2013020143.

Characterization of the novel C5aR antagonist CCX168, a potential therapeutic for ANCA-vasculitis, rheumatoid arthritis, and other autoimmune disorders. Powers JP, Bekker PJ, Dairaghi DJ, Jennette JC, Johnson DA, Leleti M, Miao S, Seitz LC, Wang Y, Xiao H, Schall TJ, Jaen JC. 2012 Annual European Congress of Rheumatology (EULAR), Berlin (Germany) June 6-9, 2012. Abstract # OP0204 (selected for oral presentation).

Clinical dose selection of the C5a receptor antagonist CCX168 for the Phase 2 ANCA-associated renal vasculitis clinical trial (the CLEAR trial). Dairaghi DJ, Johnson DA, Leleti M, Miao S, Xiao H, Jennette JC, Powers JP, Seitz LC, Wang Y, Jaen JC, Schall TJ, Bekker PJ. 49th European Renal Association – European Dialysis & Transplantation Association (ERA-EDTA) Congress; Paris (France); May 24-27, 2012. Abstract # SAP251.

Oral C5a receptor antagonist CCX168 in a Phase 2 clinical trial in ANCA associated renal vaculitis. Bekker P, Potarca A, Dairaghi D, Miao S, Powers J, Jaen J, Schall TJ. 49th European Renal Association – European Dialysis & Transplantation Association (ERA-EDTA) Congress; Paris (France); May 24-27, 2012. Abstract # SAP304.

Advances in the discovery of C5a receptor antagonists. Powers JP, Dairaghi DJ, Jaen JC. Ann. Reports Med. Chem. 2011; 46, 171-186.

Phase 1 Clinical Pharmacokinetic and Pharmacodynamic Evaluation of the Novel C5aR Antagonist CCX168, a Potential Therapeutic for ANCA-Vasculitis. Dairaghi D, Johnson DA, Deshayes K, Miao S, Seitz L, Wang Y, Leleti MR, Powers JP, Bekker P, Schall TJ, Jaen JC; 43rd Annual Meeting of the American Society of Nephrology, Denver (CO); November 16-21, 2010. Abstract # SA-PO2111. J. Am. Soc. Nephrol. 21: 595A.