Complement Inhibition in aHUS Dialysis Patients

This study evaluates the effect of CCX168, a C5aR Antagonist, Oral Administration on Ex Vivo Thrombus Formation and Disease Activity in ten patients with diagnosis of Atypical Hemolytic Uremic Syndrome with or without genetic abnormalities in the complement system or thrombomodulin, on stable chronic extracorporeal or peritoneal dialysis therapy since at least 6 months.

Inherited defects that determine uncontrolled activation of the alternative complement pathway have been well documented in atypical Hemolytic Uremic Syndrome (aHUS) patients. Research in recent years has identified more than 120 different mutations, accounting for around 40%-60% of cases, in the genes encoding complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI), C3, complement factor B (CFB), and thrombomodulin (THBD). A therapeutic approach could be the administration of molecules that pharmacologically target complement activation, which is the primary common pathogenic mechanism in all genetic forms of aHUS. Eculizumab has been successfully used as prophylaxis of aHUS recurrences in subjects with plasma dependent or plasma resistant disease or in renal transplant recipients at high risk of recurrence due to CFH, CFI, or C3 complement gene mutations. However the drug must be administered chronically and drug spacing or discontinuance was associated with disease recurrence in the graft. The C5aR receptor antagonist CCX168 could present an appealing alternative to eculizumab for post-transplant prophylaxis of aHUS recurrences since it is orally administrable with lower cost of goods. In addition, CCX168 is theoretically associated with lower risk of infections than eculizumab since the former does not target C5b and leaves the terminal complement pathway intact.

Eligibility Criteria:
Inclusion Criteria:

* Age \>18 years;
* Diagnosis of aHUS with or without identified genetic abnormalities in the complement system or thrombomodulin;
* Stable chronic extracorporeal or peritoneal dialysis therapy since at least 6 months;
* Written informed consent.

Exclusion Criteria:

* Women of childbearing potential or women who are breastfeeding;
* Shiga toxin-associated HUS or secondary forms of thrombotic microangiopathy;
* ADAMTS13 activity \<10 % or circulating anti ADAMTS13 autoantibodies consistent with the diagnosis of thrombotic thrombocytopenic purpura;
* Need for specific intervention with plasma therapy and/or complement inhibitors as deemed clinically appropriate;
* Plasma therapy or treatment with complement inhibitors or antiplatelet and antithrombotic agents over the last two weeks;
* Liver function impairment (serum liver enzymes or bilirubin levels \>3 x upper limit of normal);
* Neutrophil count \< 2000/μL or lymphocyte count \< 1000/μL;
* Infection requiring antibiotic treatment within the previous 4 weeks prior to screening;
* Participated in any clinical study of an investigational product within 30 days prior to screening or within 5 half-lives after taking the last dose;
* History or presence of any medical condition or disease which, in the opinion of the Investigator may place the subject at unacceptable risk for study participation;
* Inability to understand the potential risks and benefits of the study;
* Legal incapacity.