Alexion and independent investigators are studying eculizumab in a range of nephrology indications, including Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS), risks associated with kidney transplantation, dense deposit disease and C3 nephropathy.
Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS) is an ultra-rare and life-threatening complement-mediated disorder that results from exposure to Enterohemorrhagic E. coli, or EHEC. As in several other severe complement-mediated conditions, including atypical HUS (aHUS), complement activation in STEC-HUS causes platelet activation, thrombosis (blood clots), hemolysis (red blood cell destruction), and inflammation in small blood vessels throughout the body, a process known as systemic thrombotic microangiopathy, or systemic TMA. Due to systemic TMA, STEC-HUS patients are at risk for progressive damage to multiple vital organs including the brain, heart, lungs, kidneys and organs of the gastrointestinal system. This severe organ damage also causes significant and early mortality in affected patients.
Although similar in their life-threatening TMA manifestations, aHUS and STEC-HUS are different diseases: aHUS is a life-long genetic disease of uncontrolled complement activation, while STEC-HUS is not genetic and uncontrolled complement activation follows an isolated episode of infection.
Due to the unprecedented number of STEC-HUS cases that resulted from the EHEC outbreak in Germany in late May 2011, Alexion Pharmaceuticals, in collaboration with the Paul-Ehrlich-Institut (PEI, Germany's healthcare regulatory body for biological products) and leading physicians in Germany, initiated a multi-center, open-label study to evaluate the safety and efficacy of eculizumab in patients with STEC-HUS.
Case studies published in the New England Journal of Medicine1 describe encouraging results from the drug's use in several patients with STEC-HUS.
Patients undergoing kidney transplantation may experience acute humoral rejection, or AHR, in the early post-transplant period, characterized by the acute onset of kidney failure and rapid progression to destruction of the transplanted kidney. AHR occurs when antibodies in the transplant recipient vigorously attack the blood vessels of the donated kidney. In severe cases, these donor specific antibodies (DSA) bind to the blood vessel lining of the donor organ and initiate activation of the complement cascade, resulting in severe blood vessel inflammation and clotting.
Eculizumab is being investigated as a treatment for patients undergoing kidney transplant who are at elevated risk of AHR. Interim data show that eculizumab significantly reduces AHR and also reduces the need for post-transplant plasma therapy and splenectomy. A company-sponsored multi-national kidney transplant trial in patients receiving living donor grafts in multiple centers in the U.S. and EU is currently enrolling patients. Another multi-national kidney transplant trial in patients receiving deceased donor grafts will be initiated in early 2012.
Dense Deposit Disease (DDD) and C3 Nephropathy
- DDD, also called Type II membrano-proliferative glomerulonephritis (MPGNII), is a rare and severe kidney disease characterized by genetic mutations in complement inhibitor genes that can lead to sustained complement activation and inflammation. In most cases, the disease evolves into chronic renal failure, requiring dialysis and renal transplantation. Independent investigators are evaluating the use of eculizumab in patients with DDD in a Phase 2 study.
- C3 nephropathy, also known as C3 glomerulonephritis, is an uncommon kidney disease characterized by the presence of isolated glomerular C3 deposits. As many as 15 percent of patients with C3 nephropathy progress to end-stage renal disease. Dysregulation of the complement system is believed to play an important role in C3 nephropathy. Independent investigators are evaluating the use of eculizumab in patients with C3 nephropathy in a Phase 2 study.2
Alexion will evaluate the Phase 2 data to learn whether there are sub-populations of patients with these disorders who might be candidates for further investigation with eculizumab therapy.
- Lapeyraque A-L, Malina M, Fremeaux-Bacchi V, et al. Complement blockade in severe Shigatoxin-associated HUS. N Engl J Med 2011. DOI: 10.1056/NEJMc1100859.
- Fakhouri, F. et al. C3 glomerulopathy: a new classification Nat. Rev. Nephrol. 6, 494–499(2010).