Phase II Study of Ecluzimab in Kidney Transplant Patients Finds No Reduction in Ab-Mediated Rejection
After a long string of regulatory successes with its flagship monoclonal antibody eculizumab (Soliris), Alexion Pharmaceuticals recently reported disappointing results from a phase II clinical trial evaluating whether eculizumab could prevent antibody-mediated rejection (AMR) in kidney transplant patients. An estimated 10% of patients develop AMR after kidney transplant, and 30% of these patients lose their new kidney.1
Recipients of a kidney allograft from a donor who has different human leukocyte antigens (HLA) than the patient develop antibodies (donor-specific antibodies, or DSAs) that activate the complement system. This triggers a complex series of events that have a toxic effect on the donated organ, which can result in loss of the allograft or even death. Some transplant patients have evidence of previous exposure to foreign HLAs, possibly through a blood infusion, pregnancy, infection, or even a prior transplant. As many as 41% of these high-risk patients may develop AMR.2
In the open-label, multicenter trial, participants undergoing a kidney transplant were randomly assigned to eculizumab or standard care to prevent rejection for 9 weeks. All 102 patients had elevated DSA levels and thus were at greater risk of developing AMR. Patients in the standard care arm suspected of developing AMR during the trial were allowed to receive eculizumab therapy. The study’s composite endpoint was biopsy-proven AMR, graft loss, patient death, or loss to follow-up at study conclusion. At the 9-week mark, the composite endpoint occurred in 10% of patients in the eculizumab arm and 16% of patients in the control arm, a difference that was not statistically significant (P
In a press release
, Alexion said the results with eculizumab were in line with other studies in which high-risk patients treated with eculizumab had low rates of AMR.3
However, the rate of AMR in the control arm was lower than historical rates according to Alexion. Undeterred by the apparent setback, Martin Mackay, PhD, Executive Vice President and Global Head of R&D at Alexion, said the company is “currently developing plans to commence a clinical trial with eculizumab as a treatment for patients diagnosed with AMR.”3
Eculizumab inhibits the C5 complement protein. It is approved in multiple countries (including the United States) for 2 rare genetic disorders: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The US Food and Drug Administration has also granted orphan drug designations to eculizumab for myasthenia gravis, delayed graft function, and neuromyelitis optica.
Kim M, Martin ST, Townsend KR, Gabardi S. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy. 2014;34:733-744.
Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol. 1999;10:2208-2214.
Alexion provides update on phase 2 clinical trial with eculizumab in antibody-mediated rejection (AMR) in living-donor kidney transplant recipients [press release]. http://news.alexionpharma.com/press-release/company-news/alexion-provides-update-phase-2-clinical-trial-eculizumab-antibody-mediat . Published January 7, 2015. Accessed January 21, 2015.