Alexion’s eculizumab fails to meet primary endpoint in phase 2/3 trial

The primary endpoint of incidence of DGF with a two-dose regimen of eculizumab compared with placebo did not reach statistical significance.

DGF is an early and serious complication of organ transplantation in which the transplanted organ fails to function normally immediately following transplantation, and was defined in the study as the requirement for dialysis for any reason in the first 7 days post-transplant.

The primary endpoint also included incidence of death, graft loss, and loss to follow-up, including discontinuation.

Alexion executive vice president R&D global head Martin Mackay, Ph.D said: “We are disappointed that this trial did not meet its primary endpoint, given the urgent need for preventive therapies for patients at risk of DGF and the potential role of the complement cascade in the development of this serious and life-threatening complication.

“We continue to analyze the data to better understand what the findings mean for patients undergoing a kidney transplant. Importantly, the safety of eculizumab in this trial appears consistent with the favorable safety profile observed in nearly a decade of real-world experience with this highly innovative therapy.”

The PROTECT Study is a randomized, parallel-group, double-blind, placebo-controlled, multi-center study of eculizumab administered in an acute setting for the prevention of DGF in adult recipients of a deceased-donor kidney transplant who are at increased risk of DGF.

A total of 288 patients were treated across North America, South America, Europe, and Australia. Patients had dialysis-dependent renal failure (initiated more than 2 months prior to transplant) and were scheduled to receive a first kidney transplant from a deceased standard criteria donor (SCD) or expanded criteria donor (ECD) with a DGF risk score of ≥25 percent using the Irish scale.

Patients were randomized 1:1 to receive either eculizumab or placebo in the following dosing regimen: one dose of eculizumab 1200 mg or placebo just prior to the time of reperfusion of the kidney allograft and one dose of eculizumab 900 mg or placebo within 18 to 24 hours of the completion of administration of the first dose.

Randomization was stratified according to whether the donor kidney was preserved by cold storage or by machine perfusion, as well as by donor type (ECD vs. SCD). Patients were evaluated over a primary study period through 26 weeks and a follow-up period through 52 weeks.

In the primary endpoint of the study, assessed in 286 patients who were treated and received a transplant, the incidence of DGF, death, graft loss, or loss to follow-up at 7 days post-transplant was 35.9 percent for patients receiving a two-dose regimen of eculizumab compared with 41.7 percent for patients receiving placebo (p=0.398).

In the first 60 days following treatment, rates of serious adverse events were higher for patients in the placebo group compared with the eculizumab group (54.1 percent vs. 44.4 percent). There were 4 deaths in the placebo group vs. 1 in the eculizumab group in the same time frame. Alexion expects that data from the study will be published at a later date.

Eculizumab received orphan drug designation (ODD) in 2014 from the U.S. Food and Drug Administration for the prevention of DGF in renal transplant patients, and from the European Medicines Agency for the prevention of DGF after solid organ transplantation.

Soliris (eculizumab) is not approved in any country for the treatment or prevention of DGF.