Alexion Pharma Reports New Data from Phase 2 Clinical Trial of Soliris in Prevention of Acute AMR in Sensitized Decreased-Donor Kidney Transplant Recipients

Alexion Pharmaceuticals, Inc. ALXN today announced that researchers presented preliminary 1-year data from a single-arm Phase 2 study of eculizumab (Soliris^®) in the prevention of acute antibody-mediated rejection (AMR) in sensitized deceased-donor kidney transplant recipients. Acute AMR is a serious and potentially life-threatening condition that can lead to severe allograft damage resulting in rapid loss of function and possible loss of the transplanted organ.^1 In a late-breaking oral session today, researchers reported that the composite efficacy endpoint of post-transplant treatment failure occurred in 18.8% of patients (15/80) at 1 year, with a 10% incidence of AMR, in this ongoing, open-label study. Graft and patient survival at 1 year were 87.1% and 97.4%, respectively.^2 These data were presented at the 2015 American Transplant Congress (ATC) in Philadelphia, where researchers also presented the following: * Late-breaking data from a burden-of-disease study in which AMR development was associated with greater resource utilization and significantly higher post-transplant costs compared to patients who did not develop AMR^3 * Data from a non-clinical animal-model study providing support that the terminal complement pathway plays an important role in the development of delayed graft function (DGF) following kidney transplantation^4 * Data from a post-hoc sub-analysis from a prospective, open-label, single arm trial of Soliris in adult patients with atypical hemolytic uremic syndrome (aHUS) in which an increased percentage of patients experienced improvements in hematologic and renal outcomes with longer-term Soliris treatment, regardless of transplant history^5 "The data presented at the 2015 American Transplant Congress enhance our understanding of AMR and DGF, two serious and potentially life-threatening complications of kidney transplantation. We continue to advance the development of eculizumab in these settings to address the significant barriers to transplantation and burden of disease that the community currently faces," said Martin Mackay, Ph.D., Executive Vice President and Global Head of R&D at Alexion. "Separately, the aHUS data presented today further underscore the clinical benefits of ongoing Soliris therapy in adult patients with aHUS, irrespective of transplant history." Soliris is a first-in-class terminal complement inhibitor approved in nearly 50 countries as a treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH) and in nearly 40 countries as a treatment for patients with aHUS. Both PNH and aHUS are life-threatening ultra-rare diseases caused by chronic uncontrolled complement activation. Soliris is not approved in any country for the prevention or treatment of AMR or DGF. The following data were presented at the 2015 ATC: Eculizumab in Prevention of Acute Antibody-Mediated Rejection in Sensitized Deceased-Donor Kidney Transplant Recipients: 1-Year Outcomes (Abstract 3039) In a late-breaking oral session, Denis Glotz, M.D., Ph.D., Chief of the Department of Nephrology and Transplantation at Hôpital Saint-Louis, Paris, presented 1-year results from an open-label, single-arm, multicenter Phase 2 trial (N=80) evaluating the safety and efficacy of eculizumab in the prevention of acute AMR in sensitized deceased-donor kidney transplant recipients. Preliminary nine-week data from this study were reported at the European Society for Organ Transplantation (ESOT) Annual Congress in 2013.^6 Dr. Glotz today reported preliminary 1-year outcomes from this ongoing trial, which is now fully enrolled. The composite efficacy endpoint of week 9 post-transplant failure, defined as biopsy-proven AMR, graft loss, patient death, or loss to follow-up, occurred in 12.5% (10/80) of patients, with a 7.5% rate of AMR (6/80) based on locally read biopsies, compared with the historical 30% rate of AMR expected with best available care in this highly sensitized population.^2,7 At 1 year, post-transplant failure occurred in 18.8% (15/80) of patients, including a 10.0% incidence of AMR (8/80) based on locally read biopsies. Graft and patient survival at 1 year were 87.1% and 97.4%, respectively. The preliminary results presented at ATC were based on local laboratory data; a central read of the laboratory data is ongoing as required for the pre-specified primary endpoint of this study. Mean creatinine levels were 7.44 mg/dL (n=78) and 1.80 mg/dL (n=45) at baseline and 1 year, respectively.^2 No new safety signals were identified in this study. At 1 year, the most common treatment-emergent serious adverse events were transplant rejection (26.3%), acute renal failure (13.8%) and complications of the transplanted kidney (10.0%). Two patients (2.5%) in the study died, one due to multi-organ failure and one due to proximal small bowel perforation, both deemed not related to eculizumab. ^ 2 "Acute AMR is a significant clinical barrier to transplantation in sensitized patients, who make up approximately 60% of the transplant waiting list and currently have no approved options available to address this severe and potentially life-threatening risk," said Dr. Glotz. "While we recognize the limitations of the single-arm study design and the need for further exploration, the findings suggest that eculizumab may be effective in reducing the incidence of acute AMR in sensitized deceased-donor kidney transplant patients, with rates of graft survival, patient survival and kidney function at 1 year that were similar to those expected for non-sensitized kidney transplant recipients." Burden of Early Antibody-Mediated Rejection (AMR) (Poster A296) In a late-breaking poster session, Ramandeep S. Banga, M.D., of the Mayo Clinic, Rochester, presented results from a retrospective study that assessed complications, resource utilization and costs of acute AMR (up to 1 year post-transplant) in adult patients (N=48; 21 with AMR, 27 without AMR) with high levels of donor-specific antibody who underwent kidney transplantation. In the study, acute AMR was associated with higher rates of resource utilization, including hospital days (24.3 vs. 12.9, p=0.014), plasma exchange sessions (20.38 vs. 11.04, p=0.003), renal biopsies (5.9 vs. 3.6, p<0.001), IVIG doses (17.9 vs. 10.3, p=0.02), and more surgical procedures, including splenectomy and wound dehiscence. In addition, while pre-transplant costs were similar between the groups, AMR was associated with significantly higher post-transplant costs ($159,705 vs. $94,352; p=0.02). No significant difference in rates of medical and surgical complications was observed between the two groups.^3 Targeting Complement Pathways during Ischemia and Reperfusion: Implications for the Prevention of Delayed Graft Function (Abstract 789) In an oral session, Alexion researcher Zhao-Xue Yu, Ph.D, M.D., presented data from a nonclinical study that evaluated the effects of inhibiting the complement alternative pathway and terminal pathway during cold ischemia and reperfusion of the kidney on the development of DGF in a rat model of kidney transplantation. DGF is an early and serious complication of organ transplantation characterized by the failure of a transplanted organ to function normally immediately following transplantation. Researchers concluded that in this animal model, blockade of the terminal pathway improved graft function and survival, and may effectively protect against ischemia-reperfusion injury and subsequent DGF.^4 1-Year Safety and Efficacy of Eculizumab in Adult aHUS Patients, With or Without a History of Renal Transplant (Abstract 1243) In an oral session, Christophe M. Legendre, M.D., of the Université Paris Descartes and Hôpital Necker, Paris, presented a post-hoc sub-analysis from the C10-004 study that evaluated the safety and efficacy of Soliris at 26 weeks and 1 year in adult patients with aHUS (n=41) with and without a history of renal transplant. As previously reported at the American Society of Nephrology meeting in 2014, at 26 weeks, the primary endpoint of complete TMA response—defined as platelet count normalization, LDH normalization and preservation of renal function—was achieved in 78% (25/32) of non-transplant patients and in 56% (5/9) of transplant patients. At 1 year, complete TMA response was achieved in a greater proportion of patients: 84% (27/32) of non-transplant patients and 67% (6/9) of transplant patients. Dr. Legendre also reported that^5: * At 26 weeks, 97% (31/32) of non-transplant and 100% (9/9) of transplant patients achieved platelet count normalization compared with 100% (32/32) of non-transplant and 100% (9/9) of transplant patients at 1 year * At 26 weeks, 94% (30/32) of non-transplant and 78% (7/9) of transplant patients achieved LDH normalization, compared with 100% (32/32) of non-transplant and 89% (8/9) of transplant patients at 1 year * At 26 weeks, 56% (18/32) of non-transplant and 44% (4/9) of transplant patients achieved eGFR improvement from baseline of ≥15 mL/min/1.73 m^2 compared with 66% (21/32) of non-transplant and 44% (4/9) of transplant patients at 1 year * 86% of non-transplant and 67% of transplant patients discontinued dialysis by week 26. All patients who discontinued dialysis remained dialysis-free at 1 year, and none progressed to end-stage renal disease or required a subsequent graft "In this 1-year analysis, we observed that ongoing treatment with Soliris continued to inhibit complement-mediated TMA and led to improvements in platelet count and renal function that were achieved by a greater percentage of patients at 1 year. These gains were more significant in patients with native kidney than in those who were transplanted," said Dr. Legendre. "Importantly, in a population of transplanted patients with a historically very high risk of graft loss, no new patients treated with Soliris in this study lost their graft at 1 year." There were no unexpected adverse events reported during the 1-year analysis period. As previously described, two patients in the C10-004 study developed meningococcal infections (one patient discontinued from the study and later recovered; the other continued treatment with no interruption and recovered without sequelae). The most common AEs reported by sub-group at 1 year were: for patients with renal transplant, diarrhea (66.7%), anemia (44.4%), urinary tract infection (33.3%), bronchitis (33.3%) and hematoma (33.3%); for patients without renal transplant, headache (40.6%), peripheral edema (28.1%), diarrhea (25.0%), nasopharyngitis (21.9%), cough (21.9%), and pyrexia (21.9%).5