Abstract 1980

Poster Board I-1002

PNH is a progressively debilitating and life-threatening disease characterized by chronic complement-mediated hemolysis. The clinical complications associated with chronic hemolysis include life-threatening thrombosis, chronic kidney disease (CKD), pulmonary hypertension, organ damage, ischemic bowel disease, and hepatic failure - all of which contribute to shortened survival of patients with PNH. CKD, a consequence of hemolysis, has significant impact on survival in Japanese patients with PNH, accounting for 18% of deaths. We previously reported results from the Japanese AEGIS study, a 12-week open-label single-arm phase II study, which demonstrated that eculizumab (ecu), a humanized monoclonal antibody against the terminal complement molecule C5, significantly reduced complement-mediated intravascular hemolysis. Ecu treatment subsequently improved anemia, fatigue and renal function in 11 Japanese patients with PNH. Given the important impact on survival of renal disease, the effects of ecu on renal function were further evaluated among 27 Japanese patients with PNH enrolled in a 26-week extension of the AEGIS study. Ecu was dosed as follows: 600mg weekly for 4 weeks; 900mg one week later; and then 900mg every other week for a total of 38 weeks of therapy. Patients received meningococcal vaccine 2 weeks prior to treatment. Consistent with the previous 12 week study report, there was a sustained reduction in intravascular hemolysis, as measured by lactate dehydrogenase (LDH), through the 38 weeks of ecu treatment. LDH decreased 87% from a median of 1,814 U/L at baseline to a median of 232 U/L at 38 weeks of treatment (P<0.001; see table). Control of hemolysis resulted in continued improvement in anemia; hemoglobin continued to increase from 7.5 g/dL at baseline to 9.75 g/dL at 38 weeks (P<0.001) despite the reduction in transfusion requirements (P=0.004). Fatigue levels, as measured by the FACIT-Fatigue instrument, continued to significantly improve with ecu treatment (P<0.001; see table). Renal function was defined by KDOQI CKD stage, recognized as objective evidence of abnormal glomerular function, determined by glomerular filtration rate (GFR), along with persistent proteinuria, from Stage 0 (normal) to Stage 5 (Kidney failure). An improvement in renal function was defined as a categorical reduction (improvement) in CKD stage. Worsening in renal function was defined as a categorical increase (decline) in CKD stage. At study entry, 65% of the Japanese group demonstrated evidence of CKD. During the 38-week treatment period, 33.3% (9/27) of all patients who entered the trial showed improvement while 66.7% (18/27) showed no change or progression from baseline and no patients worsened. Further, 52.9% (9/17) of patients with CKD at baseline demonstrated improvement. Among the 9 patients who showed improvement, 8 had stage 1-2 CKD at baseline and one had stage 3-5, underscoring the importance of early intervention with ecu in patients with mild kidney disease. The CKD results of the Japanese study were compared to the 26-week placebo-controlled TRIUMPH trial and the combined data from the multinational clinical trials (see table). In the overseas multinational trials, 64% (121/189) of patients had evidence of CKD at study entry, similar to the 65% in the Japanese cohort. The results from the 26-week placebo group in the TRIUMPH trial suggest that there is no significant change in CKD over the course of 6 months. In contrast, treatment with ecu significantly improved CKD in patients in the TRIUMPH and overseas multinational studies (P<0.001) and in the Japanese study (0% worsened, 33% improved, P<0.05). The results from both studies also demonstrate that the benefit from ecu treatment was most evident in patients with early CKD stage 1-2. In conclusion, kidney disease is an important cause of premature mortality in Japanese PNH patients. The current study suggests that evidence of CKD is common in Japanese PNH patients. Further, this study demonstrates that ecu is safe and well tolerated in Japanese patients with PNH. We see continued improvement in PNH symptoms from 12 to 38 weeks with ecu treatment. Similar to the beneficial effects of ecu in patients with PNH in overseas multinational phase III trials, reduction of hemolysis with ecu treatment was associated with clinical improvement in kidney function in Japanese patients with PNH.

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