STEC-HUS is a life-threatening disease characterized by systemic complement-mediated TMA and acute vital organ damage that can lead to serious, long-term complications. In STEC-HUS, Shiga toxin induces uncontrolled complement activation, resulting in systemic TMA and inflammation, which in turn leads to multi-organ damage and death during the acute phase of the disease. 3-9 Patients with STEC-HUS can also experience rapid and unpredictable disease progression. 10-13 TMA-related organ damage can lead to long-term complications. 14“STEC-HUS is an unpredictable, life-threatening disease with a high rate of long-term serious clinical sequelae and no approved treatment options that address the underlying pathogenesis of the disease,” said Stephen P. Squinto, Ph.D., Executive Vice President, Head of Research and Development at Alexion. Eculizumab is approved in over 40 countries as a treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH) and in the United States and European Union for patients with atypical hemolytic uremic syndrome (aHUS). PNH and aHUS are both debilitating and life-threatening ultra-rare disorders caused by chronic, uncontrolled complement activation. Eculizumab is not approved for the treatment of STEC-HUS in any country and was used in the reported study on an investigational basis. About the Eculizumab Study The 28-week, open-label, multi-center trial enrolled 198 STEC-HUS patients at 23 clinical trial sites with TMA (platelet decrease and evidence of hemolysis) and organ complications (evidence of kidney or central nervous system complications, or thrombosis). All patients showed severe, progressive disease at baseline: 96% had kidney involvement, 84% had brain involvement, 80% had involvement of both brain and kidney, 26% had seizures, 24% required respiratory support with mechanical ventilation, and 21% were in a coma. In addition, 91% of patients were receiving plasma exchange and 72% required dialysis at baseline prior to receiving eculizumab. Patients enrolled in the study received 900 milligrams (mg) of eculizumab each week for the first 3 weeks, followed by a 1200 mg dose on weeks 4, 6, and 8. After an initial 8-week eculizumab treatment period, study investigators were able to request treatment with eculizumab 1200 mg every other week for an additional 8 weeks. All patients in the study were observed for 28 weeks following eculizumab treatment initiation. 1 Nearly all (94%) of the eculizumab-treated patients had a global response to therapy by 8 weeks, prospectively defined as either a complete response (CR), which consisted of hematologic normalization, clinically important improvement in all affected vital organs, and no clinically important worsening in any vital organ; or a partial response (PR), consisting of hematologic improvement or normalization and no clinically important worsening in any vital organ. Specifically, at 8 weeks, 80% of patients had a CR and 14% had a PR. By week 28, the overall response of 94% was sustained, and there was an increased rate of complete response from 80% to 89% between weeks 8 and 28. 1 Results of the study also showed 1:
- Rapid improvement in platelet count with eculizumab treatment, which was worsening prior to eculizumab.
- Rapid improvement in renal function with eculizumab treatment, as measured by normalization in serum creatinine, which was worsening prior to eculizumab.
- Elimination of dialysis and plasma exchange with eculizumab therapy: 84% of patients who required dialysis at baseline (115/137) discontinued dialysis by 3 weeks of eculizumab therapy. By week 8, 96% of patients had discontinued dialysis and by week 28, 99% of patients had discontinued dialysis. All of the patients who required plasma exchange at baseline (181/181) had discontinued plasma exchange by 4 weeks of eculizumab therapy.
- Improvement in neurological complications with eculizumab treatment: By week 8, 64% of patients had neurological normalization, defined as a shift from ≥2 at baseline on the Modified Rankin Scale (MRS), which measures neurologic morbidity, to a MRS score of 0-1 with eculizumab. By week 28, 91% of patients achieved MRS normalization.
- By week 28, 100% of patients were out of coma (35/35), 100% were free of seizures (43/43) and 100% had discontinued mechanical ventilation (47/47).