Monday, January 28, 2019 6:30 am EST
BOSTON–(BUSINESS WIRE)–Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) today announced that the Phase 3 study of ULTOMIRIS™ (ravulizumab-cwvz), the company’s long-acting C5 complement inhibitor, met its primary objective in complement inhibitor-naïve patients with atypical hemolytic uremic syndrome (aHUS). In the initial 26 week treatment period, 53.6 percent of patients (95% CI [39.6%, 67.5%]) demonstrated complete thrombotic microangiopathy (TMA) response. ULTOMIRIS provided immediate and complete inhibition of the complement C5 protein that was sustained over the entire eight-week dosing interval.
The primary endpoint of complete TMA response was defined by hematologic normalization and improved kidney function. Treatment with ULTOMIRIS resulted in:
- reduced thrombocytopenia, as measured by normalization in platelet count, in 83.9 percent of patients (95% CI [73.4%, 94.4%]),
- reduced hemolysis (the destruction of red blood cells), as measured by normalization in lactate dehydrogenase (LDH) level, in 76.8 percent of patients (95% CI [64.8%, 88.7%]) and
- improved kidney function, as measured by ≥ 25 percent improvement in serum creatinine level from baseline, in 58.9 percent of patients (95% CI [45.2%, 72.7%]). For patients on dialysis at enrollment, baseline was established after they had come off dialysis.
To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days.
The safety profile was consistent with that observed in two large Phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH).1,2
“We are very pleased with these data, which demonstrate that ULTOMIRIS can provide clinically meaningful benefits to patients with aHUS,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function, and provide confidence that ULTOMIRIS has the potential to become the new standard of care for patients with aHUS. We are preparing regulatory submissions for ULTOMIRIS in aHUS in the U.S., European Union and Japan as quickly as possible.”
Atypical HUS is a severe and chronic ultra-rare disease that can cause progressive damage to vital organs, predominantly the kidneys, leading to kidney failure and premature death. The disease is characterized by TMA (inflammation and blood clotting in small blood vessels throughout the body) that is mediated by chronic, uncontrolled activation of the complement system.3,4,5,6,7
“If left untreated, many patients progress to end-stage renal disease or die during the first clinical manifestations of aHUS or in the first year following these manifestations despite supportive care,” said Spero Cataland, M.D., hematologist at Ohio State University Wexner Medical Center and an investigator in the study. “I am very excited about these data and the potential for an effective new treatment option that can provide hematologic normalization and improved kidney function, including the potential to stop dialysis, when administered every eight weeks.”
The most frequently observed adverse events in this study were headache, diarrhea and vomiting. The most frequently observed serious adverse events were pneumonia and hypertension. In these critically ill patients, there were four patient deaths, none of which were considered related to treatment with ULTOMIRIS. No case of meningococcal infection was observed. Meningococcal infections are a known risk with terminal complement inhibition. To minimize the risk for patients, specific risk-mitigation plans have been established for ULTOMIRIS, based on plans that have been in place for more than 11 years for SOLIRIS® (eculizumab).
Detailed results from this Phase 3 study will be presented at a future medical congress. A Phase 3 study of ULTOMIRIS in children and adolescents with aHUS is currently ongoing.
About the ULTOMIRIS aHUS-311 Study
This global, multicenter, single arm, Phase 3 study evaluated the safety and efficacy of ULTOMIRIS administered by intravenous infusion in 56 adults (≥ 18 years of age) who hadn’t been treated with a complement inhibitor before. The study consists of an up to seven-day screening period, a 26-week initial evaluation period and an extension period of up to two years, which is still ongoing. Patients received a weight-based loading dose (≥ 40 to < 60 kg = 2,400 mg; ≥ 60 to < 100 kg = 2,700 mg; ≥ 100 kg = 3,000 mg) on Day 1, followed by weight-based maintenance doses (≥ 40 to < 60 kg = 3,000 mg; ≥ 60 to < 100 kg = 3,300 mg; ≥ 100 kg = 3,600 mg) on Day 15 and once every eight weeks thereafter. The primary endpoint was defined as complete TMA response during the 26-week initial evaluation period, as evidenced by normalization of platelet count and lactate dehydrogenase (LDH) level and an improvement in serum creatinine of ≥ 25 percent from baseline. For patients on dialysis at enrollment, baseline was established after they had come off dialysis. To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days. Complete C5 inhibition was defined as free C5 levels of <0.5 µg/mL.
About atypical Hemolytic Uremic Syndrome (aHUS)
Atypical hemolytic uremic syndrome (aHUS) is a chronic, progressive and debilitating ultra-rare disease that affects both children and adults and can lead to potentially irreversible damage to kidneys and other vital organs, sudden or progressive kidney failure (requiring dialysis or transplant) and premature death.3,4,7,8 aHUS is characterized by inflammation and the formation of blood clots in small blood vessels throughout the body (thrombotic microangiopathy [TMA]) mediated by chronic, uncontrolled activation of the complement system, which is part of the body’s immune system.3,4,5,6,7 TMA consists of reduced platelet count (thrombocytopenia), hemolytic anemia (as a result of hemolysis [destruction of red blood cells]) and acute kidney injury (AKI).5,7,9,10 If left untreated, significant proportions of adults (46 percent) and children (16 percent) can progress to end-stage renal disease (ESRD) or die during first clinical manifestations of aHUS despite supportive care, including plasma exchange or plasma infusion (PE/PI). One year following clinical manifestations, 56 percent of adults and 29 percent of children can progress to ESRD or die, if left untreated.11 Early and careful diagnosis of aHUS is critical as many coexisting diseases and events are known or suspected to activate the complement cascade, and as patients may not necessarily present with the classic TMA triad of thrombocytopenia, hemolytic anemia and renal impairment12 or may have less severe renal involvement.13 Available tests can help distinguish aHUS from other hemolytic diseases with similar symptoms such as HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS) and thrombotic thrombocytopenic purpura (TTP).7