Short-term trials may not have provided the clinical response Alexion Pharmaceuticals Inc. sought for eculizumab, but longer-term studies appear to point to a need for further investigation of the candidate in treating membranous nephritis.
The Cheshire, Conn.-based company reported at the American Society of Nephrology meeting in Philadelphia that eculizumab did not reach its primary clinical efficacy endpoint of proteinuria reduction after four months of therapy. But a 12-month study showed more promising results.
"In kidney disease, one of the major concerns about therapies is whether they have a durable effect or not," Alexion CEO Leonard Bell said. "So the fact that it took a while to get an effect, but once it was there it stayed, is very encouraging."
The randomized, double-blind, placebo-controlled trial named C99-004 studied 117 patients with placebo (n=44), eculizumab 8 mg/kg every four weeks (n=29) or eculizumab 8mg/kg every two weeks (n=44). Eculizumab appeared to be well tolerated, but the primary efficacy endpoint, 24-hour urinary protein, was not significantly different between groups.
Data were much more promising from another trial, E99-004, in which 72 placebo and eculizumab patients from the four-month study were treated for an additional 12 months in an open-label study. Results showed that eculizumab was well tolerated, associated with an increased remission rate at 12 months, and associated with significant improvements in proteinuria, hyperlipidemia, hypertriglyceridemia and hypoalbuminemia after 12 months.
"I think this points to a 12-month efficacy trial of eculizumab in membranous nephritis patients," Bell told BioWorld Today. "There are two really striking observations, both long-term observations. We impacted a variety of components of nephrotic syndrome, and we actually induced remissions at 12 months in 27 percent of the patients. We'll have to determine which one would be the primary objective in the next trial.
"Typically, nephrotic syndrome patients have high protein in the urine, low albumin in the blood, high cholesterol and high triglycerides in blood," Bell said. "What's striking about the 12-month study is that by nine months we saw significant improvement in protein in the urine albumin in the blood, and by 12 months cholesterol was significantly lower and triglycerides were significantly lower as well."
Remission rate was 27 percent for the 55 evaluable patients who were treated with eculizumab for six months or longer. The longer-term study showed that eculizumab appeared to be generally well tolerated, with the most common adverse events including upper respiratory infections, nasal congestion/rhinitis and headache.
The drug candidate is being studied to treat a variety of other conditions as well. Alexion is enrolling 300 patients in a Phase IIb trial of eculizumab to treat rheumatoid arthritis after showing a significant improvement in ACR 20 scores at three months during Phase IIa. The drug is in a Phase II trial in lupus nephritis, and earlier-stage clinical results will be presented at a scientific meeting next month for the treatment of paroxysmal nocturnal hemoglobinuria. Early stage studies have showed skin rash improvement in treating dermatomyositis.
Beyond eculizumab, Alexion's other lead candidate is pexelizumab, an antibody fragment being developed in collaboration with Procter & Gamble Pharmaceuticals, a division of Procter & Gamble Co., of Cincinnati. The firms have begun a Phase III study in cardiopulmonary bypass patients, and have completed enrollment in two large Phase II studies in acute myocardial infarction patients. Bell said results of the latter trials would be presented at this month's American Heart Association meeting in Chicago.
Alexion's stock (NASDAQ:ALXN) fell 3 cents Monday to close at $9.81.
In other news from the meeting:
• Amgen Inc., of Thousand Oaks, Calif., reported that 96 percent of patients receiving Aranesp (darbepoetin alfa) dosed every other week to correct anemia in chronic kidney disease patients not on dialysis reached and maintained target hemoglobin levels. Of the 463 patients who completed the 24-week study, 445 reached study target hemoglobin levels (11.0-13.0 g/dL) in an average time of 5.7 weeks. Separately, Amgen said Phase II data suggest its investigational compound AMG 073 (cinacalcet HCl) can reduce and maintain parathyroid hormone (PTH) levels within the target range in end-stage renal disease patients with secondary hyperparathyroidism. In the randomized, placebo-controlled, double-blind, 12-week trial, AMG 73 was given at doses up to 180 mg to 82 hemodialysis patients with pre-study PTH levels greater than or equal to 300 pg/mL - a high level - despite receiving standard therapy. AMG 073 reduced PTH to the target level in 54 percent of patients who were not controlled on current therapy. Concomitant vitamin D and phosphate binder use was similar between treatment groups. AMG 073 was well tolerated and adverse events were similar in the two treatment groups.
• AnorMED Inc., of Vancouver, British Columbia, said Fosrenol (lanthanum carbonate), a phosphate binder for use in dialysis patients that is licensed to Shire Pharmaceuticals Group plc, of Andover, UK, was shown to be effective in reducing high phosphate levels associated with end-stage renal disease. It also reduces hypercalcaemia, a side effect linked to cardiovascular disease in such patients. Interim data from a 1,200-patient long-term safety study in the U.S. showed fewer serious adverse events and deaths in the Fosrenol group. The study showed a statistically significant reduction in mortality in patients receiving Fosrenol compared to standard therapies. A European study showed that Fosrenol treatment reduced to a greater extent calcium X phosphate product, associated with increased mortality and morbidity in dialysis patients, compared with calcium treatment.
• BioStratum Inc., of Research Triangle Park, N.C., said its lead candidate, Pyridorin (pyridoxamine), was shown to be safe and effective in treating diabetic nephropathy during a six-week, 12-patient, Phase IIa trial. Preclinical data had shown Pyridorin treatment dramatically reduced microscopic lesions in the kidneys of treated animals compared to untreated control animals, while other data demonstrated that Pyridorin's mechanism of action is unique and different from that of previously studied AGE inhibitors.