Alexion Reports Presentation of Membranous Nephritis Clinical Trials
Monday November 4, 7:31 am ET
- Data Trends Point Toward Treatment of Disease Through Extended Administration of Eculizumab: Alexion Plans 12 Month Treatment Trial -
CHESHIRE, Conn., Nov. 4 /PRNewswire-FirstCall/ -- At the 35th Annual Meeting and Scientific Exposition of the American Society of Nephrology, Gerald Appel, M.D., Professor of Clinical Medicine at Columbia University College of Physicians and Surgeons, presented data from Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN - News) two clinical trials with eculizumab in Membranous Nephritis (C99-004 and E99-004). Results from C99-004, a randomized, double-blind, placebo-controlled study, showed that eculizumab was well tolerated but did not reach its primary clinical efficacy endpoint of proteinuria reduction after four months of therapy. Data from trial E99-004, in which both placebo and eculizumab patients from the four-month study were treated for an additional 12 months with eculizumab therapy in an ongoing open-label trial, 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 of therapy. The trials suggest that, at the doses given, extended eculizumab therapy may be required for clinical improvement in this disease.
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Dr. Appel presented the poster titled: "Eculizumab (C5 Complement Inhibitor) in the Treatment of Idiopathic Membranous Nephropathy (IMN): Preliminary Baseline and Pharmacokinetic (PK)/Pharmacodynamic (PD) Data" yesterday at the American Society of Nephrology Scientific Sessions. The trials were sponsored by Alexion Pharmaceuticals.
"These data are from the largest trials completed to date in patients with idiopathic membranous nephritis," stated Dr. Appel. "Since we have preliminarily observed significant clinical improvements after 12 months of therapy but not with four months of therapy, the data suggest that either increased dosage and/or prolonged eculizumab administration may be associated with clinically relevant improvements in important components of the nephritic syndrome in patients with established renal disease and membranous nephritis. This view is further supported by the observation, noted from the four-month trial, of the correlation between the extent of complement inhibition and improvement in proteinuria. If these observations are confirmed in subsequent clinical studies, eculizumab may provide an important new disease-specific therapy for patients with kidney diseases, particularly membranous nephritis."
In trial C99-004, 117 patients at 23 medical centers were treated in a double-blind, randomized, placebo-controlled manner for four months, with placebo (n=44), eculizumab 8mg/kg every four weeks (n=29), or eculizumab 8mg/kg every two weeks (n=44). The primary objective of C99-004 was to observe safety of eculizumab administration during four months of therapy. Eculizumab appeared to be well tolerated, with the most common adverse events being upper respiratory tract infection, diarrhea, and headache. The primary efficacy endpoint, 24 hour urinary protein, was not significantly different between study groups. However, subset analyses showed that patients who appeared to benefit most clinically also had more complete complement inhibition; an important finding as to the pathology of the disease and to the effectiveness of eculizumab treatment.
In Trial E99-004, 72 placebo and eculizumab patients from trial C99-004 were entered into a pre-planned, open-label extension study designed to provide eculizumab 8mg/kg every two weeks for 12 months. The primary objective of the extension trial was to observe longer term tolerance of eculizumab in this patient population. The trial is still ongoing and available patient data may not be indicative of subsequent results. Eculizumab appears to be generally well tolerated with the most common adverse events being upper respiratory infections, nasal congestion/rhinitis, and headache. After nine months of therapy, eculizumab administration was associated with significant improvements in proteinuria, urinary protein/creatinine ratio, and serum albumin. At the end of 12 months of therapy, urinary protein decreased 42% from 5.9 +/- 0.7 gm/24h to 3.4 +/- 0.7 gm/24h (p<0.001), urinary protein/creatinine ratio decreased 45% from 4.0 +/- 0.5 to 2.2 +/- 0.5 gm/mg/24h (p<0.001), serum cholesterol decreased 10% from 232 +/- 10 to 208 +/- 7 mg/dl (p=0.005), serum triglycerides decreased 16% from 169 +/- 12 to 142 +/- 12 mg/dl (p=0.008), and serum albumin increased 14% from 2.9 +/- 0.1 to 3.3 +/- 0.1 mg/dl(p<0.001) in the 39 patients for whom one year of follow-up data was available. Remission rate was examined prospectively using the widely employed clinical definition of remission in nephrotic membranous nephritis patients that requires both a 50% reduction in proteinuria and a 24 hour proteinuria less than 3.5 grams. For the 55 evaluable E99-004 patients who were treated with eculizumab for six months or longer, eculizumab treatment was associated with a 27% 12 month remission rate by Kaplan-Meier analysis.
"The clinical data suggest that eculizumab therapy warrants further investigation in patients with membranous nephritis," stated Leonard Bell, M.D., Chief Executive Officer of Alexion. "These trials have provided us with substantial insight into both potential mechanisms of disease and possible mechanisms of disease amelioration by eculizumab. After completion of additional analyses, we expect to discuss these results with the FDA so as to most effectively plan subsequent clinical development in this field, targeting a 12 month treatment trial with eculizumab. Previously, Alexion was granted orphan drug and Fast Track designations for this indication." |
