Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced the results from a 12-month sub-group analysis of a National Institutes of Health (NIH), open-label, long-term research study of metreleptin, an investigational agent for the treatment of metabolic disorders associated with inherited or acquired lipodystrophy (LD), a rare disease estimated to affect a few thousand people around the world, often with an early age of onset. In this analysis, which involved 39 pediatric LD patients less than 18 years of age at the time of study enrollment, investigational metreleptin treatment led to mean reductions in HbA1c (average blood sugar levels over three months) and triglyceride levels, as well as mean reductions in liver function tests (including alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST). The full study was initiated in 2000 by investigators at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the NIH, and is currently ongoing. Results from the pediatric analysis were presented today at the 2013 Pediatric Endocrine Society (PES) Annual Meeting, being held in conjunction with the 2013 Pediatric Academic Societies (PAS) Annual Meeting in Washington, D.C.
The analysis was conducted to examine the effects of investigational metreleptin on select metabolic parameters associated with LD, including HbA1c, triglyceride levels and liver function tests, in pediatric patients enrolled in the NIH study. The four major subtypes of LD – congenital generalized LD, acquired generalized LD, familial partial LD and acquired partial LD – were represented. Patients were stratified to one of two groups: children (≤12 years) or adolescents (>12 to <18), and data were analyzed at month 12 of metreleptin treatment, where available (n=27).
In adolescents with LD, metreleptin treatment resulted in statistically significant reductions in elevated HbA1c (mean HbA1c decreased from 9.8±1.8% at baseline to 7.7±1.7% at month 12, for a mean decrease of 2.3±0.4%) and elevated triglycerides (mean triglyceride concentrations decreased from 1378±2024 mg/dL at baseline to 385±446 mg/dL at month 12, for a mean decrease of 44±14%). Elevated liver function tests also decreased (mean ALT decreased from 105±97 U/L at baseline to 59±108 U/L at month 12, for a mean decrease of 46±40%, and mean AST decreased from 87±89 U/L at baseline to 57±118 U/L at month 12, for a mean decrease of 31±38%). In younger children with LD, confirmed diabetes and hypertriglyceridemia were uncommon; however, mean liver function tests were markedly elevated at baseline and decreased with investigational metreleptin treatment (mean ALT decreased from 193±202 U/L at baseline to 155±274 U/L at month 12, for a mean decrease of 38±47%, and AST decreased from 119±112 U/L at baseline to 90±144 U/L at month 12, for a mean decrease of 30±29%). Reductions in ALT and AST did not reach statistical significance due to the small sample size and limited statistical power, but were clinically meaningful.
“Metabolic disorders resulting from lipodystrophy can develop in childhood and adolescence and are exacerbated over time,” said Rebecca Brown, M.D., Assistant Clinical Investigator, Diabetes, Endocrinology, and Obesity Branch, NIDDK. “This new analysis supports the continued study of investigational metreleptin as a potential treatment option for pediatric patients with lipodystrophy.”
In the analysis, the most common adverse events related to treatment with investigational metreleptin were decreased weight (n=3, 7.7%), hypoglycemia (n=3, 7.7%), fatigue (n=2, 5.1%), and nausea (n=2, 5.1%).
Results from the analysis are shown in Table 1 for patients who had a month 12 measurement (n=27).
Table 1. Baseline and 12-month Metabolic Measurements for the NIH Study Pediatric Analysis
|Age ≤12 (n=12)||12 < Age < 18 (n=15)|
|BL||Month 12||Change*||95% CI||BL||Month 12||Change*||95% CI|
|Mean±SD for BL and Month 12, mean±SE for Change. Absolute change for A1C, ALT, AST. *Percent change for TGs.|
“We are encouraged by the results of this longer-term analysis,” said Jean L. Chan, M.D., Medical Director, Bristol-Myers Squibb. “Bristol-Myers Squibb and AstraZeneca recognize the unmet medical need of pediatric patients affected by lipodystrophy and the importance of studying potential treatments for this rare disease.”
About the National Institutes of Health (NIH) Study and the Pediatric Analysis
The NIH study is an ongoing, open-label uncontrolled trial of investigational metreleptin in patients with rare inherited or acquired forms of lipodystrophy that was initiated in 2000 to evaluate the safety and efficacy of metreleptin for treating metabolic abnormalities associated with lipodystrophy, including insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis and steatohepatitis (also known as fatty liver disease).
The current pediatric analysis involved 39 pediatric patients (9 male and 30 female, less than 18 years of age at study enrollment [mean age 11.9±4.6]) enrolled as of a 2011 data cut. This cohort included patients representing the four major subtypes of lipodystrophy: congenital generalized lipodystrophy (n=26, 67%), acquired generalized lipodystrophy (n=9, 23%), familial partial lipodystrophy (n=2, 5%) and acquired partial lipodystrophy (n=2, 5%). Inclusion criteria included low leptin levels and at least one of the following: diabetes mellitus, fasting insulin level >30 μU/mL, or fasting triglycerides >200 mg/dL. Investigational metreleptin was administered once or twice daily by subcutaneous injection at an average dose of 4.4±2.7mg, with doses adjusted based on body weight and clinical effect. Treatment duration ranged from three months to 11 years (mean duration 3.9 years).
Metreleptin, an investigational analogue of the human hormone leptin, has received orphan designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and is being evaluated for the treatment of metabolic disorders associated with inherited or acquired lipodystrophy.
Lipodystrophy is a very rare disease, estimated to affect a few thousand people around the world. Patients with lipodystrophy experience loss of fat tissue, especially fat under the skin. This adipose tissue deficit causes a drop in the hormone leptin. Without enough fat tissue or leptin, the body’s system for regulating energy use and storage falls out of balance. The resulting serious imbalance causes fat to accumulate where it shouldn’t be found — such as in the blood or organs — which can lead to various complications.
There are two main reasons for lipodystrophy. In some patients, it is genetic and in others it may be acquired for different reasons, including cases in which the immune system may attack and destroy existing adipose tissue. Sometimes, clearly defined reasons for the development of the condition are unknown.
Bristol-Myers Squibb and AstraZeneca Collaboration
Bristol-Myers Squibb and AstraZeneca entered into a collaboration in January 2007 to research, develop and commercialize select investigational drugs for type 2 diabetes. The Bristol-Myers Squibb/AstraZeneca collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of diabetes and related metabolic disorders. The expansion of the collaboration covers the co-development and marketing of products in the Amylin Pharmaceuticals portfolio, including, among others, investigational metreleptin, a leptin analogue currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of lipodystrophy.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.
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