Sub-Group Analysis Shows Investigational Metreleptin Treatment Demonstrated Reductions in HbA1c, Triglycerides and Liver Function Tests in Pediatric Patients with Lipodystrophy During a 12-Month Period
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).
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Table 1. Baseline and 12-month Metabolic Measurements
for the NIH Study Pediatric Analysis
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Age ≤12 (n=12)
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12 < Age < 18 (n=15)
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BL
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Month 12
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Change*
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95% CI
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BL
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Month 12
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Change*
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95% CI
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A1C (%)
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6.1±1.3
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5.4±0.8
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-0.7±0.4
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-1.6,0.2
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9.8±1.8
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7.7±1.7
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-2.3±0.4
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-3.2,-1.4
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TGs (mg/dL)
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240±105
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230±195
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3.6±21*
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-43,50
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1378±2024
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385±446
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-44±14*
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-73,-15
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ALT (U/L)
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193±202
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155±274
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-38±47
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-142,66
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105±97
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59±108
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-46±40
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-131,39
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AST (U/L)
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119±112
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90±144
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-30±29
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-94,35
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87±89
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57±118
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-31±38
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-111,50
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Mean±SD for BL and Month 12, mean±SE for Change. Absolute change for
A1C, ALT, AST. *Percent change for TGs.
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“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).
About Metreleptin
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.
About 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.
About AstraZeneca
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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