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Sub-Group Analysis Shows Investigational Metreleptin Treatment Demonstrated Reductions in HbA1c, Triglycerides and Liver

  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

Business Wire

PRINCETON, N.J. & WILMINGTON, Del. -- May 06, 2013

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   Change*  95% CI   BL        Month   Change*  95% CI
                12                                  12
A1C (%) 6.1±1.3 5.4±0.8 -0.7±0.4 -1.6,0.2 9.8±1.8   7.7±1.7 -2.3±0.4 -3.2,-1.4
TGs     240±105 230±195 3.6±21*  -43,50   1378±2024 385±446 -44±14*  -73,-15
(mg/dL)
ALT     193±202 155±274 -38±47   -142,66  105±97    59±108  -46±40   -131,39
(U/L)
AST     119±112 90±144  -30±29   -94,35   87±89     57±118  -31±38   -111,50
(U/L)
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 >200mg/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 threemonths 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.

Contact:

Media:
Bristol-Myers Squibb
Shelly Mittendorf, 609-252-5799
shelly.mittendorf@bms.com
or
AstraZeneca
Kristin Rogers, 302-885-8922
kristin.rogers@astrazeneca.com
or
Investors:
Bristol-Myers Squibb
John Elicker, 609-252-4611
john.elicker@bms.com
or
AstraZeneca
Karl Hard, 44-20-7604-8123
karl.j.hard@astrazeneca.com
 
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