Published: June 06, 2009
Incyte Oral 11beta-HSD1 Inhibitor, Significantly Improves Glycemic Control, Insulin Sensitivity and Total Cholesterol for Type 2 Diabetes
NEW ORLEANS & WILMINGTON, Del. - (BUSINESS WIRE) - Incyte Corporation (Nasdaq:INCY) announced today clinical results of its
Phase IIb trial of INCB13739, an orally bioavailable inhibitor of the
enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at the
American Diabetes Association (ADA) 69th Scientific Sessions being held
in New Orleans.
Results from this double-blind, placebo-controlled Phase IIb trial
involving over 300 patients with type 2 diabetes showed that treatment
with once-daily doses of INCB13739 significantly improved glycemic
control, as measured by hemoglobin A1c (HbA1c), insulin sensitivity and
total-cholesterol levels. These results will be described by the
principal investigator for the trial, Julio Rosenstock, M.D., of the
Dallas Diabetes and Endocrine Center at Medical City and Clinical
Professor of Medicine at University of Texas Southwestern Medical
School, on Sunday from noon to 2 p.m. CT during a late breaker poster
session entitled, "Clinical Therapeutics/New Technology -
Pharmacologic Treatment of Diabetes or its Complications." The poster is
currently available at: http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9NzkwNHxDaGlsZElEPS0xfFR5cGU9Mw==&t=1
Dr. Rosenstock stated, "Agents targeting novel mechanisms to combat
cardio-metabolic disease in patients with type 2 diabetes are clearly
needed as this population continues to rapidly expand in the coming
decades. INCB13739 has provided the first proof-of-concept for the
potential therapeutic utility of 11beta-HSD1 inhibition in type 2
diabetes by demonstrating improvements on glycemic control and indirect
measurements of insulin sensitivity. Further studies are warranted to
better characterize this new and interesting class of drugs."
Summary of Phase IIb Results
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Twelve weeks of 100 mg and 200 mg once-daily INCB13739 added to
failing metformin monotherapy in patients with type 2 diabetes
resulted in a statistically significant placebo-adjusted reduction in
HbA1c of -0.47 and -0.56% respectively.
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Patients receiving 200 mg INCB13739 achieved a statistically
significant reduction in fasting plasma glucose, homeostasis model
assessment-estimated-insulin resistance and total cholesterol.
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Normal cortisol levels and rhythmicity were maintained by the expected
compensatory adrenocorticotropic hormone (ACTH) response following
INCB13739 treatment. ACTH plateaued at week 4 and returned to baseline
after cessation of therapy.
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Dehydroepiandrosterone and A4 levels increased in concert with ACTH.
Levels plateaued after 4 weeks, reversed after cessation of therapy,
and were not associated with increased testosterone or suppression of
androgenic target proteins.
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INCB13739 was well tolerated at all dose levels.
Jonathan Seckl, M.D., Ph.D., Professor of Molecular Medicine,
Endocrinology Unit Centre for Cardiovascular Science Queen's Medical
Research Institute, Edinburgh, stated, "The concept of 11beta-HSD1
inhibition as a potential therapy for humans has moved a substantial
stride forward today with the publication of a Phase II trial of
INCB13739 in patients with type 2 diabetes inadequately controlled on
metformin. We already know that inhibition of this enzyme is beneficial
for rodents with metabolic disease, but what remained crucially unknown
was whether the concept was useful in humans and whether the expected
endocrine effects of loss of glucocorticoid regeneration in the
splanchnic bed would lead to unacceptable side effects. The present data
not only show INCB13739 produces a significant lowering of HbA1c,
fasting blood glucose, insulin resistance and cholesterol levels without
weight gain, but reassure that the endocrine changes appear relatively
mild. Crucially, there were no changes in plasma cortisol in the morning
and salivary cortisol at night, underlining the compensatory nature of
the endocrine changes. Moreover, plasma testosterone levels in males and
in females examined and the androgenic target sex hormone-binding
globulin were unaltered. Thus, major short-term endocrine side effects
appear unlikely with INCB13739 therapy, although these clearly need to
be scrutinized in longer-term trials. These encouraging findings should
reassure of the value of further studies."
About the Phase IIb Trial
This was a multicenter, double-blind, placebo-controlled Phase IIb trial
in over 300 patients with type 2 diabetes who had inadequate glycemic
control (HbA1c 7-11%, inclusive) while on stable metformin monotherapy
≥10 weeks at baseline. Patients were equally randomized to once-daily
treatment with either placebo, 5 mg, 15 mg, 50 mg, 100 mg or 200 mg
INCB13739 in addition to their stable metformin regimen.
The primary objective was to evaluate the efficacy, safety and
tolerability of adding INCB13739 for 12 weeks to patients with type 2
diabetes who were inadequately-controlled on metformin monotherapy.
Secondary objectives were to examine the effect of INCB13739 on multiple
cardiovascular risk factors in type 2 diabetes patients.
About INCB13739
INCB13739 is a potent, selective small-molecule inhibitor of 11beta-HSD1
with 1.1 nM potency in cellular assays. The compound is >1000-fold
selective over 11beta-HSD2, glucocorticoid receptor, and
mineralocorticoid receptor and exhibits good oral pharmacokinetics with
an estimated half-life of 11 hours. Data from prior clinical trials
indicated that INCB13739 can be dosed to achieve complete inhibition of
adipose tissue and liver 11beta-HSD1 activity throughout the dosing
interval.
About 11beta-HSD1
11beta-HSD1 is an enzyme that converts inactive cortisone into the
potent biologically active hormone cortisol. This conversion occurs
within cells of key metabolic tissues including liver, adipose, muscle
and pancreas. Importantly, preclinical studies have shown that the
enzyme does not significantly affect neuroendocrine control of
glucocorticoid biosynthesis in the adrenal gland, but rather provides a
mechanism to specifically increase local glucocorticoid exposure within
cells in a tissue-specific manner. Unlike the hormone insulin, which is
produced by beta-cells in the pancreas and maintains normal blood
glucose levels, cortisol elevates blood glucose levels by driving
glucose production in the liver, and inhibiting the uptake and disposal
of glucose in muscle and adipose. Thus, cortisol acts as an antagonist
of insulin action, and 11beta-HSD1 mediated production of cortisol has
been hypothesized to contribute to human insulin resistance, type 2
diabetes, and the often-associated cardiovascular comorbidities.
Current treatments for type 2 diabetes typically address individual
components of the disease, and few therapies target the multiple risk
factors that lead to the elevated cardiovascular risk associated with
this condition. By selectively inhibiting 11beta-HSD1 and reducing the
level of cortisol in key metabolic tissues, INCB13739 has the potential
to simultaneously target multiple cardiovascular risk factors in
patients with type 2 diabetes.
About Type 2 Diabetes
According to the Centers for Disease Control and Prevention (CDC),
nearly 21 million Americans have diabetes. The majority of these
patients have type 2 diabetes. The CDC also reports that 41 million
people are estimated to have pre-diabetes, a predisposing condition that
occurs before the onset of type 2 diabetes.
Webcast / Conference Call Information
A live webcast to discuss the results from the Phase IIb study is
scheduled for Sunday June 7, 2009 at 5:00 p.m. ET / 4:00 p.m. CT. The
webcast with slides can be accessed on Incyte's website: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-Calendar
Please connect to Incyte's website prior to the start of the live
webcast to ensure adequate time for any software downloads that may be
necessary.
Analysts and investors are also invited to participate in the conference
call by calling the following numbers:
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Domestic Dial In Number:
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877-407-8037
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International Dial In Number:
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201-689-8037
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Conference ID #:
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324369
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If you are unable to participate, a replay of the webcast will be
available on Incyte's website for 90 days and can be accessed at www.incyte.com
under Investor Relations, Events and Webcasts.
About Incyte
Incyte Corporation is a Wilmington, Delaware-based drug discovery and
development company focused on developing proprietary small molecule
drugs to treat serious unmet medical needs. Incyte's pipeline includes
multiple compounds in Phase II clinical trials for oncology,
inflammation and diabetes. For additional information on Incyte, visit
the Company's web site at www.incyte.com.
Forward Looking Statements
Except for the historical information contained herein, the matters set
forth in this press release, including statements with respect to
11beta-HSD1 inhibition as a potential therapy for humans, the likelihood
of major endocrine side effects with INCB13739 therapy, conducting
further studies of INCB13739, the potential for INCB13739 to
simultaneously target multiple cardiovascular risk factors in patients
with type 2 diabetes, are all forward-looking statements within the
meaning of the "safe harbor" provisions of the Private Securities
Litigation Reform Act of 1995. These forward-looking statements are
subject to risks and uncertainties that may cause actual results to
differ materially, including the high degree of risk associated with
drug development and clinical trials, the potential failure of INCB13739
to demonstrate safety and efficacy in clinical testing; the therapeutic
and commercial value of INCB13739; the uncertainty of the FDA approval
process for diabetes drugs, the results of further research and
development, the impact of competition and of technological advances and
the ability of Incyte to compete against parties with greater financial
or other resources, Incyte's ability to enroll a sufficient number of
patients for its clinical trials, and other risks detailed from time to
time in Incyte's filings with the Securities and Exchange Commission,
including its Quarterly Report on Form 10-Q for the quarter ended March
31, 2009. Incyte disclaims any intent or obligation to update these
forward-looking statements.
Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=5981415〈=en
Incyte Corporation
Pamela M. Murphy
Vice
President, Investor Relations/Corporate Communications
302-498-6944
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