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Novartis International AG

LAF237, First in a New Class of Oral Antidiabetic Agents, Shown in Phase II to Provide Clinically Significant Improvement in Glycemic Control

Munich, Germany (ots/PRNewswire)

- Researchers conclude LAF237 positively influences both insulin
production and utilisation in type 2 diabetes
The investigational drug LAF237, the first in a new class of oral
anti- diabetes agents, significantly improved glycemic control in
patients with  type 2 diabetes who were not adequately controlled by
metformin alone, an  improvement that was sustained for up to a year
while taking LAF237,  according to data presented at the European
Association for the Study of  Diabetes (EASD) annual meeting.
"Although most oral antidiabetic agents are initially effective in
achieving acceptable glycemic control in patients with type 2
diabetes, control is seldom maintained in the long term, even with
combination therapy," explained study author Professor Bo Ahrén of
Lund University, Sweden. "The finding that LAF237 can achieve
acceptable hemoglobin A1c reduction and maintain it for up to a year
is very encouraging."
Several other studies presented during the meeting suggest that
LAF237, a member of an innovative class of diabetes treatments known
as DPP-4 inhibitors, works to address the insulin/glucose imbalance
that is the underlying defect of type 2 diabetes. Researchers
reported that LAF237 increases insulin secretion while suppressing
the release of glucagon in patients with diabetes. Additionally,
researchers in a small study of people with type 2 diabetes concluded
that the compound improved function of the insulin-producing beta
cells in the pancreas.
LAF237 works in a different manner than other therapies used to
treat type 2 diabetes. It increases levels of specific hormones found
in the gut (incretin hormones) called glucagon-like peptide (GLP)-1
and gastric inhibitory polypeptide (GIP), by blocking the action of
dipeptidyl peptidase (DPP)-4, an enzyme that normally inactivates
them. GLP-1 and GIP are secreted from the intestine in response to
food and stimulates insulin production by the beta cells of the
pancreas. GLP-1 also reduces the secretion of glucagon, a hormone
that signals the liver to produce glucose. In this way, LAF237 helps
to address the imbalance between insulin supply and demand, one of
the underlying causes of type 2 diabetes.
Long-term study results
In this phase II study, 42 patients were given oral LAF237 plus
metformin once daily and 29 patients received placebo plus metformin.
Hemoglobin A1c (HbA1c) levels were measured over the course of 52
weeks. In patients treated with LAF237 plus metformin, the HbA1c
levels decreased significantly and those levels were maintained up to
52 weeks. In the patients who continued on metformin alone, glycemia
control deteriorated over time. At study end, there was an average
difference of 1.1% between the two groups (p<0.0001). Glucose levels
measured after 8-12 hours of fasting and 1-2 hours after eating a
meal were also reduced in patients taking metformin plus LAF237
versus continued therapy with metformin alone.
LAF237 was found to be well tolerated, with 76.2% of patients in
the LAF237 plus metformin arm and 89.7% of patients in the metformin
plus placebo arm completing the 52-week investigation. The metformin
plus LAF237 group reported a slightly higher percent of patients with
at least one adverse event (69%) compared to the metformin plus
placebo group (58.6%). However, suspected drug-related adverse events
were 4.8% and 6.9% respectively. Four patients in the metformin plus
LAF237 group discontinued due to an adverse event. Three patients
assigned to receive the combination of metformin plus LAF237,
although these events were mild and did not lead to discontinuations.
Mechanistic studies
Results from three additional smaller studies that highlight the
drug's unique mechanism of action were also presented at the EASD
meeting. This research demonstrated the effect LAF237 has on levels
of GLP-1 and GIP and subsequently beta cell function and glucagon
secretion. Specifically, LAF237 imitates the body's own regulatory
system, providing an effect on insulin secretion and glucagon
suppression similar to that of the body's normal physiology.
In one study, patients with type 2 diabetes not previously treated
with oral agents received either LAF237 (100mg twice daily, n=9) or
placebo (n=11) for 28 days to assess the impact of LAF237 on beta
cell function. Results demonstrated that LAF237, by increasing the
active forms of GLP-1 and GIP, improved beta cell function in terms
of enhanced insulin secretion in response to glucose challenge.
In a 28-day, randomised, placebo-controlled, double-blind
crossover trial of 12 patients with type 1 diabetes treated by
insulin pump therapy, LAF237 suppressed glucagon secretion following
a meal, indicating that GLP-1 acts on glucagon secretion independent
of insulin effects. In a separate double-blind four-way crossover
study involving 16 healthy male subjects, LAF237 reduced GLP-1 and
GIP secretion in response to glucose administration. Larger follow-up
studies to confirm these findings are ongoing.
"The more we learn about LAF237, the more promise this treatment
appears to hold," said Dr. Jörg Reinhardt, Head of Development,
Novartis Pharma AG. "Clinically, we're seeing meaningful endpoints in
sustainable reductions of hemoglobin A1c levels, and when we closely
examine how the drug works, we see it closely mirrors the body's own
natural, physiological mechanism to balance out insulin supply and
demand. This effect, combined with LAF237's oral administration, good
tolerability, and the lack of weight gain seen among patients is
exciting and encouraging to the Novartis research team as we continue
the compound's phase III development programme."
The development of new diabetes treatments like DPP-4 inhibitors
is critically important given the World Health Organization's
estimate that the number of people with diabetes in Europe will rise
from approximately 33.3 million in 2000 to more than 48 million in
2030. In 2000 alone, approximately 609,000 deaths in Europe were
attributed to diabetes.
The phase III clinical trial program of LAF237 is currently
ongoing, with first regulatory submissions expected in 2006. The
development of LAF237 is driven by Novartis' cardiovascular and
metabolic business franchise. A worldwide leader in cardiovascular
care and in the treatment of a variety of metabolic disorders, the
cardiovascular and metabolic business franchise currently markets the
diabetes treatment Starlix(R) (nateglinide), the anti-lipidemia
therapies Lescol(R)/Lescol(R)XL (fluvastatin) and the hypertensive
therapies Diovan(R) (valsartan) and
Co-Diovan(R) (valsartan and hydrochlorothiazide).
The foregoing release contains forward-looking statements that can
be identified by terminology such as "investigational", "first in a
new class", "suggest", "long-term", "follow-up studies ... are
ongoing", "the more promise this treatment appears to hold",
"continue", "will rise", "expected" or similar expressions, or by
discussions regarding potential approvals to market LAF237 or
regarding the long-term impact of a patient's use of LAF237. Such
forward-looking statements involve known and unknown risks,
uncertainties and other factors that may cause actual results with
LAF237 to be materially different from any future results,
performance or achievements expressed or implied by such statements.
There can be no guarantee that LAF237 will be approved for sale in
any market. In particular, management's expectations regarding LAF237
could be affected by, among other things, additional analysis of
LAF237 clinical data; unexpected clinical trial results; unexpected
regulatory actions or delays or government regulation generally; the
company's ability to obtain or maintain patent or other proprietary
intellectual property protection; competition in general; government,
industry and general public pricing pressures, and other risks and
factors referred to in the Company's current Form 20-F on file with
the US Securities and Exchange Commission. Should one or more of
these risks or uncertainties materialize, or should underlying
assumptions prove incorrect, actual results may vary materially from
those anticipated, believed, estimated or expected. Novartis is
providing the information in this press release as of this date and
does not undertake any obligation to update any forward-looking
statements contained in this press release as a result of new
information, future events or otherwise.
About Novartis
Novartis AG (NYSE: NVS) is a world leader in pharmaceuticals and
consumer health. In 2003, the Group's businesses achieved sales of
USD 24.9 billion and a net income of USD 5.0 billion. The Group
invested approximately USD 3.8 billion in R&D. Headquartered in
Basel, Switzerland, Novartis Group companies employ about 80,000
people and operate in over 140 countries around the world. For
further information please consult http://www.novartis.com.

Contact:

Contacts: Karen Sutherland, Novartis Pharma Communications,
+41-61-324-7143 (direct), +41-79-593-1085 (mobile),
karen.sutherland@pharma.novartis.com; John Gilardi, Novartis Global
Media Relations, +41-61-324-3018 (direct), +41-79-596-1408 (mobile),
john.gilardi@group.novartis.com

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