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.

ots Originaltext: Novartis International AG
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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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