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Arisaph Pharmaceuticals Announces at the ADA that Its Potent DPP 4 Inhibitor (ARI-2243) Possesses an Additional Mechanism that Contributes to Improved Glucose Control

- ARI-2243 showed a 29% reduction of glucose in DPP 4 knock-out mice

BOSTON, June 08, 2008 /PRNewswire/ -- Arisaph Pharmaceuticals, Inc., a privately held drug discovery biopharmaceutical company, announced today at the 68th session of the American Diabetes Association meeting in San Francisco, CA that its potent DPP-4 inhibitor, ARI-2243, possesses an additional beneficial mechanism that contributes to superior glucose control. The results showed that ARI-2243 produced a 29% reduction in glucose excursion during an oral glucose tolerance test (OGTT) in DPP 4 knock-out mice. Such animals are devoid of the DPP 4 enzyme, indicating that ARI-2243 also works through a DPP 4 independent mechanism, which contributes to its superior efficacy compared to other DPP 4 inhibitors. In multiple animal models for diabetes, ARI-2243 consistently produced dramatic efficacy results, including a 2.5% reduction of HbA1c in Zucker Diabetic Rats, a refractory model of diabetes. The dual mechanism of action related to ARI-2243 is expected to produce a clinically differentiated efficacy profile in the treatment of Type II diabetes. Arisaph filed an IND for ARI-2243 during the first quarter of 2008 and has initiated a first-in-man safety study in healthy volunteers.

"We are very excited about the results demonstrating that ARI-2243 is a multi-mediator, possessing both DPP 4 dependent and independent glucose lowering effects," commented Christopher P. Kiritsy, President and Chief Executive Officer of Arisaph Pharmaceuticals. "This provocative finding helps explain the superior efficacy observed with ARI-2243 in multiple preclinical animals studies and gives us confidence that ARI-2243 will be a best-in-class treatment for diabetes."

In studies performed using mice that were genetically bred without the DPP 4 enzyme, ARI-2243 significantly reduced glucose excursion by 29% compared with vehicle treatment. Sitagliptin did not show an effect on glucose excursion in the DPP 4 knock-out mice even at high doses. ARI-2243 did not increase the insulin/glucose ratio in the knock-out animals on acute dosing, suggesting that the pathway may not be incretin related. Additionally, evaluation of the effects of ARI-2243 on other targets reveals that ARI-2243 does not induce PPAR gamma gene expression. Although ARI-2243 does not operate mechanistically as a thiazolidinediones, ARI-2243 shows improved insulin sensitivity following 14 days of dosing in Zucker fa/fa animals. Sitagliptin has no effect on insulin sensitivity in this diabetic animal experiment.

"Now that we have demonstrated a DPP 4 independent mechanism, we are optimistic that we will obtain an understanding of what mechanisms are involved in contributing to the compound's surprising antidiabetic efficacy," said William Bachovchin, PhD., Executive Vice President and Chief Scientific Officer of Arisaph and Professor of Medicine at . "Delineating the mechanism may lead to new targets and opportunities for antidiabetic agents."

In studies presented at last year's ADA, ARI-2243 showed maximal glucose lowering of approximately 85% with a low dose of 0.1 mg/kg during OGTT in normal mice compared with about 55% reduction of glucose excursion with 10 - 100 times greater doses of sitagliptin. The ~50% greater response versus sitagliptin, indicates that ARI-2243's DPP 4 independent mechanism is contributing to its enhanced efficacy. Moreover, at 18 hours post dose, ARI-2243 lowered plasma AUC 25% compared with no effect from sitagliptin, demonstrating the long duration of action and once-daily dosing with ARI-2243.

In addition to the compelling preclinical efficacy, ARI-2243 is functionally selective through a smart, "soft drug" inactivation process. Specifically, ARI-2243 binds rapidly and tightly to DPP 4 and once bound, the complex dissociates very slowly, thereby preventing the degradation of GLP-1 at the site of action. Unbound ARI-2243 then undergoes a unique non-enzymatic conversion as it passes through the gut and into systemic circulation, which limits the exposure of the active species to unwanted targets, such as DPP 8 and 9. Such "soft drug" properties of ARI-2243 confer functional selectivity and are believed to contribute to a favorable therapeutic index in animals(1).

About Arisaph

Arisaph, located in Boston, Massachusetts, is an emerging drug discovery biopharmaceutical company with active programs to develop differentiated therapies for diabetes, cancer and cardiovascular disease. Arisaph utilizes proprietary drug discovery platforms to develop ultra-smart drugs that are efficacious and act on select targets. Arisaph has successfully applied its specificity profiling and retro-inversal chiral chemistry technology platforms to synthesize promising candidate drugs for seven targets, including ARI-2243, a lead candidate for DPP 4 inhibition to treat Type II diabetes and ARI-1778 or reverse D-4F, an orally active mimetic peptide, being developed in collaboration with Abbott Laboratories to treat atherosclerosis. Through a licensing agreement with the Company has exclusive worldwide rights to several important issued patents in the diabetes area and several pending patents that have utility for the treatment of cancer and cardiovascular disease.

About DPP-4:

Dipeptidylpeptidase (DPP) - 4 is a naturally occurring, proteolytic enzyme that rapidly degrades the incretin hormones, gastric inhibitory polypeptide (GIP) and glucagon-like protein (GLP-1). GLP-1 has a favorable anti-diabetic role because it stimulates glucose dependent insulin secretion from the pancreas, slows gastric emptying and decreases glucagon secretion. Inhibitors to DPP 4 improve glycemic control in patients with Type II diabetes by increasing the half-life of native GLP-1. DPP 4 is a validated target for the treatment of Type II diabetes and inhibitors of DPP-4 have been shown to lower post-prandial glucose and HbA1c levels. Diabetes is a major healthcare problem throughout the world with the prevalence of the disease projected to double to 360 million cases worldwide by the year 2030, according to the World Health Organization(2).

Certain statements in this press release, including statements regarding the Company's research and development effort, the Company's expectation to complete human clinical studies, the Company's ability to finance its development programs into human clinical testing, and the Company's ability to successfully capitalize on the early stage research are subject to risks and uncertainties. These risks and uncertainties include risks and uncertainties related to: our ability to discover and develop new compounds and products using a novel approach to drug discovery; the early stage of all of our discovery and development efforts; our ability to complete preclinical and clinical development of our products; our ability to obtain and maintain regulatory approvals for our products; competition from other technologies and technologies similar to ours; obtaining, maintaining and protecting intellectual property utilized by our products; changes in legislation and regulations affecting our products and potential product candidates; our need to obtain additional funding to support our business activities; our dependence on collaborators and other third parties for development, manufacture, marketing, sales and distribution of products; the ability of our licensees to achieve developmental, regulatory and other milestones and to commercialize their products; the effect of conditions in the pharmaceutical industry and the economy in general, as well as certain other risks and uncertainties.


    1. Sanford DG, et al: ARI2243, a highly potent and selective dipeptidyl IV

       (DPP4) inhibitor with exceptional anti-hyperglycemic activity for the

       treatment of Type 2 diabetes.  2007 Chicago American Diabetes

       Association. Abstract Number: 604-P

    2. Wild S, et al.: Global Prevalence of Diabetes, Estimates for the year

       2000 and projections for 2030.  Diabetes Care 27: 1047-1053, May 2004

CONTACT: Christopher Kiritsy, President and CEO, Arisaph Pharmaceuticals,Inc., +1-617-292-3322

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Posted: June 2008