New analyses of long-term LIALDA (mesalamine) data presented at ACG

Oct 16 2007

Post-hoc and other analyses of secondary endpoints of a long-term safety and tolerability study of Shire plc's ulcerative colitis (UC) drug LIALDA (mesalamine) provide further data on LIALDA in patients with mild to moderate ulcerative colitis.

These analyses of LIALDA's 303 trial, a long-term, Phase III, open-label 12-14 month extension study, are being presented this week at The American College of Gastroenterology (ACG) meeting in Philadelphia.

The primary endpoint of study 303 was safety and tolerability and findings – that LIALDA is generally well tolerated in mild to moderate UC patients – were presented at the British Society of Gastroenterology (BSG) meeting in Glasgow, Scotland in March 2007.

"Earlier studies showed that LIALDA is well-tolerated and effective at inducing remission in patients with active, mild to moderate UC. Post-hoc analysis of secondary endpoints provided evidence that LIALDA maintained remission in a variety of UC patients,” said Gary R. Lichtenstein, M.D., director of the Center for Inflammatory Bowel Diseases at the Hospital of the University of Pennsylvania.

A summary of key scientific presentations of post-hoc analyses of secondary endpoints of study 303 follows.

Once or Twice Daily LIALDA for Mild vs. Moderate Ulcerative Colitis
Poster Presentation: Tuesday, October 16, 2007, Exhibit Hall B, #950

A post-hoc analysis of secondary endpoints from the long-term 303 study was performed to review the efficacy of LIALDA for maintaining remission in patients with mild versus moderate ulcerative colitis. In the 303 study, patients were randomized to receive LIALDA 2.4g/day (given once daily [QD]) or 2.4g/day (1.2g given twice daily [BID]). Study 303 defined patient remission using stringent clinical and endoscopic measures: modified UC Disease Activity Index (UC-DAI) score of =1 with scores of 0 for rectal bleeding and stool frequency, a combined Physician's Global Assessment and sigmoidoscopy score of =1, with a sigmoidoscopy score reduction of =1 point from baseline and no mucosal friability. Of the 451 patients included in the analysis, this post-hoc analysis showed that 70.5 percent (117/166) of patients with mild ulcerative colitis and 64.2 percent (183/285) of patients with moderate ulcerative colitis were in remission at 12 months.

LIALDA for Maintenance of Remission of Mild-to-Moderate Ulcerative Colitis Irrespective of Patient's Previous Relapse History
Poster Presentation: Sunday, October 14, 2007, Exhibit Hall B, #283

A different post-hoc analysis of secondary endpoints from study 303 was done to understand the effect of relapse history in patients with mild-to-moderate ulcerative colitis on the efficacy of maintenance therapy. A total of 438 patients with complete relapse records at baseline (prior to enrolling in either parent study 301 or 302) were analyzed in this post-hoc analysis with LIALDA 2.4g/day. Of patients who previously experienced <3 relapses in the two years prior to parent study baseline, the analysis showed 70.1 percent (192/274) achieved remission at 12 months. In comparison, 59.8 percent (98/164) of patients who previously experienced =3 relapses in the two years prior to parent study baseline achieved remission at 12 months.

LIALDA for Maintenance in Both Left-Sided and Extensive Ulcerative Colitis
Poster Presentation: Tuesday, October 16, 2007, Exhibit Hall B, #949

Another post-hoc analysis of secondary endpoints from study 303 assessed the efficacy of LIALDA 2.4g/day (given once daily or in two divided doses) for the maintenance of remission in ulcerative colitis patients with a medical history of either a left-sided or extensive condition. Of the 450 patients with known extent of disease included in the analysis, it was demonstrated that 67 percent (233/348) and 64.7 percent (66/102) of the patients with left-sided or extensive disease, respectively, were in remission at 12 months.

Post-hoc analysis of secondary endpoints of pivotal trials shows LIALDA offers initial resolution of UC symptoms within weeks

Also being presented at ACG are secondary endpoints from LIALDA's pivotal trials, the 301 and 302 studies, which were eight-week, phase III, placebo-controlled, double-blind, double-dummy studies.

Time to Initial Symptom Resolution with LIALDA for Active, Mild to Moderate Ulcerative Colitis
Poster Presentation: Monday, October 15, 2007, Exhibit Hall B, #619

An important endpoint for both patients and physicians when treating active, mild-to-moderate ulcerative colitis is the time between initiation of therapy and initial symptom resolution. A post-hoc analysis of pooled data from the LIALDA 301 and 302 studies examined the treatment time required for patients to experience initial symptom resolution of rectal bleeding and normalization of stool frequency. Patients with active, mild-to-moderate UC were randomized to receive LIALDA 2.4g/day (given once or twice daily) or 4.8g/day (given once daily) or placebo, for eight weeks. The time required for patients to reach an initial resolution of symptoms was analyzed and defined as the time between the first dose of medication and the first day of symptom resolution. A total of 517 patients were included. This post-hoc analysis showed median time to initial resolution of symptoms (stool frequency and rectal bleeding) was 25, 26 and 44 days, in the LIALDA 2.4g/day (n=172), 4.8g/day (n=174) and placebo (n=171) groups, respectively. The data in this post-hoc analysis included both stool frequency and rectal bleeding when determining the median time to initial resolution of symptoms.

Other posters to be presented at ACG include:

• The effect of prolonged therapy with LIALDA in patients with acute, mild-to-moderate ulcerative colitis
  Poster Presentation: Tuesday, October 16, 2007, Exhibit Hall B, #953

• Long-term remission rates in patients with mild-to-moderate ulcerative colitis who require a LIALDA dose increase to induce initial remission
  Poster Presentation: Monday, October 15, 2007, Exhibit Hall B, #614

About LIALDA

LIALDA is part of a drug class called aminosalicylates, which contain 5-aminosalicyclic acid (5-ASA). 5-ASA is a well-established drug of choice and often a first-line treatment for UC. LIALDA is indicated for the induction of remission in patients with active, mild to moderate UC. The safety and efficacy of LIALDA have been established for up to eight weeks. LIALDA is the first new formulation in this class to be approved since 2000. LIALDA is the only ulcerative colitis treatment that utilizes MMX® Technology. LIALDA with MMX Technology combines a pH dependent gastro-resistant coating, which delays the release of the medication to the colon (the site of the inflammation in ulcerative colitis), with a tablet core containing mesalamine with hydrophilic and lipophilic excipients.

Shire has licensed from Giuliani SpA the exclusive rights to develop and commercialize LIALDA in the U.S., Canada, Europe -- known as MEZAVANT™ -- (excluding Italy) and the Pacific Rim. Giuliani SpA retains the development and commercialization rights in Italy. Cosmo Pharmaceuticals SpA, Milan, developed the MMX Technology.

For more information about LIALDA and for Full Prescribing Information, please visit www.LIALDA.com.

Important Safety Information

LIALDA tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Safety and effectiveness of LIALDA beyond eight weeks have not been established.

LIALDA is contraindicated in patients with hypersensitivity to salicylates (including mesalamine) or to any of the components of LIALDA. Caution should be exercised when treating patients with pyloric stenosis or those allergic to sulfasalazine. Mesalamine has been associated with an acute intolerance syndrome (three percent of patients in clinical trials with mesalamine or sulfasalazine) that may be difficult to distinguish from a flare of inflammatory bowel disease. If acute intolerance syndrome is suspected, prompt withdrawal is required. Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported. Reports of renal impairment have been associated with mesalamine medications. In patients with renal impairment, caution should be exercised, and LIALDA should be used only if the benefits outweigh the risks. No information is available for patients with hepatic impairment.

LIALDA is generally well tolerated. The majority of adverse events in the double-blind, placebo-controlled trials were mild or moderate in severity. In clinical trials (n=535), the most common treatment-related adverse events with LIALDA 2.4g/day, 4.8g/day and placebo were headache (5.6 percent, 3.4 percent and 0.6 percent, respectively) and flatulence (4 percent, 2.8 percent and 2.8 percent, respectively). Pancreatitis occurred in less than 1 percent of patients during clinical trials and resulted in discontinuation of therapy with LIALDA.

SHIRE PLC

Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit and hyperactivity disorder (ADHD), human genetic therapies (HGT), gastrointestinal (GI) and renal diseases. The structure is sufficiently flexible to allow Shire to target new therapeutic areas to the extent opportunities arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in niche markets with strong intellectual property protection either in the US or Europe. Shire believes that a carefully selected portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

For further information on Shire, please visit the Company's website: www.shire.com

GIULIANI SpA

Giuliani SpA, founded in 1889, is a privately owned specialty biopharmaceutical company strategically focused in gastroenterology and dermatology. It is currently marketing proprietary products for the treatment and management of ulcerative colitis, Crohn's disease, food intolerances and dermatological disorders. Giuliani's R&D pipeline includes new chemical entities and biotechnological products targeted to treat inflammatory and autoimmune diseases.

COSMO Pharmaceuticals SpA

Cosmo is a speciality pharma company that aims to become a global leader in optimized therapies for certain gastrointestinal diseases. The company's proprietary clinical development pipeline specifically addresses innovative treatments for IBD, such as ulcerative colitis and Crohn's disease, and colon infections. Cosmo's most advanced development product is LIALDA™/ MEZAVANT™, a treatment for ulcerative colitis that is licensed globally to Giuliani and Shire Pharmaceuticals. Cosmo's proprietary MMX Technology is at the core of the company's product pipeline and was developed from its expertise in formulating and manufacturing gastrointestinal drugs for international clients at its GMP (Good Manufacturing Practice) facilities in Lainate, Italy. For further information on Cosmo, please visit the Company's website: www.cosmopharmaceuticals.com.