Shire Announces Results from a Multidisciplinary Analysis of the Drug Release Profiles of LIALDA (mesalamine) and Asacol (mesalamine) for the Treatment of Ulcerative Colitis (UC) at the American College of Gastroenterology (ACG) Meeting

PHILADELPHIA, Oct. 6 /PRNewswire-FirstCall/ -- Shire plc (NASDAQ:SHPGY) , the global specialty biopharmaceutical company, announced the results from a multidisciplinary analysis of in vitro and in vivo data of LIALDA(R) (mesalamine) versus Asacol(R) (mesalamine) that investigated factors including transit and disintegration of tablets along with tablet coating thickness that may affect a consistent release of 5-aminosalicylate acid (5-ASA) in both therapies. This analysis will be presented at The American College of Gastroenterology (ACG) meeting in Orlando.
 

"Previous studies have demonstrated that LIALDA is an effective and generally well-tolerated treatment for patients who have active, mild-to-moderate UC," said Srini Tenjarla, PhD, lead study investigator and senior director of pharmaceutical sciences at Shire. "The time of initial release of 5-ASA in the colon, as well as the duration of continued release, is important in the treatment of UC. Now, through a combination of analyses, we have data that shows LIALDA demonstrated a steady 5-ASA release throughout the entire colon."
 

The clinical significance of the results from this analysis has not been established. This analysis was not designed to evaluate or compare the clinical efficacy of LIALDA and Asacol.
 

Understanding 5-Aminosalicyclic Acid Release Profiles from pH-dependent, Delayed-release Formulations: A Multidisciplinary Approach
 

Poster Presentation: Tuesday, October 7, 2008, Florida Exhibit Halls
 

Recent data from scintigraphic and imaging and dissolution studies, Study 1 and Study 2 respectively, of LIALDA and two formulations of Asacol (Giuliani SpA, Italy in Study 1 and P&G, Cincinnati OH as reported by Spencer et al in Study 2) was gathered to evaluate factors that affect the release of each 5-ASA formulation.
 

Study 1 was an open-label, single-dose, two-way cross-over study during which healthy subjects (n=8) were randomized to receive LIALDA or Asacol (Giuliani SpA, Italy). Subjects received either a single radiolabeled LIALDA tablet (one 1.2 g radiolabeled tablet) or three radiolabeled tablets of pH-dependent, delayed-release mesalamine (400 mg radiolabeled tablets) as a single dose, and crossed over to the other treatment after a washout period of >/=7 days. Scintigraphic images were taken to evaluate the transit and disintegration of the tablets, as well as the distribution of 5-ASA through the GI tract. Images were taken at 20-minute intervals until eight hours post-dose, at 30-minute intervals until 16 hours post-dose, and at two-hour intervals until 24 hours post-dose.
 

Results of Study 1 found that initial disintegration of LIALDA occurred in the GI tract between the mid-small bowel and ascending colon at 4.75+/-1.31 hours after dosing and initial disintegration of Asacol occurred between the distal small bowel and the transverse colon at 6.16+/-1.80 hours after dosing. [Initial disintegration was defined as the mean hours +/- standard deviation (SD).] Further, complete disintegration occurred in the GI tract for LIALDA (between the ascending and descending colon 17.37+/-8.63 hours following dosing and complete disintegration of Asacol occurred between the iliocaecal junction and the transverse colon 7.27+/-2.13 hours following dosing, with the vast majority of disintegration occurring in the ascending colon. Overall, scintigraphic data suggest a steady release of 5-ASA from radiolabeled LIALDA, with a prolonged period of disintegration throughout the colon.
 

Study 2 (imaging and dissolution) utilized non-destructive, three-dimensional terahertz pulse imaging to measure mean coating thickness of LIALDA tablets from three batches. This study was conducted according to the methodology described by Spencer et al (J Pharm Sci, 2008). Dissolution testing was subsequently performed on the same tablets at pH 6.8 and 7.2 (to represent altered pH in the GI tract of patients with UC) using USP II apparatus (50 rpm).
 

Results of Study 2 showed that the coating thickness of LIALDA ranged from 109.2 microns (+/-16.8) to 113.8 microns (+/-19.8). Additionally, LIALDA tablets demonstrated steady release of 5-ASA at both pH values with complete release achieved over >8 hours at pH 6.8 and over >12 hours at pH 7.2.
 

Combined results of the two studies (Study 1 and Study 2) suggest that 5-ASA will be released from LIALDA in a consistent and steady manner throughout the colon.
 

Also being presented at ACG is a post hoc analysis of secondary endpoints from LIALDA Study 303, which evaluated the time to resolution of symptoms in UC patients taking up to eight additional weeks of high-dose LIALDA (4.8 g/day). The primary endpoints of Study 303, a long-term, open-label, phase III extension study, were safety and tolerability of LIALDA over 12 months.
 

MMX Mesalamine Therapy for the Induction of Remission Beyond Eight Weeks: How Long Before Symptom Resolution?
 

Poster Presentation: Sunday, October 5, 2008, Florida Exhibit Halls
 

A post hoc analysis of secondary endpoints from the long-term 303 safety study was conducted to evaluate when patients (n=304) with active, mild-to-moderate UC who did not achieve clinical and endoscopic remission in two LIALDA Phase III studies (parent studies 302 and 301) after up to eight weeks could achieve complete symptom resolution when they received up to 16 weeks of treatment of LIALDA. Patients in the original 301 and 302 studies were randomized to receive placebo, LIALDA 2.4 g/day, LIALDA 4.8 g/day, or Asacol 2.4 g/day for eight weeks. All patients enrolled in the 303 extension study received LIALDA 4.8 g/day (given 2.4 g BID) for up to an additional eight weeks.
 

Clinical and endoscopic remission was stringently defined as a total modified UC Disease Activity Index (UC-DAI) score of /=1-point reduction from baseline in sigmoidoscopy score. Time to initial resolution of symptoms was estimated using Kaplan-Meier methodology. Time to initial symptom resolution was defined as the time between the first dose of study medication and the first day of rectal bleeding cessation and stool frequency normalization based on the modified UC-DAI.
 

In total, nearly 60 percent (59.5 percent) of patients (181/304) who continued treatment with LIALDA 4.8 g/day in the 303 extension study achieved clinical and endoscopic remission. The median time to initial resolution of UC symptoms (defined as the day when 50 percent of patients achieved symptom resolution) in patients who had achieved clinical and endoscopic remission with up to an additional eight weeks of LIALDA was 15 days.
 

Important Safety Information for LIALDA
 

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 (3% 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 2.4 g/day, 4.8 g/day and placebo were headache (5.6%, 3.4% and 0.6%, respectively) and flatulence (4%, 2.8% and 2.8%, respectively). Pancreatitis occurred in less than 1% of patients during clinical trials and resulted in discontinuation of therapy with LIALDA.
 

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

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 only ulcerative colitis treatment that utilizes MMX(R) 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 components.
 

Shire has licensed from Giuliani SpA the exclusive rights to develop and commercialize LIALDA in the US, Canada, Pacific Rim, and Europe (excluding Italy). LIALDA is known as MEZAVANT XL(TM) in the UK and Ireland, and MEZAVANT(R) elsewhere outside of the US. Giuliani SpA retains the development and commercialization rights in Italy. Cosmo Pharmaceuticals SpA, Milan, developed the MMX technology.
 

   For further information please contact:

   Media  Blythe Bertolo (GolinHarris on behalf of Shire)  +1 312 729 4463

  Notes to editors

  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) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced 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: http://www.shire.com/.
 

THE "SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995
 

Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company's results could be materially affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of pharmaceutical research, product development, manufacturing and commercialization including, but not limited to, the establishment in the market of VYVANSE(R) (lisdexamfetamine dimesylate) (Attention Deficit and Hyperactivity Disorder ("ADHD")); the impact of competitive products, including, but not limited to, the impact of those on the Company's ADHD franchise; patents, including but not limited to, legal challenges relating to the Company's ADHD franchise; government regulation and approval, including but not limited to the expected product approval date of INTUNIV(TM) (guanfacine extended release) (ADHD); the Company's ability to secure new products for commercialization and/or development; the Company's proposed offer for Jerini AG, including but not limited to, the Company's ability to successfully complete the offer and integrate Jerini AG, as well as realize the anticipated benefits of the acquisition; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission, including the Company's Annual Report on Form 10-K for the year ended December 31, 2007.
 

  Asacol(R) is a registered trademark of Medeva Pharma Schweiz AG.

  LIALDA(R) is a registered trademark of Shire LLC.

MMX(R) is a registered trademark owned by Cosmo Technologies Ltd, Ireland, a wholly-owned subsidiary of Cosmo Pharmaceuticals SpA.
 

Source: Shire plc

CONTACT: Blythe Bertolo of GolinHarris, +1-312-729-4463, for Shire plc
 

Web site: http://www.shire.com/
 

Posted: October 2008

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