Shire Announces Results from a Multidisciplinary Analysis of the Drug Release Profiles of LIALDA(R) (mesalamine) and Asacol(R) (mesalamine) for the Treatment of Ulcerative Colitis (UC) at the American College of Gastroenterology (ACG) Meeting
"Previous studies have demonstrated that LIALDA is an effective andgenerally well-tolerated treatment for patients who have active,mild-to-moderate UC," said Srini Tenjarla, PhD, lead study investigator andsenior director of pharmaceutical sciences at Shire. "The time of initialrelease 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 throughoutthe entire colon."
The clinical significance of the results from this analysis has not beenestablished. This analysis was not designed to evaluate or compare theclinical 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, Study1 and Study 2 respectively, of LIALDA and two formulations of Asacol (GiulianiSpA, Italy in Study 1 and P&G, Cincinnati OH as reported by Spencer et al inStudy 2) was gathered to evaluate factors that affect the release of each5-ASA formulation.
Study 1 was an open-label, single-dose, two-way cross-over study duringwhich healthy subjects (n=8) were randomized to receive LIALDA or Asacol(Giuliani SpA, Italy). Subjects received either a single radiolabeled LIALDAtablet (one 1.2 g radiolabeled tablet) or three radiolabeled tablets ofpH-dependent, delayed-release mesalamine (400 mg radiolabeled tablets) as asingle dose, and crossed over to the other treatment after a washout period of>/=7 days. Scintigraphic images were taken to evaluate the transit anddisintegration of the tablets, as well as the distribution of 5-ASA throughthe GI tract. Images were taken at 20-minute intervals until eight hourspost-dose, at 30-minute intervals until 16 hours post-dose, and at two-hourintervals until 24 hours post-dose.
Results of Study 1 found that initial disintegration of LIALDA occurred inthe GI tract between the mid-small bowel and ascending colon at 4.75+/-1.31hours after dosing and initial disintegration of Asacol occurred between thedistal 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 followingdosing and complete disintegration of Asacol occurred between the iliocaecaljunction and the transverse colon 7.27+/-2.13 hours following dosing, with thevast 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 ofLIALDA tablets from three batches. This study was conducted according to themethodology described by Spencer et al (J Pharm Sci, 2008). Dissolutiontesting was subsequently performed on the same tablets at pH 6.8 and 7.2 (torepresent altered pH in the GI tract of patients with UC) using USP IIapparatus (50 rpm).
Results of Study 2 showed that the coating thickness of LIALDA ranged from109.2 microns (+/-16.8) to 113.8 microns (+/-19.8). Additionally, LIALDAtablets demonstrated steady release of 5-ASA at both pH values with completerelease 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 that5-ASA will be released from LIALDA in a consistent and steady mannerthroughout the colon.
Also being presented at ACG is a post hoc analysis of secondary endpointsfrom LIALDA Study 303, which evaluated the time to resolution of symptoms inUC patients taking up to eight additional weeks of high-dose LIALDA (4.8g/day). The primary endpoints of Study 303, a long-term, open-label, phase IIIextension 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 safetystudy was conducted to evaluate when patients (n=304) with active,mild-to-moderate UC who did not achieve clinical and endoscopic remission intwo LIALDA Phase III studies (parent studies 302 and 301) after up to eightweeks could achieve complete symptom resolution when they received up to 16weeks of treatment of LIALDA. Patients in the original 301 and 302 studieswere randomized to receive placebo, LIALDA 2.4 g/day, LIALDA 4.8 g/day, orAsacol 2.4 g/day for eight weeks. All patients enrolled in the 303 extensionstudy received LIALDA 4.8 g/day (given 2.4 g BID) for up to an additionaleight weeks.
Clinical and endoscopic remission was stringently defined as a totalmodified UC Disease Activity Index (UC-DAI) score of =1, calculated as:scores of 0 for rectal bleeding and stool frequency, a combined Physician'sGlobal Assessment (PGA) score and sigmoidoscopy score of =1, with no mucosalfriability, and a >/=1-point reduction from baseline in sigmoidoscopy score.Time to initial resolution of symptoms was estimated using Kaplan-Meiermethodology. Time to initial symptom resolution was defined as the timebetween the first dose of study medication and the first day of rectalbleeding cessation and stool frequency normalization based on the modifiedUC-DAI.
In total, nearly 60 percent (59.5 percent) of patients (181/304) whocontinued treatment with LIALDA 4.8 g/day in the 303 extension study achievedclinical and endoscopic remission. The median time to initial resolution of UCsymptoms (defined as the day when 50 percent of patients achieved symptomresolution) in patients who had achieved clinical and endoscopic remissionwith 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 patientswith active, mild to moderate ulcerative colitis. Safety and effectiveness ofLIALDA 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 shouldbe exercised when treating patients with pyloric stenosis or those allergic tosulfasalazine. Mesalamine has been associated with an acute intolerancesyndrome (3% of patients in clinical trials with mesalamine or sulfasalazine)that may be difficult to distinguish from a flare of inflammatory boweldisease. If acute intolerance syndrome is suspected, prompt withdrawal isrequired. Mesalamine-induced cardiac hypersensitivity reactions (myocarditisand pericarditis) have been reported. Reports of renal impairment have beenassociated with mesalamine medications. In patients with renal impairment,caution should be exercised, and LIALDA should be used only if the benefitsoutweigh the risks. No information is available for patients with hepaticimpairment.
LIALDA is generally well tolerated. The majority of adverse events in thedouble-blind, placebo-controlled trials were mild or moderate in severity. Inclinical trials (n=535), the most common treatment-related adverse events withLIALDA 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). Pancreatitisoccurred in less than 1% of patients during clinical trials and resulted indiscontinuation of therapy with LIALDA.
For more information about LIALDA and for Full Prescribing Information,please visit http://www.LIALDA.com.
LIALDA is part of a drug class called aminosalicylates, which contain5-aminosalicyclic acid (5-ASA). 5-ASA is a well-established drug of choice andoften a first-line treatment for UC. LIALDA is indicated for the induction ofremission in patients with active, mild to moderate UC. The safety andefficacy of LIALDA have been established for up to eight weeks. LIALDA is theonly ulcerative colitis treatment that utilizes MMX(R) Technology. LIALDAwith MMX Technology combines a pH dependent gastro-resistant coating, whichdelays the release of the medication to the colon (the site of theinflammation in ulcerative colitis), with a tablet core containing mesalaminewith hydrophilic and lipophilic components.
Shire has licensed from Giuliani SpA the exclusive rights to develop andcommercialize LIALDA in the US, Canada, Pacific Rim, and Europe (excludingItaly). LIALDA is known as MEZAVANT XL(TM) in the UK and Ireland, andMEZAVANT(R) elsewhere outside of the US. Giuliani SpA retains the developmentand commercialization rights in Italy. Cosmo Pharmaceuticals SpA, Milan,developed the MMX technology.
Shire's strategic goal is to become the leading specialtybiopharmaceutical company that focuses on meeting the needs of the specialistphysician. Shire focuses its business on attention deficit and hyperactivitydisorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI)diseases as well as opportunities in other therapeutic areas to the extentthey arise through acquisitions. Shire's in-licensing, merger and acquisitionefforts are focused on products in specialist markets with strong intellectualproperty protection and global rights. Shire believes that a carefullyselected and balanced portfolio of products with strategically aligned andrelatively 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 REFORMACT OF 1995
Statements included herein that are not historical facts areforward-looking statements. Such forward-looking statements involve a numberof risks and uncertainties and are subject to change at any time. In the eventsuch risks or uncertainties materialize, the Company's results could bematerially affected. The risks and uncertainties include, but are not limitedto, risks associated with: the inherent uncertainty of pharmaceuticalresearch, 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 butnot limited to, legal challenges relating to the Company's ADHD franchise;government regulation and approval, including but not limited to the expectedproduct approval date of INTUNIV(TM) (guanfacine extended release) (ADHD); theCompany's ability to secure new products for commercialization and/ordevelopment; the Company's proposed offer for Jerini AG, including but notlimited to, the Company's ability to successfully complete the offer andintegrate Jerini AG, as well as realize the anticipated benefits of theacquisition; and other risks and uncertainties detailed from time to time inthe Company's filings with the Securities and Exchange Commission, includingthe 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.For further information please contact: Media Blythe Bertolo (GolinHarris on behalf of Shire) +1 312 729 4463 Notes to editors
SOURCE Shire plc
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