Axcan Public Presentation for the FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting Jul

1. Axcan Public Presentation for the FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee MeetingJuly 23, 2008

2. Bioequivalence testing serves to confirm therapeutic equivalence to assure comparable (substitutable) safety and effectiveness in patients

3. Mesalamine Suppository Release Characteristics are Multifactorial and Unique • Variability with suppository • Melting in the rectal cavity • Post-melting dispersion and dissolution • Drug partitions between the lipophilic base and the present fluid • Distribution equilibrium between the base and fluid can occur rather than complete dissolution • Presence of fecal material, blood and mucous • Systemic exposure is a post effect-site phenomenon that can involve variable absorption across rectal mucosa

4. Scientific and Regulatory points to considerfor Locally Acting Rectal Suppositories (1) Axcan supports the FDA “Draft Guidance on Mesalamine ” for rectally administered suppositories, published in May 2007. The FDA Draft Guidance recommends that in vivo bioequivalence be demonstrated with: • “Bioequivalence study with clinical endpoints” and • “Bioequivalence studies with pharmacokinetic endpoints (fasting)”

5. Scientific and Regulatory points to consider for Locally Acting Rectal Suppositories (2) There is no scientifically agreed upon methodology to establish the bioequivalence of locally acting mesalamine suppositories FDA recognizes the lack of agreed upon methodologies for certain products and route of administration and is seeking input via the FDA Critical Path Initiative and Advisory Committee meetings. • FDA Critical Path Opportunities* • “In vivo Drug Release for GI Acting Products: Direct comparison of in vivo drug release (perfusion, tissue sampling, or imaging) could be used to validate dissolution tests as a bioequivalence method for modified release products.” • “For locally acting drugs that are absorbed and can be detected in plasma, the rate of absorption could be related to the local concentrations in the GI tract.” • “Imaging and PK studies could establish the correlation between the drug delivered to the site of action and the measured plasma concentration.” *Critical Path Opportunities for Generic Drugs, Office of Generic Drugs, Office of Pharmaceutical Science. Center for Drug Evaluation and Research. May 1, 2007

6. Scientific and Regulatory points to considerfor Locally Acting Rectal Suppositories (3) In vitro and in vivo methodologies have not been agreed upon to establish bioequivalence of mesalamine delivered by locally acting rectal suppositories. • "...it is challenging to find a standard method to test in vitro drug release from lipophilic suppositories“* • "However, no simulated rectal fluid exists at the moment to simulate the in vivo dissolution of suppositories“* *International Journal of Pharmaceutics, Volume 328, Issue 1, 2 January 2007, Pages 12-21

7. Scientific and Regulatory points to considerfor Locally Acting Rectal Suppositories (4) Factors leading to the high variability of systemic blood levels of mesalamine limit the potential for systemic PK being a surrogate or biomarker for effect-site bioavailability. These include: • Suppository location within the rectum • Retention time within the rectum • Limited volume within the rectum • Limited water within the rectum • Variable presence of fecalmaterial, blood and mucous • Degree of damage to the rectal mucosa = inflammation of tissue. Allen LV. Chapter 4: Pharmaceutic, biopharmaceutic and pharmacokinetic factors involving suppositories. In: Suppositories. 2008. pp. 51-75.

8. Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in healthy volunteers. From NDA Biopharm Review: Table 1. Summary of Pharmacokinetic Parameters of 5-ASA in Patients with Ulcerative Colitis and Healthy Subjects Treated with Mesalamine 500 mg Rectal Suppositories as a Single Dose and on the Last Day of Multiple Dose Administration Every Eight Hours for Six Days.

9. Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in ulcerative proctitis patients. From NDA Biopharm Review: Table 1. Summary of Pharmacokinetic Parameters of 5-ASA in Patients with Ulcerative Colitis and Healthy Subjects Treated with Mesalamine 500 mg Rectal Suppositories as a Single Dose and on the Last Day of Multiple Dose Administration Every Eight Hours for Six Days. 9

10. Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable inulcerative proctitis patients. “Based on these data, following rectal administration of mesalamine (FIV-ASA®) 500 mg suppository to subjects with ulcerative colitis, systemic drug exposure is highly variable between individuals as evidenced by high variability in AUC and Cmax. This could be relatedto variability in bioavailability secondary to differences between individuals in suppository location and/or retention time in the rectum.” Excerpt from the FDA Biopharm Review of Mesalamine Suppository NDA 21-252: Ulcerative Proctitis

11. Standard pharmacokinetic parameters observed upon rectal administration of mesalamine suppositories “bear little relationship to clinical efficacy.” “Since the therapeutic efficacy of mesalamine is thought to result from a predominately topical effect, standard pharmacokinetic parameters bear little relationship to clinical efficacy. However, pharmacokinetics and bioavailability data may contribute to the characterization of safety.” Excerpt from the FDA Medical Review of Mesalamine Suppository NDA 21-252: Ulcerative Proctitis Mahmud N et al. Ir J Med Sc 1999; 168: 228-32.

12. Current State of Dissolution Testing Release of a drug from lipophilic suppositories is multifactorial • Melting in the rectal cavity • Drug partitions between the lipophilic base and the present fluid • Distribution equilibrium between the base and fluid can occur rather than complete dissolution There is no in vivo/in vitro correlation for an in vitro dissolution test for a “hard fat” mesalamine suppository. • The dissolution test for mesalamine suppositories was developed as a quality control test and was not constrained by a desire to mimic In Vivo conditions. “FIP/AAPS Guidelines to Dissolution/in Vitro Release Testing of Novel/Special Dosage Forms” Siewert M et al. AAPS PharmSciTech 2003; 4 (1) Article 7.

13. Summary of Scientific and Regulatory Considerations There is no scientifically agreed upon methodology to establish the bioequivalence of locally acting mesalamine suppositories. In vitro and in vivo methodologies have not been agreed upon to establish bioequivalence of locally acting mesalamine suppositories. High variability in blood levels from rectal mesalamine suppositories limit the use of systemic PK as a surrogate (biomarker) for effect-site bioavailability to confirm clinical effectiveness. Systemic blood levels of mesalamine suppositories are highly variable in healthy volunteers and in ulcerative proctitis patients . Standard PK parameters observed upon rectal administration of mesalamine suppositories “bear little relationship to clinical efficacy.” Release of a drug from lipophilic suppositories is multifactorial. There is no in vivo/in vitro correlation for an in vitro dissolution test for a “hard fat” mesalamine suppository.

14. ConclusionThe currently available data support: The FDA “Draft Guidance on Mesalamine” for rectally administered suppositories, published in May 2007. • The FDA Draft Guidance recommends that in vivo bioequivalence be demonstrated with: • “Bioequivalence study with clinical endpoints” and • “Bioequivalence studies with pharmacokinetic endpoints (fasting)” The FDA approach of treating the bioequivalence testing required for locally acting mesalamine products that use different release mechanisms or routes of administration on a case-by-case basis.* *Docket no. 2005P-0146