Novel treatment agent of overactive bladder syndrome Fesoterodine

Novel treatment agent of overactive bladder syndrome Fesoterodine 서울성모병원 김수진

2 Desired Profile of an Optimised Antimuscarinic: Individualised Approach for OAB Treatment • Consistent efficacy and good tolerability in improving OAB symptoms at therapeutic doses • Consistent improvements in patient-reported outcomes, including HRQL • Dose flexibility – At least two doses, preferably with distinct dose-related efficacy yet similar safety and tolerability – “Dose flexibility allows for individual titration of therapy to produce a maximum efficacy versus tolerability in individual cases” Kaplan SA et al. JAMA. 2006; 296: 2319 -2328. Rogers R et al. Int Urogynecol J. 2008; 19: 1551 -1557. Hegde SS. Br J Pharmacol. 2006; 147(suppl 2): S 80 -S 87. Chapple CR et al. Eur Urol. 2008; 54: 543 -562.

3 Introduction to Fesoterodine • Fesoterodine is a new once-daily antimuscarinic for the treatment of OAB symptoms • Fesoterodine is structurally related to tolterodine – Rapidly and extensively converted to 5 -hydroxymethyl tolterodine (5 -HMT), which is also the active metabolite of tolterodine • Fesoterodine has been developed in two strengths : 4 mg once daily and 8 mg once daily – Tolterodine ER has one recommended strength (4 mg once daily) Chapple C et al. Eur Urol. 2007; 52: 1204 -1212. Detrusitol® SR Sm. PC. 2007. Pfizer Inc. Toviaz® Sm. PC. 2008. Pfizer Inc.

4 What Links Fesoterodine to Tolterodine? Tolterodine Fesoterodine O O HO H Rapid conversion by ubiquitous esterases N Both fesoterodine and tolterodine form 5 -HMT (the active metabolite) via different pathways OH HO H N OH H N Liver metabolism (CYP 2 D 6) The ratio between tolterodine 5 -HMT alone is responsible and 5 -HMT depends on for the antimuscarinic effects the patient’s CYP 2 D 6 status* of fesoterodine 5 -Hydroxymethyl tolterodine (5 -HMT)† *The metabolic capacity in individuals can differ from ultrarapid and extensive to poor metabolisers (EMs or PMs), based on genotype or drug interactions. †Also known as SPM 7605 and DD 01. Michel M. Expert Opin Pharmacother. 2008; 9: 1787 -1796. Malhotra B et al. Int J Clin Pharmacol Ther. 2008; 46: 556 -563. Brynne N et al. Clin Pharmacol Ther. 1998; 63: 529 -539.

Fesoterodine PK Is Simple and Predictable Fesoterodine Conversion to 5 -HMT Is Simple and Predictable Fesoterodine Esterases Ubiquitous 5 -HMT Tolterodine Metabolism Is More Complex and Less Predictable Tolterodine CYP 2 D 6 Liver, Gut Tolt + + 5 -HMT Extensive Metabolisers 78% 5 Tolt 5 -HMT Intermediate Metabolisers Poor Metabolisers 7% Michel M. Expert Opin Pharmacother 2008; 9: 1787 -1796. Malhotra B et al. Int J Clin Pharmacol Ther. 2008 46: 556 -563. Brynne N et al. Clin Pharmacol Ther. 1998; 63: 529 -539. Zanger UM et al. Naunyn-Schmiedebergs Arch Pharmacol. 2004; 369: 23 -27. Bradford LD et al. Int J Neuropsychopharmacol. 1998; 1: 173 -185.

6 Key Pharmacokinetic Properties of Fesoterodine • Fesoterodine acts like a prodrug of 5 -HMT, to which it is rapidly and extensively converted • 5 -HMT has a favourable pharmacokinetic profile – Linear, dose-proportional pharmacokinetics – Terminal half-life is about 7 hours, allowing for once-daily dosing with little drug accumulation – No clinically relevant food effect – No gender, age, or racial differences – No effect on QTc interval in thorough QT study – No clinically significant variation in PK with morning and evening dosing Malhotra B et al. Presented at Br Pharmacol Soc Winter Meeting 2007. Cole P. Drugs Future. 2004; 29: 715 -720. Toviaz® Sm. PC. 2008.

Phase 3 Results 7

8 UUI Episodes/24 h† Feso 4 mg (n=427) Feso 8 mg (n=441) Yes 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 Placebo (n=416) Treatment Response, % -42. 9% -75. 0% * -83. 3% P<0. 05 * Mean Voided Volume, m. L 40 35 30 25 20 15 10 5 0 P<0. 05 * 22. 2 * 33. 6 9. 0 Placebo (n=539) Feso 4 mg (n=531) Feso 8 mg (n=540) LS Mean Change Median % Change Pooled Analysis of Phase 3 Data: Key OAB Endpoints 90 80 70 60 50 40 30 20 10 0 * 69% P<0. 05 * 77% 49% Placebo (n=545) Feso 4 mg (n=532) Feso 8 mg (n=543) Continent Days/wk†‡ 3. 5 * 2. 6 3. 0 P<0. 05 * 3. 1 2. 5 2. 0 1. 8 1. 5 1. 0 0. 5 0. 0 Comparison of 8 mg vs 4 mg was a post-hoc analysis. Placebo (n=416) Feso 4 mg (n=427) Feso 8 mg (n=441) *P<0. 05 vs placebo; †Analysis includes only subjects with UUI at baseline; ‡Extrapolated from 3 -day diary data. LS = least square. Khullar V et al. Urology. 2008; 71: 839 -843.

Post Hoc Analysis of Int’l Trial Showed Statistically Significant Difference Between Fesoterodine 8 mg and Tolterodine ER 4 mg on Key OAB Endpoints Tolt ER 4 mg (n=290) Feso 8 mg (n=287) -25 -50 -75 -100 P<0. 001 * LS Mean Change Continent Days/wk‡§ 4 P<0. 05 * 3 2 1 0 Placebo Tolt ER 4 mg Feso 8 mg (n=283) (n=290) (n=287) *P<0. 001 vs placebo; †P<0. 05 vs placebo; ‡Analysis includes only subjects with UUI at baseline; § 3 -day diary data extrapolated to 7 days. Median % Change 0 Placebo (n=283) Micturition Frequency/24 h LS Mean Change in MVV (m. L) Median % Change UUI Episodes/24 h‡ 0 -5 -10 -15 -20 -25 -30 Placebo (n=283) Tolt ER 4 mg Feso 8 mg (n=290) (n=287) † * Mean Voided Volume, m. L P<0. 05 40 * 30 † 20 10 0 Placebo (n=283) Tolt ER 4 mg (n=290) Feso 8 mg (n=287) Chapple C et al. BJU Int. 2008; 102: 1128 -1132. 9

Pooled, Post Hoc Analysis of Efficacy of Fesoterodine in Subjects With Different Baseline Severity of UUI Moderate (2 to <4 UUI episodes) Mild (>0 to <2 UUI episodes) Mean Change in UUI Episodes BL= 1. 1 BL= 1. 0 BL= 1. 1 * -100%† * BL= 2. 7 BL= 2. 8 10 Severe (≥ 4 UUI episodes) BL= 7. 0 BL= 2. 7 BL= 7. 3 BL= 7. 0 -100%† * -68%† * -86%† P<0. 05 * -62%† * -71%† P<0. 05 *P<0. 05 vs placebo; †Median percent change. Cardozo L et al. Int Urogyn J. 2008; 19(Suppl 1): S 38(#8).

Pooled Analysis: Patient-Reported Outcomes Were Improved With Fesoterodine Treatment Placebo (n=545) Feso 4 mg (n=532) Feso 8 mg (n=543) Severity (coping) -7. 4 -11. 3* -13. 7*† Emotions -9. 1 -12. 4* -15. 3*† Role limitations -12. 5 -18. 5* -21. 4* Physical limitations -11. 4 -17. 2* -19. 6* Social limitations -7. 9 -11. 6* -13. 8* Sleep/energy -7. 8 -10. 7* -12. 3* Personal relationship -5. 9 -7. 8 -9. 6* Impact on life -14. 2 -19. 6* -22. 5* General health -2. 4 -2. 9 -2. 6 -2. 2 -3. 6* -4. 2* Pooled Analysis of SP 583 and SP 584 King’s Health Questionnaire (KHQ) ICIQ-SF *P<0. 05 vs placebo; †P<0. 05 vs Feso 4 mg (post hoc analysis). Least-squares mean change from baseline at Week 12 shown for KHQ and ICIQ-SF. Minimally important difference (MID) = 5 for KHQ and its domains. 11 Kelleher CJ et al. BJU Int. 2008; 102: 56 -61. ICIQ-SF = International Consultation of Incontinence Questionnaire, Short Form.

Adverse Events Reported by 2% of Subjects* and Exceeding Placebo Rate in Phase 3 Trials Treatment-Emergent Adverse Event (all causality) Placebo (n=554) % Tolt 4 mg (n=290) % Feso 4 mg (n=554) % Feso 8 mg (n=566) % Dry mouth 7 17 19 35 Constipation 2 3 4 6 UTI 3 1 3 4 Dry eyes 0 <1 1 4 Dyspepsia <1 2 2 2 Dysuria <1 1 1 2 Nausea 1 2 <1 1 <1 2 Dry throat • Urinary retention rate was 1% in the fesoterodine 4 - and 8 -mg groups • Total discontinuations due to dry mouth in fesoterodine patients: <1% *In at least 1 of the active treatment groups. 12 UTI = urinary tract infection. Chapple C et al. Eur Urol. 2007; 52: 1204 -1212. Nitti VW et al. J Urol. 2007; 178: 2488 -2494. Khullar V et al. Urology. 2008; 71: 839 -843.

Long-Term Open-Label Efficacy and Safety Study 13 • 3 -year, open-label extension study of one (Int’l) Phase 3 trial • Of 417 subjects entering the extension study: – – – 85% 79% 73% 59% 56% remained remained enrolled enrolled at at at 4 8 1 2 3 months years • All 417 subjects started on 8 mg, with an opportunity to reduce dose after 1 month of treatment and at later visits – 19% of subjects chose to decrease dose to 4 mg at 1 month – Long-term (3 y) treatment with fesoterodine was safe and well tolerated, with 75% to 80% of patients remaining on 8 mg Van Kerrebroeck PEV et al. Abstract presented at EAU 2009.

Long-Term Open-Label Efficacy and Safety Study: Results • Safety and Tolerability – Over the 3 years, discontinuations due to adverse events occurred in 12% of subjects • Due to dry mouth: 2. 0% • Due to constipation: 1. 0% – There were no unexpected adverse events – There were no clinically relevant changes in vital signs, ECG, or laboratory parameters • Efficacy – Long-term treatment with fesoterodine resulted in maintained or continued improvement in all efficacy and health-related quality of life measures • Results for long-term US study were similar 14 Van Kerrebroeck PEV et al. Abstract presented at EAU 2009.

Summary of the Phase 3 Study • Robust efficacy on diary endpoints and patient-reported outcomes with both the 4 -mg and 8 -mg doses of fesoterodine – Pooled analyses showed that fesoterodine 8 mg resulted in significantly larger improvements vs fesoterodine 4 mg on key OAB symptoms – The earliest on-treatment assessment of efficacy was at 2 weeks; by then, statistically significant improvements were seen vs placebo on key OAB symptoms • • Fesoterodine 8 mg resulted in significantly larger improvements vs tolterodine ER on key OAB symptoms Good tolerability profile at both the 4 and 8 mg doses Overall discontinuations due to dry mouth were low (<1%) Constipation remained relatively low even with the higher, 8 mg dose of fesoterodine – Placebo (2%), fesoterodine 4 mg (4%), fesoterodine 8 mg (6%) Chapple C et al. Eur Urol. 2007; 52: 1204 -1212. Nitti VW et al. J Urol. 2007; 178: 2488 -2494. Khullar V et al. Urology. 2008; 71: 839 -843. Chapple C et al. BJUI. 2008; 102: 1128 -1132. 15