MANAGEMENT OF CHRONIC CONSTIPATION BEYOND LAXATIVES

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Everett Curtis
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1 Enrique Rey Professor of Medicine Head. Department of Digestive Diseases Hospital Clínico San Carlos Complutense University Madrid, Spain MANAGEMENT OF CHRONIC CONSTIPATION BEYOND LAXATIVES

2 CONSTIPATION: MANAGEMENT Self-reported Constipation Chronic Constipation Lifestyle changes g fiber intake daily liters of liquid intake daily Daily physical exercise (1 hour) Laxatives PEG g/day SPS 10 mg/day 4-6 weeks Non controlled Constipation (refractory)

3 NEW HORIZONS

4 SEROTONINE AND MOTILITY

5 SEROTONINE AND GI TRACT Sanger GJ. Neurogastroenterol Mot 1996; 8: Gershon MD. Aliment Pharmacol Ther 1999; 13 (Suppl 2): De Ponti. Gut 2004;53: Tonini. Dig Dis Sci 2006; 24: 59

Aliment Pharmacol Ther 1999; 13 (Suppl 2): 15-30

6 SEROTONINA Y TUBO DIGESTIVO Sanger GJ. Neurogastroenterol Mot 1996; 8: Gershon MD. Aliment Pharmacol Ther 1999; 13 (Suppl 2): De Ponti. Gut 2004;53: Tonini. Dig Dis Sci 2006; 24: 59

7 5HT4 RECEPTORS De Ponti. Gut 2004;53:

8 5-HT4 AGONISTS

Antagonist Channel herg Inhibitor Renzapride Agonist Antagonist Channel

9 5-HT4 AGONISTS Drug 5-HT4 receptor 5HT3 receptor Other receptors Metoclopramide Agonist Antagonist D 2 Antagonist Cisapride Agonist Antagonist Channel herg Inhibitor Renzapride Agonist Antagonist Channel herg Inhibitor Tegaserod Prucalopride Agonist Agonist 5-HT 1 Agonist 5-HT 2 Antagonista

10 AFFINITY FOR KEY RECEPTORS 5-HT4 herg 5-HT1D y 2B Cardiovascular side effects Cisapride Tegaserod herg gen related K+ Channel 5HT-1D and 5-HT- 2B De Maeyer et al. Neurogastroenterol Motil 2008; 20:99 112

11 AFFINITY FOR KEY RECEPTORS 5-HT4 herg 5-HT1D y 2B Cardiovascular side effects Cisapride Tegaserod herg gen related K+ Channel 5HT-1D and 5-HT- 2B De Maeyer et al. Neurogastroenterol Motil 2008; 20:99 112

12 AFFINITY FOR KEY RECEPTORS 5-HT4 herg 5-HT1D y 2B Cardiovascular side effects Cisapride Tegaserod herg gen related K+ Channel 5HT-1D and 5-HT- 2B De Maeyer et al. Neurogastroenterol Motil 2008; 20:99 112

13 PRUCALOPRIDE: PHARMACOKINETICS Low binding to plasmatic proteins (28-33%) 4% No interaction with cytochrome P450 (CYP 3A4) Oral availability: 90% Not interfere by food 96% After a single dose of 2 mg: C max 7.5 ng/ml in 2-3 hours t ½ 30 h

14 PRUCALOPRIDE: PHYSIOLOGICAL EFFECTS

15 5-HT4 AGONISM : EFFECTS ON COLONIC MUSCULAR FIBERS Prins et al. Br J Pharmacol 2000 Celleck et al. Neurogastro Motil 2006; 18:853-61

Total Right Colon Left Colon Rectosigmoid Schryver et al.

16 Tiempo de transito colónico (h) PRUCALOPRIDE: EFFECT ON COLONIC MOTILITY (HEALTHY SUBJECTS) Placebo PRU 2 mg * * * 0 Total Right Colon Left Colon Rectosigmoid Schryver et al. Aliment Pharmacol Ther 2002; 16: Poen et al. Aliment Pharmacol Ther 1999; 13:

T ½ (hours) PRUCALOPRIDE: EFFECTS ON TRANSIT (CONSTIPATION) 250 200

* * 8 6 * 4 50 2 0 Gastric emptying Small (min) Bowel transit

17 T ½ (hours) PRUCALOPRIDE: EFFECTS ON TRANSIT (CONSTIPATION) Placebo PRU 2 mg PRU 4 mg Placebo PRU 2 mg PRU 4 mg * * 8 6 * Gastric emptying Small (min) Bowel transit time(min) 0 Right colon emptying Bouras et al. Gastroenterology 2001;120:

18 PRUCALOPRIDE: MAIN CHARACTERISTICS High selective 5-HT 4 receptor agonist Excellent oral bioavailability, long half life, and renal excretion One daily dose Acts on enteric nervous system Stimulates colonic motility Increases high amplitude contractions Acelerates colonic transit

19 PRUCALOPRIDE: EFFICACY

20 OUR PATIENT WITH CONSTIPATION

PRUCALOPRIDE: DEVELOPMENT PROGRAM Phase Number of studies Number of participants exposed (PRU) Phase I 48 797 Phase II DBPC trial (Chronic constipation) 10 Phase III DBPC trial (Chronic

21 PRUCALOPRIDE: DEVELOPMENT PROGRAM Phase Number of studies Number of participants exposed (PRU) Phase I Phase II DBPC trial (Chronic constipation) 10 Phase III DBPC trial (Chronic constipation) Phase II/III follow up (open trial) Phase II Postoperative ileo Pase II Multiple sclerosis/ spinal injury with Crhonic constipation TOTAL 83 >3.000 pacientes (PRU)

22 MAIN DBPC TRIALS USA-11 N = 620 (88% women) Multicenter USA (38 centers) Camilleri et al. N Engl J Med 2008; 358: 2344 INT-6 N = 716 (91% women) Multicenter international (65 centers; Europe, Australia, Canada y Southafrica) Tack et al. Gut 2009; 58: 357 USA-13 N = 641 (87% women) Multicenter USA (41 center) Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

23 DESIGN Placebo, od Prucalopride 2 mg, od Prucalopride 4 mg, od Open run-in (2 wk) Doble blind period of intervention Screening Rescue: Bisacodile (up to 15 mg) when no bowel movements in 3 days Randomization Endpoint Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

24 INCLUSION CRITERIA AND ENDPOINTS 18 y-o Chronic constipation, defined as: 2 spontaneous and complete BM weekly for at least 6 months 1 of the following criteria in at least 25% of BM: Hard or very hard stools Feeling of incomplete evacuation Straining Primary Endpoint Proportion of patients with a weekly mean of 3 spontaneous and complete evacuations for 12 weeks Secondary Endpoints Proportion of patients with least an increased of weekly mean of spontaneous and complete evacuations for 12 weeks Changes in constipation related symptoms (PAC-SYM) Changes in constipation related quality of life (PAC-QOL)

25 CHARACTERISTICS OF INCLUDED PATIENTS Variable Placebo (N = 645) Prucalopride 2 mg (N = 640) Prucalopride 4 mg (N = 639) Constipation Duration (years) Number of weekly spontaneous evacuations (%) None One Previous laxative use (%) Reported Efficacy of laxatives Failure Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

PRIMARY ENDPOINT: % RESPONDERS Placebo Prucalopride 2 mg Prucaloprida 4 mg 11,3% 23,6% * 24,7% * 9,6% 19,5% * 23,6% 23,9% 23,5% * * * 12,1% 12,0% 30,9% * 28,4% * n=645 n=640 n=639 n=240 n=236 n=237

26 PRIMARY ENDPOINT: % RESPONDERS Placebo Prucalopride 2 mg Prucaloprida 4 mg 11,3% 23,6% * 24,7% * 9,6% 19,5% * 23,6% 23,9% 23,5% * * * 12,1% 12,0% 30,9% * 28,4% * n=645 n=640 n=639 n=240 n=236 n=237 n=207 n=209 n=204 n=209 n=207 n=204 Grouped Tack, 2009 Camilleri, 2008 Quigley, 2009 * p<0,01 Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

27 SECONDARY ENDPOINT: SYMPTOMS (PAC-SYM) Bloating Discomfort Pain Cramps Incomplete Evacuation Tenesm Straining Stools too hard Stools too loose Painful defecation Anal burning sensation Anal bleeding Placebo (n=538) Improvement PRU 2 mg (n=521) Kerstens et al. UEGW 2010

28 SECONDARY ENDPOINT: QUALITY OF LIFE Placebo Prucalopride 2 mg Prucaloprida 4 mg 22,2% 44,0% 43,3% * * 16,4% 33,5% * 29,4% * 26,0% 43,5% 44,4% * * 24,1% 44,9% * 48,7% * n=645 n=640 n=639 n=240 n=236 n=237 n=207 n=209 n=204 n=209 n=207 n=204 Grouped Tack, 2009 Camilleri, 2008 Quigley, 2009 Patients with an increase of at least one point in PAC-QOL at week (%) * p<0,01 Camilleri et al. N Engl J Med 2008; 358: 2344 Tack et al. Gut 2009; 58: 357; Quigley et al. Aliment Pharmacol Ther 2009; 29: 315

29 % respondedores OVERALL CLINICAL BENEFIT 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 3 SCBM Δ 1 SCBM Δ 1 Satisf Δ 1 SBM Modificado de Stanghellini et al. UEGW 2010

30 PRUCALOPRIDE: SAFETY

31 % of patients % de pacientes ADVERSE EVENTS 30% 25% 30% 25% 20% 15% 10% 5% 20% 15% 10% 5% 0% Headache Nausea Diarrhea Abdominal pain 0% Headache Nausea Diarrhea Abdominal pain Placebo PRU 2 mg PRU 4 mg Placebo PRU 2 mg PRU 4 mg Tack et al. DDW 2008

32 QT INTERVAL QT Interval Placebo Prucalopride 2 mg Prucalopride 4 mg QTcB n=583* n=574* n=580* ms (%) ms (%) >500 ms (%) QTcF n=621* n=604* n=601* ms (%) ms (%) >500 ms (%) *Number of patients with QT interval within normal range at screening QTcB: intervalo QT corregido con la fórmula de Bazett QTcF: intervalo QT corregido con la fórmula de Fridericia Tack et al. DDW 2008

Intervention: DBPC: 3 doses of prucalipride (0.

33 SAFETY IN THE ELDERLY Population: Chronic constipation (N=89 patients) Setting: Nursing home (mean agea>80 años; over 70% under active treatment for cardiovascular diseases Intervention: DBPC: 3 doses of prucalipride (0.5, 1 and 2 mg) vs placebo No serious adverse events related to Prucalopride Camilleri et al. Neurogastroenterol Motil (2009) 21, 1256 e117

34 SAFETY IN THE ELDERLY No changes in heart rate or blood pressure ECG Holter: no increase in the number of ventricular extra beats or episodes of ventricular tachiarrithmias Camilleri et al. Neurogastroenterol Motil (2009) 21, 1256 e117

PORT-MARKETING EXPOSURE Prucalopride is approved in a total of 46 countries and is currently being marketed in 16 of those countries (Australia,

35 PORT-MARKETING EXPOSURE Prucalopride is approved in a total of 46 countries and is currently being marketed in 16 of those countries (Australia, Belgium, Canada, Cyprus, France, Germany, Spain, Greece, Aus tria, Switzerland, Malta, Sweden, Ireland, Italy, UK and Singapore). Shire Data on File SPD555-15

36 PRUCALOPRIDE: MAIN CHARACTERISTICS High selective 5-HT 4 receptor agonist Excellent oral bioavailability, long half life, and renal excretion One daily dose Acts on enteric nervous system Stimulates colonic motility Increases high amplitude contractions Accelerates colonic transit Effective in chronic constipation Safe, even in the elderly

37 ALGORITMO MANEJO Tack et al. Neurogastro Motil 2011; 23:

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