PACE Gastrointestinal Master Class New perspectives on Chronic Management of Gastrointetinal Diseases Prokinetics in Chronic Professor Magnus Simrén, MD, PhD Institute of Medicine, Dept of Internal Medicine Sahlgrenska Academy University of Gothenburg Gothenburg, Sweden

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company:

None healthcare a of Owner

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Stockholder of a healthcare healthcare a of Stockholder None

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Ferring

Consulting: , , Albireo Novartis, Shire, , Almirall , Danone

contracts: Research Pharma Aros Research, Danone

potential conflicts of interest of conflicts potential of Disclosure

Magnus Simrén Magnus

Prokinetics in Chronic Constipation M.Simrén Prevalence – Chronic constipation

Risk factors: Female sex, increasing age, low socioeconomic status, IBS

Suares et al Am J Gastroenterol 2011 Prokinetics in Chronic Constipation M.Simrén Functional Bowel Disorders

Simrén et al Gut 2013 Prokinetics in Chronic Constipation M.Simrén Functional constipation: ROME III

. Symptom onset ≥6 months prior to diagnosis . 2 or more of the following for the last 3 months • straining • lumpy or hard stools in at least 25% • sensation of incomplete evacuation of defecations • sensation of anorectal obstruction/blockage • manual manoeuvres needed • fewer than 3 defecations per week . Loose stools are rarely present without laxatives . For IBS-C diagnosis additional symptoms are required Longstreth et al. Gastroenterology 2006 Prokinetics in Chronic Constipation M.Simrén IBS-C vs. Functional constipation • ↑ abdominal pain/discomfort • ↑ constipation symptoms • ↑ constipation severity • ↓ quality of life • ↑ psychological distress

≈ 1/3 switched diagnoses at 12 months Wong et al Am J Gastroenterol 2010 Prokinetics in Chronic Constipation M.Simrén

Lifestyle changes Stimulant laxatives Dietary fibre Osmotic laxatives

Prokinetics

Bulking agents Secretagogues Constipation Opioid antagonists Colectomy

Anorectal surgical procedures Biofeedback

BoTox Injection

Sacral Nerve Stimulation Prokinetics in Chronic Constipation M.Simrén Patient dissatisfaction with traditional treatments for constipation

Fibre (n=268) Prescription Laxatives (n=42) OTC Laxatives (n=146) 80 Ineffective relief of bloating 52 67

79 Lack of predictability 75 71

66 Ineffective relief of multiple symptoms 50 60

50 Ineffective relief of constipation 50 44 Patients (%)

Johanson & Kralstein. Aliment Pharmacol Ther 2007

8 Prokinetics in Chronic Constipation M.Simrén Prokinetics

A gastroprokinetic agent, gastrokinetic, or prokinetic, is a type of drug which enhances gastrointestinal motility by increasing the frequency of contractions in the intestine or making them stronger, but without disrupting their rhythm. They are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heartburn, nausea, and vomiting.

Cisapride; ; ; Erythromycin; Pruclaopride; ; Neo-, Pyridostigmine…

Source: Wikipedia Prokinetics in Chronic Constipation M.Simrén Colonic dysmotility in constipation

Dinning & Di Lorenzo Best Pract Res Clin Gastroenterol 2011 Prokinetics in Chronic Constipation M.Simrén Pancolonic spatiotemporal mapping: Regional deficiencies in, and disorganization of colonic propagating pressure waves in severe constipation

Dinning et al Neurogastroenterol Motil 2010 Prokinetics in Chronic Constipation M.Simrén Small bowel dysmotility Functional gut disorders

29% of FGID pts abnormal (3% of controls)

Malagelada et al Neurogastroenterol Motil 2012 Prokinetics in Chronic Constipation M.Simrén

5-HT4 plays a key role in gut motility

Smooth muscle

Myenteric plexus

Submucosa

Mucosa

Enterochromaffin cell 5-HT

5-HT4 receptor Intrinsic primary afferent neurone (IPAN)

1Tonini & Pace. Dig Dis Sci 2006; 24: 5913 Prokinetics in Chronic Constipation M.Simrén

5-HT4 plays a key role in gut motility

Intraluminal stimuli promote the release of 5-HT from enterochromaffin cells Smooth muscle

Myenteric plexus

Submucosa

Mucosa Stimuli Enterochromaffin cell 5-HT

5-HT4 receptor Intrinsic primary afferent neurone (IPAN)

1Tonini & Pace. Dig Dis Sci 2006; 24: 5914 Prokinetics in Chronic Constipation M.Simrén

5-HT4 plays a key role in gut motility

5-HT stimulates IPANs via 5-HT4 receptors

Smooth muscle

Myenteric plexus

Submucosa

Mucosa

Enterochromaffin cell 5-HT

5-HT4 receptor Intrinsic primary afferent neurone (IPAN)

1Tonini & Pace. Dig Dis Sci 2006; 24: 5915 Prokinetics in Chronic Constipation M.Simrén

5-HT4 plays a key role in gut motility

IPANs activate neurones in the myenteric plexus  peristaltic contractions Smooth muscle

Myenteric plexus

Submucosa

Mucosa

Enterochromaffin cell 5-HT

5-HT4 receptor Intrinsic primary afferent neurone (IPAN)

1Tonini & Pace. Dig Dis Sci 2006; 24: 5916 Prokinetics in Chronic Constipation M.Simrén Tegaserod – chronic constipation Proportion of subjects with increase from baseline of ≥1 CSBM/week

50 *** *** *** *** 40

30 Responder Placebo rate (% of Tegaserod 2mg bid patients) 20 Tegaserod 6mg bid

10

0 Weeks 1-4 Weeks 1-12

*** p<0.0001 vs. placebo Johanson et al Clin Gastroenterol Hepatol 2004 Prokinetics in Chronic Constipation M.Simrén

Prucalopride

5HT4

Prokinetics in Chronic Constipation M.Simrén Resolor ® (): Developed to target impaired motility

Approved for symptomatic treatment of chronic constipation in First compound of a women in whom laxatives fail to provide adequate new class of selective relief high affinity 5-HT4 receptor

Targets impaired motility associated with chronic constipation

•Binds to 5-HT4 receptors involved in bowel motility

19 Prokinetics in Chronic Constipation M.Simrén Prucalopride - Pivotal trials: Study design

Placebo once-daily

Prucalopride 2mg once daily

Prucalopride 4mg once daily

Run-in (2 weeks) Double-blind treatment period (12 weeks) 0 2 4 8 12

→ Daily diaries Screening → Assessments at 2, 4, 8, and 12 weeks Patient global assessment, PAC-SYM, AE, vital signs Randomisation → Assessments at 4 and 12 weeks PAC-QOL, ECG, clinical laboratory parameters, physical exam

Tack et al Gut 2009; Quigley et al APT 2009; Camilleri et al NEJM 2008 Prokinetics in Chronic Constipation M.Simrén

Main inclusion criteria Prucalopride Pivotal Trials

• Adult patients (≥18 years) of either gender • History of chronic constipation, defined as: • 2 or fewer spontaneous complete bowel movements (SCBM) per week for a minimum of 6 months and • 1 or more of the following symptoms for at least 25% of stools: • very hard (little balls) and/or hard stools • a sensation of incomplete evacuation • straining during defecation.

Tack et al Gut 2009; Quigley et al APT 2009; Camilleri et al NEJM 2008 Prokinetics in Chronic Constipation M.Simrén Study endpoints Prucalopride Pivotal Trials

Primary efficacy endpoint: • % Patients with a mean of ≥3 SCBM per week over a 12-week treatment period Main secondary endpoint: • % Patients with an average increase of ≥1 SCBM per week Other secondary endpoints included endpoints derived from validated disease-specific questionnaires: • PAC-SYM = patient’s assessment of constipation – symptoms • PAC-QOL = patient’s assessment of constipation – quality of life

Tack et al Gut 2009; Quigley et al APT 2009; Camilleri et al NEJM 2008 Prokinetics in Chronic Constipation M.Simrén Bowel movement categories Prokinetics in Chronic Constipation M.Simrén Prucalopride

Proportion of patients with ≥ 3 spontaneous complete bowel movements (SCBM)/week

Tack et al Gut 2009; Quigley et al APT 2009; Camilleri et al NEJM 2008

24 Prokinetics in Chronic Constipation M.Simrén Prucalopride Proportion of patients with increase of ≥ 1 SCBM / week

**p ≤ 0.001 vs. placebo Tack et al Gut 2009; Quigley et al APT 2009; Camilleri et al NEJM 2008

25 Prokinetics

in Chronic in Chronic Constipation Time (days) 25 10 15 20 0 5 Medianto timeSCBMafter (days)first intakefirst study ofmedication

Tack al Gut et 20.5 Tack et al. 2009

4.7 **

2.1 **

2009; Prucalopride Quigleyal et APT Camilleri 2008 2009; alNEJM et Quigley et al. 2009 13.0

2.3 **

1.9 **

Camilleri Camilleri et al. 2008 12.6

4.7 placebo **p≤0.001

1.3 ** Prucalopride Prucalopride 2mg Placebo Prucalopride

vs 1.0 **

.

4mg 4mg

M.Simrén

Prokinetics in Chronic Constipation M.Simrén Prucalopride

% Patients with average increase of ≥1 point on the PAC-QOL Satisfaction subscale per week over 12 weeks

**p ≤0.001 vs. placebo Placebo Prucalopride 2mg Prucalopride 4mg§ 60% ** ** ** 48.7% 50% ** ** ** ** 45.6% 45.8% ** 44.9% 44.0% 43.3% 43.5% 44.4% 40%

30% 26.0% 24.1% 22.2% 21.8% 20%

10%

0% 2 Pooled data1 Tack et al. 2009 Quigley et al. 20093 Camilleri et al. 20084

Tack et al Gut 2009; Quigley et al APT 2009; Camilleri et al NEJM 2008 Prokinetics in Chronic Constipation M.Simrén Prucalopride - Adverse events …

…occurred predominantly at the start of therapy and usually disappeared within a few days with continued treatment. A. 12 -week treatment period B. 12-week treatment period including first day excluding first day

25 25

Placebo (n=661) 20 20 Prucalopride 2mg (n=659) Prucalopride 4mg (n=657)

15 15 Frequency % Frequency 10 10

5 5

0 0

Adverse events reported at a rate >10% Prokinetics in Chronic Constipation M.Simrén Prucalopride in the elderly

% Patients with average of ≥3 SCBM/week at weeks 1-4

60 Placebo (n=70) * Prucalopride 1mg (n=76) 48.7 47.2 50 45.1 Prucalopride 2mg (n=75) 43.8 43.7

42.1 41.1 Prucalopride 4mg (n=79) 37.5 *p<0.05 vs. placebo 40 36.1 36.6

29.7 30.6 30 26.1 26.9 26.2 24.6

20

10

0 week 1 week 2 week 3 week 4 Müller-Lissner et al. Neurogastroenterol Motil. 2010 Prokinetics in Chronic Constipation M.Simrén Prucalopride in the elderly

% Patients with average increase from baseline of ≥1 SCBM/week

80 Placebo (n=70) * Prucalopride 1mg (n=76) 68.4 70 * * Prucalopride 2mg (n=75) 63.0 62.5 61.8 * § 59.2 Prucalopride 4mg (n=79) 60 53.4 54.9 *p<0.05 vs. placebo 50.0 48.6 47.9 48.6 45.8 50 43.3 40.6 38.5 40 33.8 30

20

10

0 week 1 week 2 week 3 week 4 Müller-Lissner et al. Neurogastroenterol Motil. 2010 Prokinetics in Chronic Constipation M.Simrén Prucalopride - Open label extension trials: PAC-QOL satisfaction subscale results

Extremely 4 dissatisfied *p<0.001 vs. double-blind baseline 3,5

3

2,5

2 * 1,5

1

0,5 Not at all 0 dissatisfied Baseline Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 (n=1455) (n=1322) (n=1076) (n=915) (n=780) (n=681) (n=509)

Camilleri et al Aliment Pharmacol Ther 2010 Prokinetics in Chronic Constipation M.Simrén Prucalopride: Cumulative overall response rate at week 12.

Tack et al United European Gastroenterology Journal 2013 Prokinetics in Chronic Constipation M.Simrén Prucalopride: Weekly response rates

≥ 3 SCBMs/week Increase of ≥ 1 SCBMs/week

Tack et al United European Gastroenterology Journal 2013 Prokinetics in Chronic Constipation M.Simrén Effect of prucalopride on symptoms of chronic constipation

Tack et al Neurogastroenterol Motil 2013 Early Online Prokinetics in Chronic Constipation M.Simrén Prucalopride – Chronic constipation Asian trial

Responder: ≥3 SCBM/week

Ke et al Neurogastroenterol Motil 2012 Prokinetics in Chronic Constipation M.Simrén Other 5‐HT4 agonists

Velusetrag ATI-7505 - Naronapride

Geometric centre

Camilleri et al NMO 2007 Goldberg et al APT 2010 Prokinetics in Chronic Constipation M.Simrén Other 5‐HT4 agonists

Mosapride citrate in patients with diabetes and constipation

Ueno et al Diab Res Clin Pract 2012 Prokinetics in Chronic Constipation M.Simrén Pyridostigmine – diabetes mellitus and constipation

Bharucha et al Gut 2012 Prokinetics in Chronic Constipation M.Simrén Diagnosis and treatment of chronic constipation – a European perspective

Tack et al Neurogastroenterol Motil 2011