Nuove terapie per il trattamento della stipsi

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1 Nuove terapie per il trattamento della stipsi Roberto De Giorgio DIMEC, Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna

Un caso di gonfiore addominale F, 39 aa, BMI 18 - nulla di rilevante all

Nausea (saltuariamente); non sintomi da MRGE; senso di peso addominale

Cefalea Senso di peso e cefalea regrediscono se si induce vomito 3 L di

che mangiava in abbondanza gonfiore Slower Type 1 Type 2 Type 3 Less

2 Un caso di gonfiore addominale F, 39 aa, BMI 18 - nulla di rilevante all APF e all APR, tranne: > 10 aa gonfiore con distensione add. Nausea (saltuariamente); non sintomi da MRGE; senso di peso addominale postprandiale, ma NON dolore. Cefalea Senso di peso e cefalea regrediscono se si induce vomito 3 L di acqua / die; preferisce cibi integrali; ha ridotto l assunzione di frutta che mangiava in abbondanza gonfiore Slower Type 1 Type 2 Type 3 Less Transit Type 4 Water Type 5 content Faster Type 6 Type 7 More Saad et al., Am J Gastroenterol 2010;105: Alvo 1-3 ev / die Bristol 2-3

3 What is constipation? UEGW Oslo, 1994

Defininition of Chronic Constipation Rome III Criteria* waiting for Rome IV Chronic constipation must include 2 or more of the following: (self-report) During at least 25% of defecations Straining

4 Defininition of Chronic Constipation Rome III Criteria* waiting for Rome IV Chronic constipation must include 2 or more of the following: (self-report) During at least 25% of defecations Straining Lumpy or Hard Stools Sensation of Incomplete Evacuation Sensation of Anorectal Obstruction/ Blockage Manual Maneuvers to Facilitate Defecations <3 Defecations per Week Loose stools are rarely present without the use of laxatives Insufficient criteria for IBS * Criteria fulfilled for at least 3 months, with symptom onset at least 6 months prior to diagnosis Longstreth G.F., et al., Gastroenterology 2006;130:

Chronic constipation Primary Altered rectal

5 Chronic constipation Primary Altered rectal emptying Secondary Drugs IBS-C Normal transit constipation Endocrine / metabolic Reversible Megacolon: HSCR / non-hscr Aging / Neurological Autoimmune diseases STC / Inertia coli Skeletal muscle diseases Intestinal pseudoobstruction

6 How to treat constipation?

7 Evidence-based grading of current laxatives Agent Brandt et al., 2005 Rao et al., 2007 Polyethylene Glycol (PEG Macrogol 3350 / 4000) A 1A Lactulose A 2B Soluble Fiber (Psyllium) B 2B Non-soluble Fiber IE 3C Magnesia IE 3C Senna IE 2C Bisacodyl IE 3C * IE = Insufficient evidence for recommendation Rao, SS. Gastroenterol Clin 2007; 36:687; Brandt et al. Am J Gastro 2005: 100 (S1): S1-S22

8 Evidence-based grading of current laxatives Agent Brandt et al., 2005 Rao et al., 2007 Polyethylene Glycol (PEG Macrogol 3350 / 4000) A 1A Lactulose A 2B Soluble Fiber (Psyllium) B 2B Non-soluble Fiber IE 3C Magnesia IE 3C Senna IE 2C Bisacodyl IE 3C * IE = Insufficient evidence for recommendation Rao, SS. Gastroenterol Clin 2007; 36:687; Brandt et al. Am J Gastro 2005: 100 (S1): S1-S22

9 PEG / Macrogol: All you wanted to know in 1 min! transit (> left vs. right colon) Global, long-term efficacy in constipation Binding water = Iso-osmotic effect Corazziari E.S., et al., Dig Dis Sci 1996; 41: Schiller L.R., et al., Gastroenterology 1988;94: Ford AC & Suares NC., Gut 2011;60: st line-therapy in many patient subtypes No major adverse events Well tolerated (bloating, flatulence may occur) Corazziari E.S., et al., Gut 2000; 46: PEG no electrolytes = PEG + electrolytes Seinela L., et al., Drugs Aging 2009; 26: De Giorgio R., et al., Eur Rev Med Pharmacol Sci 2011; 15:960-66

10 Why new therapeutic options are needed?

11 Inadequacy of treatment efficacy of currently used laxatives n = 557 % Johanson JF & Kralstein J, Alim Pharm Ther 2007;25:

North West Centre 20% North East South &

12 L.I.R.S. - Laxative Inadequate Response Study 39 centres = 878 pts interviewed; an average of 23 pts / centre distributed as follows: North West Centre 20% North East South & islands 20% 24% 36% Neri M., et al., United European Gastroenterol J 2014; 2:138-47

Only 1 out of 5 pts is satisfied with chronic constipation therapy 3.68 3.

13 Only 1 out of 5 pts is satisfied with chronic constipation therapy % 72% 34% 33% Neri M., et al., United European Gastroenterol J 2014;2:138-47

14 New approaches in the management of chronic constipation Serotonergic enterokinetic agents Cisapride, Tegaserod, Prucalopride (EMA approved) and other compounds... Guanylate cyclase stimulants Linaclotide (FDA & EMA approved for CC / IBS-C and CC, resp.), Plecanitide Chloride channel activators Lubiprostone (available in the USA, and now in EU UK, Switzerland) Future options IBAT, Elobixibat PAMORAs, Naloxegol

15 New approaches in the management of chronic constipation Serotonergic enterokinetic agents Cisapride, Tegaserod, Prucalopride (EMA approved) and other compounds... Guanylate cyclase stimulants Linaclotide (FDA & EMA approved for CC / IBS-C and CC, resp.), Plecanitide Chloride channel activators Lubiprostone (available in the USA, and now in EU UK, Switzerland) Future options IBAT, Elobixibat PAMORAs, Naloxegol

Frequent: day, after meal Transport colonic content Courtesy Dr.

16 High Amplitude Propagated Contractions (HAPCs): A propulsive motor pattern of the colon Aboral propagation High amplitude ( 100 mmhg) Rare events ( 6 times/day) Frequent: day, after meal Transport colonic content Courtesy Dr. Dinning and Costa, Flinders University, SA Associated with: borborigmy, defecatory stimulus, defecation

17 Peristalsis in motion: How neurons control (propulsive) motility

18 ~95% of human body serotonin (5-HT) is in the gut Silver staining Human sigmoid biopsy Chromogranin A Serotonin Yoyo, a nucleic acid stain Many receptor subtypes, e.g. 5-HT4 Courtesy Prof. G.M. Mawe

Peristalsis and related neuronal circuitries and 5-HT 4

5-HT 4 + 5-HT 4 + Excitatory motor neuron Ach / TK EC 5-HT +

19 Peristalsis and related neuronal circuitries and 5-HT 4 receptors 5-HT HT/SOM/ NO/VIP/ACh ACh/TK Sensory neuron 5-HT HT 4 + Excitatory motor neuron Ach / TK EC 5-HT + 5-HT 4 Inhibitory motor neuron NO / VIP / (ATP) Intraluminal content Ascending reflex contraction s. muscle enterocytes 5-HT 4 5-HT 4 + Descending reflex relaxation Tonini et al., Neuroscience 1996;73:287-97

Prucalopride Summary of prucalopride phase 3 studies Placebo PRU 2 mg PRU 4 mg % subjects with an average of 3 SCBM per week over 12 weeks (normalisation) 35% 30% 28.9*** 28.9*** 25% 23.6*** 24.

20 Prucalopride Summary of prucalopride phase 3 studies Placebo PRU 2 mg PRU 4 mg % subjects with an average of 3 SCBM per week over 12 weeks (normalisation) 35% 30% 28.9*** 28.9*** 25% 23.6*** 24.7*** 23.6*** 23.9** 23.5** 20% 19.5** 15% 10% % 0% 1 Pooled data Camilleri et al., 2008 n=240 n=236 n=237 n=212 n=214 n=215 n=193 n=190 n=187 2 Tack et al., Gut, Quigley et al., APT, Camilleri et al., NEJM, 2008 **P < 0.01 vs. placebo ***P < vs. placebo 1 Camilleri et al. Gastroenterology 2008;134(4):A548; 2 Tack et al. Gut 2009;58:357-65; 3 Quigley et al. Aliment Pharmacol Ther 2009;29: ; 4 Camilleri et al. N Engl J Med 2008;358:

21 Patients (%) Prucalopride safety and tolerability: Adverse events 30 Most common drug-related adverse events Placebo (n=661) Prucalopride 2 mg (n=659) Prucalopride 4 mg (n=657) Events during treatment period Events excluding Day 1 1 Camilleri et al. Gastroenterology 2008;134(4):A548; 2 Tack et al. Gut 2009;58:357-65; 3 Quigley et al. Aliment Pharmacol Ther 2009;29: ; 4 Camilleri et al. N Engl J Med 2008;358:

22 New Approaches in the Management of Chronic Constipation Serotonergic enterokinetic agents Cisapride, Tegaserod, Prucalopride (EMA approved) and other compounds... Guanylate cyclase stimulants Linaclotide (FDA & EMA approved for CC / IBS-C and CC, resp.), Plecanitide Chloride channel activators Lubiprostone (available in the USA, and now in EU UK, Switzerland) Future options IBAT, Elobixibat PAMORAs, Naloxegol

23 Linaclotide: mechanisms of action GC-C: guanylate cyclase c - LIGANDS: linaclotide, (uro)guanylin (EE - goblet cells), E.Coli / Yersinia enterotoxin GTP: guanosine triphosphate cgmp: cyclic guanosine monophosphate PKG: cgmp-dependent protein kinase CFTR: cystic fibrosis transmembrane conductance regulator A) linaclotide / GC-C GTP cgmp CFTR phosphoryl Cl-/HCO3- secretion B) linaclotide / GC-C GTP cgmp firing submucosal (colonic) nocicpetors Layer & Stanghellini, Aliment Pharmacol Ther 2014;39:371-84

24 12 wks of treatment *P 0.001, vs. PLA Most common AE: Diarrhea (16% linaclotide vs. 5% Pla) **P 0.01, vs. PLA Lembo et al., N Engl J Med 2011;365:527-36

25 Global improvement of pts with CC treated with plecanatide * Responder defined as patients experiencing 3 CSMB/wk from baseline Most common AE: Diarrhea (9.7% plecanatide vs. 1.3% Pla) Miner et al. Gastroenterology 2013; 144(5): 5-163

26 New Approaches in the Management of Chronic Constipation Serotonergic enterokinetic agents Cisapride, Tegaserod, Prucalopride (EMA & FDA approved) and other compounds... Guanylate cyclase stimulants Linaclotide (FDA & EMA approved for IBS-C / CC and CC, resp.), Plecanitide Chloride channel activators Lubiprostone (available in the USA, and now in EU UK, Switzerland) Future options IBAT, Elobixibat PAMORAs, Naloxegol

27 Chloride-C2 Channel Antagonists (ClC 2 ) selective activation of ClC 2 channels, enhancing fluid secretion small bowel and colonic transit time Lubiprostone: approved in the UK for CC and women with IBS-C and OIC; CC and IBS-C in Switzerland

28 Mean CFB weekly SBM, n Mean CFB weekly SBM, n Mean CFB weekly SBM, n Change from baseline SBM frequencies in patients with CC Placebo Lubiprostone 48 mcg 1 SC-0131 (US;N=242) 2 SC-0232 (US; N=237) 3 CC-0831 (Japan; N=124) ,88 4,26 # 3,63 # 3,83 3,87 # # 1,6 1,26 1, ,62 # ** # 3,67 2,46 2,03 1,84 4,25 *** 1,93 4, ,5 1,21 # 1,32 ** 2,66 1,49 2,54 # 1,65 *** 2, SBM = Spontaneous bowel movements. *P <.05, **P <.01, ***P <.001, #P <.0001 Lubiprostone 48 mcg vs. placebo. 1 Johanson JF, Morton D, Greenen J, et al. Am J Gastroenterol. 2008:103: Barish CF, Drossman D, Johanson JF, et al. Dig Dis Sci. 2010:55: Fukudo S, Hongo M, Kaneko H et al. Clin Gastroenterol Hepatol 2014; pii: S (14)

29 Intensity of adverse events Pivotals, Placebo (N=302) Pivotals, Lubiprostone 48 mcg (N=301) All Active Doses (N=1321) Maximum Intensity Mild 68 (22.5%) 109 (36.2%) 359 (27.2%) Moderate 44 (14.6%) 63 (20.9%) 461 (34.9%) Severe 12 ( 4.0%) 17 ( 5.6%) 156 (14.8%) ncidence of Severe Cases of Most Common AEs -Well-Controlled Studies All Active Doses All Events Severe Events All Events Severe Events Lubiprostone 48 mcg (N=301) Lubiprostone 48 mcg (N=301) Lubiprostone 48 mcg (N=1321) Lubiprostone 48 mcg (N=1321) eddra System Organ lass / Preferred Term Placebo (N=302) Placebo (N=302) astrointestinal isorders Nausea 16 ( 5.3%) 81 (26.9%) 0 5 ( 1.7%) 406 (30.7%) 40 (3.0%) Diarrhoea 3 ( 1.0%) 29 ( 9.6%) 0 3 ( 1.0%) 241 (18.2%) 37 (2.8%) Vomiting 2 ( 0.7%) 8 ( 2.7%) (5.5%) 9 (0.7%) Abdominal pain 5 ( 1.7%) 18 ( 6.0%) 0 1 ( 0.3%) 99 (7.5%) 17 (1.3%) Flatulence 3 ( 1.0%) 11 ( 3.7%) (5.3%) 5 (0.4%) Abdominal distension 5 ( 1.7%) 5 ( 1.7%) 2 ( 0.7%) 1 ( 0.3%) 80 (6.1%) 17 (1.3%)

30 talking to HAL 9000 A look to the future 2001: A Space Odyssey S. Kubrick, 1968

Ileal Bile Acid Transporter (IBAT) Elobixibat (A3309)

luminal side Cholesterol C4 Bile acids No effect on fat

plasma LDL cholesterol Enterohepatic circulation of bile

Bile acids Bile acids to colon secretion and motility

31 Ileal Bile Acid Transporter (IBAT) Elobixibat (A3309) mechanism of action LDL IBAT blocked by elobixibat from luminal side Cholesterol C4 Bile acids No effect on fat soluble nutrient absorption IBAT inhibition leads to plasma LDL cholesterol Enterohepatic circulation of bile acids Ileal Bile Acid Transporter A3309 Small Intestine Bile acids Bile acids to colon secretion and motility Mosinska P., et al., World J Gastroenterol 2015 ; 21(24):

A3309 (Elobixibat): Phase IIb Multicenter Study Primary endpoint *P< 0.05; **P< 0.01 # P< 0.

32 A3309 (Elobixibat): Phase IIb Multicenter Study Primary endpoint *P< 0.05; **P< 0.01 # P< Most common AEs: Abd pain (4%, 10%, 11%, 25%); Diarrhea (4%, 8%, 11%, 17%) Severe AEs: None Tolerance: 29 pts discontinued medication [12.8% PLA, 12.5% (5mg), 12.8% (10mg), 22.9% (15mg)] Chey et al., Am J Gastroenterol 2011; 106:

Opioid-induced constipation Increased use of opioids Indications for opioid prescribing In 2012, >240 million prescriptions for opiate analgesics in the USA ~40-80% of pts taking opiods for chronic,

33 Opioid-induced constipation Increased use of opioids Indications for opioid prescribing In 2012, >240 million prescriptions for opiate analgesics in the USA ~40-80% of pts taking opiods for chronic, non-cancer pain develop OIC Up to 94% of patients with advanced illness who take opiods require laxatives Standars laxatives are often insufficient for treatment of OIC and fail in 50% of cases Camilleri M., Am J Gastroenterol. 2011;106(5):835-42; IMS Health 2012 (reported by Fauber J. J Sentinel. March 6, 2013); Holzer P., Eur Rev Med Pharmacol Scl. 2008; 12 (S1): ;6

Periferally Acting Mu-Opioid Receptor Antagonists (PAMORAs) Currently available therapeutics: Methylnaltrexone (6 trials)*; Alvimopan (4 trials); Naloxone (4 trials); Naloxegol (2 trials) Antagonize

34 Periferally Acting Mu-Opioid Receptor Antagonists (PAMORAs) Currently available therapeutics: Methylnaltrexone (6 trials)*; Alvimopan (4 trials); Naloxone (4 trials); Naloxegol (2 trials) Antagonize peripheral constipating effect of opioids BBB Restricted ability to cross BBB No effect on analgesia * FDA approved for review see: Camilleri M., et al., Neurogastroenterol Motil 2014;26(10):

35 PAMORAs: Metanalysis Ford AC, Brenner DM, and Schoenfeld P. AJG 2013; 108(10):

Naloxegol: KODIAC 04-05 results Primary EP: Responder rate 3 SCBMs / wk with 1 SBM / wk increase over baseline for 9 wks of the 12 for

36 Naloxegol: KODIAC results Primary EP: Responder rate 3 SCBMs / wk with 1 SBM / wk increase over baseline for 9 wks of the 12 for at least 4 wks of treatment * * * n= mg n= mg n= mg n= mg Chey W, et al., N Engl J Med 2014;370(25):

38 Biofeedback vs Laxatives Chiaroni G., et al., Gastroenterology 2006; 130:

39 Conclusions CC is the prototype of all FBD; causes QoL and costs PEG / Macrogol still first line Rx for most patients with CC New effective compounds are now available (usually second-step strategy): - enterokinetics (e.g., prucalopride); naronapride and velusetrag (next in pipeline) - secretagogues (linaclotide) and lubiprostone (not yet available in Italy) Future includes: - PAMORAs (methylnaltrexone; naloxegol, etc.) for OIC; - IBAT (elobixibat); - Biofeedback can be effective in specific subsets (dyssynergic defecation)

40 The Translational Neurogastroenterology Lab, University of Bologna Thank you!

Emerging Treatments for IBS-C and Clinical Trial Endpoints

Emerging Treatments for IBS-C and Clinical Trial Endpoints Lin Chang, M.D. Oppenheimer Family Center for Neurobiology of Stress David Geffen School of Medicine at UCLA Learning Objectives Describe current