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 FDA guidance on the optimal design for clinical trials conducted in IBS Discuss current agents in development for the management of IBS-C in general Discuss specific data on late-stage agents for the management of IBS-C, including linaclotide, prucalopride, and A3309
IBS Guidance Trial Design A randomized, placebo-controlled trial design include a 1- to 2-week single-blind or open-label screening period an 8- to 12-week treatment period a 2-week post-treatment period The 1- to 2-week screening period is used to establish the presence of entry criteria train patients in the mode of PRO data collection selected for the trial FDA IBS Guidance Draft
Clinical Trials in IBS: Current FDA Recommendations General items asking patients to rate overall change in IBS symptoms as primary endpoints to support efficacy claims are no longer recommended Recommend the development of a multi-item PRO instrument that captures all of the clinically important signs and symptoms of IBS Prospectively defined changes in the scores measured by this PRO instrument between treatment arms should be used as the primary endpoint in IBS clinical trials FDA IBS Draft Guidance 2010
The PRO Instrument Development and Modification Process US Food and Drug Administration. Guidance for Industry: Patient- Reported Outcome Measures Use in Medical Product Development to Support Labeling Claims. Silver Spring, MD, 2009.
Rome III Diagnostic Criteria for IBS Recurrent abdominal pain or discomfort for 3 days per month in the last 3 months, associated with 2 of the following: Improvement with defecation Onset associated with a change in stool frequency Onset associated with a change in stool form (appearance) Diagnostic criteria fulfilled for the last 3 months with symptom onset 6 months prior to diagnosis Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.
IBS Subtypes Based on Stool Form Bristol Stool Form Scale 1 Type 1 Separate hard lumps, like nuts (hard to pass) Type 2 Sausageshaped but lumpy Type 3 Like a sausage but with cracks on its surface Type 4 Like a sausage or snake, smooth and soft Type 5 Soft blobs with clearcut edges (passed easily) Type 6 Fluffy pieces with ragged edges, a mushy stool Type 7 Watery, no solid pieces, entirely liquid IBS-C 2 Hard/lumpy stools 25% Loose/watery stools <25% IBS-M 2 Hard/lumpy stools 25% Loose/watery stools 25% IBS-D 2 Hard/lumpy stools <25% Loose/watery stools 25% IBS-C=constipation-predominant IBS; IBS-D=diarrhea-predominant IBS; IBS-M=mixed IBS; IBS-U=unsubtyped IBS. O Donnell LJD et al. BMJ. 1990;300:439-440. Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.
FDA IBS Guidance: Target Population Rome III Diagnostic Criteria for IBS IBS-Constipation IBS-Diarrhea Because the clinical signs and symptoms associated with IBS-C and IBS-D can be significantly different, the two conditions ordinarily should be studied in separate clinical trials FDA IBS Draft Guidance 2010
FDA IBS Guidance: Primary Endpoint Because IBS is defined as abdominal pain or discomfort that is improved with defecation, the FDA recommends evaluation of a primary endpoint that includes the two major IBS symptoms: Abdominal pain AND Defecation FDA IBS Draft Guidance 2010
Interim Endpoint: IBS-C Entry Criteria Proposed Baseline Enrollment Criteria: Pain Severity Weekly average of worst pain in past 24 hours score of > 3.0 in a 0 to 10 point scale Stool Frequency < 3 Complete Spontaneous Bowel Movements (CSBM)/Week Efficacy Assessments: Daily symptom diary Weekly global assessment
Interim Endpoint: IBS-C Responder Definition Proposed Primary Endpoints: Patient is a weekly responder in BOTH pain severity AND stool frequency Pain Severity Responder Decrease in weekly average of worst abdominal pain in past 24 hours score of > 30% Stool Frequency Responder An increase of at least 1 complete spontaneous bowel movement (CSBM) per week from baseline
Agents in Development for IBS-C Drug Description Development Phase 1 2 3 Linaclotide Guanilib TD-5108 DDP-773 Olsalazine/ colchicine Guanylate cyclase-c agonist Guanylate cyclase-c agonist 5-HT 4 agonist Partial 5-HT 3 agonist 5-aminosalicylate/intestinal secretion Note: Prucalopride currently under investigation for chronic constipation. Camilleri M, Chang L. Gastroenterology. 2008;135:1877-1891. Maneerattanaporn M et al. Gastroenterol Clin North Am. 2011:223 243.
Linaclotide: First in Class GC-C Agonist Stable peptide analog of guanylin and uroguanylin Activates GC-C receptor: increases intracellular and extracellular cgmp Extracellular cgmp: inhibits afferent nerve firing Intracellular cgmp: activates anion channels
Linaclotide Phase 3 IBS-C trial Composite Responder (FDA Interim End Point) DB, PC, rand study Modified Rome II IBS <3 CSBM/wk, 5 SBM/wk, abdominal pain 3 (0-10 NRS) Linaclotide 290 mcg daily (n=401) Placebo (n=403) 30% abdominal pain reduction + increase 1 CSBM from baseline; in the same week Abdominal Pain Responder CSBM + 1 Responder 3 weeks 2 weeks 26 weeks Screening Pretreatment Treatment CSBM=complete spontaneous bowel movement; SBM=spontaneous bowel movement Chey WD et al. DDW abstract 2011
Phase 3 IBS-C: Topline Efficacy (U.S.) Responder Rates (%) Primary Endpoints 256 mcg Placebo P-value Composite responder 1 (abdominal pain 30, CSBM 3+1, 9/12) 12 5 =0.0004 CSBM responder 1 (CSBM 3+1, 9/12) 20 6 <0.0001 Abdominal pain responder 1 (abdominal pain 30, 9/12) 34 27 =0.0262 Composite responder 2 (abdominal pain 30, CSBM +1, 6/12) 34 21 <0.0001 Secondary Endpoints CSBM+1 responder 2 (CSBM +1, 6/12) 49 30 <0.0001 Abdominal pain responder 2 (abdominal pain 30, 6/12) 50 37 =0.0003 Abdominal pain (12 week) Yes <0.0001 Percent of abdominal pain-free days (12-week) Yes =0.0003 Abdominal discomfort (12-week) Yes <0.0001 Bloating (12-week) Yes <0.0001 CSBM frequency rate (12-week) Yes <0.0001 SBM frequency rate (12-week) Yes <0.0001 Stool consistency (12-week) Yes <0.0001 Severity of straining (12-week) Yes <0.0001 Ironwood Press Release, Sept 2010
Linaclotide Phase 3 IBS-C Trial: 6/12 Week Responder Primary End Point Responders (%) 50 Composite Responder (6/12 Week APC + 1) 40 30 33.7%* 20 13.9% 10 0 Placebo N=403 Linaclotide 290 mcg N=401 *P<.0001, ITT population (290 mcg vs placebo) Chey WD, et al. DDW abstract 2011
Change in Abdominal Pain (%) Linaclotide Phase 3 IBS-C Trial: Abdominal Pain Over 26 Weeks Linaclotide 290mcg Placebo 0-10 -20-30 -40-50 -60 BL 2 4 6 8 10 12 14 16 18 20 22 24 26 Trial Week P=.007 for Week 1 P<.0001 for Weeks 2-26 ITT population, observed cases, LS-means presented: P-values based on ANCOVA at each week. Bars represent 95% CI. Chey WD, et al. DDW abstract. 2011.
Weekly CSBMs Linaclotide Phase 3 IBS-C: Rapid and Sustained Improvement in CSBMs 3 Treatment Period Randomized Withdrawal Period 2 *** *** *** *** *** *** *** *** *** *** *** *** 1 0 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Treatment Period 290 mcg Placebo *p 0.05, ** p < 0.01, *** p < 0.001 Trial Week RW Treatment Sequence 290 mcg 290 mcg 290 mcg Placebo Placebo 290 mcg Chey WD, et al. DDW abstract. 2011.
Effect of Linaclotide on Change in Bloating Severity from Baseline to 12 Weeks in IBS-C Bloating Severity Baseline 12 Weeks 10 9 8-1.0-1.9* Phase 3 trials Very severe 7 6 5 4 3 2 1 0 Placebo (n=797) Linaclotide, 290 mcg (n=805) None *p=0.0001 vs. placebo Chey WD, et al. DDW abstract. 2011.
Linaclotide Phase 3 IBS-C Trial Treatment-emergent adverse events (TEAEs) occurring in 3% in linaclotide 290 mcg and at a rate greater than placebo Placebo N=403 Weeks 1 12 Weeks 1 26 Lin 290 mcg N=402 Placebo N=403 Lin 290 mcg N=402 Any TEAE 187 (46%) 212 (53%) 228 (57%) 263 (65%) Diarrhea 7 (2%) 71 (18%) 10 (2%) 79 (20%) Nausea 17 (4%) 17 (4%) 24 (6%) 23 (6%) URI 13 (3%) 14 (3%) 22 (5%) 22 (5%) Abdominal pain 14 (3%) 15 (4%) 16 (4%) 18 (4%) Flatulence 7 (2%) 13 (3%) 9 (2%) 15 (4%) Gastroenteritis viral 4 (1%) 8 (2%) 9 (2%) 15 (4%) Headache 8 (2%) 13 (3%) 11 (3%) 13 (3%) Chey WD, et al. DDW abstract. 2011.
Multiple Serotonergic (5-HT) Receptor Subtypes Are Expressed in the Gut Five different serotonin receptor types are present in the mammalian gut 5-HT 1 5-HT 2 5-HT 3 5-HT 4 5-HT 7 Two main drug classes that act on 5-HT receptors have been developed for therapeutic purposes 5-HT 3 antagonists (eg, alosetron, cilansetron) 5-HT 4 agonists (eg, tegaserod, prucalopride)
IBS - Physiology - Serotonin Receptors Excitatory motor neuron 5-HT 4 Inhibitory motor neuron ACh 5-HT 3 5-HT 1A 5-HT 1D NO, VIP Contraction Relaxation
Efficacy of the 5HT 4 agonist Prucalopride on Primary End Point in CC Percent of Patients with >3 SCBMs/Wk 50 45 40 35 30 25 20 15 10 5 Both P<0.001 Both P<0.001 Both P<0.001 Both P<0.001 Placebo Prucalopride, 2 mg Prucalopride, 4 mg 0 Run-In Period 1-12 1-4 5-8 9-12 Week Interval No. Receiving Study Drug Placebo 209 209 209 204 204 Prucalopride, 2mg 207 207 207 193 190 Prucalopride, 4mg 204 204 204 190 190 Camilleri M et al. N Engl J Med. 2008;358:2344-2354.
Responders 3 SCBM/ week (%) Prucalopride for Chronic Constipation Results from a Phase III RCT 30 25 20 15 10 Placebo PRU 2 mg PRU 4 mg *** 23 *** 26 **p 0.01 ***p 0.001 12 10 10 9 ** 19 *** 24 ** 20 *** 26 ** 18 *** 23 5 2 2 3 0 Run-in Weeks 1-4 Weeks 5-8 Weeks 9-12 Weeks 1-12 ITT Population = 713 pts Laxative use and QoL improved with prucalopride Tack J et al. Gut. 2009;58:357-367.
Phase III Studies of Prucalopride for Chronic Constipation: Adverse Events % Reported AE Prucalopride Placebo Headache 25-30% 12-17% Nausea 12-24% 8-14% Diarrhea 12-19% 3-5% SAE 2.7% 2% Discontinuation 4-15% 2-7% Prucalopride 2 or 4 mg daily No effect on vital signs or ECG parameters. Tack J et al. Aliment Pharmacol Ther. 2012, in press
A3309 : Ileal Bile Acid Transporter Inhibitor- Mechanism of Action Increasing delivery of bile acids to colon induces secretion and motility 1 Liver LDL Cholesterol C4 Bile acids Enterohepatic circulation of bile acids Small Intestine Bile acids A3309 partially blocks the ileal bile acid transporter from the luminal side, increasing delivery of bile acids to the colon inducing secretion and motility. A3309 only affects the delivery of bile acids to the colon: No effect on the uptake of fat soluble nutrients. As synthesis of bile acids from cholesterol requires increased uptake of cholesterol, IBAT inhibition by A3309 leads to decreases in plasma LDL cholesterol Ileal Bile Acid Transporter A3309 Bile acids to colon Decreased bile acid synthesis & bile acid concentration may contribute to the pathogenesis of slow transit constipation 2 Chey WD et al. Am J Gastroenterol. 2011; 106:1803-1812 Camilleri M. Am J Gastroenterol. 2011;106:835-842
A3309 in CC: Mean Change from Baseline in Weekly Stool Frequency Over 8 Weeks SBM Frequency CSBM Frequency Overall 5 mcg vs. placebo p=0.113 10 mcg vs. placebo p=0.017 15 mcg vs. placebo p<0.001 Overall 5 mcg vs. placebo p=0.021 10 mcg vs. placebo p=0.017 15 mcg vs. placebo p<0.001 # of SBMs/week # of CSBMs/week 9 6 8 7 6 5 4 3 *** * Placebo 5 mg 10 mg 15 mg 5 4 3 2 *** * * Placebo 5 mg 10 mg 15 mg 2 1 1 0 BL 1 2 3 4 5 6 7 8 Weeks 0 BL 1 2 3 4 5 6 7 8 Weeks mitt Population mitt Population Chey WD et al. Am J Gastroenterol. 2011;106:803-12
A3309: Adverse Events and Discontinuations Placebo n=46 A3309 5 mg n=48 A3309 10 mg n=47 A3309 15 mg n=48 Any TEAE, n (%) 20 (44) 22 (46) 29 (62) 31 (65) Serious AEs 1(2.2) 1(2.1) 1(2.1) 0 Treatment discontinuations 6 (12.8) 6 (12.5) 6 (12.8) 11 (22.9) Gastrointestinal Adverse Events Total 5 (10.9) 12 (25.0) 11 (23.4) 19 (39.6) Mild 2 (4.3) 6 (12.5) 5 (10.6) 6 (12.5) Moderate 2 (4.3) 5 (10.4) 4 (8.5) 8 (16.7) Severe 1 (2.2) 1 (2.1) 2 (4.3) 5 (10.4) Abdominal Pain 0 5 (10.4) 5 (10.6) 13 (27.1) Diarrhoea 1 ( 2.2) 4 (8.3) 3 (6.4) 6 (12.5) Abdominal Distension 1 (2.2) 4 (8.3) 2 (4.3) 3 (6.3) Flatulence 3 (6.5) 4 (8.3) 3 (6.4) 2 (4.2) Nausea 2 (4.3) 2 (4.2) 2 (4.3) 3 (6.3) TEAE, treatment emergent adverse event; AE, adverse event Chey WD et al. Am J Gastroenterol. 2011;106:803-12
Summary IBS Clinical Trial regulatory issues are an evolving process Current IBS trials are required to use interim primary endpoints Efficacy data are dependent on primary endpoint criteria which has varied in clinical trials IBS trials are still aimed at a predominant bowel habit Linaclotide has been shown to be efficacious in IBS-C and chronic constipation in phase 3 trials- Application for FDA approval submitted in 2011 New and emerging agents for chronic constipation include the ileal bile acid transporter inhibitor A3309 and the 5HT 4 agonist Prucalopride