FDA s GREAT Workshop. Industry Perspective: Development Activities Towards Phase 3 Endpoints. September 19, 2012

Transcription

1 FDA s GREAT Workshop Industry Perspective: Development Activities Towards Phase 3 Endpoints Malcolm Hill, Pharm.D. Meritage Pharma, Inc. San Diego, CA 09/19/12 1 September 19, 2012

2 Presentation Overview Clinical Trial Perspectives (PEER Study) Dysphagia Symptom Questionnaire (DSQ) Development History Proposed use of the DSQ as a Clinical Endpoint in Interventional Clinical Trials 09/19/12 2

3 Oral Budesonide Suspension (OBS) Pediatric EoE Trial (PEER Study) Objective: Design: Doses: Subjects: Primary endpoint: Other parameters: Duration: Efficacy and safety to aid in selection of a dose for Phase 3 trials Placebo-controlled, double-blind, dose-ranging study Vary by age (2-9 vs yrs.) and are in volumes of 7 or 10 mls Placebo; Low: mg/day; Med: mg/day; High: mg b.i.d. 82, 2-18 years of age, 20 eos/hpf at 2 levels of the esophagus, and EoE clinical symptom score 3 50% decrease in the EoE clinical symptom score and peak eosinophil count 6/HPF at all esophageal levels full analysis set Safety, PK and endoscopy score 19 weeks (4 wks screening, 12 wks treatment, 3 wks taper) 09/19/12 3 Data presented at DDW May 2011

4 Primary (Compound) Endpoint: Response to OBS 100 Placebo 80 OBS -Low Dose OBS -Medium Dose Percentage of Resp ponders OBS - High Dose ** 47.1 * 0 * p < 0.05 ** p < 0.01 *** p < vs placebo 09/19/12 4 Full Analysis Set

5 Histologic Response: Max peak 6 eos/hpf Placebo OVB -Low Dose ** Percentage of Respo onders OVB -Medium Dose OVB - High Dose * * p < 0.01 ** p < /19/12 5 All Subjects

6 EoE Symptom Score Over 12 Weeks: PEER Study 10 Placebo OVB - Low dose 8 OVB - Medium dose OVB - High dose Total Score Six Domain Symptom Score: heartburn, abdominal pain, nocturnal awakening with symptoms, nausea/regurg/vomiting, anorexia/early satiety, dysphagia/odynophagia food impaction Baseline (Week 0) Week 2 Week 4 Week 8 Final Treatment 09/19/12 6

7 PEER Results: Possibilities OBS reduced esophageal inflammation (histologically and endoscopically) in a dose dependent fashion. EoE symptoms improved in all groups, including placebo Dissociation between the degree of esophageal inflammation and clinical symptoms may exist Inherent difficulties of assessment of symptom response in pediatric patients using a multi-domain instrument where self-reporting is not always possible make it difficult to correlate symptoms and histology 09/19/12 7

8 Symptom Rankings by Patients And Caregivers in EoE: Emergence of Dysphagia with Increasing Age Symptom Category 2-5 years* (n=10) 6-11 years (n=10) years (n=10) Most severe 1. Vomiting 2. Abdominal pain 3. Diarrhea 4. Odynophagia 1. Dysphagia 2. Vomiting 3. Abdominal pain 4. Heartburn 1. Dysphagia 2. Abdominal pain 3. Heartburn 4. Vomiting Most bothersome 1. Vomiting 2. Abdominal pain 3. Diarrhea 4. Odynophagia Most frequent 1. Cough/gag 2. Regurgitation 3. Vomiting 4. Dysphagia Most important 1. Vomiting 2. Cough/gag 3. Abdominal pain 4. Odynophagia 1. Abdominal pain 2. Heartburn 3. Dysphagia 4. Vomiting 1. Abdominal pain 2. Heartburn 3. Dysphagia 4. Vomiting 1. Vomiting 2. Dysphagia 3. Abdominal pain 4. Odynophagia 1. Dysphagia 2. Abdominal pain 3. Reflux 4. Chest Pain 1. Dysphagia 2. Abdominal pain 3. Heartburn 4. Throat pain 1. Dysphagia 2. Abdominal pain 3. Heartburn 4. Vomiting Symptom rankings determined during concept elicitation interviews (PAESS) * Caregivers only 09/19/12 8

9 Rationale for Development of a Dysphagia PRO Daily recall via electronic diary reduces instrument variability Narrower age range and symptom target decreases the influence of potential patient-level confounders Evaluating one symptom domain (dysphagia) simplifies the instrument Daily, weekly, or 2-week average data cuts are possible with daily diary Dysphagia is a bothersome symptom in both adolescent and adult subjects Study entry criteria will select subjects with prominent dysphagia (frequency) Expands patient access and sample sizes Straumann et al. (2010) 1 demonstrated significant reduction using dysphagia instrument Eliminating investigator and caregiver involvement reduces placebo response in trials of other GI Diseases; see Ford & Moayyedi (2010) 2 ; Musial et al. (2007) 3 1 Straumann et al, Gastroenterology Ford & Moayyedi, Aliment Pharmacol Ther Musial et al, World J Gastroenterol /19/12 9

10 Development of a PRO Instrument: An Iterative Process i. Hypothesize conceptual framework v. Modify instrument PRO Claim ii. Adjust conceptual framework and draft instrument iv. Collect, analyze, and interpret data (clinical trials, etc.) 09/19/12 10 iii. Confirm conceptual framework and assess other measurement properties a report that comes directly from the patient about the status of a patient s health condition without amendment or interpretation of the patient s response by a clinician or anyone else 12/2009 Guidance

11 Meritage Dysphagia Symptom Questionnaire (DSQ) Background/Overview DSQ Development The DSQ Field Trial Background Key Features Analysis/Results Application of the DSQ in the next clinical trial 09/19/12 11

12 Field Trial DSQ 09/19/12 12 frequency intensity

13 DSQ Diary Device: epro LogPad from PHT (Charlestown, MA) Easy to use and transmit daily diary data Daily data viewable on a web portal as part of qualification process (only compliance after randomization) 09/19/12 13

14 Field Trial Study Design: Key Features Non-interventional, 30 day field trial was conducted using the epro Conducted at EoE specialty centers (Atlanta, Richmond, Chapel Hill, Chicago). Intended to enroll 40 subjects; 37 completers (adolescents/adults) Subjects had a documented diagnosis of EoE that includes histological evidence of esophageal eosinophilia with 15 eos/hpf in at least one level Subjects must have experienced frequent dysphagia in the month prior to the enrollment (on approximately eight days in a two-week period), and may have (or have a history of) other symptoms suggesting esophageal dysfunction e.g., abdominal pain, heartburn, vomiting, food impaction, and weight loss 09/19/12 14

15 DSQ Field Trial Demographic and Health Information Gender Adolescents (N=18) n (%) Adults (N=19) n (%) Total (N=37) n (%) Male 11 (61.1%) 9 (47.4%) 20 (54.1%) Female 7 (38.9%) 10 (52.6%) 17 (45.9%) Age Range Mean (SD) 15.2 (1.6) 31.7 (9.3) 23.6 (10.7) Race Black or African American 1 (5.6%) 0 (0.0%) 1 (2.7%) White/Caucasian 16 (88.9%) 19 (100.0%) 35 (94.6%) Other 1 (5.6%) 0 (0.0%) 1 (2.7%) EoE Treatments During Course of Field Trial Topical Steroid 13 (72.2%) 7 (36.8%) 20 (54.1%) Proton Pump Inhibitor, Dietary Therapy or No Treatment 5 (27.8%) 11 (57.9%) 16 (43.2%) 09/19/12 15

16 Field Trial Subject Disposition: DSQ Analysis 37 EoE Patients Completed Field Trial (30 days) 35 EoE Patients Subject to DSQ Analysis (28 days or 4 wks) 2 Pts excluded; DSQ compliance <70% and < 6 dysphagia events in 30 days 18 EoE Pts on Topical Steroids: 12 Pts y.o. 15 pts y.o. 3 pts > 25 y.o. 17 EoE Pts not on Topical Steroids: 5 Pts y.o. 7 pts y.o. 10 pts > 25 y.o. 09/19/12 16

17 Field Trial Results: Selected Findings Compliance was good (83%) for the duration of the study Solid food avoidance was infrequent Dysphagia was very common Action taken to get relief appears well ordered: 09/19/12 17 Action Taken Adolescent Adult None (%) Drink liquid (%) Cough/gag (%) Vomit (%) Medical attention (%)

18 Frequency (count) of Dysphagia Days Per Week EoE Patients Reported Over 4 Weeks Adolescents (12-17) [n=17] Adults (>17) [n=18] Frequency Dysphagia Days per Week 09/19/12 18

19 Dysphagia More Frequent in Adults than in Adolescents Cumulative Fre equency 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Adolescents [n=17] Adults >17 [n=18] Dysphagia Days per Week 09/19/12 19

20 Fewer Dysphagia Days for Patients on Topical Steroids vs. Non-topical Steroid Treatment 100% 90% 80% Cumulative Fr requency 70% 60% 50% 40% 30% 20% 10% 0% Dysphagia Days per Week Pts on Topical Steroids [n=18] Pts Not on Topical Steroids [n=17] 09/19/12 20

21 Dysphagia Score (/days reported) DSQ Score Algorithm: Dysphagia Frequency Driven 6.0 Steroid Patients 5.0 Non Steroid Patients Dysphagia Episodes per week/days reported 09/19/12 21

22 Interim FDA Feedback on DSQ Consider inclusion of a odynophagia component to the PRO Clinical relevance of pain with swallowing in EoE is not well understood Inclusion of an additional item (pain) as part of the epro may be useful to support single domain of dysphagia Pain with swallowing food may considered outside of the DSQ score 09/19/12 22

23 MPI Protocol Synopsis Drug: Oral budesonide suspension and matched placebo Doses: Placebo and Active B.I.D.; For OLE, once-daily OBS will be used (unless BID is needed) Subjects: Goal is to complete 80 EoE subjects y.o. with persistent dysphagia at baseline, 15 eos/hpf at 2 levels of the esophagus, threshold DSQ score Primary endpoint: Histologic and Symptom Response Other parameters: Safety Duration: 16 week blinded treatment period (active or placebo) plus 24 week open label Screening and Baseline Visits OBS OBS Once Daily or BID n=50 Treatment Period (Double Blind) n=50 Placebo 16 Weeks 09/19/12 Open-Label Extension n=80 24 Weeks NCT

24 Summary FDA Input: Get it early and often Since EoE is a clinicopathological disorder, a meaningful and well developed clinical endpoint can used together with esophageal histology to create useful clinical trial endpoints Collaborate with clinical experts and patients to help determine proper assessments Selection of the best patient population for study Focus on subjects with persistent dysphagia in whom it is likely that there is the ability to measure response to drug therapy Consider broadening of study populations when more clinical trial experience is gained with well developed symptom endpoints Emphasize subject compliance with study drug and epro use 09/19/12 24