Oral Methylnaltrexone for the. Constipation in Patients with Chronic Non-cancer Pain

Transcription

1 Oral Methylnaltrexone for the Treatment of Opioid-induced Constipation in Patients with Chronic Non-cancer Pain Richard L. Rauck, 1 John F. Peppin, 2 Robert J.Israel, 3 Jennifer Carpenito, 3 Jeffrey Cohn, 4 Shirley Huang, 4 Enoch Bortey, 4 Craig Paterson, 4 William P. Forbes 4 1 Carolinas Pain Institute, Winston-Salem, NC 2 The Pain Treatment Center, Lexington, KY 3 Progenics Pharmaceuticals, Inc., Tarrytown, NY 4 Salix Pharmaceuticals, Inc., Raleigh, NC DDW 2012

2 Disclosures Salix Pharmaceuticals, Inc. is investigating oral methylnaltrexone as a potential new treatment option for opioid-induced constipation (OIC) in patients with chronic non-cancer pain 3201 is a phase 3, multicenter, randomized, doubleblind, placebo-controlled, parallel group study sponsored by Salix Oral methylnaltrexone is not currently FDA approved Dr. Peppin was an investigator in the study, has consulted for Salix, and is currently serving on the Salix advisory board 2

3 Background Opioid use for chronic non-cancer pain may be complicated by dose-limiting opioid-induced induced constipation, impacting quality of life and pain control Methylnaltrexone bromide Peripherally acting, selective μ-opioid receptor antagonist with restricted CNS penetration Subcutaneous injection approved for OIC in patients with advanced illness in over 50 countries (RELISTOR ) ~1300 subjects studied in the oral clinical development program 3

4 3201 Study Design Phase 3, multicenter, randomized, double-blind, placebo-controlled, controlled parallel group study OIC in subjects with chronic non-cancer pain Screening Double-blind blind Treatment Follow-up (- 14 to -1 (14 days) days) Daily Dosing (QD) 28 days Dose as Needed (PRN) 56 days 150 mg (N = 201) 300 mg (N = 201) 450 mg (N = 200) Placebo (N = 201) Day

5 Key Inclusion & Exclusion Criteria Inclusion Chronic non-cancer pain for 2 months and requiring 50 mg oral morphine equiv/day for 14 days prior to screening Required laxative therapy for 30 days prior to screening (discontinued at screening) At least 1 bowel movement (BM) during the screening period OIC during screening: < 3 RFBMs/week on average associated with 1 or more of the following Bristol Stool Form Scale type 1 or 2 for 25% of RFBMs Straining during at least 25% of RFBMs Sensation of incomplete evacuation after 25% of RFBMs Exclusion Mechanical bowel obstruction Rectal outlet obstruction or fecal impaction at screening Negative urine drug screen for opioids 5

6 Baseline Characteristics ITT Population Placebo (N = 201) All 150 mg 300 mg 450 mg (N = 201) (N = 201) (N = 200) (N = 602) Avg Number of RFBMs Per Week* Mean (SD) (1.05) (0.91) (0.89) (0.79) (0.87) # of Pts. with Avg RFBMs Per Week < 3 (93.5%) (95%) (97%) (97.5%) (96.5%) n(%) Oral Morphine Equivalents, mg/day Mean (SD) (199.7) (206) (358.3) (191.9) (264.1) *Defined as 7 x (number of RFBMs / number of days with diary data) 6

7 Efficacy Endpoints Primary Percentage of doses resulting in any rescue-free bowel movement (RFBM*) within 4 hrs of dosing during daily dosing period Key Secondary Change in weekly number of RFBMs from baseline during daily dosing Responder** to study drug during daily dosing *RFBM **Responder Defined as a bowel movement that occurred without laxative use (i.e., no laxative use within 24 hrs prior to the bowel movement) 3 RFBMs/week, with 1 RFBM/week increase over baseline, for 3 of first 4 weeks 7

8 Primary Efficacy Endpoint ITT Population, Daily Dosing Period Percentage of Doses Resulting in any RFBM within 4 hrs 30 p < % Doses s Resultin ng in RFB BM % p = % p = % 27.40% 0 Placebo 150 mg 300 mg 450 mg p-value adjusted for multiple comparisons based on Hochberg method 8

9 Time to First RFBM from the First Dose Probability of Reachi ing the End dpoint Time (hr) 300mg p-value < mg p-value < mg p-value = Placebo

10 Primary Efficacy Endpoint ITT Population, 12 Week Combined Dosing Periods p, g Average Proportion (%) of RFBMs per subject within 4 hrs of all doses Placebo (N=201) 150 mg (N=201) 300 mg (N=201) 450 mg (N=200) Mean % (SD) (17.22) (20.34) (21.98) (24.02) p-value vs. PBO < Combined QD (4 week) & PRN (8 week) Dosing Period 10

11 Key Secondary Efficacy Endpoint Change in Weekly Number of RFBMs from Baseline During Daily Dosing Period Baseline Weekly RFBMs Mean (SD) Median (min, max) Placebo (N = 201) 1.49 (1.045) 1.40 (0, 7.5) 150 mg 300 mg 450 mg (N = 201) (N = 201) (N = 200) 1.46 (0.911) 1.50 (0, 4.2) 1.35 (0.891) 1.40 (0, 4.4) 1.37 (0.789) 1.40 (0, 3.2) Mean (SD) (1.940) (2.123) (2.727) (2.448) Change from Baseline Weekly RFBMs Median (min, max) Adjusted p-value vs. PBO 1.42 (-2.3, 9.3) 1.67 (-2.3, 9.6) 1.92 (-2.2, 17.2) 1.98 (-2.1, 12.4) n.s

12 Key Secondary Efficacy Endpoint Percentage of Subjects Responding* During Daily Dosing Period Placebo (N = 201) 150 mg (N = 201) 300 mg (N = 201) 450 mg (N = 200) Responders, n (%) 74 (36.8) 83 (41.3) 96 (47.8) 101 (50.5) % Difference vs. PBO (95% CI) 4.5 (-5.1, 14) 10.9 (1.3, 20.5) 13.7 (4.1, 23.3) Odds Ratio: /PBO (95% CI) (0.82,1.84) (1.04,2.32) (1.20,2.69) Adjusted p value vs. PBO n.s *Responder: 3 RFBMs/week, with 1 RFBM/week increase over baseline, for 3 of first 4 weeks. Each RFBM was a bowel movement that occurred without laxative use (no laxative use within 24 hrs prior to the bowel movement). 12

13 Efficacy of Oral vs. Subcutaneous Injection ITT Population, First 4 Weeks p, Percentage of Doses Resulting in any RFBM within 4 hrs Doses (% %) Perce entage of Oral Formulation 35 Primary Efficacy Endpoint Placebo 150 mg 300 mg 450 mg SC Formulation Co-Primary Efficacy Endpoint PBO 12 mg QOD 12 mg QD PBO QOD Doses Active Doses 13

14 Most Common Adverse Events Safety Population, 12 Week Study Period y p, y Preferred Term, n (%) Placebo (N = 201) 150 mg (N = 201) 300 mg (N = 201) 450 mg (N = 200) Abdominal pain 17 (8.5) 11 (5.5) 5) 16 (8.0) 21 (10.5) Nausea 18 (9.0) 13 (6.5) 16 (8.0) 12 (6.0) Diarrhea 7 (3.5) 7 (3.5) 13 (6.5) 16 (8.0) Flatulence 9 (4.5) 11 (5.5) 7 (3.5) 10 (5.0) URTI 9 (4.5) 9 (4.5) 7 (3.5) 8 (4.0) Back pain 7 (3.5) 12 (6.0) 6 (3.0) 5 (2.5) UTI 7 (3.5) 7 (3.5) 8 (4.0) 7 (3.5) Anxiety 3 (1.5) 6 (3.0) 9 (4.5) 7 (3.5) Hyperhidrosis 4 (2.0) 6 (3.0) 8 (4.0) 6 (3.0) Headache 8 (4.0) 2 (1.0) 8 (4.0) 9 (4.5) Vomiting 9 (4.5) 3 (1.5) 6 (3.0) 7 (3.5) 14

15 Key Safety Findings No notable differences in clinical laboratory results, vital signs, ECG findings, or use of concomitant medications Mean opioid withdrawal scores and pain scores did not demonstrate any clinically significant change from baseline Incidence of SAEs was 3% in the all group versus 4% in the placebo group None were considered related to study drug No events of GI perforation There were no deaths during the study 15

16 Conclusions Oral methylnaltrexone 300 mg and 450 mg significantly increased the percentage of doses resulting in any RFBM within 4 hrs QD period (primary endpoint) and overall 12 week study period Oral methylnaltrexone at 150 mg, 300 mg, and 450 mg demonstrated a linear dose response (p<0.0001) 0001) Significant differences for 3 RFBMs/week with an increase of 1 RFBM/week over baseline (key secondary endpoint) 300 mg and 450 mg QD dosing Efficacy of the oral formulation was comparable to subcutaneous injection Low incidence of adverse events similar across treatment groups and placebo 16