The efficacy of RELISTOR injection in the treatment of OIC in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21 to 100 years); 51% were females. In both studies, patients had advanced illness and received care to control their symptoms. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer's disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had been receiving palliative opioid therapy (median daily baseline oral morphine equivalent dose of 172 mg), and had OIC (either less than 3 bowel movements in the preceding week or no bowel movement for 2 or more days). Patients were on a stable opioid regimen 3 or more days prior to randomization (not including PRN or rescue pain medication) and received their opioid medication during the study as clinically needed. Patients maintained their regular laxative regimen for at least 3 days prior to study entry, and throughout the study. Rescue laxatives were prohibited from 4 hours before to 4 hours after taking an injection of study medication.

Study 4 was a double-blind, placebo-controlled study which compared a single, subcutaneous dose of RELISTOR injection 0.15 mg/kg, and RELISTOR injection 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label 4-week dosing period, where RELISTOR injection could be used as needed, no more frequently than one dose in a 24-hour period. Throughout both study periods, patients maintained their regular laxative regimen. A total of 154 patients (47 RELISTOR 0.15 mg/kg, 55 RELISTOR 0.3 mg/kg, 52 placebo) were enrolled and treated in the double-blind period. The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication. RELISTOR-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo‑treated patients (14%); p <0.0001 for each dose versus placebo ( Figure 1). 

Study 5 was a double-blind, placebo-controlled study which compared subcutaneous doses of RELISTOR injection given every other day for 2 weeks versus placebo. Patients received opioid medication for at least 2 weeks prior to receiving study medication. During the first week (Days 1, 3, 5, 7) patients received either 0.15 mg/kg RELISTOR injection or placebo. In the second week the patient's assigned dose could be increased to 0.3 mg/kg if the patient had 2 or fewer rescue-free laxations up to Day 8. At any time, the patient's assigned dose could be reduced based on tolerability. Data from 133 (62 RELISTOR, 71 placebo) patients were analyzed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medication and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of study medication. RELISTOR-treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p <0.0001 ( Figure 1). RELISTOR-treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p <0.0001. In both studies, in approximately 30% of patients, laxation was reported within 30 minutes of a dose of RELISTOR. 

Figure 1: Laxation Response within 4 Hours of the First Dose in Studies 4 and 5

In both studies, there was no evidence of differential effects of age or gender on safety or efficacy. No meaningful subgroup analysis could be conducted on race because the study population was predominantly Caucasian (88%).

Durability of Response

Durability of response was explored in Study 5, and the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2-week, double-blind period.

The efficacy of RELISTOR injection was also demonstrated in open-label treatment administered from Day 2 through Week 4 in Study 4, and in two open-label extension studies (Study 4 EXT and Study 5 EXT) in which RELISTOR was given as needed for up to 4 months. During open-label treatment, patients maintained their regular laxative regimen. A total of 136, 21, and 82 patients received at least one open-label dose in Studies 4, 4 EXT, and 5 EXT, respectively. Laxation response was also explored in this open-label setting and appeared to be maintained over the course of 3 to 4 months of open-label treatment.

Opioid Use and Pain Scores

No relationship between baseline opioid dose and laxation response in RELISTOR-treated patients was identified in exploratory analyses of these studies. In addition, median daily opioid dose did not vary meaningfully from baseline in either RELISTOR-treated patients or in placebo-treated patients. There were no clinically relevant changes in pain scores from baseline in either the RELISTOR or placebo-treated patients.