Opioid Use Disorder

June 26, 2017

Indivior issued results of a phase III trial of RBP-6000 for moderate to severe opioid use disorder (OUD) as part of a complete treatment plan to include counseling and psychosocial support. A total of 504 treatment-seeking adults, aged 19 to 64 with moderate or severe OUD (not currently receiving medication-assisted treatment, or MAT) were randomized to either one of two dosage regimens of RBP-6000 (n=404) or placebo (n=100). Prior to randomization, subjects were inducted and dose-stabilized onto transmucosal buprenorphine-containing product according to the prescribing information to suppress opioid withdrawal signs and symptoms and ensure lack of allergy to buprenorphine. Randomized subjects received six once-monthly 300mg doses (300/300mg), two once-monthly 300mg doses followed by four once-monthly 100mg doses (300/100mg) or six once-monthly subcutaneous injections of placebo. The results showed that RBP-6000 met the primary efficacy endpoint, with both RBP-6000 dosage regimens demonstrating abstinence rates that were significantly higher versus placebo (300/300mg: 41.3%; 300/100mg: 42.7%; placebo: 5.0%, p<0.0001). Both RBP-6000 dosages also met the key secondary endpoint of treatment success (300/300mg: 29.1%; 300/100mg: 28.4%; placebo: 2.0%, p<0.0001). In addition to the efficacy findings, a pharmacokinetic-pharmacodynamic (exposure-response) analysis demonstrated a positive relationship between buprenorphine exposure, mu-opioid receptor occupancy and clinical endpoints of abstinence, withdrawal symptoms and opioid craving. Significantly more subjects in both RBP-6000 dosage groups completed the study compared with those on placebo (300/300mg: 64.3%; 300/100mg: 61.3%; placebo: 33.3%, p<0.0001). RBP-6000 was generally well-tolerated, though 2.7% of subjects on RBP-6000 (both dosage regimens combined) experienced a serious treatment-emergent adverse event (TEAE) compared with 5.0% of subjects on placebo. There were no related serious TEAEs across groups. Indivior submitted a New Drug Application (NDA) to the FDA to seek marketing approval for RBP-6000 for the treatment of adults with moderate to severe OUD as part of a complete treatment plan to include counseling and psychosocial support.

May 8, 2017

Braeburn Pharmaceuticals and Camurus released long-term phase III results of CAM2038 (weekly and monthly buprenorphine depots) in patients with moderate to severe opioid use disorder. The trial was an open-label, multicenter, 12-month (48-week) safety study comprised of three phases: screening phase, treatment phase and follow-up phase with 48 weeks of CAM2038 treatment and four weeks of follow-up (52 weeks in total). A total of 228 patients were enrolled in the study conducted at 29 sites across the U.S., Europe and Australia, and 162 (71%) patients completed the 48-week study treatment period. The safety profile of CAM2038 was similar to that observed in previous shorter term trials. A total of 17 (7%) serious adverse events were reported, of which none was considered related to the study medication. Importantly, no opioid overdoses were reported for patients treated with CAM2038 depot injections. Overall, headache, nausea, vomiting, nasopharyngitis and urinary tract infection were the most common adverse events, in each case reported by less than 10% of patients. Injection site reactions occurred in 20% of the participants and were generally mild (16.3%) or moderate (3.5%). Severe injection site pain was reported for one patient (0.4%). The companies will finalize regulatory submissions in order to seek approval in the U.S., Europe and other key global markets.

December 5, 2016

Braeburn Pharmaceuticals and Camurus issued results of a pivotal, phase III, randomized, double-blind, double-dummy, active controlled trial of weekly and monthly injections of buprenorphine (CAM2038) for treatment of moderate to severe opioid use disorder. In the study, which enrolled 428 patients with opioid use disorder, CAM2038 achieved the main objective of statistical non-inferiority compared to the active comparator of SL BPN/NX for both the FDA and the EMA specified endpoints of responder rate (RR) (CI -3.5%, 10.4%; p<0.001) and percent negative urine samples for opioids (CI -0.2%, 13.7%; p<0.001), respectively. While the study was designed and powered for assessing non-inferiority, the protocol also planned to test superiority against SL BPN/NX based on the pre-defined secondary endpoint of cumulative distribution function (CDF) of the percent urines negative for opioids combined with self-reports for weeks five through 24. The superiority of CAM2038 over SL BPN/NX was established with p=0.004. The retention rate in the trial was approximately 57.5% and, as expected, similar across both treatment arms. The overall safety profiles were comparable between the two treatment groups, with few serious adverse events (SAEs) reported for the CAM2038 and SL BPN/NX (3.2% vs 6%, respectively). There were no reported overdoses in the CAM2038 arm compared to four non-fatal overdoses (three on heroin, one on Klonopin) in the SLBPN/NX arm. Injection site reactions occurred in 19% of the CAM2038 participants vs 22% of the SL BPN/NX participants. Seventy-four percent of the injection site reactions were reported as mild, 26% as moderate, and none were reported as severe. Braeburn and Camurus will work with the FDA and EMA to begin the submission process. The FDA has granted Fast Track designation for CAM2038 subcutaneous injectable products for the treatment of opioid addiction. 

September 19, 2016

RespireRx Pharmaceuticals reported results of a phase IIa study of CX1739 for the respiratory depressive effects of remifentanil (REMI) and acute opioid overdose and chronic opioid use. The trial was conducted in two separate stages over a four week period. Stage 1, a randomized, double-blind, crossover study comparing 300mg of CX1739 to placebo, was considered a primary outcome study. Acute bolus injection of REMI caused a rapid and dramatic decline in respiration, with Emax ranging from 15% to 100% across subjects. When subjects in Stage 1 were pre-treated with 300mg of CX1739, a statistically significant reduction of recovery time (RT) was observed. RT was reduced from a mean of 6.8+/-0.98 after placebo pre-treatment to a mean of 4.4+/-0.77 after 300mg of CX1739 pre-treatment (p=0.01, paired t test). In Stage 2, RT was reduced for both doses, although no significant differences (p>0.05) were observed when these doses were compared to either placebo or 300mg. While this difference between 300mg and the higher doses might reflect greater efficacy at the 300mg dose, the company believes that this lack of significance for the higher doses might also reflect inter-subject variability in what doses produced the optimum decline in RT. Supporting this idea, responder analysis revealed that decreases in RT were observed, in a statistically significant proportion of subjects (13 out of 15, p<0.005, z test), after one or more doses of CX1739. Using these data from optimum doses, mean RT was significantly (p<0.002, paired t test) reduced from 6.8 +0.98 minutes after placebo to 3.7 +0.70 minutes after CX1739. Future studies are being designed and planned.

August 22, 2016

Indivior released results of a phase III trial of RBP-6000 buprenorphine monthly depot for the treatment of opioid use disorder as part of a complete treatment plan to include counseling and psychosocial support. The multicenter, randomized, double-blind, placebo-controlled study randomized 489 subjects. RBP-6000 achieved the primary endpoint of the cumulative distribution function of the percentage of urine samples negative for opioids combined with self-reports negative for illicit opioid use collected from week five through week 24 (p<0.0001 for both dosage regimens v. placebo). The key secondary endpoint in this study was treatment success defined as any subject with 80% of urine samples negative for opioids combined with self-reports negative for illicit opioid use from week five through week 24. The secondary endpoint was also achieved for both dosage regimens at p<0.0001 v. placebo. RBP-6000 was generally well-tolerated in this study. Available safety findings suggest that 2.8% of subjects on RBP-6000 experienced a serious treatment-emergent adverse event (TEAE) compared with 5.1% of subjects on placebo. There were no related serious TEAEs across groups. RBP-6000 has previously received Fast Track designation from the FDA. Subject to satisfactory completion of the analysis and, assuming the FDA review and approval is achieved within the assumed six month Priority Review timeline, it is possible that a marketing authorization could be granted in Q4 2017 per previous guidance.

May 9, 2016

Merck & Co. reported results of a phase III trial of Zepatier (elbasvir and grazoprevir) in patients with a history of intravenous drug use who are receiving opioid agonist therapy. C-EDGE CO-STAR is a double-blind, placebo-controlled study. The study included an immediate treatment group (ITG) that received blinded ZEPATIER for 12 weeks (n=201) and a deferred treatment group (DTG) that received 12 weeks of placebo (n=100), followed by 12 weeks of open-label ZEPATIER (n=95). The secondary efficacy analysis evaluated SVR24 in the modified full analysis set (n=271), which included patients from both treatment groups who received ZEPATIER for 12 weeks and completed 24 weeks of follow-up, excluding those who discontinued for non-treatment related reasons. An additional analysis evaluated the reinfection incidence among all patients who completed active study therapy (n=296). Following 12 weeks of treatment with ZEPATIER, 94% (175/186) and 96% (82/85) of patients achieved SVR24 in the ITG (blinded) and DTG (open-label), respectively. The analysis of 296 patients showed six probable HCV reinfections occurred, including five through follow up week 12 in the ITG and one additional by FU24 in the DTG. These results represent a reinfection incidence of 8.4 cases (95% CI: 3.1, 18.5) per 100 person years after 24 weeks of follow up. Patients in the trial will be evaluated regularly for three years following the 24-week period. Most common AEs among patients receiving blinded ZEPATIER or placebo were fatigue (16%, 20%), headache (13%, 14%), nausea (11%, 9%) and diarrhea (10%, 9%), respectively. Reported AEs in the open-label treatment group were similar to the blinded group (fatigue, 14%; headache, 13%; nausea, 7%; diarrhea, 8%). One patient receiving ZEPATIER and one patient receiving placebo reported serious treatment-related AEs. In addition, one patient receiving ZEPATIER and one patient receiving placebo discontinued due to AEs.