Substance Abuse

February 5, 2018

Elite Pharmaceuticals reported positive topline results from a pilot study conducted for SequestOx, Elite’s immediate release Oxycodone Hydrochloride product that incorporates its proprietary abuse-deterrent technology. An objective of the study was to assess whether the reformulated SequestOx could achieve a Tmax (the mean or median time to the maximum drug concentration in subjects) comparable to the reference drug, Roxicodone, when dosed with the standard high fat meal specified by the FDA. As opposed to the earlier formulation, based on pilot results, the modified SequestOx is expected to achieve bioequivalence with a Tmax range equivalent to the reference product when conducted in a pivotal trial under fed conditions. Elite intends to review with the FDA the study results and discuss the pharmacokinetic study requirements for a re-submission of the NDA. The study was a Phase I pilot, randomized, single-dose, single period, pharmacokinetic study in healthy male and female volunteers in the fed state.

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. 

November 14, 2016

Omeros reported results of a phase II clinical trial evaluating the effects of a peroxisome proliferator-activated receptor (PPAR)-gamma agonist in heroin-dependent subjects. In the double-blind, placebo-controlled trial, 30 non-treatment-seeking heroin users were admitted to an inpatient unit and randomized to receive either a PPAR-gamma agonist (n=14) or placebo (n=16) daily for up to three weeks. All patients were maintained on buprenorphine/naloxone (8/2mg). Measures of heroin self-administration, positive subjective drug effects, craving and anxiety were recorded at multiple time points. The data reveal a statistically significant reduction in heroin craving in patients treated with the PPAR-gamma agonist compared to placebo controls. The PPAR-gamma agonist also attenuated anxiety, a behavior often associated with relapse, though no effect was detected on heroin self-administration or heroin-induced positive subjective effects. 

October 24, 2016

Omeros announced positive results from a phase II clinical trial evaluating the effects of a peroxisome proliferator-activated receptor (PPAR)-gamma agonist in patients with cocaine use disorder (CUD). In the double-blind, placebo-controlled trial, 30 treatment-seeking CUD patients were randomized to receive either a PPAR-gamma agonist (n=15) or placebo (n=15) daily for 12 weeks. Measures of impulsivity, decision-making and cocaine craving were recorded at multiple time points. A subgroup of 19 patients (10 placebo patients and 9 PPAR-gamma-treated patients) underwent brain scans using diffusion tensor imaging (DTI) to measure white matter integrity before and after the course of treatment. The data reveal a statistically significant time-dependent reduction in cocaine craving in PPAR-gamma-agonist-treated patients compared to placebo controls. Treated patients also showed improvement in white matter integrity in four target DTI regions of interest, specifically in the corpus callosum and in two associated thalamic tracts. During treatment, side effects reported were minimal and similar between the PPAR-gamma agonist and placebo groups. These clinical findings are consistent with results of earlier mechanistic and target-based preclinical studies showing that PPAR-gamma agonists protect against neuronal damage and block reinstatement of cocaine, heroin and alcohol seeking in animal models of drug abuse. 

May 25, 2015

Pain Therapeutics reported results of a phase III study of Remoxy Extended-Release Capsules CII designed to discourage certain common methods of drug tampering and misuse. The study was randomized, double-blind, placebo and active controlled, using a four-way crossover design in healthy, non-dependent recreational opioid users. Nearly 60 subjects completed this study, with an average age of 27 years. The study’s primary objective was to measure the abuse potential of chewed and intact 40mg Remoxy compared to 40mg immediate-release (IR) oxycodone when taken orally. Study subjects were instructed to chew Remoxy capsules vigorously for up to five minutes, but none were able to do so in light of Remoxy’s high viscosity, texture or taste. On the co-primary endpoint of “drug liking,” scores were significantly lower for intact Remoxy (p<0.0001) and for chewed Remoxy (p<0.0001) compared to IR oxycodone. On the co-primary endpoint of “drug high,” scores were significantly lower for intact Remoxy (p<0.0001) and for chewed Remoxy (p<0.0001) compared to IR oxycodone. On the secondary endpoint of “good drug effects,” scores were significantly lower for intact Remoxy (p<0.0001) and for chewed Remoxy (p<0.0001) compared to IR oxycodone. On the secondary endpoint of “bad drug effects,” scores were significantly higher for intact Remoxy (p<0.0001) and for chewed Remoxy (p<0.0079) compared to IR oxycodone. On the secondary endpoint of “nausea,” scores were significantly lower for intact Remoxy (p<0.0001) and for chewed Remoxy (p<0.0143) compared to IR oxycodone. On the secondary endpoint of “feel sick,” scores were significantly lower for intact Remoxy (p<0.0002) and for chewed Remoxy (p<0.039) compared to IR oxycodone.

November 10, 2014

Cara Therapeutics released results of a human abuse liability (HAL) trial of an intravenous (I.V.) formulation of CR845, a kappa opioid agonist. The double-blind, randomized, active- and placebo-controlled, four-way crossover trial evaluated the abuse potential of I.V. CR845 in 40 non-dependent, recreational polydrug users with lifetime and recent hallucinogenic drug use. Top-line results showed therapeutic and supratherapeutic doses of I.V. CR845 met the trial’s primary endpoint by demonstrating highly statistically significant lower “drug liking” scores as measured by visual analog scale (VAS) Emax (p <0.0001) when compared to I.V. pentazocine, a schedule IV opioid receptor agonist. I.V. CR845 also demonstrated highly statistically significant lower “feeling high” and “overall liking” scores (p <0.0001) as compared to pentazocine. Additionally, both doses of I.V. CR845 were rated equivalent to placebo on “overall drug liking” and “take drug again” measures. “Drug liking,” “feeling high,” “overall liking” and “take drug again” scores are standard subjective measures recommended by the FDA to assess a drug’s abuse liability, both for recommended scheduling as well as labeling. The company plans to advance I.V. CR845 into phase III clinical trials in early 2015.

August 25, 2014

MediciNova issued positive interim results of a phase IIa trial of MN-166 (ibudilast) in opioid dependence. The study is a randomized, placebo-controlled, double-blind, inpatient phase IIa study of MN-166 (ibudilast) in opioid-dependent abusers of prescription opioids and/or heroin. The study duration is approximately six weeks per subject. The crossover study design includes initial detoxification followed by randomization to ibudilast 50mg BID or placebo. Subjects are maintained on each dose for at least two to three consecutive weeks (one week stabilization + 1.5 week testing). During test weeks, participants receive oxycodone (zero mg, 15mg or 30mg PO) in random order on separate days. For each dose, a sample followed by a choice session is completed. During the choice session, a drug versus money self-administration paradigm is employed. MN-166 significantly decreased the craving for heroin (p<0.05), cocaine (p<0.05) and tobacco (p<0.05). MN-166 also decreased the positive subjective effects of oxycodone measured by mean responses to statements such as “I Feel High” (p<0.05) and “I Liked the Dose” (p<0.05). MN-166 also enhanced the analgesic effects of oxycodone. MN-166 reduced the sum score on the McGill Pain Questionnaire, reduced the mean rating on the Painful scale, and reduced the mean rating on the Bothersome scale (p<0.05). Finally, MN-166 decreased the reinforcing effects of oxycodone.

April 14, 2014

Collegium Pharmaceutical reported results of a phase II study evaluating the effect of physical manipulation by crushing Oxycodone DETERx compared with reformulated Oxy- Contin. The objective was to assess pharmacokinetics of Oxycodone DETERx when the capsule was taken intact after oral administration compared with opening the capsule and crushing the capsule contents (microspheres) prior to oral administration. These treatments were compared with OxyContin intact, OxyContin crushed and an immediate-release (IR) oxycodone tablet formulation crushed in naltrexone-blocked, healthy subjects (n=42). The study was an open label, randomized, active-controlled, five-treatment, five-period, cross-over comparison design. Crushed Oxycodone DETERx capsule contents (microspheres) (Cmax = 62.9ng/mL) were bioequivalent based upon Cmax and AUC to intact Oxycodone DETERx capsules) (Cmax = 67.5ng/mL) with similar Tmax demonstrating that crushing the contents of Oxycodone DETERx capsules did not alter the pharmacokinetics. Crushed OxyContin tablets (Cmax = 78.4ng/mL) were bioequivalent based upon Cmax and AUC to crushed IR tablets (Cmax = 79.4ng/mL), demonstrating that crushing OxyContin compromised the integrity of the time-release formulation, transforming the drug-release profile from an ER profile to an IR profile. The mean Abuse Quotient (“AQ” = Cmax/Tmax) value for crushed Oxycodone DETERx was lower than that of Oxycodone DETERx intact. The AQ for crushed OxyContin was approximately four times higher than the AQ value for OxyContin intact and similar to the crushed oxycodone IR tablets. The product’s abuse-deterrent characteristics are being evaluated in phase III trials, which have completed enrollment. The company is on track to file an NDA in Q4 of this year.

January 27, 2014

Collegium Pharmaceutical has released results of a phase II trial of Oxycodone DETERx, an abuse-deterrent, oxycodone microspherein- capsule product. The randomized, doubleblind, double-dummy, positive- and placebocontrolled, single-dose, four-treatment, four-period crossover comparison study was designed to evaluate the abuse potential and pharmacokinetics of crushed 40mg Oxycodone DETERx intranasal, intact 40mg of Oxycodone DETERx oral and crushed 40mg of IR oxycodone intranasal. The study enrolled 36 non-dependent, recreational opioid users. The primary endpoint for the study was drug liking, measured up to 24 hours after dosing, using a bipolar visual analogue scale (VAS). Oxycodone DETERx (both crushed intranasal and intact oral) had significantly lower peak “drug liking” (Emax) when compared with intranasal crushed IR oxycodone (p<0.0001). Furthermore, when comparing Oxycodone DETERx treatments, Emax for “drug liking” after administration of crushed intranasal Oxycodone DETERx was significantly lower than for intact oral administration of DETERx (p<0.05). The secondary measure of “bad drug effects” was numerically highest for intranasal crushed Oxycodone DETERx. A phase III trial currently is enrolling.

August 26, 2013

Titan Pharmaceuticals reported results of a placebo- and active drug-controlled confirmatory phase II study of Probuphine for the treatment of opioid dependence in 287 adult patients. Probuphine results were statistically significant for the trial’s protocol defined primary endpoint based on the percentages of urine samples that were negative for illicit opioid use, and incorporating patient self-reported opioid use over the 24-week treatment period (p < 0.0001). Patients receiving the Probuphine implant had a higher study completion rate relative to placebo (64& v. 26% (p < 0.0001). Patients receiving the Probuphine implant had lower clinician-rated (p < 0.0001) and patient-rated (p < 0.0001) withdrawal, lower patient-rated (p < 0.0001) craving and better patients’ (p = 0.031) and clinicians’ (p = 0.022) global ratings of improvement. An NDA to the FDA has been submitted.

April 11, 2005

Alkermes reported positive results of a phase III trial of Vivitrex (naltrexone long-acting injection), for the treatment of alcohol dependence. Data met their primary endpoint, producing a significant reduction in the incidence of heavy drinking vs. placebo (p=0.0245). Efficacy was also seen in a number of secondary endpoints in the highest dosing group, including reduction in median number of heavy drinking days per month (3, vs. 19 for placebo), and a reduction of heavy drinking (5 or more drinks per day for men, 4 or more for women) within the first month of treatment. Adverse events were generally mild and decreased over the course of treatment, with injection site reactions occurring most frequently. This multi-center, double-blind, placebo-controlled clinical trial included 624 subjects with a history of alcohol dependence, who were randomized to receive once monthly injections of Vivitrex 380 mg (n=205), Vivitrex 190 mg (n=210), or a placebo (n=209) for 6 months, in addition to low-intensity supportive counseling.

January 13, 2003

DrugAbuse Sciences reported positive results from a phase III trial investigating a sustained release formulation of Naltrexone Depot for the treatment of alcoholism. Results showed that after six months of treatment with the drug subjects were approximately four times less likely to drink heavily and approximately eight times more likely to avoid alcohol altogether than those compared to placebo and psychotherapy. Subjects from 29 treatment sites throughout the U.S. were treated with five sessions of motivational enhancement therapy over the first 12 weeks in the study.

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