Simufilam suppresses overactive mTOR and restores its sensitivity to insulin in Alzheimer's disease patient lymphocytes.

Introduction: Implicated in both aging and Alzheimer's disease (AD), mammalian target of rapamycin (mTOR) is overactive in AD brain and lymphocytes. Stimulated by growth factors such as insulin, mTOR monitors cell health and nutrient needs. A small molecule oral drug candidate for AD, simufilam targets an altered conformation of the scaffolding protein filamin A (FLNA) found in AD brain and lymphocytes that induces aberrant FLNA interactions leading to AD neuropathology. Simufilam restores FLNA's normal shape to disrupt its AD-associated protein interactions. Methods: We measured mTOR and its response to insulin in lymphocytes of AD patients before and after oral simufilam compared to healthy control lymphocytes. Results: mTOR was overactive and its response to insulin reduced in lymphocytes from AD versus healthy control subjects, illustrating another aspect of insulin resistance in AD. After oral simufilam, lymphocytes showed normalized basal mTOR activity and improved insulin-evoked mTOR activation in mTOR complex 1, complex 2, and upstream and downstream signaling components (Akt, p70S6K and phosphorylated Rictor). Suggesting mechanism, we showed that FLNA interacts with the insulin receptor until dissociation by insulin, but this linkage was elevated and its dissociation impaired in AD lymphocytes. Simufilam improved the insulin-mediated dissociation. Additionally, FLNA's interaction with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), a negative regulator of mTOR, was reduced in AD lymphocytes and improved by simufilam. Discussion: Reducing mTOR's basal overactivity and its resistance to insulin represents another mechanism of simufilam to counteract aging and AD pathology. Simufilam is currently in Phase 3 clinical trials for AD dementia.

Long-term safety of Remoxy® (extended-release oxycodone) in patients with moderate to severe chronic osteoarthritis or low back pain.

OBJECTIVE: Evaluate the long-term safety, tolerability, and efficacy of Remoxy® (extended-release oxycodone) in patients with chronic pain related to osteoarthritis of the hip and/or knee or chronic low back pain. DESIGN: Open-label, 12-month, phase 3 trial. SETTING: Fifty-nine US sites. PATIENTS: Men and women with moderate to severe hip and/or knee pain caused by osteoarthritis or persistent moderate to severe low back pain. INTERVENTION: Remoxy 5 mg twice daily, which could be increased in fixed increments up to 80 mg twice daily. OUTCOME MEASURES: Safety and tolerability assessments included adverse events (AEs), laboratory tests, vital signs, physical examinations, and electrocardiograms. Efficacy was assessed through ratings of pain intensity, quality of analgesia, and global assessment of study drug. RESULTS: Of the 828 patients enrolled, 823 received ≥1 dose of Remoxy, with 469 exposed for ≥180 days and 381 for ≥358 days. At least one AE was experienced by 678 patients (82%), the most common of which were opioid related, including constipation, nausea, and somnolence; 173 patients (21%) discontinued treatment because of AEs. No clinically relevant changes were seen in other safety assessments. Mean pain intensity scores decreased significantly from baseline at all time points (P < 0.001). At month 12, quality of analgesia and global assessment of study drug were rated positively (good, very good, or excellent) by 64% and 61% of patients (last observation carried forward), respectively. CONCLUSIONS: Long-term treatment with Remoxy was safe, well tolerated, and efficacious in patients with chronic pain related to osteoarthritis of the hip and/or knee or chronic low back pain.

Abuse-deterrent properties of REMOXY® ER, a high-viscosity extended-release oxycodone formulation.

OBJECTIVE: These in vitro studies compared abuse-deterrent properties of REMOXY ER (extended-release oxycodone), a novel, high-viscosity gel formulation, versus the two currently marketed ER oxycodone formulations. METHODS: Tampering methods were tailored to each product to maximize oxycodone release with the least complexity, time, and effort, based on the physical/chemical properties of each formulation. Oral abuse was simulated by extracting oxycodone from each manipulated formulation in Common Ingestible Liquids and in Advanced Solvents (not ingestible and requiring additional separation). To simulate injection abuse, oxycodone was extracted from each manipulated formulation in low volumes of injection vehicles, heated or unheated. Inhalation abuse potential was assessed by volatilization. RESULTS: In oral abuse simulations, manipulated REMOXY ER released 2-22 percent of its oxycodone in 20 minutes in five Common Ingestible Liquids, versus 77-85 percent oxycodone released from OxyContin® ER in 5 minutes in four of the five. In six Advanced Solvents, REMOXY ER released 3-37 percent at 20 minutes, versus 55-89 percent released from OxyContin ER at 5 minutes. Minimal oxycodone was extracted from REMOXY ER in five injection vehicles, heated or unheated. In contrast, OxyContin ER released 65-87 percent of its oxycodone within 10 minutes in all vehicles, regardless of heating. Xtampza® ER released 96 percent of its oxycodone in a heated injection vehicle and released 50-60 percent in two unheated injection vehicles. Showing minimal inhalation abuse potential, 9 percent of oxycodone was vaporized from manipulated REMOXY ER at 20 minutes compared to 8.8 percent at 5 minutes for OxyContin ER. CONCLUSIONS: In these studies, REMOXY ER demonstrated robust and meaningful abuse-deterrence relative to OxyContin ER and Xtampza ER. PERSPECTIVE: Abuse-deterrent drugs were intended to help fight opioid abuse. Yet, the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are sorely needed. A new, high-viscosity, ER oxycodone formulation showed much improved abuse-deterrent properties in simulations of oral, injection, and inhalation abuse, compared to earlier, first-generation formulations.

A nasal abuse potential randomized clinical trial of REMOXY® ER, a high-viscosity extended-release oxycodone formulation.

OBJECTIVE: This study examined the nasal abuse deterrence of REMOXY ER, a novel high-viscosity extended-release oxycodone formulation. DESIGN: An Institutional Review Board-approved, single-center, randomized, double-blind, placebo, and active-controlled, four-way crossover study of intranasal REMOXY ER gel, manipulated or intact, and ground oxycodone immediate-release (IR). An open label extension examined pharmacokinetics of OxyContin® ER in the first 20 subjects. PARTICIPANTS: Healthy, adult nondependent recreational opioid users with a history of intranasal abuse. Thirty-eight subjects enrolled; 36 completed. SETTING: A clinical research in-patient unit. INTERVENTIONS: Cross-over arms included nasal self-administration of the entire contents of REMOXY ER 40 mg capsules (manipulated or intact), ground oxycodone IR 40 mg tablets, and placebo. The open-label arm was ground OxyContin ER. MAIN OUTCOME MEASURES: The primary endpoint was the maximum effect (Emax) of visual analog scale ratings of Drug Liking. Secondary endpoints included Take Drug Again (12 and 24 hours), Drug High Emax, area under effect curves through 12 hours, pupillometry, peak oxycodone concentrations (Cmax), time to maximum concentration (Tmax), and Abuse Quotient (Cmax/Tmax). RESULTS: Intranasal REMOXY ER (manipulated or intact) elicited lower Drug Liking and Drug High compared to ground oxycodone IR. Secondary endpoints also reflected reduced Abuse Potential. Intranasal REMOXY ER (manipulated or intact) led to fourfold lower Cmax, a 57 to 128 percent longer Tmax, a >10-fold lower Abuse Quotient and lower Take Drug Again scores compared to both OxyContin ER and oxycodone IR. CONCLUSION: In this study, REMOXY ER demonstrated significantly lower nasal abuse potential compared to oxycodone IR or OxyContin ER. PERSPECTIVE: Abuse-deterrent drugs are intended to help fight opioid abuse. Yet the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are needed. A new, high-viscosity, extended-release oxycodone formulation showed robust abuse-deterrence against the nasal route of abuse in an Food and Drug Administration-advised clinical trial in recreational opioid users.

Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain.

UNLABELLED: Physical dependence or withdrawal is an expected effect of prolonged opioid therapy. Oxytrex (oxycodone + ultralow-dose naltrexone) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing. In this 719-patient, double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid. Each oxytrex tablet contains 1 microg naltrexone; oxytrex bid and qid treatments provide 2 and 4 microg naltrexone/day, respectively. Following a washout, patients with pain >or=5 on a 0-10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief (

Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.

UNLABELLED: Oxytrex is a novel drug that combines oxycodone with ultralow-dose naltrexone, an opioid antagonist. Ultralow-dose opioid antagonists have been demonstrated to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rodents. This 3-week, Phase II clinical trial assessed safety and analgesic efficacy of Oxytrex in patients with moderate to severe pain from osteoarthritis. Patients with a pain score > or =5 received placebo, oxycodone 4 times a day (qid), Oxytrex qid, or Oxytrex twice a day (bid). All active treatment groups received the same total daily dose and dose escalation of oxycodone starting at 10 and ending at 40 mg/day. Importantly, the Oxytrex bid group received a lower daily dose of naltrexone than Oxytrex qid (0.002 vs 0.004 mg/day). Oxytrex bid produced a 39% reduction in pain intensity, which was significantly greater than that of placebo (P < .001), oxycodone qid (P = .006), and Oxytrex qid (P = .003). Oxytrex bid was also superior to placebo in quality of analgesia (P = .002), duration of pain control each day (P = .05), patients' global assessments (P = .04), and the Western Ontario and MacMaster Universities Osteoarthritis Index total score (P = .03). The incidence of side effects was comparable between active treatments. In this Phase II dose-ranging study, Oxytrex bid demonstrated greater pain relief with a more convenient dosing schedule compared to oxycodone qid. PERSPECTIVE: Preclinical data have shown ultralow-dose opioid antagonists to enhance and prolong opioid analgesia while reducing analgesic tolerance and physical dependence. Recent molecular pharmacology data show a mechanism of action to be the prevention of aberrant G protein coupling by opioid receptors that underlies opioid tolerance and dependence.

The pharmacokinetics of oxycodone and its metabolites following single oral doses of Remoxy®, an abuse-deterrent formulation of extended-release oxycodone, in patients with hepatic or renal impairment.

OBJECTIVE: Remoxy® (Pain Therapeutics, Inc., Austin, TX) is an abuse-deterrent formulation of extended-release oxycodone. The effects of renal or hepatic impairment on the pharmacokinetics (PK) of single, oral doses of Remoxy 20 or 10 mg, respectively, were assessed in two phase 1 studies in subjects aged 18-80 years. METHODS: PK parameters included maximum plasma concentration (C(max)) and area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC(0-t)), and extrapolated to infinity (AUCinf). Adverse events (AEs) were monitored. RESULTS: Mean (SD) oxycodone Cmax values following Remoxy 20-mg administration were 17.6 (9.1), 21.9 (11.2), 25.9 (18.2), and 31.6 (14.5) ng/mL and AUC0-t values were 210.7 (82.1), 271.6 (83.3), 299.5 (76.3), and 493.5 (175.9) ng·h/mL in subjects with normal or mild (n = 6 each), moderate (n = 5), and severely impaired renal function (n = 6), respectively. Mean (SD) oxycodone Cmax following Remoxy 10-mg administration was 7.6 (3.3), 7.8 (2.3), and 13.1 (5.3) ng/mL and AUC(0-t) was 105.7 (49.5), 134.7 (38.3), and 218.0 (74.1) ng·h/mL in subjects with normal, mild, and moderately impaired hepatic function (n = 6 each), respectively. Differences in exposure values between the different renal and hepatic groups were significant. Treatment-emergent AEs were reported by 14.3, 66.7, 66.7, and 50.0 percent of subjects with normal, mild, moderate, and severely impaired renal function, respectively, and by 50.0, 33.3, and 66.7 percent of subjects with normal, mild, and moderately impaired hepatic function, respectively. CONCLUSIONS: As renal or hepatic function decreased, oxycodone Cmax and AUC(0-t) were up to approximately twofold higher following single, oral doses of extended-release Remoxy. AEs were those typically reported for opioids. Lower doses of Remoxy may thus be safely prescribed to subjects with renal or hepatic impairment.

Efficacy and safety of an extended-release oxycodone (Remoxy) formulation in patients with moderate to severe osteoarthritic pain.

OBJECTIVE: To evaluate the efficacy and safety of an encapsulated, highly viscous formulation of extended-release oxycodone designed to resist common physical manipulation and chemical challenges (Remoxy; King Pharmaceuticals, Inc., Bristol, TV, which was acquired by Pfizer Inc. in March 2011). DESIGN: An enriched enrollment randomized withdrawal trial design was used whereby patients entered a double-blind, multicenter, placebo-controlled trial after completing an open-label titration phase. SETTING: Sixty-one US clinics. PATIENTS: All patients (40-75 years) had experienced moderate to severe chronic osteoarthritic pain in the hip or knee for > or = 3 months. INTERVENTIONS: During 2 weeks of open-label treatment (N = 558), patients were titrated from Remoxy 5 mg twice daily (bid) to 20 mg bid. Patients who tolerated the drug were randomly assigned to Remoxy or placebo bid for 12 weeks. Dose titration was permitted during weeks 1-4 (range, 10-80 mg/d) and fixed thereafter. MAIN OUTCOME MEASURES: The area under the curve (AUC) for change in pain intensity (PI) scores from prerandomization to the end of the 12-week period was the primary endpoint. Patient assessment of quality of analgesia, global assessment of study medication, quality of life, and safety were also evaluated. RESULTS: The mean AUC for change in PI score was significantly greater for Remoxy than for placebo (p = 0.007). Patients receiving Remoxy reported significantly better scores on quality of analgesia (p = 0.004) and global assessment of study medication (p = 0.007) when compared with patients receiving placebo. Remoxy had a safety profile consistent with other opioids. CONCLUSIONS: Remoxy significantly improved analgesia among patients with moderate to severe chronic osteoarthritic pain with an adverse event profile similar to other opioids.