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Safety, tolerability, and pharmacokinetics of ADL6906, a novel dual norepinephrine reuptake inhibitor and serotonin receptor antagonist
P54
The Journal of Pain
(312) Impact of pain relief with fulranumab in the treatment of patients with moderate to severe osteoarthritis pain S Vallow, P Sanga, E Polverejan, S Wang, K Kelly, and J Thipphawong; Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ Chronic pain impacts many aspects of patients’ lives, including their ability to perform daily activities and obtain adequate sleep. Fulranumab, a human recombinant monoclonal antibody to human nerve growth factor, is being investigated for chronic pain treatment. Impact of pain relief on patient-reported functioning, activities and sleep was evaluated during the 12-week efficacy phase of an ongoing 104-week, phase 2, double-blind, placebo-controlled trial designed to assess fulranumab’s analgesic efficacy and tolerability, in addition to current pain therapy, in patients with inadequately controlled moderate-tosevere osteoarthritis pain (hip and knee). Randomized patients received subcutaneous injections in one of six groups: placebo, fulranumab 1mg or 3mg every 4 weeks (Q4wk), or fulranumab 3mg, 6mg, or 10mg every 8 weeks (Q8wk). The SF-36, Brief Pain Inventory-Short Form (BPI), and MOS Sleep Scale (MOS-SS) were completed at baseline and endpoint (12 weeks). Patients also answered a daily question on pain interference with sleep. Primary efficacy and detailed safety results are presented elsewhere. Patients (N=466, intent-to-treat) were 58% women, 85% white, age 61 years. Most SF-36 subscales, including physical functioning, improved: significant improvements versus placebo occurred for Bodily Pain subscale (3mgQ4wk and 10mgQ8wk groups; p<0.04), Vitality Subscale (3mgQ4wk, 3mgQ8wk, 6mgQ8wk and 10mgQ8wk groups; p<0.04), and Physical Component Subscale (10mgQ8wk group; p=0.01). Fulranumab, significantly (p<0.03 versus placebo) improved the BPI Pain Intensity Subscales and Pain Interference with Activities subscale scores (3mgQ4wk and 10mgQ8wk groups). Fulranumab 3mgQ4wk, 3mgQ8wk, and 10mgQ8wk also significantly (p<0.05 versus placebo) improved pain interference with sleep. Sleep Adequacy (MOS-SS) improved across fulranumab groups (p<0.03 versus placebo). Fulranumab, in addition to improving pain, improved functioning, vitality and the degree to which pain interfered with activities of daily living and sleep, areas often impacted in patients with moderate-to-severe osteoarthritis pain. Funded by Johnson & Johnson Pharmaceutical Research & Development, LLC.
Abstracts (314) Safety of the transcranial direct current stimulation (tDCS): evaluation of 815 tDCS sessions in 100 chronicpain patients H Knotkova, A Nafissi, Z Leuschner, D Das, I Dhokal, and R Cruciani; Beth Israel Medical Center, New York, NY There is a growing body of evidence that tDCS can alleviate pain in patients with various pain syndromes, suggesting clinical potential of tDCS in pain management. The purpose of this retrospective study was to evaluate safety and tolerability of tDCS in patients who underwent tDCS treatment at the Institute for Non-Invasive Brain Stimulation, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, between November 2008 and September 2010. TDCS was delivered with Phoressor II 850 PM in five 20-min sessions on 5 consecutive days, at 2 mA, applying either anodal (excitatory) tDCS over the motor cortex or cathodal (inhibitory) tDCS over the somatosensory cortex, using 2 saline-soaked electrodes of 36cm2. One hundred patients with various chronic pain syndromes received 815 tDCS sessions (639 anodal and 176 cathodal) delivered as 172 five-day treatment blocks (131 anodal, 35 cathodal; 80 patients received only anodal treatment blocks, 14 patients only cathodal blocks, 6 received both). Neither anodal nor cathodal tDCS resulted in any serious adverse events (AEs). The most frequently reported non-serious AEs were: transient Tingling/Burning/Itching under the electrode during the stimulation in 27 (4.2%) of anodal and 14 (7.9%) of cathodal sessions; transient Headache after the stimulation: 16 (2.5%) anodal, 2 (1.1%) cathodal); Fatigue: 7 (1.1%) anodal, 0 cathodal; Nausea: 4 (0.6%) anodal, 1 (0.6%) cathodal; Discomfort: 3 (0.5%) anodal, 1 (0.6%) cathodal; Dizziness: 1 (0.2%) anodal, 4 (2.3%) cathodal; Insomnia: in 3 (0.5%) of anodal and 1 (0.6%) of cathodal sessions. The adherence to the tDCS treatment was very good: patients completed 92% (111 of 121) of anodal five-day treatment blocks and 100% (35 of 35) of cathodal blocks, indicating high acceptability of tDCS procedure. In conclusion, the findings contribute to the evidence on tDCS safety, supporting clinical potential of tDCS in chronic pain management.
(313) Safety and efficacy of NGX-4010, a prescription strength capsaicin 8% patch, for the management of postherpetic neuralgia (PHN) in the older population
(315) Safety, tolerability, and pharmacokinetics of ADL6906, a novel dual norepinephrine reuptake inhibitor and serotonin receptor antagonist
G Irving, M Backonja, L Webster, J Tobias, G Vanhove, and S Chen; Swedish Pain Center Seattle, WA
B Berger, A Adedoyin, and A Marion; ICON Development Solutions, Omaha, NE
NGX-4010, a capsaicin 8% patch, has been shown to significantly reduce pain in patients with postherpetic neuralgia (PHN). 1, 2 Integrated data from four randomized, double-blind, 12-week controlled PHN studies investigated NGX4010 efficacy and safety in the older population subgroup (median age 80 years). Included were 305 patients ($73 years) receiving a single 60-minute treatment with NGX-4010 and 277 patients receiving a low-dose (0.04%) capsaicin control patch. Endpoints included the mean percentage change from baseline in ‘‘average pain for the past 24 hours’’ Numeric Pain Rating Scale (NPRS) score and the proportion of patients with $30%, $50% or $2 units decrease in NPRS scores. Adverse events (AEs) were also evaluated. NGX-4010 decreased pain associated with PHN in the older patient subpopulation. NGX4010-treated group experienced a mean percentage NPRS score reduction from baseline of 25.8% compared with 17.1% in control (p=0.0005), 35.4% of NGX-4010-treated group achieved $30% reduction in NPRS scores (26.0% for control, p=0.0164), 23.6% had a reduction of $50% in NPRS scores (12.6% for control, p=0.0009) and 33.8% had a decrease of $2 units (28.4% for control, p=0.0002) during weeks 2-8. Similar results were obtained during weeks 2-12. The most common AEs in the older NGX-4010 patients were capsaicin-related application site erythema, pain, papules and pruritus (>5%) and their incidence and severity was similar to the younger NGX-4010 patients. Most of these AEs were mild to moderate and self-limited. These data demonstrate that a single application of NGX-4010 can produce significant pain reduction for 12 weeks in the older patients with PHN. The most common AEs were application site events and the incidence and severity was similar between the older patients compared to the younger. This study supported by NeurogesX. (1. Backonja, Lancet Neurol,2008; 2. Backonja, Pain Med, 2010).
ADL6906 is a novel dual norepinephrine reuptake inhibitor/serotonin (5-HT2) receptor antagonist with robust activity in a broad range of preclinical chronic and acute pain models. For example, in a neuropathic pain model (L5 spinal nerve ligation), tactile allodynia was significantly reversed at a dose that produced a maximum plasma concentration of approximately 300 ng/mL. Based on the preclinical analgesic efficacy, a phase 1 study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ADL6906 administered by mouth twice daily (BID) for 10 days. BID doses of 25 mg, 50 mg, 100 mg and 200 mg were studied in healthy volunteers (8 active, 2 placebo per cohort) with additional cohorts for evaluation in elderly ($ 65 years old) and in fed/ fasted states. Pharmacokinetic parameters for ADL6906 assessed after a single dose and at steady state included maximum plasma drug concentration (Cmax), time to Cmax (tmax), area under the concentration time curve (AUC) 0-N, and AUC0-12. Safety endpoints included adverse events (AEs). ADL6906 exposure was approximately dose proportional and covered the efficacious exposure in the animal pain model with mean AUC0-N ranging from 6,022-24,732 h*ng/mL and mean Cmax ranging from 281-956 ng/mL at steady state. Compared with single dose data, accumulation at steady state was approximately 2-fold. Median tmax was achieved between 2 and 3 hours with mean t1/2 ranging from 17-19 hours. The elderly pharmacokinetic profile was similar to healthy volunteers. Food had no effect on exposure but resulted in moderately increased tmax (5 hours). The incidence of AEs was low and the great majority were mild. Headache was the most commonly reported AE. Of note, ADL6906 was well tolerated overall and at plasma levels equivalent to those that produced analgesic efficacy in preclinical models. Authors are Adolor Corporation employees or conducted the study.
The Journal of Pain
(312) Impact of pain relief with fulranumab in the treatment of patients with moderate to severe osteoarthritis pain S Vallow, P Sanga, E Polverejan, S Wang, K Kelly, and J Thipphawong; Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ Chronic pain impacts many aspects of patients’ lives, including their ability to perform daily activities and obtain adequate sleep. Fulranumab, a human recombinant monoclonal antibody to human nerve growth factor, is being investigated for chronic pain treatment. Impact of pain relief on patient-reported functioning, activities and sleep was evaluated during the 12-week efficacy phase of an ongoing 104-week, phase 2, double-blind, placebo-controlled trial designed to assess fulranumab’s analgesic efficacy and tolerability, in addition to current pain therapy, in patients with inadequately controlled moderate-tosevere osteoarthritis pain (hip and knee). Randomized patients received subcutaneous injections in one of six groups: placebo, fulranumab 1mg or 3mg every 4 weeks (Q4wk), or fulranumab 3mg, 6mg, or 10mg every 8 weeks (Q8wk). The SF-36, Brief Pain Inventory-Short Form (BPI), and MOS Sleep Scale (MOS-SS) were completed at baseline and endpoint (12 weeks). Patients also answered a daily question on pain interference with sleep. Primary efficacy and detailed safety results are presented elsewhere. Patients (N=466, intent-to-treat) were 58% women, 85% white, age 61 years. Most SF-36 subscales, including physical functioning, improved: significant improvements versus placebo occurred for Bodily Pain subscale (3mgQ4wk and 10mgQ8wk groups; p<0.04), Vitality Subscale (3mgQ4wk, 3mgQ8wk, 6mgQ8wk and 10mgQ8wk groups; p<0.04), and Physical Component Subscale (10mgQ8wk group; p=0.01). Fulranumab, significantly (p<0.03 versus placebo) improved the BPI Pain Intensity Subscales and Pain Interference with Activities subscale scores (3mgQ4wk and 10mgQ8wk groups). Fulranumab 3mgQ4wk, 3mgQ8wk, and 10mgQ8wk also significantly (p<0.05 versus placebo) improved pain interference with sleep. Sleep Adequacy (MOS-SS) improved across fulranumab groups (p<0.03 versus placebo). Fulranumab, in addition to improving pain, improved functioning, vitality and the degree to which pain interfered with activities of daily living and sleep, areas often impacted in patients with moderate-to-severe osteoarthritis pain. Funded by Johnson & Johnson Pharmaceutical Research & Development, LLC.
Abstracts (314) Safety of the transcranial direct current stimulation (tDCS): evaluation of 815 tDCS sessions in 100 chronicpain patients H Knotkova, A Nafissi, Z Leuschner, D Das, I Dhokal, and R Cruciani; Beth Israel Medical Center, New York, NY There is a growing body of evidence that tDCS can alleviate pain in patients with various pain syndromes, suggesting clinical potential of tDCS in pain management. The purpose of this retrospective study was to evaluate safety and tolerability of tDCS in patients who underwent tDCS treatment at the Institute for Non-Invasive Brain Stimulation, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, between November 2008 and September 2010. TDCS was delivered with Phoressor II 850 PM in five 20-min sessions on 5 consecutive days, at 2 mA, applying either anodal (excitatory) tDCS over the motor cortex or cathodal (inhibitory) tDCS over the somatosensory cortex, using 2 saline-soaked electrodes of 36cm2. One hundred patients with various chronic pain syndromes received 815 tDCS sessions (639 anodal and 176 cathodal) delivered as 172 five-day treatment blocks (131 anodal, 35 cathodal; 80 patients received only anodal treatment blocks, 14 patients only cathodal blocks, 6 received both). Neither anodal nor cathodal tDCS resulted in any serious adverse events (AEs). The most frequently reported non-serious AEs were: transient Tingling/Burning/Itching under the electrode during the stimulation in 27 (4.2%) of anodal and 14 (7.9%) of cathodal sessions; transient Headache after the stimulation: 16 (2.5%) anodal, 2 (1.1%) cathodal); Fatigue: 7 (1.1%) anodal, 0 cathodal; Nausea: 4 (0.6%) anodal, 1 (0.6%) cathodal; Discomfort: 3 (0.5%) anodal, 1 (0.6%) cathodal; Dizziness: 1 (0.2%) anodal, 4 (2.3%) cathodal; Insomnia: in 3 (0.5%) of anodal and 1 (0.6%) of cathodal sessions. The adherence to the tDCS treatment was very good: patients completed 92% (111 of 121) of anodal five-day treatment blocks and 100% (35 of 35) of cathodal blocks, indicating high acceptability of tDCS procedure. In conclusion, the findings contribute to the evidence on tDCS safety, supporting clinical potential of tDCS in chronic pain management.
(313) Safety and efficacy of NGX-4010, a prescription strength capsaicin 8% patch, for the management of postherpetic neuralgia (PHN) in the older population
(315) Safety, tolerability, and pharmacokinetics of ADL6906, a novel dual norepinephrine reuptake inhibitor and serotonin receptor antagonist
G Irving, M Backonja, L Webster, J Tobias, G Vanhove, and S Chen; Swedish Pain Center Seattle, WA
B Berger, A Adedoyin, and A Marion; ICON Development Solutions, Omaha, NE
NGX-4010, a capsaicin 8% patch, has been shown to significantly reduce pain in patients with postherpetic neuralgia (PHN). 1, 2 Integrated data from four randomized, double-blind, 12-week controlled PHN studies investigated NGX4010 efficacy and safety in the older population subgroup (median age 80 years). Included were 305 patients ($73 years) receiving a single 60-minute treatment with NGX-4010 and 277 patients receiving a low-dose (0.04%) capsaicin control patch. Endpoints included the mean percentage change from baseline in ‘‘average pain for the past 24 hours’’ Numeric Pain Rating Scale (NPRS) score and the proportion of patients with $30%, $50% or $2 units decrease in NPRS scores. Adverse events (AEs) were also evaluated. NGX-4010 decreased pain associated with PHN in the older patient subpopulation. NGX4010-treated group experienced a mean percentage NPRS score reduction from baseline of 25.8% compared with 17.1% in control (p=0.0005), 35.4% of NGX-4010-treated group achieved $30% reduction in NPRS scores (26.0% for control, p=0.0164), 23.6% had a reduction of $50% in NPRS scores (12.6% for control, p=0.0009) and 33.8% had a decrease of $2 units (28.4% for control, p=0.0002) during weeks 2-8. Similar results were obtained during weeks 2-12. The most common AEs in the older NGX-4010 patients were capsaicin-related application site erythema, pain, papules and pruritus (>5%) and their incidence and severity was similar to the younger NGX-4010 patients. Most of these AEs were mild to moderate and self-limited. These data demonstrate that a single application of NGX-4010 can produce significant pain reduction for 12 weeks in the older patients with PHN. The most common AEs were application site events and the incidence and severity was similar between the older patients compared to the younger. This study supported by NeurogesX. (1. Backonja, Lancet Neurol,2008; 2. Backonja, Pain Med, 2010).
ADL6906 is a novel dual norepinephrine reuptake inhibitor/serotonin (5-HT2) receptor antagonist with robust activity in a broad range of preclinical chronic and acute pain models. For example, in a neuropathic pain model (L5 spinal nerve ligation), tactile allodynia was significantly reversed at a dose that produced a maximum plasma concentration of approximately 300 ng/mL. Based on the preclinical analgesic efficacy, a phase 1 study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ADL6906 administered by mouth twice daily (BID) for 10 days. BID doses of 25 mg, 50 mg, 100 mg and 200 mg were studied in healthy volunteers (8 active, 2 placebo per cohort) with additional cohorts for evaluation in elderly ($ 65 years old) and in fed/ fasted states. Pharmacokinetic parameters for ADL6906 assessed after a single dose and at steady state included maximum plasma drug concentration (Cmax), time to Cmax (tmax), area under the concentration time curve (AUC) 0-N, and AUC0-12. Safety endpoints included adverse events (AEs). ADL6906 exposure was approximately dose proportional and covered the efficacious exposure in the animal pain model with mean AUC0-N ranging from 6,022-24,732 h*ng/mL and mean Cmax ranging from 281-956 ng/mL at steady state. Compared with single dose data, accumulation at steady state was approximately 2-fold. Median tmax was achieved between 2 and 3 hours with mean t1/2 ranging from 17-19 hours. The elderly pharmacokinetic profile was similar to healthy volunteers. Food had no effect on exposure but resulted in moderately increased tmax (5 hours). The incidence of AEs was low and the great majority were mild. Headache was the most commonly reported AE. Of note, ADL6906 was well tolerated overall and at plasma levels equivalent to those that produced analgesic efficacy in preclinical models. Authors are Adolor Corporation employees or conducted the study.