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Chronic subcutaneous infusion therapy with apomorphine in advanced Parkinson's disease: Effects on motor and non motor symptoms with brain metabolism correlations
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Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
Institute of Health, Madrid, Spain; 3 Clinical Investigation Centre CIC 1436, INSERM; and University Hospital, Toulouse, France; 4 Mundipharma Research Ltd., Cambridge, United Kingdom; 5 Mundipharma Research GmbH & Co. KG, Limburg a. d. Lahn, Germany Objectives: OXN PR provides comparable analgesia and improved bowel function vs oxycodone PR. We report the first randomized, double-blind study to investigate OXN PR vs placebo for severe PD-related pain. Methods: PD patients (Hoehn & Yahr Stage IIeIV) with severe pain in 1 section of King’s PD Pain Scale (KPPS) and average 24-h pain score 6 (0 ‘no pain’ to 10 ‘worst pain imaginable’) were randomized to OXN PR (n¼93; titrated to 20/10 mg bid) or placebo (n¼109) for 16 weeks. Primary endpoint was average 24-h pain score at Week 16 (Full Analysis Population [FAP]). Results: Average 24-h pain at Week 16 was numerically improved with OXN PR vs placebo (least squares mean difference [95% CI] -0.6 [-1.26, 0.02] points, p¼0.058) while significant treatment benefits were seen at Weeks 4, 8 and 12 (nominal p0.021; Figure). Responder rates (30% reduction from baseline) for average 24-h pain at Week 16 were greater with OXN PR vs placebo (FAP: 47$7% vs 34$0%; p¼0$021). Patients randomized to placebo reported more discontinuations due to lack of efficacy vs OXN PR (12.8% vs 3.2%). Other secondary endpoints also indicated potential treatment benefits with OXN PR and no unanticipated safety signals. Conclusions: While the improvement in primary endpoint was not statistically significant (FAP: average 24-h pain at Week 16, p¼0.058), secondary endpoints support the potential efficacy of OXN PR in severe PDrelated pain.
12 months), intrusive ICD occurred later in treatment (median 34 months). Baseline age, disease duration and onset, concomitant treatments and rotigotine dosages were not associated with different rates of withdrawal. Retention rates were 80% and 50% at 12 and 36 months of treatment, respectively (fig 1). For patients above the age of 70 at baseline (n¼60), retention rates were 70% and 60% at 12 and 36 months, respectively. Conclusions: Rotigotine patch is well tolerated by PD patients across all age groups and disease stages. The most common causes of withdrawal are cutaneous side effects.
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P 2.084. ROTIGOTINE EFFICACY ON SLEEP DISTURBANCES IN PARKINSON’S DISEASE PATIENTS: EVIDENCE FROM A POLYSOMNOGRAPHIC STUDY Claudio Liguori 1, Mariangela Pierantozzi 2, Fabio Placidi 1, Alessandro Stefani 2. 1 Sleep Disorders Centre, Department of Systems Medicine, University Tor Vergata, Rome, Italy; 2 Movement Disorder Center, Dept System Medicine, University tor Vergata, Rome, Italy
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P 2.083. A STUDY OF REAL LIFE TOLERABILITY OF ROTIGOTINE TRANSDERMAL PATCH IN PARKINSON’S DISEASE ACROSS ALL MOTOR STAGES Rui Barreto, Anna Sauerbier, Alexandra Rizos, Ray Chaudhuri. National Parkinson Foundation, Department of Neurology, King's College Hospital, London, United Kingdom Objectives: To assess the clinical tolerability of the long-term use of transdermal rotigotine in Parkinson’s disease (PD) patients. Methods: Retrospective analysis of patients that initiated transdermal rotigotine treatment between January 2006 and June 2012, with assessments at baseline, treatment discontinuation and last available registry to date. Results: We analysed 142 patients (mean age 66.3 years (SD 11.1), baseline median Hoehn & Yahr 3.0). At the end of a mean follow-up of 59.4 months (range 6-105), mean duration of treatment was 38±27.6 months and 42.3% of the patients continued therapy. The main reason for withdrawal was skin reaction while impulse control disorder (ICD) led to withdrawal in only 8% of all treated patients. While skin reactions occurred early (median
Objectives: Amongst non-motor symptoms of Parkinson disease (PD), the sleep disturbances are frequent and difficult to treat. So far, the efficacy of extended release dopamine is corroborated only by some open-label studies lacking polysomnographic (PSG) analysis. Methods: Out of 72 moderately advanced PD patients suffering of sleep disturbances, 48 were recruited (24 dropped for modest compliance or Apnea-Hypopnea Index 15 per hour at baseline PSG) and randomly assigned to either active branch with rotigotine or placebo. Patch was maintained for up to 12 hours from 8 PM. All subjects underwent a subjective and objective evaluation of their sleep quality by sleep questionnaires (Parkinson Disease Sleep Scale - PDSS, and Pittsburgh Sleep Quality Index) and through repeated full nocturnal PSG; in addition, the study included the assessment of morning akinesia. Results: Significant benefit of the rotigotine treatment (mean 9,14 mg) emerged. Sleep efficiency was strongly ameliorated, in combination with reduced WASO and sleep latency and, notably, an augmentation of time dedicated to REM sleep. This objective improvement of the sleep structure was paralleled by the amelioration of PDSS and PSQI scores together with a significant improvement of morning akinesia. Conclusions: In line with previous literature1,2, but with updated PSG technique, the rotigotine patch proved its effectiveness on sleep structure, attributable to a) stable pharmacokinetic profile and, likely, to b) its pharmacological profile. References: 1. Poewe WH, Rascol O, Quinn N, et al. Lancet Neurol 2007;6:513-520. 2. Trenkwalder C, Kies B, Rudzinska M, et al. Mov Disord 2011;26:90-99. P 2.085. CHRONIC SUBCUTANEOUS INFUSION THERAPY WITH APOMORPHINE IN ADVANCED PARKINSON'S DISEASE: EFFECTS ON MOTOR AND NON MOTOR SYMPTOMS WITH BRAIN METABOLISM CORRELATIONS rin 3, Jean-François Manon Auffret 1, Anne Maurus 2, Marc Ve Houvenaghel 3, Florence Le Jeune 4, Sophie Drapier 3. 1 EA 4712 Behavior and Basal Ganglia, University of Rennes 1, Rennes, France; 2 Department of Neurology, Teaching Hospital (CHU) of Rennes, Rennes, France; 3 EA 4712 Behavior and Basal Ganglia, University of Rennes 1, Department of Neurology, CHU of Rennes, Rennes, France; 4 EA 4712 Behavior and Basal
Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
Ganglia, University of Rennes 1, Centre Eug ene Marquis, CHU of Rennes, Rennes, France Objectives: Non-motor symptoms of Parkinson’s disease (PD) severely impair functional and social patients’ daily life. For elderly PD patients contra-indicated for deep brain stimulation, one of the few remaining therapeutic options is continuous dopaminergic stimulation with subcutaneous apomorphine (APO). Our study aimed to identify motor, nonmotor and metabolic brain changes induced by APO in a group of 12 PD patients using clinical scales and 18FDG-PET and to highlight the anatomofunctional pathways underlying the therapeutic effects. Methods: The same clinical and metabolic evaluation was performed in a control group of 6 PD patients treated with conventional oral therapy (COT). In both groups, clinical and metabolic evaluations were performed at baseline and six months. Results: After six months, neither clinical nor metabolic change was observed in the COT group. By contrast, both clinical and metabolic significant changes were noted in the APO group. Motor UPDRS, motor diaries and quality of life were improved. APO has a positive effect on both executive functions and apathy. Moreover, significant changes in brain glucose metabolism (increase in the right occipito-temporal area and decrease in the left frontal lobe) were observed, significantly correlated with improvement of motor and executive functions but also with decrease of apathy. Conclusions: APO should therefore be fully considered as a new strategy to restore and improve PD patients’ quality of life by triggering changes in brain areas involved in motricity, cognition and motivation.
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Objectives: APL-130277 is a sub-lingual film strip designed to acutely manage Parkinson’s disease (PD) OFF episodes by delivering apomorphine via the oral mucosa. We present a subgroup analysis from a Phase 2 study evaluating the effects of APL-130277 on the rapid reversal of OFF episodes in PD. Methods: PD patients with at least one OFF episode/day and > 2 hours of daily OFF time were included. Patients were dosed in the OFF state, starting with APL-130277 10 mg and, if needed, increased in 5 mg increments until a full ON was achieved, to a maximum of 30 mg. Change in MDS-UPDRS Part III and physician/patient assessment of OFF/ON were evaluated. Results: Of the 19 patients dosed, 15 converted from OFF to full ON, all within 30 minutes and nearly half within 15 minutes. When evaluating patients by # OFF episodes, age, levodopa dose, number of classes of PD medications and years of OFF episodes, the percentage of patients turning ON with APL-130277, absolute MDS-UPDRS improvement and percent MDS-UPDRS improvement were similar between groups. (Figure 1 and Figure 2). Conclusions: APL-130277 rapidly converts PD patient from the OFF to the full ON state regardless of disease severity. Phase 3 studies are ongoing to further evaluate efficacy and safety of APL-130277.
P 2.086. EFFICACY OF SUBLINGUAL APOMORPHINE (APL-130277) FOR THE TREATMENT OF OFF EPISODES IN PATIENTS WITH PARKINSON'S DISEASE Albert Agro 1, Jordan Dubow 1, Bruce Dzyngel 1, Thierry Bilbault 1, Anthony Giovinazzo 1, Holly Shill 2, Robert Hauser 3. 1 Cynapsus Therapeutics, Toronto, Canada; 2 Dignity Health, Phoenix, United States; 3 University of Southern Florida Health Byrd Parkinson's Disease and Movement Disorders Center, Tampa, United States Objectives: APL-130277 is an apomorphine sub-lingual film strip to acutely manage Parkinson’s disease (PD) OFF episodes. We evaluated the efficacy of single treatments of APL-130277 in patients with Parkinson's disease in a Phase 2 study. Methods: PD patients with at least one OFF episode/day and > 2 hours of daily OFF were included. Patients were dosed in the morning OFF state, starting with APL-130277 10 mg and increased in 5 mg increments until a full ON was achieved, to a maximum of 30 mg. MDS-UPDRS Part III and ON/ OFF status was determined pre-dose and 15, 30, 45, 60 and 90 minutes after dosing. Results: Fifteen of 19 patients dosed achieved a satisfactory full ON following APL administration. Of the 15 responders, all turned fully ON within 30 minutes of dosing and 6 within 15 minutes. Thirteen of 15 remained fully ON for at least 30 minutes and 9/15 for at least 60 minutes. Mean MDS-UPDRS Part III change from pre-dose to 15, 30, 45, 60 and 90 minutes after dosing for all 19 patients was -11.5, -14.6, -15.0, -13.5 and -9.2 respectively. Conclusions: APL-130277 rapidly converted PD patient from the OFF to the full ON state and provided clinically meaningful improvement in MDSUPDRS Part III scores. Much of the benefit was sustained through 90 minutes. APL-130277 may be an effective, easy to administer medication for the on-demand management of OFF episodes in PD patients. P 2.087. THE EFFECTS OF SUBLINGUAL APOMORPHINE (APL-130277) BY DISEASE SEVERITY ON THE ACUTE REVERSAL OF OFF EPISODES IN PARKINSON’S DISEASE PATIENTS Jordan Dubow, Bruce Dzyngel, Thierry Bilbault, Anthony Giovinazzo, Albert Agro. Cynapsus Therapeutics, Toronto, Canada
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P 2.088. BASELINE DISEASE SEVERITY NOT PREDICTIVE OF SUBLINGUAL APOMORPHINE (APL-130277) DOSE NEEDED TO CONVERT A PD PATIENT FROM THE OFF TO ON STATE Jordan Dubow, Bruce Dzyngel, Thierry Bilbault, Anthony Giovinazzo, Albert Agro. Cynapsus Therapeutics, Toronto, Canada Objectives: APL-130277 is a sub-lingual film strip designed to acutely reverse Parkinson’s disease (PD) OFF episodes by delivering apomorphine via the oral mucosa. We evaluated whether baseline disease severity predicted the effective APL-130277 dose. Methods: PD patients with at least one OFF episode/day and > 2 hours of daily OFF time were included. Patients were dosed in the OFF state, starting with APL-130277 10 mg and, if needed, increased in 5 mg increments until
Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
Institute of Health, Madrid, Spain; 3 Clinical Investigation Centre CIC 1436, INSERM; and University Hospital, Toulouse, France; 4 Mundipharma Research Ltd., Cambridge, United Kingdom; 5 Mundipharma Research GmbH & Co. KG, Limburg a. d. Lahn, Germany Objectives: OXN PR provides comparable analgesia and improved bowel function vs oxycodone PR. We report the first randomized, double-blind study to investigate OXN PR vs placebo for severe PD-related pain. Methods: PD patients (Hoehn & Yahr Stage IIeIV) with severe pain in 1 section of King’s PD Pain Scale (KPPS) and average 24-h pain score 6 (0 ‘no pain’ to 10 ‘worst pain imaginable’) were randomized to OXN PR (n¼93; titrated to 20/10 mg bid) or placebo (n¼109) for 16 weeks. Primary endpoint was average 24-h pain score at Week 16 (Full Analysis Population [FAP]). Results: Average 24-h pain at Week 16 was numerically improved with OXN PR vs placebo (least squares mean difference [95% CI] -0.6 [-1.26, 0.02] points, p¼0.058) while significant treatment benefits were seen at Weeks 4, 8 and 12 (nominal p0.021; Figure). Responder rates (30% reduction from baseline) for average 24-h pain at Week 16 were greater with OXN PR vs placebo (FAP: 47$7% vs 34$0%; p¼0$021). Patients randomized to placebo reported more discontinuations due to lack of efficacy vs OXN PR (12.8% vs 3.2%). Other secondary endpoints also indicated potential treatment benefits with OXN PR and no unanticipated safety signals. Conclusions: While the improvement in primary endpoint was not statistically significant (FAP: average 24-h pain at Week 16, p¼0.058), secondary endpoints support the potential efficacy of OXN PR in severe PDrelated pain.
12 months), intrusive ICD occurred later in treatment (median 34 months). Baseline age, disease duration and onset, concomitant treatments and rotigotine dosages were not associated with different rates of withdrawal. Retention rates were 80% and 50% at 12 and 36 months of treatment, respectively (fig 1). For patients above the age of 70 at baseline (n¼60), retention rates were 70% and 60% at 12 and 36 months, respectively. Conclusions: Rotigotine patch is well tolerated by PD patients across all age groups and disease stages. The most common causes of withdrawal are cutaneous side effects.
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P 2.084. ROTIGOTINE EFFICACY ON SLEEP DISTURBANCES IN PARKINSON’S DISEASE PATIENTS: EVIDENCE FROM A POLYSOMNOGRAPHIC STUDY Claudio Liguori 1, Mariangela Pierantozzi 2, Fabio Placidi 1, Alessandro Stefani 2. 1 Sleep Disorders Centre, Department of Systems Medicine, University Tor Vergata, Rome, Italy; 2 Movement Disorder Center, Dept System Medicine, University tor Vergata, Rome, Italy
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P 2.083. A STUDY OF REAL LIFE TOLERABILITY OF ROTIGOTINE TRANSDERMAL PATCH IN PARKINSON’S DISEASE ACROSS ALL MOTOR STAGES Rui Barreto, Anna Sauerbier, Alexandra Rizos, Ray Chaudhuri. National Parkinson Foundation, Department of Neurology, King's College Hospital, London, United Kingdom Objectives: To assess the clinical tolerability of the long-term use of transdermal rotigotine in Parkinson’s disease (PD) patients. Methods: Retrospective analysis of patients that initiated transdermal rotigotine treatment between January 2006 and June 2012, with assessments at baseline, treatment discontinuation and last available registry to date. Results: We analysed 142 patients (mean age 66.3 years (SD 11.1), baseline median Hoehn & Yahr 3.0). At the end of a mean follow-up of 59.4 months (range 6-105), mean duration of treatment was 38±27.6 months and 42.3% of the patients continued therapy. The main reason for withdrawal was skin reaction while impulse control disorder (ICD) led to withdrawal in only 8% of all treated patients. While skin reactions occurred early (median
Objectives: Amongst non-motor symptoms of Parkinson disease (PD), the sleep disturbances are frequent and difficult to treat. So far, the efficacy of extended release dopamine is corroborated only by some open-label studies lacking polysomnographic (PSG) analysis. Methods: Out of 72 moderately advanced PD patients suffering of sleep disturbances, 48 were recruited (24 dropped for modest compliance or Apnea-Hypopnea Index 15 per hour at baseline PSG) and randomly assigned to either active branch with rotigotine or placebo. Patch was maintained for up to 12 hours from 8 PM. All subjects underwent a subjective and objective evaluation of their sleep quality by sleep questionnaires (Parkinson Disease Sleep Scale - PDSS, and Pittsburgh Sleep Quality Index) and through repeated full nocturnal PSG; in addition, the study included the assessment of morning akinesia. Results: Significant benefit of the rotigotine treatment (mean 9,14 mg) emerged. Sleep efficiency was strongly ameliorated, in combination with reduced WASO and sleep latency and, notably, an augmentation of time dedicated to REM sleep. This objective improvement of the sleep structure was paralleled by the amelioration of PDSS and PSQI scores together with a significant improvement of morning akinesia. Conclusions: In line with previous literature1,2, but with updated PSG technique, the rotigotine patch proved its effectiveness on sleep structure, attributable to a) stable pharmacokinetic profile and, likely, to b) its pharmacological profile. References: 1. Poewe WH, Rascol O, Quinn N, et al. Lancet Neurol 2007;6:513-520. 2. Trenkwalder C, Kies B, Rudzinska M, et al. Mov Disord 2011;26:90-99. P 2.085. CHRONIC SUBCUTANEOUS INFUSION THERAPY WITH APOMORPHINE IN ADVANCED PARKINSON'S DISEASE: EFFECTS ON MOTOR AND NON MOTOR SYMPTOMS WITH BRAIN METABOLISM CORRELATIONS rin 3, Jean-François Manon Auffret 1, Anne Maurus 2, Marc Ve Houvenaghel 3, Florence Le Jeune 4, Sophie Drapier 3. 1 EA 4712 Behavior and Basal Ganglia, University of Rennes 1, Rennes, France; 2 Department of Neurology, Teaching Hospital (CHU) of Rennes, Rennes, France; 3 EA 4712 Behavior and Basal Ganglia, University of Rennes 1, Department of Neurology, CHU of Rennes, Rennes, France; 4 EA 4712 Behavior and Basal
Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
Ganglia, University of Rennes 1, Centre Eug ene Marquis, CHU of Rennes, Rennes, France Objectives: Non-motor symptoms of Parkinson’s disease (PD) severely impair functional and social patients’ daily life. For elderly PD patients contra-indicated for deep brain stimulation, one of the few remaining therapeutic options is continuous dopaminergic stimulation with subcutaneous apomorphine (APO). Our study aimed to identify motor, nonmotor and metabolic brain changes induced by APO in a group of 12 PD patients using clinical scales and 18FDG-PET and to highlight the anatomofunctional pathways underlying the therapeutic effects. Methods: The same clinical and metabolic evaluation was performed in a control group of 6 PD patients treated with conventional oral therapy (COT). In both groups, clinical and metabolic evaluations were performed at baseline and six months. Results: After six months, neither clinical nor metabolic change was observed in the COT group. By contrast, both clinical and metabolic significant changes were noted in the APO group. Motor UPDRS, motor diaries and quality of life were improved. APO has a positive effect on both executive functions and apathy. Moreover, significant changes in brain glucose metabolism (increase in the right occipito-temporal area and decrease in the left frontal lobe) were observed, significantly correlated with improvement of motor and executive functions but also with decrease of apathy. Conclusions: APO should therefore be fully considered as a new strategy to restore and improve PD patients’ quality of life by triggering changes in brain areas involved in motricity, cognition and motivation.
e103
Objectives: APL-130277 is a sub-lingual film strip designed to acutely manage Parkinson’s disease (PD) OFF episodes by delivering apomorphine via the oral mucosa. We present a subgroup analysis from a Phase 2 study evaluating the effects of APL-130277 on the rapid reversal of OFF episodes in PD. Methods: PD patients with at least one OFF episode/day and > 2 hours of daily OFF time were included. Patients were dosed in the OFF state, starting with APL-130277 10 mg and, if needed, increased in 5 mg increments until a full ON was achieved, to a maximum of 30 mg. Change in MDS-UPDRS Part III and physician/patient assessment of OFF/ON were evaluated. Results: Of the 19 patients dosed, 15 converted from OFF to full ON, all within 30 minutes and nearly half within 15 minutes. When evaluating patients by # OFF episodes, age, levodopa dose, number of classes of PD medications and years of OFF episodes, the percentage of patients turning ON with APL-130277, absolute MDS-UPDRS improvement and percent MDS-UPDRS improvement were similar between groups. (Figure 1 and Figure 2). Conclusions: APL-130277 rapidly converts PD patient from the OFF to the full ON state regardless of disease severity. Phase 3 studies are ongoing to further evaluate efficacy and safety of APL-130277.
P 2.086. EFFICACY OF SUBLINGUAL APOMORPHINE (APL-130277) FOR THE TREATMENT OF OFF EPISODES IN PATIENTS WITH PARKINSON'S DISEASE Albert Agro 1, Jordan Dubow 1, Bruce Dzyngel 1, Thierry Bilbault 1, Anthony Giovinazzo 1, Holly Shill 2, Robert Hauser 3. 1 Cynapsus Therapeutics, Toronto, Canada; 2 Dignity Health, Phoenix, United States; 3 University of Southern Florida Health Byrd Parkinson's Disease and Movement Disorders Center, Tampa, United States Objectives: APL-130277 is an apomorphine sub-lingual film strip to acutely manage Parkinson’s disease (PD) OFF episodes. We evaluated the efficacy of single treatments of APL-130277 in patients with Parkinson's disease in a Phase 2 study. Methods: PD patients with at least one OFF episode/day and > 2 hours of daily OFF were included. Patients were dosed in the morning OFF state, starting with APL-130277 10 mg and increased in 5 mg increments until a full ON was achieved, to a maximum of 30 mg. MDS-UPDRS Part III and ON/ OFF status was determined pre-dose and 15, 30, 45, 60 and 90 minutes after dosing. Results: Fifteen of 19 patients dosed achieved a satisfactory full ON following APL administration. Of the 15 responders, all turned fully ON within 30 minutes of dosing and 6 within 15 minutes. Thirteen of 15 remained fully ON for at least 30 minutes and 9/15 for at least 60 minutes. Mean MDS-UPDRS Part III change from pre-dose to 15, 30, 45, 60 and 90 minutes after dosing for all 19 patients was -11.5, -14.6, -15.0, -13.5 and -9.2 respectively. Conclusions: APL-130277 rapidly converted PD patient from the OFF to the full ON state and provided clinically meaningful improvement in MDSUPDRS Part III scores. Much of the benefit was sustained through 90 minutes. APL-130277 may be an effective, easy to administer medication for the on-demand management of OFF episodes in PD patients. P 2.087. THE EFFECTS OF SUBLINGUAL APOMORPHINE (APL-130277) BY DISEASE SEVERITY ON THE ACUTE REVERSAL OF OFF EPISODES IN PARKINSON’S DISEASE PATIENTS Jordan Dubow, Bruce Dzyngel, Thierry Bilbault, Anthony Giovinazzo, Albert Agro. Cynapsus Therapeutics, Toronto, Canada
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P 2.088. BASELINE DISEASE SEVERITY NOT PREDICTIVE OF SUBLINGUAL APOMORPHINE (APL-130277) DOSE NEEDED TO CONVERT A PD PATIENT FROM THE OFF TO ON STATE Jordan Dubow, Bruce Dzyngel, Thierry Bilbault, Anthony Giovinazzo, Albert Agro. Cynapsus Therapeutics, Toronto, Canada Objectives: APL-130277 is a sub-lingual film strip designed to acutely reverse Parkinson’s disease (PD) OFF episodes by delivering apomorphine via the oral mucosa. We evaluated whether baseline disease severity predicted the effective APL-130277 dose. Methods: PD patients with at least one OFF episode/day and > 2 hours of daily OFF time were included. Patients were dosed in the OFF state, starting with APL-130277 10 mg and, if needed, increased in 5 mg increments until