APOMORPHINE OLD DRUG ; NEW LIFE? Dr Susan H Fox MRCP (UK), PhD Professor Neurology, University of Toronto Movement Disorders Clinic, Toronto Western Hospital CNSF, Halifax June 25 th 2018
DISCLOSURES Nature of relationship(s) Any direct financial payments including receipt of honoraria Membership on advisory boards or speakers bureaus Funded grants or clinical trials Name of for-profit or notfor-profit organization(s) WPC; CHDI; AAN; MDS Merz; Orion; Sunovion*; Palidan*; Teva; Seqirus; Zambon Michael J Fox Foundation for Parkinson Research; Edmund J Safra Foundation; Parkinson Canada; NIH; CIHR. Biotie; Cynapsus (Sunovion)* ; Eisai; Kyowa Description of relationship(s) Honoraria for participation on Committee/Conference Speaker/Chair. Advisory board and Speaker Funding for research Site PI for Clinical Trials * Companies developing Apomorphine products in Canada
Apomorphine Short-acting dopamine D2>D1 receptor agonist Derived from morphine; but no opioid properties
Clinical Uses Erectile dysfunction - first described by Ancient Egyptians (naturally occurring in blue lotus N. caerulea) Emetic Alcoholism; The Keeley Cure (1870s to 1900) contained apomorphine; animal medicine Parkinson's disease Weil, 1884 Schwab RS, Amador LV, Lettvin JY (1951). Apomorphine in Parkinson's disease. Transactions of the American Neurological Association. 56: 251 3
Use of Apomorphine in PD Subcutaneous administration due to low oral bioavailability (first pass metabolism) Intermittent injection Infusion Benefit in PD Effective anti-parkinsonian action Intermittent s.c. injection provides rapid onset More reliable that oral levodopa (no GI issues) Licensed for use in many countries (Available Europe since 1980s; US 2004 ) as adjunct in advanced PD for treating OFF periods
Efficacy of intermittent subcutaneous injections of apomorphine shown in many studies Rapid onset: mean onset in 6 to 14 minutes Short duration: mean duration of effect is 36 to 61.9 minutes Overall decrease in daily 'off' time is - 2.6 to - 4 hours of the waking day Average dose of each injection = 2 6 mg Up to 3x per day Review of 21 studies, including 8 DBRCT (n=126), 6 crossover; 13 open-label studies (n=202). Chen J J, Obering C. Clinical Therapeutics 2005; 27(11): 1710-1724
Dose dependent improvement in PD motor scores
Apomorphine : Side effects of drug Orthostatic hypotension = 10% Reason to discontinue 2% Dose-related Initial and long-term Rx
Apomorphine; available in Canada Intermittent subcutaneous injections Canada Jan 23 rd 2018: The CADTH Canadian Drug Expert Committee (CDEC) recommended apomorphine hydrochloride (apomorphine) be reimbursed for the acute, intermittent treatment of hypomobility off episodes ( end-of-dose wearing off and unpredictable on/off episodes) if the following criterion and conditions are met: Criterion: Apomorphine should only be used as adjunctive therapy in patients who are receiving optimized PD therapy (levodopa and derivatives and dopaminergic agonists) and still experiencing off episodes. Conditions: Patients treated with apomorphine should be under the care of a physician with experience in the diagnosis and management of PD. Reduction in price submitted unit price of $42.95 per 3 ml (30 mg) pen of apomorphine
Injectable Preloaded Pen 10mg/ml 3ml prefilled pen Pictorial representation only Inject s.c. into lower abdomen or outer thigh Store at room temp; lasts 48 hours after first opening. Do not use if solution has turned green.
Practicalities: Initial dose finding Pre-treat with anti-emetic Domperidone 10mg TID for 3 days (- > 50% discontinue after 6-8 weeks ) ECG (for QTc) (small dose related increased QTc if > 6mg used) In-clinic dose finding Suggested method Omit morning PD meds ie. OFF and 1h post 10mg domperidone Measure BP (lying and standing) Start with 1 mg or 2mg (- depending on BMI; risk of lowering BP) Assess benefit (ideally UPDRS part III) after 30 min and BP If no effect wait 1.5 hour post injections and repeat with 2 or 3mg If no effect bring back a second day or wait 1.5 hour post injection and repeat with 3 or 4 mg (total daily dose of apomorphine HCl should not exceed 100mg and individual bolus injections should not exceed 10 mg).
Practicalities: Long term use Requires patient (and physician education) Support for patient -? Telephone Ideal In clinic and home visit PD specialist Nurses?
Continuous subcutaneous apomorphine perfusion pump Licensed: 23 countries; UK>25 years.? Canada
Use of Apo Pump in PD Indication: Advanced PD with disabling motor fluctuations and dyskinesia Alternative to Levodopa-Carbidopa Gel Infusion (Duodopa) Alternative to Deep brain stimulation surgery Open-label/un-controlled studies/case series: Reduces OFF time Reduces dyskinesia, Reduces L-dopa dosing Phase III DBRCT (abstract only)
Apomorphine pumps reduce OFF time and Dyskinesia Garcia-Ruiz et al Mov Disord 2008
TOLEDO: randomized, double-blind, placebo-controlled Phase III study of subcutaneous apomorphine infusion in patients with Parkinson s disease and motor fluctuations not well controlled on optimized oral medical treatment Katzenschlager R, et al AAN Boston April 2017 107 patients in 23 centers, 7 countries 3 h OFF/day despite optimized treatment Slides courtesy of Dr Katzenschlager 52 week open-label phase COMT, catechol-o-methyl transferase inhibitor, DA, dopamine agonists; MAO-B, monoamine oxidase-b inhibitor.
Main results ON time without troublesome dyskinesia: treatment difference: 1 97 hours [95% CI: 0.69, 3.24; p=0.0008] Primary endpoint: absolute change in OFF time from baseline to Week 12 derived from patient diaries OFF time treatment difference - 1.89 hours (95% CI: -3.16, -0.62; p=0.0025) Safety and tolerability APO (n=54) Placebo (n=53) At least one treatment-emergent AE (TEAE) 50 (92.6%) 30 (56.6%) Most common TEAE ( 10% of patients) Skin nodules at infusion site Nausea Somnolence Skin erythema at infusion site Dyskinesia Headache Insomnia 24 (44.4%) 12 (22.2%) 12 (22.2%) 9 (16.7%) 8 (14.8%) 7 (13.0%) 6 (11.1%) 0 5 (9.4%) 2 (3.8%) 2 (3.8%) 0 2 (3.8%) 1 (1.9%) Serious AEs 5 (9.3%) 2 (3.8%) Patient Global Impression of Change: Favored apomorphine (p<0.0001) Level 1 evidence: Significant, clinically meaningful reduction in OFF time, Significant increase in ON time without troublesome dyskinesia
Additional Side effects of Apo Pump Subcutaneous nodules (50%) Ultrasound reduces induration Rotation of injection Rare: Coombs positive Haemolytic anemia (6%) ; check complete blood count and hemolytic parameters q6 monthly Symptoms = pallor, dyspnea, jaundice
Intervention ADD-ON THERAPY FOR MOTOR FLUCTUATIONS Efficacy conclusions Safety Implications for clinical practice Dopamine agonists Non-ergot Pramipexole Efficacious Acceptable risk Clinically useful Pramipexole ER Efficacious Clinically useful Ropinirole Efficacious Clinically useful Ropinirole PR Efficacious Clinically useful Rotigotine Efficacious Clinically useful Apomorphine Intermittent s.c Efficacious Clinically useful Apomorphine infusion Likely Efficacious Possibly Useful Piribedil Insufficient evidence Investigational Clinically useful Bromocriptine Likely Efficacious specialized monitoring Possibly useful Cabergoline Likely Efficacious Possibly useful Controlled release Insufficient evidence Investigational Extended IPX066 Efficacious Clinically useful Intestinal Infusion Efficacious Acceptable risk with specialized monitoring Clinically useful Ergot Pergolide Efficacious Acceptable risk with Levodopa/ peripheral decarboxylase inhibitor
Other delivery strategies for apomorphine? Prior failures with Intravenous Nasal rectal local skin reactions Acidic; ph 3.0 to 4.0 Intravenous - crystallizes causing thrombosis
Sublingual apomorphine? tried before.. Montastruc et al Sublingual apomorphine: a new pharmacological approach in Parkinson's disease? J Neural Transm Suppl 1995;45:157-61. Sublingual apomorphine was shown to reduce extrapyramidal symptoms. Sublingual apomorphine has the advantage of being easier to administer than subcutaneous injection. For the moment, the long-term use of sublingual apomorphine is limited by two major problems: 1. Time for dissolution and switch "on" (which is longer than after subcutaneous route) 2. Local side effects (stomatitis)... Further clinical studies using either more efficient (tablets with faster dissolution) and better tolerated sublingual formulations.should be carried on before recommending this approach in the treatment of Parkinson's disease.
Sublingual Apomorphine APL-130277: soluble, sublingual, strip formulation. Thin bilayer apomorphine and optimising absorption ; second layer - buffer Drink water before using Place on bottom of tongue Don t swallow for 2 mins FDA granted APL-130277 fast track designation as a treatment for Parkinson s off episodes Aug 2016. New Drug Application for APL-130277 : filed with FDA March 2018. Health Canada: in submission
Open-label 20 PD subjects 78% subjects fully - ON at 30 mins 6/25/2018
Open-label dose-titration study of APL-130277 N = 76 PD with early AM OFF and total daily OFF time 2 hours/day Titration sequence for APL-130277 was 10mg, 15mg, 20mg, 25mg, 30mg. MDS-UPDRS Part III at 15, 30, 45, 60 and 90 minutes. Results» 83% of patients full ON with median dose 20mg. Mean Onset in 5-12 minutes. 15 Min ON in 22 % 30 Min ON in 59%» At 30 and 90 minutes there was a 22 and 16-point improvement in the MDS-UPDRS Part III, respectively. R. Hauser, S. Isaacson, A. Espay, R. Pahwa, D. Truong, E. Pappert, P. Gardzinski, B. Dzyngel, A. Agro, H. Fernandez. Efficacy of sublingual apomorphine film (APL-130277) for the treatment of OFF episodes in patients with Parkinson s disease: results from the Phase 3 study dose-titration phase [abstract]. Mov Disord. 2017; 32 (suppl 2).
Phase 3 APL-130277 for the Acute Treatment of OFF Episodes in Parkinson's Disease (CTH 300) 141 PD with motor fluctuations (total daily "OFF" time duration of 2 hours ) APL-130277 (10-35 mg) /placebo ; Two phases:- 1. In clinic open label dose titration: to determine dose at which patient achieved Full- ON: (22% discontinued; 8.5 % AE; 7% lack of benefit) 2. 12 week treatment phase: 109 subjects randomized to dose /placebo use of APL up to 5x /d (16% placebo v 37% APL discontinued) Primary endpoint: MDS UPDRS III at 30 min post dose after 12 weeks Multiple secondary endpoints % subjects with Full ON at 12 w; CGI;PGI; UPDRS II (ADL); home diary rate of Full ON after dose 1-2d prior to visit; PDQ36 (QAL); UPDRS III at 15 min Safety and tolerability Olanow CW et al Poster 2 nd Pan American Section of the International Parkinson and Movement Disorder Society meeting, Jun 23rd, 2018
Results Significantly improved MDS-UPDRS Part III score at 30 minutes (- 7.6 points v placebo) at Week 12 (P = 0.0002) 35% APL subjects full ON at 30 min v 16% placebo (P < 0.001) Median time to onset of effect = 22 min (22% ON at 11 min) Home diary 79% APL full ON at 30 min v 31% placebo Treatment-emergent adverse events in APL group (TEAEs led to withdrawals in 27% of APL v 9% in placebo) Nausea (27.0 %), Somnolence (14.9 %), Dizziness (14.2 %), (no significant OH) Oral mucosal erythema 7.4% = glossodynia, lip edema, lip swelling, oropharyngeal swelling, and throat irritation. CTH 301 NCT02542696 Long-term safety, efficacy (n = 226)
Comparison s.c. vs s.l apomorphine Subcutaneous Faster acting (onset 5-10 min) More reliable effect (93% on) Side effects Orthostatic hypotension can be significant; nodules Ease of use: assembling injections; Patient training/preference? Cost? Sublingual Onset in 20 min Variability in effect (31-78% full on at 30 min) Side effects less OH but oral mucosal reactions (idiosyncratic?) Ease of use: strip easier? Patient training/preference? Cost?
Open-Label, Randomized, Crossover Trial to evaluate sublingual administered APL-130277 (apomorphine) compared to subcutaneously administered apomorphine (NCT03391882) Open-label, crossover titration subjects will be randomly assigned to APL- 130277 or APO s.c. and titrated to the dose that turns them from the practically defined "OFF" state to the full "ON" state. Then crossed over to the other drug and similarly titrated to the dose that provides a full "ON" state. PD with motor fluctuations (n = 85) End point Percentage of subjects preferring sublingual APL-130277 (apomorphine) compared to percentage of subjects preferring subcutaneous APO (apomorphine) at 3 months
Conclusions Apomorphine is a short acting dopamine D1,2 receptor agonist Effective anti parkinsonian action Uses: Advanced PD for disabling off periods especially sudden/unpredictable offs. Subcutaneous delivery (sublingual pending FDA/HC reviews) Side-effects : as per dopamine agonists plus subcutaneous effects local effects.