Where are we going with Job code: ON/JUN18/UK/256; Date of - PowerPoint PPT Presentation

Where are we going with Job code: ON/JUN18/UK/256; Date of preparation: June 2018 PD medication? Dr Daniel van Wamelen Neurologist and Clinical Research Fellow King’s College London Parkinson’s Foundation Centre of Excellence in Parkinson’s and Movement Disorders King ’ s College Hospital London This meeting is sponsored by Bial Pharma UK. 4 July 2018 Visit us at www.parkinsons-london.co.uk

The views expressed in this presentation are those of the speaker and are not necessarily those of the meeting sponsor Visit us at www.parkinsons-london.co.uk

Conflicts of interest Clinical research fellowship at King’s College London partly funded by Britannia Pharmaceuticals Ltd. and Global Kinetics Corporation Ltd. No other conflicts of interest to declare Visit us at www.parkinsons-london.co.uk

• Update on existing medication • New indications for existing therapy • New medication being developed Visit us at www.parkinsons-london.co.uk

Visit us at www.parkinsons-london.co.uk

MAO-B inhibitors Visit us at www.parkinsons-london.co.uk

Probability that one agent was better than another given alone Selegiline Rasagiline Rasagiline 0.58 0.68 Selegiline - 0.65 Probability that one agent was better than another in combination with levodopa Rasagiline + LD Entacapone + LD Safinamide + LD Selegiline + LD 1 1 1 Rasagiline + LD - 0.9 1 Entacapone + LD - - 0.91 Probability that one agent was better than another in combination with levodopa and considering duration of disease as an explanation variable Rasagiline + LD Safinamide + LD Entacapone + LD Selegiline + LD 1 1 1 Rasagiline + LD - 0.78 0.76 Safinamide + LD - - 0.58 Binde et al. Br J Clin Pharmacol. 2018. doi: 10.1111/bcp.13651 Visit us at www.parkinsons-london.co.uk

Safinamide Schapira et al. JAMA Neurol. 2017;74(2):216-224 Visit us at www.parkinsons-london.co.uk

MAO-B inhibitors • When given as monotherapy no difference between Selegiline, Rasagiline and Safinamide • MAO-B inhibitors given in combination with levodopa – Selegiline most effective (with respect to motor outcome) – Rasagiline second best – Safinamide: more studies needed for meaningful conclusion • No difference between rasagiline or safinamide with dopamine agonist compared to placebo and dopamine agonist Binde et al. Br J Clin Pharmacol. 2018. doi: 10.1111/bcp.13651 Visit us at www.parkinsons-london.co.uk

NICE guidelines • 1.3.5. Offer levodopa to people in the early stages of Parkinson's disease whose motor symptoms impact on their quality of life • 1.3.6. Consider a choice of dopamine agonists, levodopa or monoamine oxidase B (MAO-B) inhibitors for people in the early stages of Parkinson's disease whose motor symptoms do not impact on their quality of life Visit us at www.parkinsons-london.co.uk

COMT inhibitors Visit us at www.parkinsons-london.co.uk

Opicapone • Newest COMT inhibitor: available since October 2016 • High-affinity, selective and reversible binding of COMT with long duration of action (> 24 hours) • Indication: Adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors (DDCI) in adult patients with Parkinson’s disease and end -of-dose motor fluctuations who cannot be stabilised on those combinations. • Dose: 50 mg once daily at bedtime (Entacapone 3-5 times daily) • Generally well-tolerated Visit us at www.parkinsons-london.co.uk

Opicapone Opicapone 50 mg Placebo Opicapone demonstrated non-inferiority when compared to entacapone in a DB trial (p=0.0051 for non- inferiority vs. entacapone Ferreira et al. Neurology 2018;90(21):e1849-e1857 Lees et al. JAMA Neurol 2017;74(2):197-206 Visit us at www.parkinsons-london.co.uk

Opicapone • Opicapone 50mg: £93,90 for one month • Entacapone 200mg (4-5 times daily): around £15 for one month • But from clinical practice Entacapone often diarrhea, discolouring of urine Visit us at www.parkinsons-london.co.uk

MAO-B and COMT Increased enzyme activity Increased enzyme activity Sampaio et al. J Clin Pharmacol. 2018. doi: 10.1002/jcph.1096 Visit us at www.parkinsons-london.co.uk

Amantadine Visit us at www.parkinsons-london.co.uk

Amantadine prolonged release (ADS-5102) Oertel et al. Mov Disord. 2017;32(12):1701-1709 Visit us at www.parkinsons-london.co.uk

Amantadine prolonged release (ADS-5102) • In open lable trials improvement of dyskinesia score • When switched from IR to prolonged release up to 35% improvement Isaacson et al. Mov Disord Clin Pract. 2018;5(2):183-190 Visit us at www.parkinsons-london.co.uk

Need for non-oral therapies in PD Chaudhuri et al. NPJ Parkinsons Dis. 2016;2:16023 Visit us at www.parkinsons-london.co.uk

Apomorphine Visit us at www.parkinsons-london.co.uk

Martinez-Martin et al. Mov Disord. 2015;30(4):510-6 Visit us at www.parkinsons-london.co.uk

Sublingual Apomorphine Ondo et al. Clin Neuropharmacol. 1999;22(1):1-4 Visit us at www.parkinsons-london.co.uk

Sublingual Apomorphine Long-term safety (CTH- 301 extension study) now being performed Results should be know next year Hauser et al. Mov Disord. 2016;31(9):1366-72 Visit us at www.parkinsons-london.co.uk

Apomorphine inhaler Inhaled dry powder Apomorphine (1.5 or 3 mg) N=12 N=31 Grosset et al. Acta Neurol Scand. 2013;128(3):166-71 Visit us at www.parkinsons-london.co.uk

Visit us at www.parkinsons-london.co.uk

• Apomorphine reduced intraneural amyloid-  as well as p-Tau deposition along with a strong improvement in memory function in AD transgenic mice • In a post-mortem study (n=36) strong reduction of amyloid-  in PD patients treated with Apomorphine • Ongoing study at King’s College London to assess Amyloid load (PET scan) in PD patients on Apomorphine (IRAS 214953) Yarnall et al. Mov dis. 2016:31;668-675 Himeno et al. Ann neurology. 2011:69;248-256 Visit us at www.parkinsons-london.co.uk

Duodopa Visit us at www.parkinsons-london.co.uk

Martinez-Martin et al. Mov Disord. 2015;30(4):510-6 Visit us at www.parkinsons-london.co.uk

Improvement Antonini et al. Parkinsonism Relat Disord. 2017;45:13-20 Visit us at www.parkinsons-london.co.uk

Subcutaneous Duodopa Visit us at www.parkinsons-london.co.uk

Non-dopaminergic treatments Visit us at www.parkinsons-london.co.uk

FAIRPARK • Excess iron is primarily detected in the substantia nigra pars compacta , where dopaminergic neurons are exposed to high levels of oxidative stress produced by mitochondrial disorders and dopamine metabolism • Moderate-dose Deferiprone (DFP; 30 mg/kg/day) for 40 weeks • Primary outcome: change in motor and non-motor handicap scores on the Total Movement Disorders Society Unified Parkinson’s Disease Rating Scale Visit us at www.parkinsons-london.co.uk

Devos et al. Antioxid Redox Signal. 2014;21(2):195-210 Visit us at www.parkinsons-london.co.uk

Non-invasive brainstem modulation (caloric vestibular stimulation) Visit us at www.parkinsons-london.co.uk

Caloric vestibular stimulation Wilkinson et al. In preparation Visit us at www.parkinsons-london.co.uk

a -synuclein antibody (PRX002/RG7935) Jankovic et al. JAMA Neurol. 2018; doi: 10.1001/jamaneurol.2018.1487 Visit us at www.parkinsons-london.co.uk

Jankovic et al. JAMA Neurol. 2018; doi: 10.1001/jamaneurol.2018.1487 Visit us at www.parkinsons-london.co.uk

Jankovic et al. JAMA Neurol. 2018; doi: 10.1001/jamaneurol.2018.1487 Visit us at www.parkinsons-london.co.uk

Aptamers for PD • Aptamers: short, single-stranded DNA or RNA molecules that can bind to a wide range of target proteins with high affinity and specificity • Not typically recognized by the human immune system as foreign agents (neither immunogenic nor toxic) • In PD aptamers to inhibit a -synuclein aggregation Visit us at www.parkinsons-london.co.uk

a -syn domains No aptamer Random aptamer F5R1 F5R2 Zheng et al. Mo Ther Nucleic Acids. 2018;11:228-242 Visit us at www.parkinsons-london.co.uk

Human neuroblastoma cell line Both aptamers could effectively reduce α -syn aggregation in vitro and in cells and target the α -syn to intracellular degradation through the lysosomal pathway Zheng et al. Mo Ther Nucleic Acids. 2018;11:228-242 Visit us at www.parkinsons-london.co.uk

Summary • MAO-B inhibitors • Duodopa – Randomised controlled trial • Opicapone – Subcutaneous formulation • Amantadine prolonged release • Non-dopaminergic treatments • Need for non-oral therapies – Deferiprone • Apomorphine – Caloric vestibular stimulation – Randomised controlled trial – Alpha-synuclein antibodies – Sublingual and inhaler formulations – Alpha-synuclein aptamers – Effect on Amyloid Visit us at www.parkinsons-london.co.uk

Thank you Indication : Adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors (DDCI) in adult patients with Parkinson’s disease and end -of-dose motor fluctuations who cannot be stabilised on those combinations. Visit us at www.parkinsons-london.co.uk

Indication : Adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors (DDCI) in adult patients with Parkinson’s disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations. Visit us at www.parkinsons-london.co.uk