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

▶
where are we going with
SMART_READER_LITE
LIVE PREVIEW

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

Mar 29, 2024 325 likes •782 views

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 Kings College London Parkinsons Foundation Centre of Excellence in

slide-1
SLIDE 1

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

Where are we going with 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

4 July 2018

This meeting is sponsored by Bial Pharma UK.

Job code: ON/JUN18/UK/256; Date of preparation: June 2018

slide-2
SLIDE 2

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

The views expressed in this presentation are those

  • f the speaker and are not necessarily those of the

meeting sponsor

slide-3
SLIDE 3

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

slide-4
SLIDE 4

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

  • Update on existing medication
  • New indications for existing therapy
  • New medication being developed
slide-5
SLIDE 5

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

slide-6
SLIDE 6

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

MAO-B inhibitors

slide-7
SLIDE 7

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

slide-8
SLIDE 8

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

Safinamide

Schapira et al. JAMA Neurol. 2017;74(2):216-224

slide-9
SLIDE 9

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

slide-10
SLIDE 10

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

  • 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

NICE guidelines

slide-11
SLIDE 11

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

COMT inhibitors

slide-12
SLIDE 12

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
slide-13
SLIDE 13

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

Ferreira et al. Neurology 2018;90(21):e1849-e1857 Lees et al. JAMA Neurol 2017;74(2):197-206

Opicapone

Placebo Opicapone 50 mg

Opicapone demonstrated non-inferiority when compared to entacapone in a DB trial (p=0.0051 for non- inferiority vs. entacapone

slide-14
SLIDE 14

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

  • 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

Opicapone

slide-15
SLIDE 15

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

Sampaio et al. J Clin Pharmacol. 2018. doi: 10.1002/jcph.1096

Increased enzyme activity Increased enzyme activity

MAO-B and COMT

slide-16
SLIDE 16

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

Amantadine

slide-17
SLIDE 17

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

Oertel et al. Mov Disord. 2017;32(12):1701-1709

Amantadine prolonged release (ADS-5102)

slide-18
SLIDE 18

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

  • 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

Amantadine prolonged release (ADS-5102)

slide-19
SLIDE 19

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

Need for non-oral therapies in PD

Chaudhuri et al. NPJ Parkinsons Dis. 2016;2:16023

slide-20
SLIDE 20

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

Apomorphine

slide-21
SLIDE 21

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

Martinez-Martin et al. Mov Disord. 2015;30(4):510-6

slide-22
SLIDE 22

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

Sublingual Apomorphine

Ondo et al. Clin Neuropharmacol. 1999;22(1):1-4

slide-23
SLIDE 23

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

Hauser et al. Mov Disord. 2016;31(9):1366-72

Long-term safety (CTH- 301 extension study) now being performed Results should be know next year

Sublingual Apomorphine

slide-24
SLIDE 24

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

N=12 N=31

Apomorphine inhaler

Inhaled dry powder Apomorphine (1.5 or 3 mg)

Grosset et al. Acta Neurol Scand. 2013;128(3):166-71

slide-25
SLIDE 25

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

slide-26
SLIDE 26

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

slide-27
SLIDE 27

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

Duodopa

slide-28
SLIDE 28

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

Martinez-Martin et al. Mov Disord. 2015;30(4):510-6

slide-29
SLIDE 29

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

Improvement Antonini et al. Parkinsonism Relat Disord. 2017;45:13-20

slide-30
SLIDE 30

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

Subcutaneous Duodopa

slide-31
SLIDE 31

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

Non-dopaminergic treatments

slide-32
SLIDE 32

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

slide-33
SLIDE 33

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

Devos et al. Antioxid Redox Signal. 2014;21(2):195-210

slide-34
SLIDE 34

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

Non-invasive brainstem modulation (caloric vestibular stimulation)

slide-35
SLIDE 35

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

Caloric vestibular stimulation

Wilkinson et al. In preparation

slide-36
SLIDE 36

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

slide-37
SLIDE 37

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

Jankovic et al. JAMA Neurol. 2018; doi: 10.1001/jamaneurol.2018.1487

slide-38
SLIDE 38

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

Jankovic et al. JAMA Neurol. 2018; doi: 10.1001/jamaneurol.2018.1487

slide-39
SLIDE 39

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
slide-40
SLIDE 40

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

a-syn domains F5R1 F5R2 No aptamer Random aptamer Zheng et al. Mo Ther Nucleic Acids. 2018;11:228-242

slide-41
SLIDE 41

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

slide-42
SLIDE 42

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

Summary

  • MAO-B inhibitors
  • Opicapone
  • Amantadine prolonged release
  • Need for non-oral therapies
  • Apomorphine

– Randomised controlled trial – Sublingual and inhaler formulations – Effect on Amyloid

  • Duodopa

– Randomised controlled trial – Subcutaneous formulation

  • Non-dopaminergic treatments

– Deferiprone – Caloric vestibular stimulation – Alpha-synuclein antibodies – Alpha-synuclein aptamers

slide-43
SLIDE 43

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.

slide-44
SLIDE 44

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.

slide-45
SLIDE 45

Visit us at www.parkinsons-london.co.uk Ongentys (opicapone)▼ Please refer to the SPC before prescribing. Presentation: Capsules containing 50 mg of

  • picapone. Indication:

Adjunctive therapy to preparations

  • f

levodopa/DOPA decarboxylase inhibitors (DDCI) in adult patients with Parkinson’s disease and end-of-dose motor fluctuations who cannot be stabilised

  • n those

combinations. Dosage and administration: The recommended dose of opicapone is 50 mg. It should be taken once- daily at bedtime at least

  • ne hour before
  • r after levodopa combinations. Opicapone

enhances the effects of levodopa. Hence, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating the treatment with opicapone. Elderly patients: No dose adjustment is needed for elderly patients. Caution must be exercised in patients ≥ 85 years of age as there is limited experience in this age group. Patients with renal impairment: No dose adjustment is necessary in patients with renal impairment, as

  • picapone is not excreted by

the kidney. Patients with hepatic impairment: No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh Class B). Caution must be exercised in these patients and dose adjustment may be necessary. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh Class C), therefore, Ongentys is not recommended in these patients. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Phaeochromocytoma, paraganglioma,

  • r
  • ther catecholamine

secreting neoplasms. History

  • f neuroleptic

malignant syndrome and/or non-traumatic rhabdomyolysis. Concomitant use with monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine and moclobemide) other than those for the treatment of Parkinson’s disease. Pregnancy: Ongentys is not recommended during pregnancy and in women of childbearing potential not using contraception. Lactation: Breast-feeding should be discontinued during treatment with Ongentys. Warnings and precautions: Opicapone enhances the effects of levodopa. To reduce levodopa-related dopaminergic adverse reactions (e.g. dyskinesia, hallucinations, nausea, vomiting and orthostatic hypotension), it is often necessary to adjust the daily dose of levodopa by extending the dosing intervals and/or reducing the amount of levodopa per dose within the first days to first weeks after initiating treatment with Ongentys, according to the clinical condition of the patient. Ongentys contains lactose. Patients with rare hereditary problems

  • f

galactose intolerance, the Lapp lactase deficiency

  • r

glucose-galactose malabsorption should not take Ongentys. Patients and caregivers should be made aware that impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or

  • ther

dopaminergic treatments. Patients should be monitored regularly for the development of impulse control disorders and review of treatment is recommended if such symptoms develop. Increases in liver enzymes were reported in studies with nitrocatechol inhibitors

  • f

catechol-O-methyltransferase (COMT). For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered. Drug interactions: Concomitant use

  • f opicapone with MAO inhibitors (e.g. phenelzine, tranylcypromine and moclobemide)
  • ther than those for the treatment of Parkinson’s disease is contraindicated. Concomitant

use of opicapone and MAO inhibitors for the treatment of Parkinson’s disease, e.g. rasagiline (up to 1 mg/day) and selegiline (up to 10 mg/day in oral formulation or 1.25 mg/day in buccal absorption formulation), is permissible. Opicapone may interfere with the metabolism of medicinal products containing a catechol group that are metabolised by COMT, e.g. rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dopexamine or dobutamine, leading to potentiated effects

  • f

these medicinal products. Careful monitoring of patients being treated with these medicinal products is advised when opicapone is used. Concomitant use with tricyclic antidepressants and noradrenaline re-uptake inhibitors (e.g. venlafaxine, maprotiline and desipramine) should be considered with appropriate caution. Particular consideration should be given to medicinal products metabolised by CYP2C8 and their co- administration must be avoided. Particular consideration should be given to medicinal products transported by OATP1B1 and their concomitant use should be considered with appropriate caution. Adverse events: Refer to the SPC for all side effects. Very common side effects ≥1/10): Dyskinesia. Common side effects (≥ 1/100 to <1/10): Abnormal dreams, Hallucination, Hallucination visual, Insomnia, Dizziness, Headache, Somnolence, Orthostatic hypotension, Constipation, Dry mouth, Vomiting, Muscle spasms, Blood creatine phosphokinase increased. Uncommon side effects (≥ 1/1,000 to < 1/100): Decreased appetite, Hypertriglyceridaemia, Anxiety, Depression, Hallucination auditory, Nightmares, Sleep disorder, Dysgeusia, Hyperkinesia, Syncope, Dry eye, Ear congestion, Palpitations, Hypertension, Hypotension, Dyspnoea, Abdominal distention, Abdominal pain, Abdominal pain upper, Dyspepsia, Muscle twitching, Musculoskeletal stiffness, Myalgia, Pain in extremity, Chromaturia, Nocturia, Weight decreased. Legal Category: POM. Basic UK NHS cost: Ongentys pack of 30: £93.90. Marketing authorisation numbers: EU/1/15/1066/003. Marketing authorisation holder: Bial-Portela & Ca., S.A., A Avenida da Siderurgia nacional 4745-457 Coronado (S. Romao e S. Mamede) – Portugal. Further Information from: Bial Pharma UK Ltd., Admiral House, St. Leonards Road, Windsor, SL4 3BL, UK. Job code: ON/OCT16/UK/072. Date of preparation: October 2016. .

Prescribing Information: Ongentys▼

Adverse events should be reported. For UK healthcare professionals: reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bial on +44 (0)1628 531171 or bial@wainwrightassociates.co.uk