PARKINSON’S DISEASE

Mallory Carter, PharmD

March 22, 2023
OBJECTIVES

Explain the dopaminergic pathophysiology of Parkinson’s

Disease

Describe the risk factors and complications of Parkinson’s Express

Disease and of its treatment excitement over
drugs in the
pipeline!
Compare and contrast the efficacy and safety/tolerability
of the agents used to treat Parkinson’s Disease

Develop a first-line treatment regimen based on guideline

recommendations and patient-specific factors
2
 EPIDEMIOLOGY
Prevalence Incidence

• 1 million in the US • Increasing Age

• Increasing • Male sex
• 2nd most common
neurodegenerative
disorder
• 90,000 people
diagnosed each
year

3
Parkinson’s Foundation. Understanding Parkinson’s: statistics. Parkinson.org. Accessed March 13, 2023.
 DEFINITION & DIAGNOSIS

A progressive
neurodegenerative
disorder that affects
dopaminergic neurons in
the substantia nigra
• Typically diagnosed
later in life

4
Chou K. 2023.
 PRESENTATION

5
Chou K. 2023.
STAGES

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 NONMOTOR COMPLICATIONS

Cognitive Psychotic
Dementia
Dysfunction Symptoms

Paranoid Mood
Hallucinations
Delusions Disorders

7
Chou K. 2023.
 PATHOPHYSIOLOGY
Death of dopamine neurons in substantia nigra

Lower levels of dopamine in basal ganglia

Loss of signal transmission to motor neurons

Decreased muscle activity and contraction

8
Hauser RA. Why we need more treatment options for early-stage PD. Webinar video. Pharma Two B; 2022.
PROGRESSION

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 NEW ADVANCEMENTS
α-synuclein = protein that is linked (genetically and pathologically) to PD
• Abnormal conformations  misfolding  accumulation  neuronal
death

10
Stefanis L. alpha-synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med. 201;2(2):a009399. doi: 10.1101/cshperspect.a009399
TREATMENT

11
 NONPHARMACOLOGIC
Exercise • Strength and balance training

• Whole-foods, plant-based
Diet • Increase fiber and water

• PT/OT, Speech
Specialists • Neurology

• Therapy
Support • Caregiver support groups
National Health Service. Treatment: Parkinson’s disease. NHS.uk. 12
Lazarus J. Can we put the brakes on Parkinson’s progression?. Parkinson.org. Published May 5, 2022.
PHARMACOLOGIC

Levodopa/ Dopamine MAO-B

Carbidopa Agonists Inhibitors

COMT
Anticholinergics Amantadine
Inhibitors
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MECHANISMS

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 CARBIDOPA/LEVODOPA
• Superior effects on motor function, ADLs, and QOL
• Works best on rigidity and bradykinesia
“Gold-Standard”
• Must be in combination but with
• Active component: levodopa  dopamine
complications
• Carbidopa allows levodopa to pass through BBB

• IR preferred
• Titratable
• Frequent dosing required (TID)
Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of the 15
AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 THE COMPLICATIONS
With Long-Term
ADEs Serious ADEs
Use
• Nausea* • Confusion • Motor
• Somnolence • Hallucinations fluctuations
• Dizziness • Delusions • Dyskinesias
• Headache • Psychosis • “Wearing-off”
• Orthostatic
Hypotension

*Protein and amino acids impact absorption. Can take with food but carries a sacrifice.
16
Spindler M, Tarsy D. 2023
WEARING-OFF

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 DOPAMINE AGONISTS
• Alternative first-line agents
• Adjunctive
• Lesser efficacy

Lesser risk of
dyskinesia, motor
fluctuations Increased risk of
nonmotor effects

Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of 18
the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 MEDICATIONS
Pramipexole Ropinerole Rotigotine Apomorphine

Rescue
IR and ER IR and ER Transdermal
therapy

Begin with Begin at Begin with Sublingual

0.125mg TID 0.25mg TID 2mg/24hrs film or subq

Management Most benefit

Management
at 1.5-4.5mg at 12-16mg
at 6mg/24hrs
daily daily
19
Spindler M, Tarsy D. 2023
 NONMOTOR EFFECTS

Orthostatic
Edema Somnolence Dizziness
Hypotension

Excessive
Cognitive Impulse Control
Hallucinations Daytime
Impairment Disorders (ICDs)
Sleepiness (EDS)

20
Spindler M, Tarsy D. 2023
 IMPULSE CONTROL DISORDERS
Risk Factors

• Male Sex
• Younger Age
• History of ICDs or
mood disorders
• Apathy
• Family history of
ICDs and addiction

Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of 21
the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 MAO-B INHIBITORS
• Alternative first-line agents
• Adjunctive
• Mild efficacy for mild symptoms

Low
potency Once daily
dosing
Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of 22
the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 MEDICATIONS
• Less selectivity for MAO-B
Selegiline • Causes more confusion in older adults

• Most commonly used

Rasagiline • Associated with ICDs

• Approved for adjunctive use for “off”

Safinamide episodes
23
Spindler M, Tarsy D. 2023
 ADVERSE EFFECTS

Nausea Headache Confusion

Hallucinations Constipation

24
Spindler M, Tarsy D. 2023
 AMANTADINE
• MOA: Increases dopamine release from presynaptic terminals,
inhibits dopamine reuptake, stimulates dopamine receptors
• Anticholinergic effects
• NMDA inhibitor
• Alternative treatment for young patients
• Especially with predominant tremor
• Adjunctive Not
first-line
Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of 25
the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 ADVERSE EFFECTS
Livedo reticularus

Ankle Edema

Hallucinations

Insomnia, nightmares

Confusion

Orthostatic Hypotension
26
Spindler M, Tarsy D. 2023
 ANTICHOLINERGICS
• MOA: antagonize ACh neurotransmitter to restore
balance to basal ganglia
• Can be used as monotherapy
• Younger patients with tremor
• Adjunctive

Trihexyphenidyl Benztropine

• 0.5-1mg BID • 0.5mg-2mg

• Can increase BID
to 2mg TID

Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of 27
the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 ADVERSE
EFFECTS
AVOID in older
adults and patients
with cognitive
impairment

28
Spindler M, Tarsy D. 2023
 COMT INHIBITORS
• Adjunctive only
• Reduces levodopa dosing requirements
• Decrease dose by up to 30%
• Useful in later stages to manage “wearing off”
episodes

Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of 29
the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
 MEDICATIONS
Entacapone Tolcapone Opicapone

Central and
Peripheral Peripheral
peripheral

Administer Noninferior to
Hepatotoxicity
with levodopa entacapone

0.6 hours more

Explosive
of “on” time
diarrhea
daily
30
Patel B, Mlaty I. Parkinson disease treatment advances. Pract. Neurol. 2022:54-58.
 OTHER INTERVENTIONS
Deep Brain Stimulation Focused Ultrasound

• Electrodes placed in • Ultrasound beams used

brain, neurostimulator to destroy targeted brain
under skin cells
• Similar to a pacemaker • MRI imaging used for
• Stiffness, slowness, targeting
tremor • Thalamus: tremor
• Can worsen cognitive • Globus pallidus interna:
function dyskinesia
Michael J. Fox Foundation for Parkinson’s Research. Focused Ultrasound. Michaeljfox.org. 31
Michael J. Fox Foundation for Parkinson’s Research. Deep Brain Stimulation. Michaeljfox.org.
Amazing DBS Before & After | 225-769-2200 | Baton Rouge
Parkinson's Specialists – YouTube 32
 REVIEW
Dopamine MAO-B
Levodopa Amantadine
Agonists Inhibitors

33
Hauser RA. Why we need more treatment options for early-stage PD. Webinar video. Pharma Two B; 2022.
GUIDELINES/ALGORITHM

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 TREATMENT STRATEGY
• Timing of treatment determined by severity of symptoms
and impact on life
• Mild: “watch and wait” approach
• Referred to clinical trials!
• Initial treatment with levodopa provides superior motor
benefit compared to treatment with dopamine agonists
• Up to 5 years
• Treatment choice based on potential adverse effects
• Increased risk of neuropsychiatric effects vs. motor fluctuations

Dietrichs E, Odin P. Algorithms for the treatment of motor problems in Parkinson’s disease. Acta Neurol Scand. 2017;136(5): 378-385. doi: 10.1111/ane.12733 35
Grimes D, Fitzpatrick M, Gordon J, et al. Canadian guideline for Parkinson disease. CMAJ. 2019;191(36): E989-1004. doi: 10.1503/cmaj.181504
 GUIDELINE RECOMMENDATIONS
• Early disease with motor symptoms  Levodopa
• Unless age < 60 and at risk for dyskinesias  consider dopamine agonists

• Avoid dopamine agonists in patients at high risk for ADEs

• Age > 70, history of ICDs, preexisting cognitive impairment, excessive
daytime sleepiness, hallucinations

• Use IR levodopa before CR or combination with COMT inhibitor

• Ask patients about impulsive behaviors, sleep behaviors,

perceptual disturbances often
Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of the AAN guideline 36
subcommittee. J Neurol. 2021;97(20): 942-957. doi: 10.1212/WNL.0000000000012868.
REVIEW
• Initial treatment in older patients, cognitive impairment
Carbidopa/Levodopa • Added on when additional treatment is needed (occurs in most patients)

• Initial treatment if patient is young

Dopamine Agonists • Adjunctive

• Initial treatment for mild symptoms and desire for once daily dosing
MAO-B Inhibitors • Adjunctive

• Can be initial treatment if tremor is predominant symptom

Anticholinergics • Adjunctive for symptom management, AVOID in older patients

• Adjunctive to decrease levodopa requirements

COMT Inhibitors • Not monotherapy

• Initial treatment for young patients with predominant tremor

Amantadine • Adjunctive for advanced PD

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PIPELINE

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 P2B001 PHASE III STUDY
Purpose
• To determine if a combination low-dose pramipexole and rasagiline
once daily formulation provides better efficacy than pramipexole or
rasagiline alone and better tolerability than pramipexole ER alone.
Methods
• 12 week randomized, double-blind, active-controlled, parallel group
study
• 544 patients aged 35-80 years old with early onset PD (< 3 years)
randomized to 1 of 4 treatment groups
• 7 clinic visits (every 2-4 weeks) to evaluate progression and ADEs
A phase 3 study with P2B001 in subjects with early Parkinson’s. ClinicalTrials.gov identifier: NCT03329508. Updated March 21, 2023. 39
Hauser RA et al. P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson’s Disease. Adv Ther. 2022;39(5):1881-1894. doi: 10.1007/s12325-022-02097-2.
 RANDOMIZATION – P2B001

Olanow CW. Patient outcomes with P2B001*: phase 3 top-line results. Webinar video. Pharma Two B; 2022. 40
Hauser RA et al. P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson’s Disease. Adv Ther. 2022;39(5):1881-1894. doi: 10.1007/s12325-022-02097-2.
 BASELINE CHARACTERISTICS

UPDRS: Unified Parkinson’s Disease Rating Scale (higher numbers = more severe)

41
Hauser RA et al. P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson’s Disease. Adv Ther. 2022;39(5):1881-1894. doi: 10.1007/s12325-022-02097-2.
 RESULTS – PRIMARY ENDPOINT

P2B001: -7.98
Rasagiline: -4.69
Pramipexole: -5.32
Pramipexole ER: -8.35

42
Olanow CW. Patient outcomes with P2B001*: phase 3 top-line results. Webinar video. Pharma Two B; 2022.
 RESULTS – SECONDARY ENDPOINT

P2B001: -0.33
Rasagiline: -0.81
Pramipexole: 0.39
Pramipexole ER: 2.33

43
Olanow CW. Patient outcomes with P2B001*: phase 3 top-line results. Webinar video. Pharma Two B; 2022.
 P2B001 DISCUSSION
Author’s Statement
• “P2B001 has the potential to be the leading initial treatment option for
PD for neurologists and general practitioners”
Limitations
• Short study length
• Patient population
Conclusions
• Appears to be synergistic effect of low-dose dopaminergic therapy
• Similar efficacy to treatment doses with reduced dopaminergic ADEs
A phase 3 study with P2B001 in subjects with early Parkinson’s. ClinicalTrials.gov identifier: NCT03329508. Updated March 21, 2023. 44
Hauser RA et al. P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson’s Disease. Adv Ther. 2022;39(5):1881-1894. doi: 10.1007/s12325-022-02097-2.
 PASADENA TRIAL
Purpose
• To determine if prasinezumab can slow or halt Parkinson’s disease progression

Methods
• Phase II randomized, double-blind, placebo-controlled interventional study
• 316 patients with early onset PD (< 2 years) randomized to high-dose, low-dose, or
placebo infusion every 4 weeks for 52 weeks.

Patient Population
• 59.9 years old (40-80 years old), majority male (67.4%), majority white (83.2%)
• Extensive inclusion and exclusion criteria
• Exclusion: concomitant disease/condition that might interfere with treatment,
significant CV condition, significant lab abnormality
A study to evaluate the efficacy of prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s disease (PASADENA). ClinicalTrials.gov identifier: NCT03100149. Updated February 21, 2023. 45
Pagano G, Taylor KI, Anzurez-Cabrera J, et al. Trial of prasinezumab in early-stage Parkinson’s disease. N Engl J Med. 2022;387:421-432. doi: 10.1056/NEJMoa2202867
 RESULTS

• Change in variety of different rating scales

Secondary • Change in dopamine transporter imaging
Endpoints: • Time to worsening symptoms, to start of dopaminergic PD treatment

A study to evaluate the efficacy of prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s disease (PASADENA). ClinicalTrials.gov identifier: NCT03100149. Updated February 21, 2023. 46
Pagano G, Taylor KI, Anzurez-Cabrera J, et al. Trial of prasinezumab in early-stage Parkinson’s disease. N Engl J Med. 2022;387:421-432. doi: 10.1056/NEJMoa2202867
 PASADENA DISCUSSION
Author’s Impression
• Did not meet primary endpoint, but showed some signs of providing benefit and
is well tolerated
Limitations
• Assessments missed due to COVID-19
• Censoring of data when patients started PD treatment
Conclusions
• Just the beginning of targeted α-synuclein therapies to address disease
progression
A study to evaluate the efficacy of prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s disease (PASADENA). ClinicalTrials.gov identifier: NCT03100149. Updated February 21, 2023. 47
Pagano G, Taylor KI, Anzurez-Cabrera J, et al. Trial of prasinezumab in early-stage Parkinson’s disease. N Engl J Med. 2022;387:421-432. doi: 10.1056/NEJMoa2202867
 REFERENCES
• A phase 3 study with P2B001 in subjects with early Parkinson’s. ClinicalTrials.gov identifier: NCT03329508.
Updated March 21, 2023. Accessed March 21, 2023.
• A study to evaluate the efficacy of prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s
disease (PASADENA). ClinicalTrials.gov identifier: NCT03100149. Updated February 21, 2023. Accessed March
15, 2023.
• Chou K. Clinical manifestations of Parkinson disease. In: Hurtig H (Ed), UptoDate Wolters Kluwer Health Inc,
Waltham, MA. 2023.
• Dietrichs E, Odin P. Algorithms for the treatment of motor problems in Parkinson’s disease. Acta Neurol Scand.
2017;136(5): 378-385. doi: 10.1111/ane.12733
• Grimes D, Fitzpatrick M, Gordon J, et al. Canadian guideline for Parkinson disease. CMAJ. 2019;191(36): E989-
1004. doi: 10.1503/cmaj.181504
• Hauser RA et al. P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in
Development for Parkinson’s Disease. Adv Ther. 2022;39(5):1881-1894. doi: 10.1007/s12325-022-02097-2.
• Hauser RA. Why we need more treatment options for early-stage PD. Webinar video. Pharma Two B; 2022.
• Lazarus J. Can we put the brakes on Parkinson’s progression?. Parkinson.org. Published May 5, 2022. Accessed
March 13, 2023.
48
 REFERENCES
• Michael J. Fox Foundation for Parkinson’s Research. Focused Ultrasound. Michaeljfox.org. Accessed March 15,
2023.
• Michael J. Fox Foundation for Parkinson’s Research. Deep Brain Stimulation. Michaeljfox.org. Accessed March
15, 2023.
• National Health Service. Treatment: Parkinson’s disease. NHS.uk. Accessed March 13, 2023.
• Olanow CW. Patient outcomes with P2B001*: phase 3 top-line results. Webinar video. Pharma Two B; 2022.
• Pagano G, Taylor KI, Anzurez-Cabrera J, et al. Trial of prasinezumab in early-stage Parkinson’s disease. N Engl J
Med. 2022;387:421-432. doi: 10.1056/NEJMoa2202867
• Parkinson’s Foundation. Understanding Parkinson’s: statistics. Parkinson.org. Accessed March 13, 2023.
• Patel B, Mlaty I. Parkinson disease treatment advances. Pract. Neurol. 2022:54-58.
• Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease
practice guideline summary: a report of the AAN guideline subcommittee. J Neurol. 2021;97(20): 942-957. doi:
10.1212/WNL.0000000000012868.
• Spindler M, Tarsy D. Initial pharmacologic treatment of Parkinson disease. In: Hurtig H (Ed), UptoDate Wolters
Kluwer Health Inc, Waltham, MA. 2023
• Stefanis L. alpha-synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med. 201;2(2):a009399. doi:
49
10.1101/cshperspect.a009399
QUESTIONS?

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 KAHOOT
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