Read All About It: How On-Demand Therapy Has Changed the PD Landscape

NeurologyLiveApril 2023
Volume 6
Issue 2

As therapeutic development has advanced in Parkinson disease management, the introduction of on-demand options have extended ON time for patients and altered the paradigm of care.

PARKINSON DISEASE (PD) IS A progressive neurodegenerative disorder in which nigrostriatal dopaminergic degeneration leads to motor symptoms of bradykinesia, rigidity, and rest tremor. Patients’ initial response to levodopa is usually robust; however, motor fluctuations emerge in up to 50% of patients by 5 years and more than 90% by 10 years.1 The shortened duration of benefit of each levodopa dose coupled with delay in onset of the next levodopa dose results in OFF episodes, characterized by motor and nonmotor symptoms.

OFF episodes can occur in relation to the time of day (eg, morning akinesia) or meals (eg, protein effect), but they may also be unpredictable.2 Managing OFF episodes represents an ongoing therapeutic challenge for patients with PD. Medications to extend the duration of benefit of levodopa doses typically reduce daily OFF time by 1 to 2 hours, but do not treat an OFF episode once it occurs. Oral levodopa’s onset of benefit can be limited by gastrointestinal (GI) dysmotility with delayed gastric emptying, which is common in PD, and by competitive transport by dietary protein.

Recently, on-demand therapies have emerged to acutely treat an OFF episode (TABLE). These therapies can be used as needed and have more rapid onset of benefit by avoiding GI route of absorption.

Jonathan R. Isaacson, MD, Resident neurologist, MedStar Georgetown University Hospital, Washington, DC

Jonathan R. Isaacson, MD

Inhaled Levodopa

Levodopa inhalation powder (Inbrija; Acorda Therapeutics, Inc), previously known as CVT-301, can be self-administered when OFF symptoms first emerge. When inhaled into the lungs, it rapidly enters the circulating plasma, bypassing the GI tract.

The phase 3 SPAN-PD trial (NCT02240030) evaluated the safety and efficacy of the inhalation powder. This randomized, double-blind, placebo-controlled, multicenter study was an adjunct to levodopa/decarboxylase therapy.3 The primary end point was the change in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores from predose to 30 minutes post dose, assessed at week 12 during an in-clinic OFF period. The least-squares mean change from predose was –9.83 points for the 84-mg group vs –5.91 points in the placebo group. Improvement was seen as early as 10 minutes post dose, and 58% returned to an ON state and remained ON at 60 minutes post dose.3

The treatment was used up to 5 times per day in the trial and demonstrated safety and tolerability. The most common adverse effects were cough and upper respiratory infection. This study ultimately showed that inhaled levodopa was safe and effective at treating OFF periods in PD.3

(Click to enlarge)

(Click to enlarge)

Subcutaneous Apomorphine Injection

Apomorphine has been used in the treatment of patients with PD since the 1950s and has level 1 evidence for the use of its subcutaneous formulations.4 Apomorphine has poor oral bioavailability but can provide rapid and consistent delivery as a subcutaneous injection or continuous infusion because it rapidly crosses the blood-brain barrier.

It is a dopamine agonist with mixed D1/D2 receptor activity, similar to levodopa, and has robust efficacy, also like levodopa. Adverse effects are most commonly nausea, vomiting, and orthostatic lightheadedness. The FDA label for apomorphine initially recommended pretreatment with oral trimethobenzamide to reduce the risk of nausea and vomiting,5 but the label recently was updated. Clinical experience also indicated that antiemetic pretreatment is not needed. A literature review found that pretreatment with an antiemetic may be helpful for some patients, but no significant difference was identified during titration and it may be associated with more adverse events. Taken together, these data suggest subcutaneous apomorphine injection can be initiated using a slower titration without antiemetic pretreatment.6

Amit Mehta, MD, Resident neurologist, MedStar Georgetown University Hospital, Washington, DC

Amit Mehta, MD

Initial studies found subcutaneous apomorphine injection (Apokyn; Supernus Pharmaceuticals, Inc) had rapid onset within 10 minutes and reliable effect (95%) when compared with placebo in patients with PD optimized on anti-PD medications.7,8 The findings of the APO302 (NCT03391882) and APO303 (NCT00145171) studies also confirmed this durable response in motor scores in patients with PD chronically taking subcutaneous apomorphine for acute management of OFF periods.6 More recently, the phase 4 open-label AM IMPAKT study (NCT01770145) to determine the effect of daily subcutaneous morning apomorphine injection reduced time-to-ON in patients with PD with morning akinesia.9

Prolonged morning OFF is common in patients with PD treated with levodopa. Delay in patients turning ON after taking their first morning dose of levodopa can be attributed to either delayed gastric emptying or ill-defined pharmacodynamics. Patients eligible for the phase 4 study underwent 3 phases: a 7-day baseline OFF state after taking their levodopa, titration phase with subcutaneous apomorphine to achieve optimal dosing, and 7-day treatment period during which levodopa was replaced with subcutaneous apomorphine.9

A total 127 patients enrolled and entered the apomorphine titration phase, with 88 patients completing the full study. There was a statistically significant reduction from 60.86 (± 18.11) minutes at baseline with levodopa therapy to 23.72 (± 14.55) minutes at the end of the subcutaneous apomorphine treatment period.9,10 Dose failures were reduced as well. The study’s secondary efficacy variables evaluating quality-of-life scores and global impression scales supported the primary efficacy findings, with similar statistically significant changes.9,10 The most common observed adverse events from subcutaneous apomorphine were nausea, dizziness, and hypotension. Subcutaneous apomorphine was determined by the investigators to provide a safe, rapid, and reliable ON state for patients with PD who have morning akinesia.9,10

Stuart H. Isaacson, MD, FAAN, Director, Parkinson’s Disease & Movement Disorders Center, Boca Raton, FL

Stuart H. Isaacson, MD, FAAN

Sublingual Apomorphine Film

A sublingual film formulation containing apomorphine (Kynmobi; Sunovion Pharmaceuticals, Inc) recently was approved by the FDA based on the findings from a phase 3 multicenter, randomized, double-blind, placebo-controlled study (CTH-300; NCT02469090).11 The investigators randomly assigned 109 patients to receive either apomorphine sublingual film at the tolerated dose that provided a full-on response during titration or an identical matched placebo. A 12-week maintenance phase followed during which clinic efficacy assessments were done at specified time points in addition to home administration of the study drug for the management of up to 5 OFF episodes per day.10 The primary end point was a mean change from predose to 30 minutes post dose in the Movement Disorder Society UPDRS (MDS-UPDRS) part 3 score at the 12-week visit. The key secondary end point was the percentage of patients with self-rated full-on response within 30 minutes at the 12-week visit.11

Both end points reached significance: a 12-week MDS-UPDRS score change of –11.1 and 35% self-rated full-on response in the sublingual apomorphine cohort compared with –3.5 and 16% in the placebo group.11 Nausea and oropharyngeal disorders were the most common treatment-emergent adverse events during the apomorphine sublingual film titration and maintenance phases, respectively.11 This study supports the therapeutic effects of sublingual apomorphine film for patients with PD in need of a rapid and reliable on-demand therapy for OFF episodes.

Time for a Paradigm Shift?

During OFF episodes, patients experience significant impairment of daily activities and quality of life. Prior guidelines call for adjusting the dose or frequency of levodopa or switching to an extended-release formulation. Alternatively, adjunct medications can be added to increase the duration of levodopa (ON extenders) because they increase daily ON time. However, neither method reverses an acute OFF episode.

On-demand, non–GI-delivered therapies can be used as needed whenever an OFF episode occurs. These tend to be more reliable and more rapidly turn patients ON than oral levodopa, because they bypass GI dysmotility. Evidence has emerged that utilizing these therapies earlier in the disease course may be beneficial, empowering patients to reverse an OFF episode and turn ON. This is supported by variability in oral absorption in PD, persistent symptoms despite adjunctive treatment, and variability of oral levodopa absorption. The emerging consensus is to use on-demand therapy as an earlier tool for patients throughout the disease process.2


On-demand therapy has the potential to transform the management of PD and empower patients to have control over reversing OFF episodes when needed. These therapies have provided rapid and reliable benefit by bypassing GI absorption, which is often variable and delayed. On-demand treatments may delay more invasive surgical interventions such as percutaneous endoscopic gastrostomy-jejunostomy tube, focused ultrasound, or deep brain stimulation. On-demand medications can be used earlier in the treatment paradigm, in combination with ON extenders, to provide as-needed acute treatment of OFF episodes for patients with PD.

1. LeWitt PA. Treatment strategies for extension of levodopa effect. Neurol Clin. 1992;10(2):511-526.
2. Isaacson SH, Pagan FL, Lew MF, Pahwa R. Should “on-demand” treatments for Parkinson’s disease OFF episodes be used earlier? Clin Park Relat Disord. 2022;7:100161. doi:10.1016/j.prdoa.2022.100161
3. LeWitt PA, Hauser RA, Pahwa R, et al; SPAN-PD Study Investigators. Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during OFF periods in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2019;18(2):145-154. doi:10.1016/ S1474-4422(18)30405-8
4. Schwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson’s disease. Trans Am Neurol Assoc. 1951;56:251-253.
5. Kynmobi. Prescribing information. Sunovion Pharmaceuticals. Updated September 2022. Accessed March 15, 2023.
6. Isaacson SH, Dewey RB Jr, Pahwa R, Kremens DE. How to manage the initiation of apomorphine therapy without antiemetic pretreatment: a review of the literature. Clin Park Relat Disord. 2022;8:100174. doi:10.1016/j. prdoa.2022.100174
7. Pfeiffer RF, Gutmann L, Hull KL Jr, Bottini PB, Sherry JH; APO302 Study Investigators. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinsonism Relat Disord. 2007;13(2):93-100. doi:10.1016/j.parkreldis.2006.06.012
8. Pahwa R, Koller WC, Trosch RM, Sherry JH; APO303 Study Investigators. Subcutaneous apomorphine in patients with advanced Parkinson’s disease: a dose-escalation study with randomized, double-blind, placebo-controlled crossover evaluation of a single dose. J Neurol Sci. 2007;258(1-2):137-143. doi:10.1016/j.jns.2007.03.013
9. Isaacson S, Lew M, Ondo W, Hubble J, Clinch T, Pagan F. Apomorphine subcutaneous injection for the management of morning akinesia in Parkinson’s disease. Mov Disord Clin Pract. 2017;4(1):78-83. doi:10.1002/mdc3.12350
10. Trenkwalder C, Chaudhuri KR, García Ruiz PJ, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson’s disease--clinical practice recommendations. Parkinsonism Relat Disord. 2015;21(9):1023-1030. doi:10.1016/j.parkreldis.2015.06.012
11. Olanow CW, Factor SA, Espay AJ, et al; CTH-300 Study Investigators. Apomorphine sublingual film for OFF episodes in Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurol. 2020;19(2):135-144. doi:10.1016/S1474-4422(19)30396-5
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