Management of “Off” Episodes in Parkinson Disease: Novel Advancements From 2022 American Academy of Neurology Annual Meeting

Michael S. Okun, MD
University of Florida Health College of Medicine

From April 2nd to 7th, 2022, clinicians gathered in Seattle, Washington, for the American Academy of Neurology (AAN) 2022 Annual Meeting. Participants also had the option to attend virtually from April 24th to 26th. Over 2000 abstracts were submitted for this year’s conference.
Michael S. Okun, MD, has served as the National Medical Director for the Parkinson Foundation since 2006 and is a professor, the chair of neurology, and the executive director of the Norman Fixel Institute for Neurological Diseases at the University of Florida Health in Gainesville.
Dr. Okun provides key takeaways from the most recent research presented at AAN 2022 on the progress made to manage “off” episodes in the treatment of Parkinson disease (PD), a period of time when the benefit of an individual dose of levodopa begins to wane, and symptoms reemerge.1
While levodopa has robust efficacy and demonstrated tolerability, almost all patients will develop “off” episodes. “Off” episodes progressively become more frequent and unexpected, last longer, and can become more abrupt in onset. Several strategies have been developed and approved as adjunct therapies to reduce “off” episodes.2 More than 20 medications or surgical procedures are available or in development to address motor fluctuations in PD.

Targeting the nigrostriatal dopamine system with levodopa remains the cornerstone of the therapeutic armamentarium for patients with PD. However, almost all patients will develop “off” episodes. How are these episodes defined and why do they occur? What is the current standard of treatment?

Approximately 50% of individuals with PD will experience motor fluctuations by 5 years into their disease. Symptoms indicating levodopa is wearing off include tremor, stiffness, bradykinesia, and challenges when walking. When medications kick “on,” these motor symptoms frequently improve. Interestingly, it is now widely recognized that “off” episodes can also present as non-motor symptoms such as depression and anxiety and these may also improve when the medications kick “on.” For 50 years, levodopa remains as the gold standard for patients with PD.
There are a variety of options for reducing “off” times, with pharmaceutical therapy being the most common strategy. As most patients take levodopa to manage their symptoms, adjusting the dose is generally a key approach for reducing “off” episodes. Devising a treatment strategy involves deciding whether to increase oral levodopa frequency or dosage, add an adjunctive extender medication to make each dose last longer, or use an on-demand therapy as needed. There are several on-demand therapies available including auto-injectable and sublingual apomorphine, a dopamine agonist, and inhaled levodopa. More recently, the US Food and Drug Administration (FDA) approved istradefylline, an adenosine receptor antagonist, to be used as adjunctive therapy.

IPX-203 is a novel oral formulation of extended-release carbidopa/levodopa (CD/LD) capsules designed for patients with PD who experience motor fluctuations. A phase 3 study compared IPX-203 and immediate-release CD/LD and found encouraging results.3 What role do you think this formulation can play in treating patients with motor fluctuations and where might it fit in the treatment regimen? Could it be offered as an alternative option to immediate-release CD/LD?

Clinicians should be cautiously optimistic about IPX-203. The phase 3 study compared IPX-203 and immediate-release CD/LD in patients with PD experiencing motor symptoms. Results indicated that patients treated with IPX-203 experienced 3.76 hours of good “on” time compared with patients treated with immediate-release CD/LD who experienced an average of 2.21 hours of good “on” time (P <.0001). A difference of over 1.5 hours can be significant in this population. IPX-203 was given 3 times a day compared with immediate-release CD/LD, which was administered 5 times a day.
Being dosed less frequently would be very popular among patients. Historically, we should keep in mind that similar hopes were dashed when sustained-release CD/LD was approved. In clinical trials, sustained-release CD/LD was dosed twice daily, a significant improvement compared with traditional treatment regimens. However, sustained-release CD/LD did not extend the life of CD/LD in the body as anticipated when real-world data became available. In practice, PD is tricky to treat and it will be interesting to see how the results hold up in the general real-world population.

An interesting drug delivery system presented at AAN 2022 included ND0612, a continuous, subcutaneous CD/LD delivery system to control motor fluctuations currently in phase 3 of clinical development.4 ND0612 is a novel solution designed to overcome the relatively narrow therapeutic window and low gastrointestinal absorption. Since this bypasses the gastrointestinal tract, could ND0612 increase bioavailability and reduce variability of CD/LD plasma levels and offer more reliable, sustained relief of motor fluctuations?

One major challenge that the field has had for many years is the elusive development of a levodopa patch. Delivering levodopa through the skin is a formidable scientific challenge even for the most skilled researchers. It is encouraging to see safety data from the BeyoND trial ( Identifier: NCT02726386). This ongoing study has 64 active patients with a treatment duration of up to 4.6 years. Most treatment-emergent adverse events were mild to moderate and there were no differences in safety between the 16- and 24-hour regimens were noted.
Completed clinical trials of ND0612L include a phase 2a, placebo-controlled, proof of concept study on 30 patients with PD who had motor response fluctuations ( Identifier: NCT01883505).5 The results showed that continuous CD/LD infusions with ND0612L was generally well tolerated and provided stable LD plasma levels compared with oral LD. Patients receiving ND0612L also experienced a 2-hour reduction in “off” time, improved sleep, better quality of life, and global clinical improvement without an increase in dyskinesias compared with patients who received placebo.
Another phase 2 trial also evaluated the efficacy, safety, tolerability, and pharmacokinetics of 2 ND0612H dosing regimens in 38 participants who were randomly assigned to receive 24- or 14-hour infusions for 28 days ( Identifier: NCT02577523).6 For the whole cohort, there was a 2-hour reduction in “off” time and a 3.3-hour improvement in “on” time with either mild or no dyskinesia.
Steady LD concentrations were associated with reduced motor fluctuations. The big test will be in practice as it is unclear whether this formulation could reduce the large number of pills most patients with PD must take each day. It is likely that this patch formulation will be a welcome addition for those with gastrointestinal absorption issues.

In one study presented at AAN 2022, the authors note that while treatments can reduce the “off” time between CD/LD doses, not much is known about patient preference and how it is affected by the adverse effects of adjunctive medications.7 Does the risk vs benefit ratio need to be clearly outlined for these therapies?

Asking patients and families what would be an acceptable trade-off to tip the scales of the benefit vs side effect profile of any new drug introduced for the management of PD is a very good idea. Many formulations are currently reasonably tolerated so the bar will be high for any therapy. Specific side effects such as nausea and dizziness will likely lead to rejection of the medication by most patients and families.

Another product in development is CVT-301, an inhaled LD formulation.8 The inhaled formulation bypasses the gastrointestinal route and enters the bloodstream rapidly. Where might this this fit into the armamentarium of management for PD? Would an inhaled formulation be a more preferable route of administration, as opposed to subcutaneous injections, for many patients? 

The inhaled LD formulation has already made a splash for many persons with PD. Patients who experience early morning “off” periods and sudden unpredictable “off” times seem to have become a niche for this formulation.
This study reported that a 84 mg dose of CVT-301 improved motor function at week 12, which was measured 30 minutes after the dose by lower United Parkinson Disease Rating Scale Part III (UPDRS-III) scores (P =.009). Additionally, 71.4% of patients in the CVT-301 group reported improvement in the Patient Global Impression of Change score compared with 46.4% of patients in the placebo group (P <.001) after 12 weeks of use.
A previous study evaluated the safety and tolerability of CVT-301 for patients experiencing early morning “off” episodes and found that it was well tolerated with no new safety concerns.9 Median time-to-“on” was 25 minutes after administration of CD/LD plus CVT-301 vs 35.5 minutes following administration of CD/LD alone (P =.26). After 30 minutes, 66.7% of patients who received CD/LD plus CVT-301 were “on” compared with 44.5% of patients who received CD/LD alone.
Gastrointestinal dysfunction is a common feature of PD and gastroparesis with delayed gastric emptying is also common. This may cause levodopa to be delayed in exiting the stomach into the small intestine where it is absorbed into the plasma through the neutral amino acid transporter.10 Therefore, select persons with gastrointestinal and other unique issues have found inhalation therapy useful. Many patients and families have found that loading the inhaler can be a challenge with PD. However, this can usually be overcome with education and pre-preparation.

Researchers have developed a functionally-scored tablet to allow for more precise dosing and patient convenience. A study found that variance in plasma LD concentrations and adverse events declined by 51% in the group who received lower and more frequent doses of CD/LD enabled by the scored tablet.11 Do you see this making dosing easier for patients with PD? Could it help stabilize LD concentrations and reduce fluctuations or possibly replace traditional oral formulations?

Pre-scoring dopamine tablets for persons and families managing PD will be a big winner and very popular provided the cost of the medication can be controlled. Many of our patients with PD split their medications into halves either by snapping them or by self-scoring the tablet. When halving a half pill into a quarter pill, this usually produces a dusty product. The dust or pill fragments can be difficult to measure and administer. Patients are then forced to add the powder into apple sauce, yogurt, or another food which may also impact absorption.

Key Takeaways

  • Almost all patients with PD will eventually experience “off” episodes and effective interventions with low toxicity remains an unmet need.
  • A variety of interventions are currently available for the management of “off” episodes, including individualized dose adjustments of levodopa, adding adjunct medications, or using rescue therapies.
  • Researchers are looking at innovative ways to help patients manage “off” episodes, including subcutaneous administration, new extended-release formulations, and unique scored tablets to manage patient dosing.
  • Patient preference is important in treatment selection. Many patients are willing to accept additional limited toxicity or side effects for additional “on” time, which contribute positively to increased quality of life.

This Q&A was edited for clarity and length.


1. Hauser RA, LeWitt PA, Comella CL. On demand therapy for parkinson’s disease patients: opportunities and choices. Postgrad Medicine. 2021;133(7):721-727. doi:10.1080/00325481.2021.1936087
2. Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson’s disease: current status and future developments. Curr Neuropharmacology. 2018;16:1239-1252. doi:10.2174/1570159X15666170510143821
3. Hauser RA, Espay AJ, LeWitt P et al. A phase 3 trial of IPX203 vs CD-LD IR in Parkinson’s disease patients with motor fluctuations (RISE-PD). Abstract presented at: 2022 American Academy of Neurology Annual Meeting; April 2-7, 2022; Seattle, Washington. Abstract 001225.
4. Isaacson S, Samuni T, Salin L, et al. Long-term safety of continuous levodopa/carbidopa infusion with ND0612: results from the ongoing BeyoND study. Abstract presented at: 2022 American Academy of Neurology Annual Meeting; April 2-7, 2022; Seattle, Washington. Abstract 002640.
5. Giladi N, Gurevich T, Djaldetti R, et al. ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson’s disease and motor response fluctuations: a randomized, placebo-controlled phase 2 study. Parkinsonism Relat Disord. 2021;91:139-145. doi:10.1016/j.parkreldis.2021.09.024
6. Olanow CW, Espay AJ, Stocchi F et al; for the 006 Study Group. Continuous subcutaneous levodopa delivery for Parkinson’s disease: a randomized study. J Parkinsons Dis. 2021;11:177-186. doi:10.3233/JPD-202285
7. Serbin M,  MansfieldC, Leach C, et al. Patients’ preferences for adjunctive Parkinson’s disease treatments: a discrete-choice experiment. Abstract presented at: 2022 American Academy of Neurology Annual Meeting; April 2-7, 2022; Seattle, Washington. Abstract 001131.
8. Isaacson S, Zhao P, Blank B, et al. SPAN-PD: subgroup analyses by baseline characteristics of patients treated with levodopa inhalation powder 84mg or placebo to treat off symptoms in patients with Parkinson’s disease (PD) as measured by Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score and Patient Global Impression of Change (PGIC). Abstract presented at: 2022 American Academy of Neurology Annual Meeting; April 2-7, 2022; Seattle, Washington. Abstract 001233.
9. Hauser RA, Isaacson SH, Ellenbogen A et al. Orally inhaled levodopa (CVT-301) for early morning off periods in Parkinson’s disease. Parkinsonism Relat Disord. 2019;64:175-180. doi:10.1016/j.parkreldis.2019.03.026
10. Camargo SMR, Vuille-dit-Bille RN, Mariotta L, et al. The molecular mechanism of intestinal levodopa absorption and its possible implications for the treatment of Parkinson’s disease. J Pharmacol Exp Ther. 2014;351(1):114-23. doi:10.1124/jpet.114.216317
11. AL-Sabbagh A, Testino S, Shah D, et al. Variability of plasma levodopa conveniently reduced by more frequent administration of smaller doses of carbidopa/levodopa using a novel functionally scored formulation. Abstract presented at: 2022 American Academy of Neurology Annual Meeting; April 2-7, 2022; Seattle, Washington. Abstract 001790.
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                                                                                                                                        Reviewed May 2022