The Importance of Treatment Nuance and Novel Options in Treating Parkinson Disease

Jill Farmer, DO, MPH

It is commonly known among movement disorder specialists and neurologists that patients with Parkinson disease (PD) experience OFF episodes, when there is a so-called wearing-off effect of their therapy. This occurs in patients who are treated with the gold standard treatment, levodopa, and in recent years has begun to be addressed with adjunctive therapy, dosing regimen adjustments, and on-demand therapies.

Some of these classes of medications include ON time extenders, such as monoamine oxidase type B (MAO-B) inhibitors or catechol-o-methyl transferase (COMT) inhibitors, as well as dopamine agonists. Although clinical trials have suggested these medicines can reduce patient OFF time, they are not one-size-fits-all, and much of their benefit results in reductions of fewer than a few hours, and their administration can carry burdens for patients. Ultimately, in common practice, it seems there has been a reliance on levodopa without consideration for newer options.

As Jill Farmer, DO, MPH, pointed out in a presentation at the 2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress in Washington, DC, June 17-19, these are not the only approaches to help address the challenges of OFF episodes. Advances in the development of treatment devices and surgical procedures—many of which are minimally or noninvasive—have led to a larger contingent of options for both patients and providers. Farmer, who is an assistant professor of neurology and the director of the Parkinson’s Disease and Movement Disorder Program at Global Neuroscience Institute, explained to a crowded room at the Mandarin Oriental Hotel that these surgical and devices options should no longer be looked at as a last resort, particularly for patients who are good candidates for these procedures.

“If you haven't heard by now, you will hear, repeatedly, this concept of the narrowing of the therapeutic window. Basically, that [therapeutic] sweet spot gets smaller and smaller as the disease progresses,” she said in her presentation. “There are a couple of theories as to why that is—no one knows exactly for sure. Some of it is the idea of the loss of buffering capacity. You have less and less dopamine being made, and you have less than less dopaminergic neurons, so you are not going to get that same level. What is also happening in the brain is you have an upregulation of adenosine receptors, and these receptors work in the indirect pathway which inhibits movement, so that's kind of taking control. And third, you have [gastrointestinal] dysmotility. I always tell patients that if things are moving slow on the outside, they're moving slow on the inside. Whether that's your GI system, whether that's your emotional adaptability, whatever it might be, you're stiffer and you're more rigid, inside and out. If your medicine isn't getting to the part of the GI tract where it needs to be absorbed, you're going to have less of it to elicit its effect. All three of these things in combination to some degree, are leading to these ON-OFF phenomena of motor fluctuations.”

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Farmer continued, explaining that the main minimally invasive or surgical approaches to this challenge are three-fold: deep brain stimulation (DBS), apomorphine subcutaneous pump, or levodopa-carbidopa intestinal gel. Although each of them carries its own risks and possible cons, she offered a breakdown of the advantages of each:

• DBS, considered the best option for patients experiencing dyskinesia—which can often accompany OFF episodes—offers a number of advantages that Farmer laid out. Firstly, it results in a lessened need for dopamine medications; additionally, it is reversible, nonablative, and a better option for those with refractory tremor.
• An apomorphine subcutaneous pump, on the other hand, can provide so-called rescue from OFF episodes while also addressing motor fluctuations, without being more than mildly invasive. Farmer explained that for those who do not tolerate oral medication or deal with absorption issues, this can be an effective option, as it crosses the blood-brain barrier quickly without competition with circulating proteins.
• Levodopa-carbidopa intestinal gel has been shown to be effective for those with frequent OFF episodes or severe dyskinesia and offers a good third option for when the former two are inappropriate or ineffective. Additionally, it can improve gait in some, without being as invasive as DBS, nor with any age limit attached to its use.

“Most of the time, when I'm having a conversation with patients, they'll be talking about irreversibility. Is it easier to reverse one surgery than the other? Is it inconspicuous? How do I live with it, are the devices more easily managed? Things like that,” Farmer said. “It really depends on the patient before you because there are pros and cons to all of them. There are some contraindications when it comes to DBS that might not be as hard on the patient as levodopa-carbidopa. But, when it comes down to the rationale for using all of these, again, you're looking at the patient that has responsiveness to medication, and that responsiveness is no longer as consistent as it needs to be. They're starting to develop motor fluctuations, what's the best way to go about managing them? They're all worthy of discussion.”

Farmer then offered a brief overview of the clinical evidence for each of the 2 therapeutic options. First, she reviewed the findings of the pivotal trial of levodopa-carbidopa intestinal gel, published in Lancet Neurology in 2014 by Olanow et al (NCT00660387 and NCT0357994).² Those data showed that from baseline to 12 weeks, mean OFF time decreased by 4.04 hour (SE, 0.65) for the 35 patients allocated to the intestinal gel group compared with a decrease of 2.14 hours (SE, 0.66) for the 31 patients allocated to immediate-release oral levodopa-carbidopa, for a difference of –1.91 hours (95% CI, –3.05 to –0.76; P = .0015).²

Then, she highlighted the available data for apomorphine, noting an important caveat for the US-based audience: the difference in administration in Europe vs the United States. “The subcutaneous injectable pen is available here. The pump is something that is widely used in Europe, and has been studied here, and hopefully, it will become available soon,” she said. Highlighting the results of the TOLEDO study (NCT02006121), she detailed the data that show among 106 individuals in the full analysis set (n = 53 in both groups), apomorphine infusion significantly reduced OFF time compared with placebo.³ Ultimately, it resulted in a −2.47 hour per day reduction (SD, 3.70) compared with −0.58 hour per day (SD, 2.80) for the placebo group, for a difference of −1.89 hours per day (95% CI, −3.16 to −0.62; P = .0025).³

Finally, Farmer offered an explanation of the process of determining candidacy for DBS, which has been shown for some time now to be an effective option for patients with PD.^4-6 “How do you go about thinking if DBS is right for your patient?” she said. “Well, having an evaluation with someone that has had Parkinson disease for about 4 years, who's starting to show these motor fluctuations that we've been discussing. If they haven't been seen by a movement disorder specialist when you're approaching this discussion, it is helpful to have one, because there's going to be a multidisciplinary team that usually needs to be involved in this type of intervention. From a neuropsychologist, cognitive testing, social work, whatever it might be. So, evaluation with a movement disorder specialist, and usually part of that team, as well as going to be a functional neurosurgeon.”

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She added that candidacy is often determined by a number of factors. First, the patient has had symptoms for at least 4 years and has PD of idiopathic nature, without cognitive impairment. Additionally, these patients should see symptomatic improvement with medication but have complaints of motor fluctuation and dyskinesia. As well, she explained, the ideal candidate also has refractory tremor and experiences moderate to advanced symptoms when their oral treatments lose their effectiveness. But most importantly, she said, “my approach is not to keep this as an option of last resort.”

“It is always about providing the education to the patients and whoever might be in the room. I use that with my patients. I don't want to overwhelm them. You have to keep the feel and the vibe of the people who you're having a discussion with,” she said. “If they want to know [their options], let them know when you're laying out the plan for how you can manage Parkinson disease. Having them know that there are so many options—and so many backup options if one doesn't work—can be really comforting and quite empowering. It's not like everyone's going to get surgery. But, if you know that if you're not getting a response to your meds that you'd like them to be, and we have this option, it can be helpful for them to realize that they haven't hit a wall, or that there's more hope at the end of the tunnel.”

Farmer closed her presentation by noting that the important takeaway is just that: there are options. She explained that the more treatment options that the physician and treating community know about, the better they can utilize them to get the most nuanced treatment plan for their patients.

“There are some practices and some organizations where it's only levodopa and levodopa alone, and they don't look at anything else. Personally, I think that is doing patients a disservice,” she said. “You have a lot of therapies that are available. None of them are without risk. You have to have that conversation with the patient and see what's best for them. But instead of just maximizing one and one alone, doing things in moderation together can potentially have a better clinical outcome for the patient because it addresses multiple things. They all know that Parkinson is more than just one thing. There's a lot at play that needs to be addressed.”

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REFERENCES
1. Farmer J. Devices and Surgical Treatment Modalities. Presented at: ATMRD Congress; June 17-19, 2022; Washington, DC.
2. Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141-9. doi:10.1016/S1474-4422(13)70293-X
3. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759. doi:10.1016/S1474-4422(18)30239-4
4. Groiss SJ, Wojtecki L, Südmeyer M, Schnitzler A. Deep Brain Stimulation in Parkinson's Disease. Ther Adv Neurol Disord. 2009;2(6):20-28. doi:10.1177/1756285609339382
5. Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009;301(1):63-73. doi:10.1001/jama.2008.929
6. Obeso JA, Olanow CW, Rodriguez-Oroz MC, Krack P, Kumar R, Lang AE. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N Engl J Med. 2001;345(13):956-63. doi:10.1056/NEJMoa000827.