Article In Brief
Eight new Parkinson's disease drugs have been approved by the US Food and Drug Administration in the past five years. Movement disorders specialists offered insights into when they would prescribe the new additions or not.
Evolutionary, not revolutionary. Sometimes significantly helpful in treating symptoms, sometimes not, but always more expensive, and rarely suitable as first-line treatment.
That, in a nutshell, is what neurologists who specialize in the treatment of Parkinson's disease say about the eight brand-name medications that have come onto the market in the past five years for the treatment of the disorder's movement symptoms.
“None of these new medications is a silver bullet for fixing the lives of people with Parkinson's disease,” said Meredith Spindler, MD, associate professor of clinical neurology at Penn Medicine and associate clinical director of its Parkinson's Disease and Movement Disorders Center. “They offer incremental improvements in quality of life for some patients. But I generally choose the off-patent, older drugs first, because they're less expensive and easier to get.”
Some movement-disorder neurologists offered a decidedly glass-half-full view of the newer PD medications.
“Some of them are no big deal, but some are true game changers,” said Rajesh Pahwa, MD, FAAN, the Laverne & Joyce Professor of Neurology, chief of the Parkinson and Movement Disorder Division, and director of the Parkinson's Foundation Center of Excellence at the University of Kansas Medical Center.
He pointed to extended-release amantadine (Gocovri) as the first drug shown to not only reduce off time but to also reduce dyskinesia. “That to me is a huge benefit,” Dr. Pahwa said. “All the other medications we use to treat off time make the dyskinesias worse.”
The expense of the newer medicines for PD, however, makes many neurologists think twice before prescribing them.
“Most of my patients throw in the towel when they see co-pays of hundreds or even thousands of dollars per month,” said Michele Tagliati, MD, vice chair of neurology and director of movement disorders at Cedars-Sinai Medical Center. “Even people who are capable of paying for them question the point when they don't offer any life-changing benefits.”
As a result, some PD specialists said they rarely prescribe the newer medicine.
“Patients sometimes request these newer medications by name, because they saw advertisements for the drug, or because another provider suggested or prescribed one,” said Melissa Nirenberg, MD, FAAN, a movement disorder specialist and professor of neurology at the Icahn School of Medicine at Mount Sinai. “They are convinced that because a drug is newer, it must be better, though this is not often the case.”
Before adding adjunctive medications, Dr. Nirenberg said, “I make sure that patients are taking their current medications properly, encouraging them to use a multicompartment medication box, set pill timers, and in some cases have a partner assit them with medication management. This is sometimes more effective than adding a new medication.”
Dr. Tagliati said his message to patients looking for improved outcomes is to focus not on the latest medicines but on lifestyle factors that are within their own control.
“I tell them to take their lives in their own hands: to exercise, eat properly, sleep well,” he said. “Exercise in particular has been shown to have a dramatic, positive effect on progression of the disease.”
Caveats and cautions aside, each of the eight newer medicines for PD has its strengths for certain patients, at certain times.
Fractionated Tablets of Levodopa/Carbidopa (Dhivy)
With the exact same dose as other immediate-release levodopa/carbidopa tablets (100 mg levodopa and 25 mg carbidopa), Dhivy's unique benefit is that it is scored into quarters, so that it can easily be snapped in half or quarters.
“We have struggled with levodopa/cardidopa dosing with some of our patients because half a tablet might not be enough and a full tablet might be too much,” said Dr. Pahwa. “Telling them to cut a pill in half was difficult: sometimes they would get 0.6 off the tablet, or 0.4. And breaking one into quarters was impossible.”
While the fractionated tablets are certainly not a profound breakthrough, Dr. Pahwa added, “For patients struggling with getting the right dose, it's a big addition.”
The FDA approved Dhivy in November 2021. Its manufacturer, Avion Pharmaceuticals, LLC, announced on February 14 that it is now available commercially.
Approved by the FDA in 2019, istradefylline is the only one of the eight new PD medicines that has a novel mechanism of action: it is the first, and so far only, adenosine A2A receptor antagonist. It is prescribed as a daily add-on therapy to levodopa for treatment of off-time.
“It's not a me-too drug, and it's relatively safe compared to other medications for Parkinson's,” Dr. Pawha said. “Some people say it's not very potent, but the clinical trials of it were done in people who had already taken the other approved drugs for reducing off time,and still needed something more. Even in that population, it was found effective enough to gain FDA approval. For some people who are truggling with off time, it can be very helpful.”
Maureen Leehey, MD, FAAN, chief of the movement disorders section and professor of neurology at the University of Colorado, said she wishes istradefylline was marketed as a first-line therapy, not only as an add-on.
“I think it would be good at an early stage, to give people something mild yet beneficial,” Dr. Leehey said. In the meanwhile, she said, “I prescribe it if someone is a little under-treated, if they don't have quite enough dopamine medication. I wouldn't give it to someone who's having dyskinesias, however.”
When she first started prescribing istradefylline, she said, “I made the mistake of telling patients to take it once a day whenever they wanted. Some of them took it before bed and couldn't sleep. It's activating for a lot of people. Now I make sure to tell them to take it in the morning.”
Not all movement disorder neurologists, however, are fans of istradefylline.
“It's a very weak drug,” Dr. Nirenberg said. “When it first went to the FDA, the approval was turned down not because of safety concerns but because of low efficacy.”
Like entacapone and tolcapone, opicapone is an inhibitor of catechol-o-methyl transferase (COMT). While all three are add-on therapies for the treatment of off-time, the older types have to be taken multiple times a day, whereas opicapone is taken just once daily at bedtime.
“It's a stronger, once-daily COMT,” Dr. Spindler said. “If a patient tried entacapone and it didn't help enough—and they don't have too much dyskinesia—I'll try Ongentys, unless they didn't tolerate entacapone well.”
Another reason some patients prefer opicapone, Dr. Pahwa said, is that it doesn't cause the diarrhea and orange-colored urine that the older COMT drugs do. What's more, “The trials in Europe showed that when patients were switched from entacapone to opicapone, they had much better control of off time. It may be a ‘me too’ drug in the COMT class, but the benefit is unique.”
Dr. Leehey added a note of caution: because of its higher strength to last throughout the day, she said, “It seems to cause dyskinesias more. It's nice that you have to take it only once a day, but for some of the more fragile patients who are fluctuating a lot, it might give them problematic dyskinesias. And for a lot of my patients, their insurance companies aren't paying for it.”
Approved in 2018 a third drug in the family of monoamine oxidase B (MAO-B) inhibitors, safinamide is indicated as adjunctive therapy for carbidopa/levodopa off-time. Like rasagiline, it is taken once daily.
Dr. Leehey said that although she hasn't prescribed it much so far, “I'm excited about it because safinamide appears to reduce pain. And a couple of studies also show that as a class of medicines, MAO-B inhibitors might—might—slow down progression of the disease. So I encourage my early-stage patients to take an MAO-B inhibitor. And if I have a patient experiencing significant pain, I'll learn toward safinamide.”
Dr. Nirenberg, however, said that if she wants to prescribe an MAO-B inhibitor, she usually chooses rasagiline or selegiline. “Safinamide has no clear advantage over other, less expensive, MAO-B inhibitors,” she said.
Levodopa Inhalation Powder (Inbrija)
Whereas safinamide, opicapone, and istradefylline are all taken on a daily basis, levodopa inhaler powder (Inbrija) is one of the two newer drugs that can be taken as needed whenever an off-period strikes. Prior to its approval, patients seeking a quick hit of levodopa to get moving again were advised to chew a tablet of carbidopa/levodopa.
“Inbrija is better than chewing the tablet to some degree because it doesn't have to go through the gut,” Dr. Leehey said. “But when I first started prescribing it, a lot of my patients had difficulty tolerating it. They would shoot it into the back of their throat, like an asthma inhaler, and it would make them cough. Now I give them a little handout with pointers about how to use it. You still spray in the back of your mouth, but the major point is to take a slow, deep, continuous breath and spray it gently. They can also wet the back of their throat with water and take sips of water in-between. Sometimes I even prescribe a lidocaine spray.”
Apomorphine HCI (Kynmobi)
The other rescue treatment for off-time is apomorphine HCI, approved by the FDA in 2020 to be taken sublingually. The challenge with prescribing it, however, is that apomorphine can cause nausea and vomiting, especially when patients begin taking it.
“Some people will get transient side effects from it,” Dr. Spindler said, “but in those who don't, apomorphine HCI is worth a try for people with unpredictable and disabling off times who cannot tolerate Inbrija.”
For people who do experience nausea, finding a medicine to treat the nausea is a challenge. One of the major class of anti-nausea drugs, the 5HT3 antagonists, are contra-indicated for anyone taking Kynmobi, because they can cause hypotension so severe that they lose consciousness. And the one antiemetic currently recommended on the label, trimethobenzamide, is no longer being manufactured by Pfizer.
Dr. Pahwa said that he can still prevent nausea in most patients by slowly titrating the dose of Kynmobri upward over a period of weeks.
Nevertheless, Dr. Leehey said, “I really am not enthusiastic about Kynmobi. I haven't prescribed it because I don't need to. I have other choices for treating as-needed off-time. I usually prescribe Inbrija or have them chew half a tablet of carbidopa/levodopa.”
Extended-release Amantadine (Gocovri and Osmolex)
The final two drugs for PD approved by the FDA since 2017 are both extended-release versions of amantadine, and like it, they are both aimed at treating dyskinesias. Gocovri is also indicated for reduction of off-times.
“Gocovri is the only medication we have for Parkinson's that treats both off time as well as dyskinesias,” Dr. Pahwa said.
Dr. Spindler also had some good things to say about the extended-release versions of amantadine. “I have seen greater improvements in dyskinesia, dystonia, tremor, and off periods with Gocovri and Osmolex than I have seen with standard amantadine, possibly due to greater adherence to the once-daily dosing,” she said. “However, on the flip side, I have also seen greater side effects, especially hallucinations. It's worth a try if other options have failed, the patient is relatively young, and they do not have any history of cognitive impairment, hallucinations, or orthostatic hypotension.”
Dr. Spindler added: “They can cause hallucinations, confusion, memory loss, constipation, and urinary retention, so we tend not to use any form of amantadine in older patients or others who are susceptible to those symptoms.”
Dr. Pahwa noted, however, that because amantadine is excreted through the kidneys, older patients with reduced renal function should be prescribed lower doses.
“You will get those side effects if you use the same dose in the elderly as you give to the younger patients,” he said. “You can get by with much lower doses.”
Better Drugs in the Pipeline
While the PD medications approved in the past five years have improved quality of life by improving symptomatic treatment, none has targeted the non-motor symptoms or slowed the progression of the disease. That may be changing with new drugs now under development.
“In Parkinson's disease, we are at a very, very interesting juncture,” Dr. Tagliati said. “For decades we have milked the dopaminergic concept. Everything has been focused on dopamine, dopamine, dopamine. We are now beginning to realize that other neurotransmitters, such as epinephrine and serotonin, might also play a role.”
Dr. Tagliati and others are also pursuing research into the use of liraglutide (Victoza) and other drugs that relieve insulin resistance.
“We are following the hypothesis that insulin resistance might be implicated in neurodegeneration,” he said. “How effective it will be, and in whom, we are still studying.”
Another new route is aimed at addressing genetic variants associated with the risk of PD: LRRK2 and glucocerebrosidase (GBA). “Although they explain only 5 percent to 15 percent of Parkinson's cases,” Dr. Tagliati said, “their enzymatic and protein abnormalities might make them useful for targeting other people who don't have those variants. Those approaches are potentially exciting, but we need to make sure the treatments actually work.”
Dr. Pahwa noted that clincial trials to treat GBA or LRRK2 mutations are already underway.
“Our biggest unmet need is to find drugs that slow the progression of the disease,” he said. “It's not for lack of trying. Scientists have tested over 100 investigational agents over the last 20 years to find something. But we are getting closer every day.”