Delays in Parkinson’s Treatment Due to Fear of Side Effects a Serious Problem, Neurologist Says

A fear of the potential side effects of Parkinson’s disease treatments, dubbed “levodopa phobia,” can cause patients and their doctors to delay the use of these therapies, a neurologist says.

However, evidence suggests that starting adequate levodopa therapy early is safe, particularly for patients with increased functional disability, according to a lecture by Joseph Jankovic, MD, a professor of neurology at Baylor College of Medicine, which was presented by the Parkinson Voice Project (PVP.)

Jankovic’s lecture, “New and Emerging Treatments for Parkinson’s Disease,” was presented to patients and caregivers via Skype as part of the PVP’s Parkinson’s Lecture Series, from the Clark and Brigid Lund Parkinson’s Education Center. A video of the presentation is available online.

Disease-modifying therapies

There are no therapies currently available that slow or prevent the progression of Parkinson’s, though several are in clinical trials. A Phase 3 trial (NCT00256204), called ADAGIO, completed in 2011, suggested that early Azilect (rasagiline) treatment might be able to delay the progression of the disease. However, the study included two dosages, 1 mg and 2 mg, and while the benefits were true for the the lowest dose, they didn’t hold up for the larger dose. Because the two doses were associated with different outcomes, the results needed careful interpretation, and the U.S. Food and Drug Administration (FDA) did not approve Azilect as a disease-modifying therapy. 

Researchers are exploring several treatments with the potential to modify the disease, including inosine (which elevates urate levels), and isradipine (a calcium channel inhibitor). Both are in Phase 3 trials (NCT02642393 and NCT02168842).

However, Jankovic said, the “most important strategy in development” is reducing alpha-synuclein, the protein that doesn’t work properly and accumulates in the brains of Parkinson’s patients, leading to neuronal death.

Jankovic and his colleagues last year published a study based on a Phase 2 trial  (NCT03100149) of an antibody — prasinezumab (PRX002/RG7935) — that’s designed to clear alpha-synuclein proteins. The 80-patient, ascending-dose study showed that the treatment was safe, and reduced alpha-synuclein concentrations in the blood over the course of 52 weeks, with no serious adverse events reported. The study supported the continuation of the Phase 2 trial.

Similar antibodies currently being tested in trials include Biogen’s BIIB054 (NCT03318523), AstraZeneca’s MEDI1341 (NCT03272165) — both currently recruiting — and AbbVie’s ABBV-951 (NCT03781167), which is not yet enrolling participants.

Early symptomatic therapies

When patients first start to experience symptoms severe enough to require treatment, they and their doctors may be reluctant to start levodopa or levodopa-carbidopa — the most commonly used treatment for Parkinson’s symptoms — for fear they will develop motor complications such as dyskinesias.

Some patients may turn to natural supplements, such as bacopa extract or mucuna pruriens. Jankovic “strongly discouraged” the use of these products for “many, many reasons,” chief among them that some supplements contain levodopa at inconsistent doses.

An alternative for patients and neurologists concerned about starting levodopa too early are dopamine agonists such as Mirapex (pramipexole), Requip (ropinirole), Dostinex (cabergoline), and Permax (pergolide). Instead of helping the brain produce more of the dopamine it lacks, these treatments directly stimulate the receptors that dopamine would normally act on.

A 2009 study, which compared pramipexole with levodopa in patients who had not yet been treated with levodopa, found that 50% of those on pramipexole experienced dyskinesia, compared with 68.4% of the levodopa patients.

“There is no doubt that delaying levodopa therapy by using dopamine agonists early may delay the onset of levodopa-related motor complications,” Jankovic said.

Although levodopa has some potential for side effects in vitro (or in the laboratory), Jankovic said there is no evidence that this translates to patients. Therefore, delaying the use of the therapy, particularly for patients with increased functional disability, is not backed by currently available scientific data, he said.

However, he believes that because every patient is different, the timing, choice, and dosage of therapy must be individualized according to the needs of each particular patient.

Emerging and experimental therapeutics

Almost all patients with severe Parkinson’s who take levodopa or levodopa-carbidopa will, over time, experience motor fluctuations and dyskinesias. Thus, many emerging therapies are designed to make the treatment more effective and reduce the side effects.

There are three therapies work to extend the effectiveness of levodopa by maintaining increased dopamine concentrations in the brain. Xadago (safinamide) inhibits monoamine oxidase, an enzyme that normally breaks down dopamine. Opicapone works by preventing a different enzyme, catechol-O-methyltransferase (COMT), from breaking down dopamine. Gocovri (amandine) prevents cells from recycling dopamine.

Several new formulations of levodopa are intended to stretch the effects of a single dose, or act almost immediately to help patients recover from “off” episodes between doses.  

Rytary, a capsule that can be taken orally, contains beads of carbidopa-levodopa that dissolve and release the medicine at different times. Since the treatment needs to be taken more than once a day, patients end up ingesting a higher dose of levodopa than they would otherwise. But the effects start sooner and last longer than the common formulation of carbidopa-levodopa.

Researchers have experimented with administering the treatment continuously for 24 hours using an intestinal gel, which is surgically implanted into the small intestine and programmed to consistently administer the treatment at the appropriate dose.

But choosing this surgery “cannot be taken lightly,” Jankovic said. While patients did increase their “on” time without dyskinesia (by 4.11 hours for those who used the intestinal gel compared with 2.24 hours for those who used oral levodopa), almost all of the 66 patients in a 2014 study experienced gastrointestinal side effects as a result of the device insertion.

Jankovic also described the “accordion” pill currently being tested in a Phase 3 trial (NCT02605434). The pill, developed by Intec Pharma, is a multilayer film that unfolds in the stomach and stays there for 12 hours, releasing a combination of levodopa and carbidopa.

Rather than extending the life of a dose of levodopa, some companies develop “rescue therapies” that can be taken during “off” periods, or when treatment wears off. These therapies take effect almost immediately, and help the patient make it until their next scheduled dose of levodopa. Several forms — both approved and in trials — are dopamine agonists injected under the skin.

Other companies are developing treatments they hope will be delivered through less invasive methods, such as under the tongue, in the case of APL-130277, or through inhalation, like Inbrija, a levodopa powder approved in December 2018.

Surgical therapies are gaining more attention, with scientists testing focused ultrasound, which was approved by the FDA at the end of 2018. However, it is available in very few centers, and costs more than $4 million.

Also during 2018, researchers conducted a pilot study of five patients suggesting that spinal cord stimulation may be able to help patients improve gait.

Jankovic says it is too early to meaningfully discuss several other experimental therapies, such as gene therapies or stem cell treatments. “Ask me in 10 years,” he said.

Different agents are being investigated to treat non-motor symptoms, including Exelon (rivastigmine) and memantine (sold under the brand name Namenda, among others) for cognitive impairment, paroxetine and venlafaxine for depression, and SEP-363856 for psychosis. Nuplazid (pimavanserin) is the only therapy currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

In addition to all the therapies on the market, Jankovic said, he “couldn’t emphasize enough the importance of physiotherapy,” and high-intensity exercise — “something that really makes you huff and puff.”