Parkinson’s Disease Clinical Trials, Therapeutic Approaches

In a slate of major Parkinson’s disease (PD) trial readouts, drug developers are taking aim at the disease’s most common symptom: motor fluctuations.

“Around 80% of people with PD have some motor symptom fluctuations,” says Dr Jeffrey Kordower, founding director of Arizona State University’s Banner Neurodegenerative Disease Research Center. “The rationale behind going after these symptoms is really strong.”

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Four major trials have readouts expected in the next six months, three of which target motor symptoms, also known as dyskinesia. Two trials focus on dyskinesia resulting from sustained use of generic levodopa, which is widely considered the standard of care in PD. A third study tests a new formulation of levodopa that could reduce treatment side effects such as dyskinesia, while a fourth trial takes aim at cognitive impairment in PD.

Parkinson’s disease is a progressive central nervous system disease associated with deficiencies in the neurotransmitter dopamine. There are no disease-altering treatments available, but levodopa can increase dopamine levels in the brain and reduce symptoms.

IRLAB, Celon target Parkinson’s disease motor symptoms

While levodopa can reduce PD symptoms by increasing dopamine levels in the brain, prolonged use can cause increased bouts of dyskinesia during “OFF time” when the drug has reduced effects. IRLAB Therapeutics and Celon Pharma have Phase II trials aiming to reduce levodopa-induced dyskinesia using two different approaches.

IRLAB’s mesdopetam, which targets the dopamine D3 receptor, has placebo-controlled Phase II trial (NCT04435431) results expected the second half of this year. Mesdopetam has estimated peak sales of $226 million in 2026, according to GlobalData’s consensus forecast. GlobalData is the parent company of Clinical Trials Arena.

As a primary endpoint, the Phase II mesdopetam trial assesses change in “ON time”, defined as hours in the day where patients experience the positive effects of levodopa without the negative effects of dyskinesia. Before and after 12 weeks of treatment, patients record their hours of “ON time” over the course of 24 hours.

Meanwhile, Celon’s CPL500036, which targets phosphodiesterase 10A (PDE10A), also has placebo-controlled Phase II (NCT05297201) results expected this year. The four-week study uses a primary endpoint of the Unified Dyskinesia Rating Scale (UDysRS), which measures the severity of dyskinesia side effects.

Of the two primary endpoints, change in “ON time” is a better measure than the UDyRS, Kordower says. “My understanding is that patients would much rather have less time spent in dyskinesias than decreased magnitude of dyskinesia,” he explains.

Aptinyx focuses on Parkinson’s disease cognitive impairment

Aptinyx is amid a Phase II trial targeting one of the biggest unmet needs in Parkinson's disease treatment: cognitive impairment and dementia.

In patients with PD, Lewy bodies and alpha-synuclein, which are implicated in the pathology of PD, can spread into the cortex, causing forms of cognitive impairment and dementia in a large percentage of patients, Kordower explains. “There’s no current treatment, so any clinical trial that has some benefit is incredibly valuable,” he says.

Aptinyx’s NYX-458, which targets the N-methyl-D-aspartate (NMDA) receptor, has placebo-controlled Phase II (NCT04148391) results expected at the end of 2022 or early 2023. The trial lists eight primary endpoints, ranging from the incidence adverse events to reductions in scales of psychosis and suicidal ideation.

"There's no current treatment, so any clinical trial that has some benefit is incredibly valuable."

Jeffrey Kordower

Targeting NMDA is a “good start,” says Dr David Eidelberg, neurologist at the Feinstein Institutes for Medical Research. However, showing reduction in cognitive impairment may be more difficult in PD than in Alzheimer’s disease, where changes are typically more pronounced, he notes.

Nevertheless, experts are encouraged that a trial is taking aim at this substantial unmet need. According to GlobalData consensus forecasts, NYX-458 has expected peak sales of $323 million in 2028.

Amneal tests a new formulation

Amneal Pharmaceuticals plans to report Phase III safety results for IPX-203, a reformulation of the common generic PD treatment combination of carbidopa and levodopa (CD/LD) that could reduce symptom fluctuations. The company said the Phase III, open-label extension study (NCT03877510) will have results available by the end of the second quarter of 2022.

CD/LD can lead to troughs and spikes of plasma levels that generate side-effects like dyskinesia, Kordower explains. A new extended-release version of CD/LD could smooth out these drops, he notes.

If approved, IPX-203 will join several other marketed reformulations of CD/LD. Amneal’s own extended-release capsule Rytary, Schwarz Pharma’s orally disintegrating tablet Parcopa, and AbbVie's enteral suspension Duopa all have FDA approval in PD. A GlobalData consensus forecasts pegs peak IPX-203 sales at $127 million in 2028.

In a separate, placebo-controlled Phase III trial (NCT03670953), IPX-203 resulted in 0.53 more hours of “ON time” than immediate-release CD/LD after seven weeks (p=0.0194). Earlier, a six-week Phase II trial of IPX-203 (NCT02271503) reported no serious treatment-emergent adverse events among the 26 patients enrolled. Experts say the long-term safety data will be key in determining IPX-203’s place among CD/LD formulations.

Where is drug development headed?

Overall, experts say the Parkinson's disease field aims to develop therapies that can slow or stop disease progression. Kordower notes several promising gene therapy and stem cell therapy approaches are entering the early stages of clinical development.

Most ongoing PD trials are at the Phase II stage, according to GlobalData’s Clinical Trial Database. While institutions are sponsoring 84 trials of the 133 ongoing Phase II studies (63%), pharma companies are running 44 trials of the 56 ongoing Phase I studies (79%).

As the field awaits results from the slew of ongoing trials, experts agree that the PD trials reading out in the remainder of 2022 could have a substantial impact. “These four trials are all very timely,” Eidelberg says. “The community of movement disorder specialists and neurologists would use these drugs because the indications we're talking about are really very common.”