HONOLULU — Glovadalen (UCB), an investigational brain-penetrant D1 receptor positive allosteric modulator (D1 PAM), is both safe and effective for patients with advanced Parkinson’s disease (PD), new research showed.

Results from the phase 2 ATLANTIS trial, which included more than 200 patients with PD and significant daily motor fluctuations, showed that those who received oral glovadalen plus standard care for 10 weeks had a greater reduction in number of OFF hours per day than those who received matching placebo, meeting the primary endpoint.

Additionally, significantly more participants receiving active treatment reported feeling better on the Patient Global Impression of Change (PGI-C) of PD symptoms scale than those receiving placebo.

Dopaminergic-related adverse events (AEs) did not differ significantly between treatment groups, and there was a discontinuation rate of just 7.2% among the entire patient population.

“Demonstrating efficacy with a very low discontinuation rate was a positive surprise,” lead investigator Milton C. Biagioni, MD, senior medical director, translational medicine at UCB Biopharma, Braine-l’Alleud, Belgium, told Medscape Medical News.

Another surprise was that there were no cases of the dopaminergic side effects of hallucinations, confusion, hypotension, syncope, or excessive daytime sleepiness, he added.

Biagioni presented the findings as a late-breaking clinical trial on October 8 at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2025.

Proof-of-Concept Research

PD is associated with the degeneration of dopamine-producing neurons and a lowering of dopamine levels in the brain.

Glovadalen is a small molecule designed to boost dopamine activity selectively, targeting the D1 receptor to improve symptom control, according to the drug’s manufacturer.

The D1 receptor selectivity and allosteric mechanism of action “reduces the risk of receptor overstimulation and offtarget signaling, thereby decreasing the likelihood of AEs that typically accompany current dopaminergic treatments,” the investigators added.

Results from an earlier phase 1 randomized study showed that no deaths or serious treatment-emergent AEs (TEAEs) occurred among participants who received glovadalen (known at the time as UCB0022).

The current phase 2a proof-of concept ATLANTIS study included participants who had been diagnosed with PD for at least 5 years at baseline, had significant daily motor fluctuations, and were already taking oral levodopa with or without oral adjunctive anti-parkinsonian treatments. They were also between the ages of 35 and 85 years and in modified Hoehn and Yahr stages I-III during ON state.

Along with standard of care, all participants were randomly assigned to receive once daily placebo (n = 70; mean age, 69.1 years; 56% men; 91% White) or glovadalen at a low dose (n = 70; mean age, 68.9 years; 64% men; 91% White) or high dose (n = 67; mean age, 68.9 years; 58% men; 98.5% White) for 10 weeks.

“This was not a dose-ranging study,” Biagioni noted. It was designed to test the proof-of-concept of the compound and to see whether there were any safety signals from the higher dose, he added.

The primary outcome was the change in mean number of hours of OFF time from baseline to day 70, as measured by patient-completed Hauser diary. Secondary outcomes included safety and tolerability.

A Clear, Positive Response

Results showed a significantly greater reduction in OFF time at day 70 for both the low- and high-dose groups than for the placebo group (mean difference, -0.8 and -0.45 h/d, respectively; probability difference, 0.996 and 0.932, respectively).

On the PGI-C, 44% of participants receiving active-treatment reported feeling “much better” or “somewhat better” compared to 22% of those receiving placebo.

“A clear positive exposure-response relationship was observed for the primary endpoint, as well as several exploratory endpoints,” Biagioni told meeting attendees.

Any TEAE was reported by 53%, 55%, and 51% of the low-dose, high-dose, and placebo groups, respectively.

The most commonly reported nonserious TEAE for the low- and high-dose groups was headache (10% and 6% vs 4% in the placebo group). Rates of dyskinesia were moderate for all the groups at 5.7%, 6%, and 4.3%, respectively.

Two, five, and eight members of the low-dose, high-dose, and placebo groups, respectively, had TEAEs leading to discontinuation or withdrawal.

First-In-Class vs Best-In-Class?

The study “provides proof of mechanism for glovadalen as a selective D1 PAM, improving OFF time…without notable worsening of dopamine-related TEAEs or dyskinesias,” the investigators wrote.

“These data support glovadalen as a potential first-in-class oral therapy for PD,” they added.

Biagioni noted that the investigational drug tavapadon (AbbVie), which had a New Drug Application submitted to the FDA in September, is a D1/D5 dopamine agonist, “with a profile of selectivity that is similar” to glovadalen. “But it retains the mechanism that is agonism while ours has an allosteric modulation,” he said.

“I think there will be a new class that will be driven by the receptor selectivity. If they get approval, then we’ll have to discuss if [our drug] is ‘best in class’ or if it would be considered a different class,” Biagioni said.

Asked about potential future research plans, he said, “we have not seen the best of what this drug can do yet”; and will want to test even higher doses in other studies to see if they can up the efficacy while retaining the same safety profile. “Dose finding will be needed,” he said.

Overall, “because of the pharmacologic promise that this mechanism of action has, in terms of the ability to only act when the dopamine is released and that it doesn’t act on its own as an agonist, we think it should be effective for all ranges of the disease,” Biagioni said. “We see enormous potential for this compound.”

‘Promising’ Findings

Commenting for Medscape Medical News, Julie Pilitsis, MD, PhD, neurosurgeon and physician executive for functional neurosurgery at Banner – University Medical Center Tucson, Arizona, called the current study “promising” and said she’s excited to see future phase 2b and phase 3 studies with the drug.

She said the drug could meet an important need if proven effective, as current treatments carry risks such as severe dyskinesias and hallucinations associated with dopamine agonists.

Pilitsis, who is also chair of the Department of Neurosurgery at University of Arizona College of Medicine in Tucson, was not involved in the research.

She noted that glovadalen’s mechanism of action is interesting.

“I thought it was a smart way to tackle [these issues] that I hadn’t seen before,” Pilitsis said. She added that the investigators asking patients how they felt after taking the drug was also important.

“So even that small decrease in OFF time seemed to make people feel much better, which I thought was compelling,” she said.

Pilitis noted that some things she’d like to see in future studies would be a more diverse patient population and a longer assessment period.

“I’m not sure you’d expect to see the development of dyskinesia within the duration of time they were watching. So I think tracking that out a little bit longer is important to really make sure those don’t arise, even if it’s in the 3-6 month range,” she said.

The study was funded by UCB. Biagioni is an employee of UCB Biopharma. Pilitsis reported having no relevant financial relationships.