Patient-Informed Phase 2 ATLANTIS Study Tests Selective D1PAM Agent Glovadalen for Parkinson Disease

Milton Biagioni, MD

At the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, a poster presentation highlighted the trial design of ATLANTIS, a patient-informed phase 2 study (NCT06055985) assessing the therapeutic potential of glovadalen (UCB), a D1 receptor positive allosteric modulator (D1PAM), as a potential treatment for Parkinson disease (PD). D1PAMs represent a promising approach for treating PD by enhancing dopaminergic signaling without directly stimulating dopamine receptors like traditional agonists.¹

The study, a multicenter, double-blind, placebo-controlled, randomized, parallel-group trial, includes 207 patients across 69 sites in the U.S. and is expected to be complete by the end of 2025. Presented by Milton Biagioni, MD, senior medical director of UCB’s Translational Medicine Neuroscience and Gene Therapy, the study’s primary end point is change from baseline to visit 9 (Day 70) in the average number of hours per day spent in the OFF state, as assessed by the participant-completed Hauser PD symptoms diary over 3 consecutive days.

In the study, glovadalen or placebo are administered as adjunctive treatment to standard of care, which includes at least levodopa therapy. Patients undergo a 6-week screening period, followed by randomization to either low-dose glovadalen, high-dose globadalen, or placebo, for a 2-week titration period, 8-week maintenance period, and 2-week safety follow-up. The trial includes several secondary end points, such as incidence of treatment-emergent adverse events (TEAEs), average C_trough at visit 9, and incidence of treatment-emergent serious AEs.

ATLANTIS, which commenced in 2023, is a proof-of-concept study, the design and implementation of which was shaped by direct and consistent involvement with patients with PD. A patient council comprising of patient organizations, patients themselves, and care partners, have been involved throughout the study to optimize patient experience and raise study awareness and outreach.

Through co-creation with the long-term patient council, direct and consistent engagement with patients with PD helped identify actionable insights and construct the study design and implementation. Some of the conversations included reduction duration of study visits and number of procedures, ensuring patient-facing materials were understood/endorsed by patients with PD, implementing a decentralized approach to the completion of selected patient-reported outcomes, and implementing a transportation service.

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To qualify for the study, participants must be 35 to 85 years old with a PD diagnosis for at least 5 years per the UK Parkinson's Disease Society Brain Bank criteria. They should experience significant daily motor fluctuations, be able to complete a Hauser PD symptoms diary, and be responsive to levodopa while currently receiving oral levodopa therapy, with or without adjunctive medications. Disease severity must be Stages I-III on the modified Hoehn and Yahr scale during ON states. Participants must weigh at least 45 kg, have a BMI between 18 and 30 kg/m², and agree not to share personal medical data on social media. Men must use contraception during treatment and for two weeks after, while female participants must not be of childbearing potential.

Exclusion criteria include any Parkinsonism other than idiopathic PD, dementia, or cognitive impairment (MoCA <23). Those with prior neurosurgical PD interventions, severe peak-dose dyskinesia, or a history of major depression or psychotic disorders in the past five years are ineligible. Additional exclusions include untreated hypertension, a history of melanoma, hypertensive crisis, or clinically significant orthostatic hypotension. Cardiovascular disqualifications include recent arrhythmias, myocardial infarction, stroke, transient ischemic attack, or moderate to severe congestive heart failure.

Glovadalen, also currently being assessed in a phase 1 study of healthy volunteers, is one of the few D1PAMs in development for PD. Unlike direct D1 agonists, which can cause receptor desensitization and adverse effects such as dyskinesias, D1PAMs enhance the effects of endogenous dopamine, allowing for more physiological signaling. These compounds work by increasing the receptor's response to naturally released dopamine without directly activating it, reducing the risk of overstimulation.

Preclinical studies have shown that D1PAMs improve motor function in PD models, and early clinical trials suggest they could offer symptom relief while minimizing side effects associated with traditional dopaminergic therapies. Researchers are exploring their potential not only for motor symptoms but also for cognitive dysfunction in PD, making them a compelling target for future therapeutic development.

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REFERENCE
1. Biagioni MC. Designing a patient-informed trial: ATLANTIS phase 2 study of the D1 receptor PAM, UCB0022, in advanced PD. Presented at: 2025 AD/PD Annual Meeting; April 1-5; Vienna, Austria. ABSTRACT 752