Lundbeck reports Phase Ib data for Lu AF28996 in advanced Parkinson’s disease, with improvements in Good ON-time and dyskinesia as DARE2 begins.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
Lundbeck has presented results from an open-label Phase Ib trial (NCT04291859) of Lu AF28996, an investigational oral prodrug of a D1-like/D2-like dopamine receptor agonist, in people with advanced Parkinson’s disease (PD). The findings were presented on October 6, 2026, at the International Congress of Parkinson’s Disease and Movement Disorders (MDS 2026) in Seoul, South Korea, and come from Part B of trial.
Lundbeck has also confirmed that the first participant has been randomized in the Phase II DARE2 trial (NCT07514858).
Targeting Motor Complications Beyond Levodopa
Levodopa remains a cornerstone of symptomatic treatment for Parkinson’s disease, but motor complications can become increasingly difficult to manage as the disease progresses. These include OFF-time, when Parkinson’s symptoms return or worsen, and dyskinesia, or involuntary movements associated with treatment. Some treatment options for advanced disease involve invasive procedures or continuous drug delivery and have specific eligibility requirements.
Lundbeck is developing Lu AF28996 as an oral, non-invasive approach for people who continue to experience motor fluctuations despite optimized non-invasive treatment. The company describes the compound as having a pharmacologic profile that may enhance dopaminergic signaling in the striatum in a prolonged manner. Its activity at both D1-like and D2-like dopamine receptors may contribute to motor control. These are proposed pharmacologic effects and remain subject to clinical validation.
A Small, Open-Label Exploratory Study
Part B of the Phase Ib study enrolled 34 participants with advanced Parkinson’s disease whose motor symptoms remained suboptimally controlled despite optimized non-invasive antiparkinsonian medication. Participants received Lu AF28996 twice daily for six weeks. Twenty-five participants entered an optional extension of up to 12 additional weeks, allowing assessment through Week 18.
The study was exploratory and did not include a placebo or active comparator. Lundbeck therefore reports the changes from baseline descriptively rather than as evidence of comparative efficacy. The Week 18 findings also come from a smaller group because participation in the extension was optional. Results from the earlier ascending-dose Part A cohorts were not included in this analysis.
Gains in Good ON-Time and Reductions in Dyskinesia
At baseline, participants had an average of 9.5 hours of Good ON-time per day, defined as ON-time without troublesome dyskinesia. Average daily OFF-time was 4.7 hours, while ON-time with troublesome dyskinesia was 1.8 hours.
At Week 6, Good ON-time increased by 3.6 hours per day, while OFF-time decreased by 2.3 hours. At Week 18, Good ON-time had increased by 3.4 hours from baseline and OFF-time had decreased by 2.0 hours.
ON-time with troublesome dyskinesia decreased by 1.2 hours at Week 6 and 1.4 hours at Week 18. Among participants who had at least one hour of troublesome dyskinesia per day at baseline, the reduction was larger, at 2.3 hours a Week 6 and 2.8 hours at Week 18.
Dyskinesia severity also declined based on the Unified Dyskinesia Rating Scale (UDysRS). The mean total score decreased by 8.5 points at Week 6 and 14.5 points at Week 18 from a baseline score of 28.3.
Because the study lacked a control group, these changes cannot by themselves establish that Lu AF28996 caused the observed improvements. The results provide an early clinical signal that requires testing in a randomized controlled setting.
Levodopa Reduction and the Question of Durability
Mean daily levodopa dose decreased by 53.4% at Week 6 and 29.2% at Week 18. Lundbeck highlighted the motor findings alongside these reductions in levodopa exposure.
However, the available announcement does not establish why the magnitude of dose reduction was smaller at Week 18. In addition, only 25 of the original 34 participants entered the optional extension. The Week 18 findings therefore represent a smaller, self-selected group and should not be interpreted as evidence that a levodopa-sparing effect is sustained over time.
The larger randomized DARE2 study will be important for determining whether changes in motor control and medication requirements are reproducible under controlled conditions.
Safety Profile Consistent with Early-Stage Evaluation
Most treatment-emergent adverse events in the Phase Ib study were reported as mild, and Lundbeck said that no unexpected safety signals were observed. Nausea, dizziness and falls were among the most common adverse events.
The company announcement does not provide detailed event counts or discontinuation data in the information available for this report. The larger Phase II study will therefore provide a more informative assessment of the safety and tolerability profile of Lu AF28996 with controlled treatment exposure and a larger participant population.
DARE2: The First Controlled Test
The Phase II DARE2 trial (NCT07514858) is a randomized, double-blind, parallel-group, placebo-controlled, flexible-dose study evaluating Lu AF28996 in approximately 150 adults with Parkinson’s disease who continue to experience motor fluctuations despite optimized non-invasive symptomatic treatment.
The primary endpoint is the change from baseline to Week 19 in daily Good ON-time, making the same clinically relevant motor-fluctuation measure a central focus of the controlled Phase II evaluation.
The first participant has been randomized, and recruitment is underway at selected sites in the United States. Additional sites are planned in the United Kingdom, Spain, Italy, Germany, France, Poland, the Czech Republic, Sweden and Japan.
What the Placebo-Controlled Data Must Show
The Phase Ib findings provide an early look at the potential effects and tolerability of Lu AF28996, but the study’s small size, open-label design and absence of a comparator limit the conclusions that can be drawn. Improvements in diary-based motor outcomes cannot be attributed definitively to the investigational drug without a control group.
DARE2 will therefore be an important test of whether the increase in Good ON-time observed in Phase Ib is maintained relative to placebo, whether the safety profile remains acceptable with flexible dosing, and whether the observed changes in motor complications can be reproduced in a larger controlled population.
For now, Lu AF28996 remains an investigational therapy and is not approved by the US Food and Drug Administration or any other regulatory agency, and its efficacy and safety have not been established. The Phase Ib results provide preliminary clinical findings, while the ongoing DARE2 trial will determine whether those observations translate into controlled evidence of benefit in people with Parkinson’s disease experiencing motor fluctuations.
References
Lundbeck presents Phase Ib data for Lu AF28996 in advanced Parkinson’s disease, as Phase II trial begins, Lundbeck, 06 October 2026
Lu AF28996 in Participants with Parkinson’s Disease (PD), ClinicalTrials.gov ID NCT04291859
A Trial Investigating Lu AF28996 in Adults with Parkinson’s Disease Who Have Motor Fluctuations (DARE2), ClinicalTrials.gov ID NCT07514858
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.