Oral D1/D2 Agonist Lu AF28996 Increases Good ON-Time in Phase 1b Advanced PD Study, Phase 2 DARE2 Trial Begins

Lundbeck recently announced that its Lu AF28996, an investigational oral prodrug of a D1-like/D2-like dopamine receptor agonist, was associated with increases in good ON-time and reductions in OFF-time, troublesome dyskinesia, and levodopa dose in an open-label phase 1b study (NCT04291859) of patients with advanced Parkinson disease (PD). The data were presented at the 2026 International Congress of Parkinson's Disease and Movement Disorders, as the company announced that the first participant has been randomized in the placebo-controlled phase 2 DARE2 trial (NCT07514858).¹

"Many people with advanced Parkinson's disease continue to experience motor fluctuations and dyskinesia that can significantly affect daily life," Tarek Samad, PhD, MS, executive vice president and head of research and development at Lundbeck, said in a statement.¹ "We are encouraged by the Phase Ib results with Lu AF28996, including the improvements observed alongside substantial reductions in levodopa dose. With the DARE2 Phase II trial now underway, we are taking the next step in evaluating its potential in a larger, randomized and controlled study."

Phase 1b Findings

The phase 1b study comprised a part A with once- and twice-daily ascending-dose cohorts and a part B with twice-daily cohorts; the MDS presentation reported part B only. In part B, 34 participants whose motor symptoms were suboptimally controlled despite optimized noninvasive antiparkinsonian medication received Lu AF28996 twice daily for 6 weeks. Twenty-five then entered an optional extension of up to 12 additional weeks. Per the trial registry, concomitant dopamine agonists were not permitted during the study.²

At baseline, participants averaged 9.5 hours of good ON-time (ON-time without troublesome dyskinesia), 4.7 hours of OFF-time, and 1.8 hours of ON-time with troublesome dyskinesia per day. At weeks 6 and 18, good ON-time increased from baseline by 3.6 and 3.4 hours, respectively, while OFF-time decreased by 2.3 and 2.0 hours and ON-time with troublesome dyskinesia decreased by 1.2 and 1.4 hours.

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Unified Dyskinesia Rating Scale (UDysRS) total scores fell from a baseline of 28.3 by 8.5 points at week 6 and 14.5 points at week 18. Mean daily levodopa dose decreased by 53.4% at week 6 and 29.2% at week 18. Among participants with at least 1 hour per day of troublesome dyskinesia at baseline, daily ON-time with troublesome dyskinesia changed by −2.3 hours at week 6 and −2.8 hours at week 18. All efficacy results were reported descriptively, without statistical testing.

Most treatment-emergent adverse events (TEAEs) were mild, and no unexpected safety signals were observed. The most common TEAEs were nausea, dizziness, and falls, which Lundbeck described as consistent with a dopaminergic mechanism.

Clinical Context

Levodopa remains the cornerstone of symptomatic PD treatment, but long-term use is commonly complicated by motor fluctuations and dyskinesia as the disease progresses.³ For patients with advanced disease, many options involve invasive procedures or continuous drug delivery with specific eligibility requirements, leaving a need for noninvasive approaches that offer more consistent motor control.

Lu AF28996 is designed as a prodrug intended to provide prolonged dopaminergic striatal signaling through concerted activation of D1-like and D2-like receptors. Lundbeck is investigating it for motor fluctuations and levodopa-induced dyskinesia. Earlier phase 1b data from the program were presented at the 2026 Alzheimer's and Parkinson's Diseases (AD/PD) Conference in Copenhagen, where the company reported the agent was generally well tolerated.⁴

Limitations and Next Steps

The current study was exploratory, small, and open-label, with no placebo or active comparator, which limits interpretation of diary-based ON/OFF outcomes. Week 18 data reflect the 25 participants who elected to continue, and the narrowing levodopa reduction between weeks 6 and 18 was not explained in the release.

The company noted that DARE2 is a randomized, double-blind, parallel-group, placebo-controlled, flexible-dose trial enrolling approximately 150 adults with PD and motor fluctuations despite optimized noninvasive treatment. The primary end point of the trial is change from baseline to week 19 in daily good ON-time. Lundbeck stated that recruitment is underway in the US, with sites planned across Europe and Japan.¹

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REFERENCES
1. Lundbeck presents Phase Ib data for Lu AF28996 in advanced Parkinson's disease, as Phase II trial begins. News release. Lundbeck. October 6, 2026. Accessed October 6, 2026. https://www.prnewswire.com/news-releases/lundbeck-presents-phase-ib-data-for-lu-af28996-in-advanced-parkinsons-disease-as-phase-ii-trial-begins-302899415.html
2. Lu AF28996 in participants with Parkinson's disease (PD). ClinicalTrials.gov identifier: NCT04291859. Updated March 2026. Accessed October 6, 2026. https://clinicaltrials.gov/study/NCT04291859
3. Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386(9996):896-912. doi:10.1016/S0140-6736(14)61393-3
4. Lundbeck advances Parkinson's research with new Phase 1b data at AD/PD 2026. News release. Lundbeck. March 16, 2026. Accessed October 6, 2026. https://www.prnewswire.com/news-releases/lundbeck-advances-parkinsons-research-with-new-phase-1b-data-at-adpd-2026-302714456.html