Objective: Evaluate safety, tolerability, and clinical effects of Lu AF28996 in patients with inadequately controlled advanced Parkinson’s disease (PD) experiencing motor fluctuations, with or without dyskinesia.

Background: Lu AF28996 is an oral prodrug of a D1-like/D2-like receptor agonist, with a pharmacologic profile that may enhance dopaminergic striatal signaling in a prolonged manner. We present results from an open-label, phase 1b trial (NCT04291859).

Method: Patients with advanced PD, experiencing motor symptoms not satisfactorily controlled despite non-invasive antiparkinsonian medication, ≥2h daily OFF-time with or without troublesome dyskinesia, received Lu AF28996 twice daily for 6 weeks, with an optional extension period of up to 12 weeks. Eligible patients for extension period had partially or completely replaced their daily levodopa dose and/or were considered to have derived clinical benefit from Lu AF28996.

Results: Participants (N=34): mean age of 65y, 19 were male, 30 were Hoehn and Yahr stage 2–3 (in ON-state). Baseline (BL) mean Good ON-time, OFF-time and ON-time with troublesome dyskinesia: 9.7h (SD:2.6), 4.6h (SD:1.6) and 1.7h (SD:2.0), respectively (standardized Hauser diary); mean MDS-UPDRS-Part-III score: 17 (SD:8); UDysRS total score: 28 (SD:20); daily levodopa dose (n=33): 913mg (SD:563). 25 eligible participants elected to enroll in the extension period. Clinically meaningful improvements in mean Good ON-time and OFF-time were reported at Week (Wk) 6 and Wk 18; similar improvements were observed in participants with and without troublesome dyskinesia at BL. In participants with ≥1h of troublesome dyskinesia daily at BL, reductions in mean ON-time with troublesome dyskinesia and UDysRS total score were seen at Wk 6 and Wk 18. Substantial mean levodopa dose reductions at Wk 6 and Wk 18 were observed, with no clinical deterioration in motor function (MDS-UPDRS-Part-III). Most treatment-emergent adverse events were considered mild, no unexpected safety signals occurred, and the safety profile was consistent with a dopaminergic mechanism of action.

Conclusion: Lu AF28996 demonstrated favorable tolerability and potential to markedly improve motor complications up to Wk 18, in people with advanced PD and persistent OFF-time despite non-invasive antiparkinsonian medication, supporting further clinical development.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/lu-af28996-a-novel-oral-d1-like-d2-like-receptor-agonist-may-improve-motor-complications-in-people-with-parkinsons-disease-results-from-an-18-week-open-label-phase-1b-trial/