The Mechanism and Promise Behind Lu AF28996 in Advanced Parkinson Disease: Johannes Streffer, MD

“What we aim to achieve is balanced activation of both the D1 and D2 pathways with a sustained effect over time. That combination could address some of the key challenges patients face as Parkinson disease progresses.”

Dopaminergic therapies remain the cornerstone of symptomatic management in Parkinson disease (PD), yet their effectiveness often diminishes as the disease progresses. While agents targeting dopamine pathways can provide meaningful motor control early in the disease course, patients with advanced PD frequently experience motor fluctuations, dyskinesias, and inconsistent symptom relief.¹ These challenges highlight the need for therapies that can deliver more stable and physiologically balanced dopaminergic stimulation over time.

One approach under investigation involves targeting both the direct and indirect motor pathways through dual dopamine receptor activation. Lu AF28996 is an oral investigational agent designed to activate both D1 and D2 receptors, with the goal of improving motor control while minimizing variability in response. The compound is being developed as a prodrug, allowing for sustained systemic exposure after oral administration, which may help address the fluctuations commonly seen with current therapies.

At the 2026 AD/PD Conference, investigators presented data from a phase 1b open-label study evaluating the safety, tolerability, pharmacokinetics, and exploratory clinical activity of Lu AF28996 in patients with advanced PD. Findings showed that the agent was generally well tolerated and demonstrated early signals consistent with its proposed mechanism of action, supporting further clinical development. As an early-phase study, these results are considered preliminary and require confirmation in larger, controlled trials.

Following the presentation, Johannes Streffer, MD, senior vice president of clinical development at Lundbeck, spoke with NeurologyLive® about the rationale behind Lu AF28996 and its potential role in treating advanced PD. In the discussion, he explains the drug’s mechanism, the importance of dual receptor activation, and how sustained dopaminergic stimulation may address unmet needs in this patient population.

REFERENCE
1. Lundbeck advances Parkinson's research with new Phase 1b data at AD/PD™ 2026. News release. Lundbeck. March 16, 2026. Accessed April 10, 2026. https://www.prnewswire.com/news-releases/lundbeck-advances-parkinsons-research-with-new-phase-1b-data-at-adpd-2026-302714458.html