Managing motor fluctuations and dyskinesia remains a significant challenge for people living with advanced Parkinson's disease, despite advances in existing treatments. Lundbeck is seeking to address this unmet need with Lu AF28996, an investigational oral therapy that has shown encouraging early results in improving motor control and reducing OFF-time. With the Phase II DARE2 trial now underway, Biopharma Boardroom speaks with Tarek Samad, Executive Vice President, Research & Development at Lundbeck, about the potential of Lu AF28996, the significance of its Phase Ib findings, the evolving treatment landscape and the company's broader strategy to advance innovative therapies for movement disorders.

Q. The Phase Ib study showed encouraging changes in motor symptoms with Lu AF28996. What stood out to you most from these early results, and what do they tell you about the drug's potential in advanced Parkinson's disease?

What stood out was the encouraging pattern of observations across several measures of motor control. We saw increases in Good ON-time, reductions in OFF-time and improvements in dyskinesia, alongside substantial reductions in levodopa dosing.

That combination is particularly interesting because achieving consistent motor control without troublesome dyskinesia remains a significant challenge in advanced Parkinson's disease.

These early findings support the scientific rationale for Lu AF28996 and give us a strong reason to continue its development. However, this was a small, open-label study, and we now need to confirm these observations in a larger, controlled setting. That is precisely what we are investigating in DARE2, our phase II trial.

Q. Many people with advanced Parkinson's continue to struggle with motor fluctuations despite taking existing medicines. What gaps in current treatment are you hoping Lu AF28996 can address?

Levodopa remains the cornerstone of Parkinson's treatment, but as the disease progresses, maintaining consistent motor control becomes increasingly difficult. Motor complications, including OFF-time and troublesome dyskinesia, can significantly affect patients' quality of life, daily functioning and independence. Importantly, treatments aimed at reducing OFF-time by increasing dopaminergic stimulation can also worsen dyskinesia, making these complications particularly challenging to manage.

There remains an important unmet need for treatments that can provide more sustained and predictable motor control while limiting treatment burden.

Lu AF28996 takes a differentiated pharmacological approach, designed to provide sustained stimulation of both D1-like and D2-like dopamine receptors, with the potential to improve motor fluctuations and reduce troublesome dyskinesia.

Importantly, as an oral treatment, Lu AF28996 could offer a non-invasive option for patients with persistent disabling motor complications, despite individually optimized treatment, potentially before they need to consider more complex, device-aided therapies.

Our objective is to establish whether this pharmacological approach can translate into meaningful and sustained clinical benefits for patients, while maintaining an acceptable safety and tolerability profile.

Q. The study reported increases in Good ON-time and reductions in OFF-time, alongside lower levodopa doses. How meaningful could these changes be for patients if they are confirmed in larger studies?

For patients, what matters is having more time during the day when their symptoms are well controlled, without troublesome involuntary movements.

In Phase Ib, we observed an increase in Good ON-time of 3.6 hours per day at Week 6, alongside a reduction in OFF-time of 2.3 hours. We also saw reductions in troublesome dyskinesia and levodopa dosing.

These observations are promising, particularly because several measures moved in a favorable direction, and more importantly, because of the robust improvements observed in participants with inadequately controlled motor symptoms on currently available oral pharmacological therapies. However, given the exploratory, open-label nature of the study these results should be interpreted with caution, as the extent to which the observed improvements can be attributed to Lu AF28996 remains to be established in a randomized, controlled trial.

If confirmed in larger, controlled studies, improvements of this nature could make a meaningful benefit in patients' daily lives, allowing them to spend more time with better motor control and less time spent in OFF time or with troublesome dyskinesias. Ultimately, that is what we want to demonstrate: our ambition is not to simply demonstrate an improvement in clinical measures, but to show a tangible benefit for people living with Parkinson's disease in helping them maintain their independence and quality of life.

Q. Lu AF28996 is being developed as an oral treatment at a stage of Parkinson's disease when some patients may need invasive procedures or continuous drug delivery. Where do you see it fitting into the current treatment landscape?

There is an important treatment gap for people within advanced Parkinson's disease who continue to experience persistent disabling motor fluctuations, with or without troublesome dyskinesia, despite optimization of their existing medications. For some of these patients, device-aided therapies may eventually become an option. While these treatments can provide substantial benefits, they also involve additional complexity and invasive treatment burden and may not be suitable or acceptable for every patient.

We see an opportunity to explore whether a differentiated oral treatment could provide meaningful and sustained motor benefit for patients whose symptoms persist despite optimization with existing non-invasive therapies, potentially offering an additional option before considering more complex, device-aided treatments.

Lu AF28996 is designed to provide sustained stimulation of both D1-like and D2-like dopamine receptors, with the potential to support more consistent motor control, through the coactivation of both direct and indirect pathways of the basal ganglia.

We believe that there is a pressing need for additional non-invasive treatment options at this stage of the disease, and Lu AF28996 represents an important opportunity to address this unmet need.

Q. The Phase II DARE2 trial is now underway, aiming to include around 150 participants. What are the main questions you want this larger, controlled study to answer that the Phase Ib trial could not?

The key question now is whether the encouraging observations from Phase Ib can be confirmed in a rigorous, controlled setting.

DARE2 is our randomized, double-blind, placebo-controlled Phase II study involving approximately 150 patients. Its primary endpoint is the change in daily Good ON-time from baseline to Week 19, reflecting the amount of time patients spend with good motor control, without troublesome dyskinesia. A planned open-label extension study, DARE2 Extend, will offer eligible participants completing DARE2 the opportunity to continue treatment while evaluating the long-term safety and tolerability of Lu AF28996.

To support progression into Phase III, we would want to see a clinically meaningful and statistically significant improvement in Good ON-time, supported by consistent effects on OFF-time and other clinically relevant outcomes.

We will also look closely at safety and tolerability as it is essential when determining the overall benefit–risk profile of LU AF28996.

Phase Ib gave us an encouraging signal and a strong rationale to move forward. Phase II is about establishing the robustness and clinical relevance of that signal and generating the evidence needed to inform the next stage of development.

Q. Parkinson's disease remains an important area of research for Lundbeck. How does Lu AF28996 fit into the company's broader neuroscience strategy, and what are the key milestones you are working towards as the programme advances?

Movement disorders are an important area for Lundbeck and one where significant unmet medical need remains.

Our strategy is to pursue differentiated science with the potential to make a meaningful difference for patients, combining our internal research capabilities with external innovation.

Lu AF28996 is a good example of innovation originating from our own research laboratories. It builds on our expertise in neuroscience and pharmacology to explore a differentiated approach to managing motor complications in Parkinson's disease.

Alongside programmes such as amlenetug, testing a disease modifying therapy in multiple system atrophy, it reflects our commitment to advancing innovative treatments across movement disorders, addressing different aspects of these complex diseases.

For LU AF28996, our immediate priority is the successful execution of DARE2, which is currently expected to complete in 2028. The results will be critical in determining the next steps in development, including the potential progression into Phase III.

Ultimately, our ambition is to translate advances in neuroscience into meaningful new treatment options for people living with brain diseases.