NLX-112 Shows Safety and Tolerability in Phase 2a Parkinson Trial, Supporting Further Development

A multicenter, randomized, double-blind, placebo-controlled, phase 2a trial (NCT05148884) found that NLX-112 (Neurolixis), a first-in-class, highly selective 5-HT_1A receptor agonist, was safe and generally well-tolerated in patients with troublesome Levodopa-induced dyskinesia (LID) Parkinson disease (PD) compared to placebo.

Published in Movement Disorders in early 2025, the study met its primary endpoint, as the drug showed positive safety and tolerability results. All in all, no serious adverse events (SAEs) were reported among patients receiving NLX-112, and there were no treatment-related clinically significant changes in vital signs, electrocardiogram findings, or laboratory parameters. Of note, the majority of AEs involved the central nervous system and occurred primarily during the up-titration period.

Led by Per Svenningsson, MD, PhD, a senior physician at Karolinska University Hospital in Solna, Sweden, the study also met its secondary and exploratory endpoints. More specifically, the drug significantly reduced LID and Parkinsonism scores from baseline, as assessed by the Unified Dyskinesia Rating Scale (UDysRS) and the Unified Parkinson’s Disease Rating Scale (UPDRS), respectively. In addition, NLX-112 demonstrated greater improvement (53%) than placebo (29%) on the Clinical Global Impression of Change (CGI-C).

The study enrolled 35 participants who were randomized to receive either NLX-112 or placebo alongside stable PD medication. In the study, patients were up-titrated over 28 days to a maximum dose of 2 mg/day (1 mg twice daily), followed by a 14-day stabilization period (through day 42), and then down-titrated over 14 days. Of the initial 35 participants, 22 completed the trial.

Inclusion criteria for participants were adults aged 30 to 85 with idiopathic PD who were already stably treated with levodopa. Participants were required to experience troublesome peak-dose dyskinesia, as documented by standardized movement assessments and patient-completed home diaries. The study also included strict measures to ensure participant safety, including confirmation of cognitive ability to complete study procedures and rigorous pregnancy prevention protocols for participants of childbearing potential.

Patients with advanced or unstable PD, significant medical or psychiatric disorders, or a history of certain medications or surgeries were excluded to minimize risk and ensure reliable results. Those with severe dementia, significant renal or liver disease, or recent suicidal behavior were also not eligible. Participants could not be enrolled if they were taking medications known to interfere with the study drug’s metabolism or if they were involved in other investigational trials.

By defining who could participate, the study aimed to focus on a population most likely to benefit from NLX-112 while maintaining safety standards. These criteria allowed researchers to evaluate the drug’s potential to reduce dyskinesia and improve motor function in Parkinson’s patients without introducing confounding variables.

“Unlike previous serotonin 5-HT1A agonists, the anti-LID activity of NLX-112 was not accompanied by a loss of antiparkinsonian activity of levodopa. Instead, NLX-112 further reduced parkinsonism,” noted study authors.¹ “These effects are notable because they occur after administration of a challenge dose of levodopa, that is, when the PwP were ‘ON’. This suggests that activation of 5-HT1A receptors by NLX-112 elicits an additional reduction of parkinsonism through a different mechanism to that engaged by DA replacement therapy.”

Prior to the phase 2a trial, NLX-122 showed promising safety and tolerability results in phase 1 and pre-clinical trials. Results from a pre-clinical study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets demonstrated that NLX-112 has anti-LID activity across various doses and resulted in reduced motor disability.² The treatment produced very little dyskinesia or locomotor activity, but the observed reduction of motor disability suggested that NLX-112 may have motor facilitation effects of its own.

Read more: European Commission Grants NLX-112 Orphan Medicinal Product Designation for Spinocerebellar Ataxia

In addition to displaying therapeutic benefits to combating LID in PD, NLX-112 was granted an orphan medicinal product designation for the treatment of Spinocerebellar ataxia (SCA).³

The decision behind this designation was based on a successful partnership between Neurolixis and Patricia Maciel’s, PhD, team at the University of Minho in Portugal. This collaboration, which was funded by the United States Department of Defense, was a result of promising preclinical data, where NLX-112 significantly reduced motor dysfunction in models of SCA type 3 (SCA3), also known as Machado-Joseph Disease.

REFERENCES
1. Svenningsson, P., Odin, P., Bergquist, F., et al. NLX-112 Randomized Phase 2A Trial: Safety, Tolerability, Anti-Dyskinetic, and Anti-Parkinsonian Efficacy. Mov Disord, 2026 40: 1134-1142. DOI: 10.1002/mds.30175
2. Fisher R., Hikima A., Morris R., et al. The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets. Neuropharmacology. 2020 1;167:107997. Doi: 10.1016/j.neuropharm.2020.107997
3. Neurolixis Secures Orphan Medicinal Product Designation for NLX-112 as a Treatment for Spinocerebellar Ataxia. News Release. Neurolixis. Published September 25, 2024. Accessed October 3, 2024. https://www.einpresswire.com/article/745834126/neurolixis-secures-orphan-medicinal-product-designation-for-nlx-112-as-a-treatment-for-spinocerebellar-ataxia