At the AD/PD 2026 International Conference on Alzheimer’s and Parkinson’s Diseases, Integrative Research Laboratories Sweden AB (IRLAB) presented results from its Phase IIb REACT-PD (NCT05258071) trial, evaluating the efficacy and safety of pirepemat for reducing the frequency of falls in patients with Parkinson’s disease (PD). Falls and other non-dopaminergic symptoms in Parkinson’s disease remain a significant unmet need, with limited effective treatment options currently available. Key opinion leaders (KOLs) interviewed by GlobalData have consistently highlighted that symptoms such as balance impairment, falls, and cognitive dysfunction are among the most challenging to manage, as they do not adequately respond to existing dopaminergic therapies. This emphasises the need for novel therapeutic approaches targeting non-motor and cortical pathways, such as pirepemat.
Pirepemat is an oral small molecule designed to enhance cortical neurotransmission by increasing the synaptic availability of dopamine and norepinephrine in the prefrontal cortex, targeting mesocortical dysfunction associated with executive impairment and postural instability. The REACT-PD study specifically assessed both the dose-response and concentration-response relationships of pirepemat in recurrent fallers with PD. The study was a randomised, placebo-controlled, multi-centre trial that was conducted across 38 sites in Europe. A total of 146 patients were screened, with 104 patients randomised to receive pirepemat 300mg, 600mg, or placebo over 12 weeks, and 90 patients completed treatment. Falls were recorded using daily patient diaries, supported by motor and balance assessments. The primary endpoint was the change in fall rate from baseline. While the primary dose-based analysis showed a 42% reduction in fall rate in the 600mg group, this did not reach statistical significance versus placebo, indicating variability in responses across fixed dosing groups.
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To better characterise this variability, IRLAB conducted a pharmacokinetic / pharmacodynamic analysis stratifying patients by plasma trough concentrations. This analysis revealed a U-shaped (biphasic) exposure-response relationship, with patients in the mid-exposure group experiencing a statistically significant (31%) reduction in fall rate versus placebo (p<0.05), while the low- and high-exposure groups did not demonstrate significant benefit. The reduction in falls in the mid-exposure group was not accompanied by changes in motor or balance scores as measured by Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), supporting a mechanism of action that is independent of traditional dopaminergic motor pathways and consistent with a cortical mode of action.
Safety findings were consistent with previous studies, with approximately 70% of patients reporting adverse events across all treatment arms, including placebo. The most commonly reported adverse events included hepatic enzyme elevations, injuries, gastrointestinal symptoms, and headache, with no clear dose-dependent safety signal. Overall, pirepemat was well tolerated, and its safety profile was considered manageable and in line with prior clinical experience.
The REACT-PD results highlight both the promise and the development challenges of pirepemat. While the study did not meet statistical significance on its primary dose-based endpoint, the exposure-response findings provide compelling evidence of clinical efficacy at optimal plasma concentrations. This suggests that fixed-dose approaches may not be appropriate for pirepemat and that future development will likely require exposure-guided dosing strategies or patient stratification to maximise its therapeutic benefit. This may present operational and commercial challenges, as individualised dosing could require additional monitoring and titration, potentially limiting ease of use and uptake versus fixed-dose therapies. From a clinical perspective, pirepemat represents a differentiated approach to fall prevention in PD, targeting cortical dysfunction rather than motor symptoms alone, which is an area of high unmet need that currently has limited available treatment options.
