Considerations on combination therapies for disease modification in Parkinson’s

While a broad range of treatments are available for symptomatic management of Parkinson’s disease (PD), there are currently no disease-modifying therapies (DMTs) – agents that slow, stop or reverse disease progression. Lack of success in clinical trials exploring potential DMTs is likely attributable to the complexity of PD, our understanding of the causal biology, variability between patients and biomarkers for stratification, advanced stage of pathology at diagnosis, and appropriateness and sensitivity of clinical endpoints 1 , 2 , 3 . In addition, the majority of potential DMTs tested to date in PD trials have been individual molecules directed towards specific molecular targets or biological pathways associated with the condition and may not address enough of the complex mechanisms to impact disease progression. Combinations of treatments are increasingly being employed in other multifaceted diseases to address molecular complexity 4 . Since combining chemotherapies for the treatment of acute leukaemia in 1965 5 , combination therapies have become a “cornerstone of cancer therapy 6 ”. Between January 2011 and December 2023, Chen et al. (2024) reported that of the 292 US Food and Drug Administration (FDA) approval entries (encompassing 110 drugs for oncological indications), one third were combinations 7 . Combinatorial approaches have also been successfully applied to antibacterial and antiviral interventions to address the multifactorial nature of the associated diseases 8 . There have been attempts at testing combinations of therapies in PD, from the DATATOP study in the 1990s 9 (involving the testing of deprenyl and tocopherol) to the more recent Australian Parkinson’s Mission Study 2, evaluating the effect of ambroxol and doxycycline both separately and in combination 10 . While strategies for combination therapies are being proposed for neurodegenerative conditions 11 , the majority of clinical studies of DMTs for PD have focused on monotherapies.