The ‘holy grail’ – disease-modifying drugs

Despite decades of research dedicated to researching disease-modifying therapies for PD, most drug candidates have failed and none has been consistently shown to alter the trajectory of disease progression.¹ Many early attempts at translating preclinical findings to positive outcomes in clinical trials were based on animal models, which are not able to fully reflect the full range of complexities of ‘real-life’ PD.^1,5,6

Ideally, disease-modifying therapies would intervene early to preserve motor function for as long as possible, and delay or even prevent the onset of overt disease in patients at high risk or people in the prodromal PD phase.^1,7 It is unlikely that any single intervention will be sufficient to achieve this, however, and so several therapies may need to be discovered and developed before the underlying disease process of PD can be effectively delayed.¹

References:
1. Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord 2015; 30 (11): 1442–1450.

2. Lang AE, Espay AJ. Disease modification in Parkinson’s disease: current approaches, challenges, and future considerations. Mov Disord 2018; 33 (5): 660–677.

3. Lang AE. Clinical trials of disease-modifying therapies for neurodegenerative diseases: the challenges and the future. Nat Med 2010; 16 (11): 1223–1226.

4. Van Dam D, De Deyn PP. Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 2006; 5 (11): 956–970.

5. Athauda D, Foltynie T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat Rev Neurol 2015; 11 (1): 25–40.

6. Barker RA, Björklund A. Animal models of Parkinson’s disease: are they useful or not? J Parkinsons Dis 2020; 10 (4): 1335–1342.

7. Mahlknecht P, Poewe W. Pharmacotherapy for disease modification in early Parkinson’s disease: how early should we be? J Parkinsons Dis 2024; 14 (S2): S407–S421.