Viewpoint: Developing drugs for levodopa‐induced dyskinesia in PD: Lessons learnt, what does the future hold?

Abstract

The drive to develop drugs to treat PD starts and ends with the patient. Herein, we discuss how the experience with drug development for LID has led the field in translational studies in PD with advancing ground‐breaking science via rigorous clinical trial design, to deliver clinical proof‐of‐concepts across multiple therapeutic targets. However, issues remain in advancing drugs efficacious preclinically to the clinic, and future studies need to learn from past successes and failures. Such lessons include implementing better early indicators of tolerability, for instance evaluating non‐motor symptoms in preclinical models; improving patient‐related outcome measures in clinical trials, as well as considering the unique nature of dyskinesia in an individual patient. The field of translational studies needs to become more patient focused to improve successful outcomes.

Dyskinesia Matters

“…). Third, relevant therapeutic targets for LID have already been identified through extensive preclinical investigations and sometimes validated through positive proof‐of‐concept clinical studies . The number of medications that have undergone phase III clinical trials is limited to amantadine extended release and sarizotan, and the latter has failed to produce significant antidyskinetic effects .…”

“…However, negative results in clinical trials do not necessarily invalidate the corresponding preclinical data because many technical reasons may underlie a failure to meet trial endpoints. In the case of LID, potential caveats of past clinical trials, and general challenges facing the translation of preclinical results, have been constructively discussed in several recent publications . In fact, the awareness and experience gained from past trials of antidyskinetic treatments may increase the likelihood of successful outcomes in future studies .…”

“…First, the translational roadmap for antidyskinetic drug development is relatively straightforward. 33,41 Second, in this area, even small trials of short duration can be highly informative to guide subsequent investments (see an example in ref. 42).…”

“…Third, relevant therapeutic targets for LID have already been identified through extensive preclinical investigations and sometimes validated through positive proof-of-concept clinical studies. 18,33,41 The number of medications that have undergone phase III clinical trials is limited to amantadine extended release and sarizotan, and the latter has failed to produce significant antidyskinetic effects. 43 However, negative results in clinical trials do not necessarily invalidate the corresponding preclinical data because many technical reasons may underlie a failure to meet trial endpoints.…”

“…3,18,33,41 In fact, the awareness and experience gained from past trials of antidyskinetic treatments may increase the likelihood of successful outcomes in future studies. 41 Finally, there is no doubt that good antidyskinetic medications are needed. Given that the prevalence of PD is bound to rise because of population aging and that approximately 80% of levodopa-treated PD patients develop LID within 10 years, 2 it is anticipated that an increasing number of PD patients will require expensive invasive treatments for the management of motor complications.…”