Developing drugs for levodopa-induced dyskinesias

This review captures important lessons learnt from studies and trials to date for the development of drugs targeting levodopa-induced dyskinesias.

It highlights the need to use objective measures tailored to measuring dyskinesia, as well as patient reported outcomes, for the development of drugs that target this cumbersome complication of Levodopa therapy.

Dyskinesias that develop from the long term use of levodopa are caused by a number of interacting factors: often due to absorption difficulties, levodopa can “hit” its target dopamine neurons in a pulsatile rather than a constant manner, causing unpredictable and uneven peaks and troughs in dopamine released by these neurons, which are additionally functioning suboptimally due to the effects of neurodegeneration.

The discovery pathway starts off in experimental animals, and research in non-human primates forms the gold standard for this work. Success at this stage may mean a drug is taken on to a small safety and tolerability study in healthy individuals, before being investigated in a small group of people with Parkinson’s. This is where many drugs fail: if a drug aimed at reducing dyskinesias is not well tolerated and causes additional problems and unwanted effects, then this spells the end of the road for that particular therapeutic. This is often dose dependent. The authors argue that more tests of tolerability should be carried out earlier on in the process, at potentially lower drug doses: achieving a relatively small clinical benefit on a well tolerated dose is worth aiming for, if the alternative is aiming for a greater clinical benefit on a dose which ultimately won’t be well tolerated.

In addition to novel drugs that target more than one type of receptor, to ensure maximal clinical benefit in the context of a complex neurochemical picture, the authors emphasise the need for a better defined clinical endpoint for dyskinesia trials. For many people with Parkinson’s, the presence and severity of dyskinesia are under-recognised, and so are under-reported. This has knock on effects on recruiting suitable individuals for trials as well as measuring potential success. There are a number of ways this important issue can be tackled, with the use of objective scales focusing specifically on dyskinesia and administered by trained clinicians.

Overall, any acceptable therapeutic or intervention must deliver significant improvement in terms of quality of life. Despite difficulties with subjective measures which can be unreliable and inconsistent across different individuals, progress is being made in terms of incorporating patient-reported outcome measures (“PROMS”) to evaluate studies. Although several scales are used in PD trials, no such specific measure exists for dyskinesias. Future studies should focus on developing this set of PROMs in order to bring us closer to therapies that work and bring about meaningful benefit in patients’ daily lives.

The authors recommend that objective scales should be incorporated into the drug development process as early on as possible, along with facilitating patient involvement and using PROMs in future trials. In addition, evaluating how early sensitization or priming can be avoided in order to prevent the emergence of dyskinesias will be important.