Motor fluctuations in Parkinson disease - a mini-review of emerging drugs

The symptomatic treatment of Parkinson Disease (PD) relies on levodopa. With disease progression, the response to levodopa becomes variable, leading to fluctuations in benefit on PD symptoms. These motor fluctuations are challenging to manage and negatively impact quality of life in PD.

We provide a review of experimental, non-approved pharmacological therapies in phase II and III clinical trials from 2018 to 2024 for PD motor fluctuations.

New formulations of levodopa to improve bioavailability are in development. These include another subcutaneous infusion with efficacy in reducing motor fluctuations and an intranasal delivery with tolerability reported. An oromucosal formulation of apomorphine was safe, further studies are needed. Preliminary results of a phase III study of dopamine D1/D5 agonist tavapadon and phase II of CVN424, a GRP6 inverse agonist suggest improved ON time. Negative studies were reported with foliglurax (MGluR4 inverse agonist) and the repurposed drugs naftazone and bumetanide. Several novel targets are in early-stage development with results awaited. Overall, it is unclear whether the field is significantly further ahead, as the benefit of these emerging drugs in comparison with currently available agents for motor fluctuations needs to be clarified.