João Massano, MD

Department of Neurology, Hospital Pedro Hispano/ULS Matosinhos, Portugal

Department of Clinical Neurosciences and Mental Health, Faculty of Medicine University of Porto, Portugal

jmassano@med.up.pt

Parkinson’s disease (PD) is a common disabling neurodegenerative disorder. Managing the full breadth of symptoms and their impact is often challenging, even for skilled clinicians. Currently available drugs, particularly levodopa, have a positive impact on patients’ lives, as they bring significant improvement of motor symptoms. However, troublesome motor complications ensue with time, adding to the already heavy burden of symptoms, disability and decreased quality of life. Unfortunately, current approaches for tackling MCs are disappointing in general. Amantadine is useful in some patients, decreasing peak dose dyskinesias. Deep brain stimulation (DBS) has been successfully used for some years in a minority of eligible patients who suffer from insufficiently controlled symptoms (including MCs), even under optimal medical treatment. Continuous subcutaneous apomorphine and levodopa/carbidopa duodenal gel infusions are also useful alternatives in some patients, although available evidence is not as robust as for DBS – anyhow, the therapeutic strategy should be selected and tailored according to the individual circumstances, as their clinical profiles and effects differ.

Significant research efforts have been carried out to develop and test therapies aiming at decreasing the frequency and severity of MCs in PD. Several modified levodopa formulations that try to circumvent the unfavorable pharmacokinetic profile of the drug progressed to clinical trials, and a few positive results have already been published, although other studies found no advantage over standard formulations. Phase III clinical trial (CT) data comparing pardoprunox, a new dopaminergic agonist, with placebo showed significant benefits with regard to “off” time in patients receiving the active drug. Safinamide, a reversible monoamine oxidase B inhibitor featuring additional pharmacodynamic properties, was shown to increase daily “on” time in PD. Opicapone, a once daily administered catechol-ortho-methyl transferase inhibitor reduced wearing-off in phase II clinical trials; encouraging phase III trial results have been publicly disclosed and results from a second phase III trial are awaited soon.

Also, drugs that modulate different neurotransmitter systems (e.g. serotonergic, noradrenergic, adenosinergic, glutamatergic, cholinergic) involved in the pathogenesis of MCs have been devised. For example, mavoglurant (mGluR5 antagonist) reduced peak dose dyskinesias in PD, and publication of further results from ongoing trials is expected.

Cell growth factors associate with challenging issues, such as the invasive method of delivery and the related risk of carcinogenesis. Interesting trial results have been published regarding glial cell line-derived neurotrophic factor (GDNF) and neurturin, which deserve detailed interpretation.

Cell therapies have great potential usefulness in PD, and preliminary clinical data is already available. Nonetheless, many challenges remain. A recent statement on this matter has been issued by the Movement Disorder Society (http://www.movementdisorders.org/about/committees/stem-cell.php).

The most compelling evidence in this field in the last couple of years came from the EARLYSTIM trial, which enrolled PD patients presenting MCs for less than 3 years. Patients were randomized to either medical therapy (MT) plus DBS of the subthalamic nucleus or MT alone. The results show that quality of life was markedly improved in the DBS/MT group during the 2-year period of research, while slightly declining in the MT group. DBS/MT was superior to MT concerning also motor disability, levodopa-induced MCs, and activities of daily living. These results will surely influence the timing defined by neurologists to offer DBS to their PD patients.

Some of the new therapeutic strategies will certainly bring additional clinical benefits in comparison to current treatment standards. Nonetheless, despite the amount of knowledge regarding the molecular pathways involved in the pathophysiology of PD, no drug impacting specifically on any of the molecular events underlying the disease was successfully developed and clinically tested so far. Such drugs would target upstream pathophysiological events, and could theoretically have positive effects on the risk of motor complications, thus improving disability and the quality of life of patients.

References

1. Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med. 2012 Jun;2(6):a008870. doi: 10.1101/cshperspect.a008870.

2. de Sousa SM, Massano J. Motor Complications in Parkinson’s Disease: A Comprehensive Review of Emergent Management Strategies. CNS Neurol Disord Drug Targets. 2013 Jul 10. [Epub ahead of print]