New Developments in Treating Parkinson’s Disease

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Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects more than 10 million people worldwide. The disease primarily results from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta part of the brain. Its key clinical features include motor symptoms of rigidity, tremor, and bradykinesia. However, recent findings have confirmed that the disease is also characterized by its non-motor symptoms that appear before the onset of motor symptoms, strongly suggesting that Parkinson’s disease is not motor-specific.

The pre-motor phase is mainly characterized by olfactory abnormality, rapid eye movement behavior, and constipation. In addition, the patient may also experience somnolence, apathy, and fatigue.

Although the disease is not curable, currently available treatments alleviate symptoms, improve the quality of life and prolong survival. This article aims to review some of the recent developments that can make a difference to the patient’s quality of life.

Levodopa: the long-time gold standard for PD

To date, levodopa (a dopamine precursor) has been considered as the most effective drug for controlling both motor and non-motor symptoms. Hence, it is regarded as the long-time gold standard for treating PD. However, as the disease progresses (4–5 years after the onset), the ability of the drug to smooth out symptoms declines, and the patients start to experience motor fluctuations and dyskinesia, i.e., excessive involuntary abnormal movements. The motor fluctuations shift between ON-time, a state when the drug is effective and symptoms are controlled, and OFF-time, a period during which control of symptoms is lost. To overcome this limitation, levodopa is usually combined with a decarboxylase inhibitor like carbidopa to diminish rapid metabolism of levodopa in the periphery and thereby increase its availability for uptake into the brain. Recent research has further improved this add-on therapy to levodopa (i.e., levodopa/carbidopa) to provide sustained-release of levodopa and thereby improve motor fluctuations in PD patients.

New adjunct therapy to levodopa

Recently, a novel extended-release formulation of levodopa/carbidopa has been introduced in the US market with the name IPX066. This newly designed formulation features both the immediate and extended release properties of carbidopa/levodopa, thus it allows for both immediate and longer duration clinical benefits. IPX066 pills can be taken orally and are recommended for all PD patients.

In two clinical trials, the efficacy of IPX066 was tested in both early and advanced PD patients. In these patients, the administration of IPX066 significantly reduced the OFF-time and increased the ON-time without causing dyskinesia.  No serious drug-related adverse effects were reported, although some patients experienced nausea, headache, dizziness, and insomnia.

Concurrently, another novel improved formulation of levodopa is XP21279. This drug is not available on the market as it is still in the earlier phases of clinical development. The XP21279 is a levodopa prodrug that is readily absorbed in the small intestine where it is metabolized into levodopa. The levodopa then enters the plasma and transfers into the brain. The efficacy of XP21279 was tested in a clinical trial conducted on 14 PD patients with motor fluctuations. Out of 10 patients who completed the study, 6 patients showed a 30% reduction in OFF-time, whereas ON-time was not affected.

Opicapone (trade name ONgentys®) is another novel drug that is used as adjunctive therapy to levodopa/carbidopa for mitigating motor complications in patients with PD. The drug was approved by the European Commission in July 2016. This is a catechol-O-methyltransferase (COMT) inhibitor that acts by blocking an enzyme that metabolizes levodopa, enhancing its efficacy and thereby significantly improving motor fluctuations. Unlike other COMT inhibitors such as tolcapone and entacaopne, opicapone is not associated with liver toxicity, as confirmed by experimental studies in animals.

The use of opicapone as adjunctive therapy to levodopa was investigated in two clinical trials: i) 14- to 15-week, double-blind, multinational trial; and ii) 1-year, open-label extension study in the same patients. The results were promising. Administration of opicapone (50 mg/day) caused a significant improvement in motor fluctuations in patients during the double blind trials. The opicapone-mediated improvements in motor fluctuations were maintained in the 1-year extension study. There were few reports of dyskinesia and decreased drug effects along with other common adverse effects, such as constipation, insomnia, and dry mouth, showed no drug relationship.

Safinamide, a highly selective MAO-B inhibitor, has been newly introduced as an add-on therapy to levodopa in mid-to-late-stage PD. The efficacy of safinamide as an adjunct to levodopa was tested in clinical trials of 6 months, 8 months, and 2 years, on middle to advanced-stage PD patients with motor fluctuations. The intake of safinamide (50–100 mg daily) in these patients had drastically increased ON-time without increased dyskinesia. The beneficial effect of increased ON-time was maintained in both 18 month and 2 year extension studies. In addition, the use of safinamide in these patients improved daily living, depression, clinical status, and quality of life.

In addition to levodopa, safinamide is also used as an add-on therapy to dopaminergic agonists in early-stage PD. Administration of safinamide at a dose of 100–200 mg/day was found as an effective PD therapy in combination with dopaminergic agonists.

Although we still have no cure for Parkinson’s disease, recent developments have helped to improve symptomatic therapy, allowing patients to experience a better quality of life.

References

Finberg, P.M.j  &  JoseM.Rabey, J.M. (2016). Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology. Front Pharmacol. 7:340. doi: 10.3389/fphar.2016.00340.

Timpk, J., Petersen, M.U., and Odin, P. (2016). Continuous dopaminergic stimulation-recent advances. Curr Opin Neurol. 29:474–479. doi: 10.1097/WCO.0000000000000354.

Kianirad, Y., & Simuni, T. (2016). Novel Approaches to Optimization of Levodopa Therapy for Parkinson’s Disease. Curr Neurol Neurosci Rep. 16: 34. doi: 10.1007/s11910-016-0635-8.

Scott, J.L. (2016). Opicapone: A Review in Parkinson’s Disease. Drugs. 76:1293–1300. doi: 10.1007/s40265-016-0623-y.

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