A new study has discussed the emerging clinical data for the repurposing of the anti-epileptic drug – Zonisamide – for the treatment of Lewy body dementia.
Lewy body Dementia
The symptomatic management of dementia with Lewy bodies (DLB) in clinical practice remains suboptimal, with there currently being no FDA-approved medications for the condition in the US. Therefore, clinicians often prescribe off-label medications, which are approved for Alzheimer’s disease, Parkinson’s disease, and other neurobehavioral diseases to alleviate symptoms of DLB. Patients with DLB often display parkinsonism, which is a combination of movement abnormalities seen in Parkinson’s diseases, hence why drugs approved for Parkinson’s disease may improve the symptoms of DLB.
The lack of therapeutics may be partially due to the lack of clinical trials on DLB. However, in 2018 the drug zonisamide, which was originally developed as an anti-epileptic agent, was shown to have therapeutic benefit in the management of parkinsonism in patients with DLB.
Zonisamide
Zonisamide is a mixed monoamide oxidase B (MAO-B) inhibitor, sodium and calcium channel blocker, glutamate release inhibitor, and carbonic anhydrase inhibitor. It was initially approved in the US in 2000 as an adjunct therapy for partial seizures in adults. A phase II and III trial for zonisamide, which took place in Japan and included 1008 patients, reported adverse effects in 52% of patients. When the data from this trial was analysed, the major adverse effects were identified as drowsiness (24%), ataxia (13%), loss of appetite (11%), gastrointestinal symptoms (7%), decrease in spontaneity (6%) and mental slowing (5%). Whereas in a meta-analysis of the data from six clinical trials, including patients between the ages of 12 to 80, there was no identified statistically significant adverse effects associated with zonisamide treatment.
DLB and Parkinson’s disease are considered subtypes of the Lewy body spectrum of diseases. The data from animal models and human clinical trials has demonstrated the success of zonisamide for the treatment of Parkinson’s disease. Given this success, zonisamide was investigated for the treatment of parkinsonism in DLB.
Randomised placebo-controlled phase II study for zonisamide and DLB
In 2018, the results from a randomized phase II trial of zonisamide as an adjunct to levodopa therapy for the treatment of parkinsonism in DLB were published. The major inclusion criteria for this trial were the presence of parkinsonism (presenting a UPDRS-III score ≥10) and a Mini-Mental State Examination (MMSE) total score of 10–26. The data from this trial showed a significant improvement in the UPDRS-III total score at week 12 in the group of patients given 50 mg zonisamide, compared with placebo. The researchers also identified that the UPDRS-III score was significantly lower at 8 weeks.
Randomised placebo-controlled phase III study for zonisamide and DLB
Between 2015 and 2017 a multicentre phase III trial was carried out in Japan to assess the effect of zonisamide on parkinsonism in patients with DLB who were being treated with a stable dose of levodopa therapy. The patients were given zonisamide for 12 weeks, in either a 25 or 50 mg dose or a placebo. Both treatment arms met the primary outcome of improvement in UPDRS-III score at week 12, compared to the placebo group. Resting tremor was the only additional factor, which showed a significant improvement compared to the placebo group in both the 25 and 50 mg groups. Moreover, there was no significant change in the results of a Neuropsychiatry Inventory score between the treatment groups and the placebo.
Findings
The results from both phase II and III suggests that there was a mild improvement to parkinsonism symptoms in DLB. Both trials also identified that the higher the dose, the more significant the improvement compared to the placebo. However, higher doses also come at the cost of more frequent or common adverse effects, as demonstrated by the data from both of these studies. Moreover, both of these studies used zonisamide with the drug levodopa, and it remains to be known whether the benefit achieved with zonisamide is beyond what could be achieved by administering a higher dose of levodopa alone. However, as higher doses of levodopa cause higher incidences of gastrointestinal side effects, zonisamide could be considered as repurposing candidate for DLB patients who cannot tolerate those side effects
Summary
Overall, the clinical data from the studies summarised in this paper suggests that zonisamide may be a safe and effective adjunct to levodopa for the management of parkinsonism in DLB patients. However, the therapeutic benefit is mild, and its use also comes with some adverse effects. Further work needs to be done to assess the long-term efficacy and adverse effects of zonisamide for the treatment of DLB, as both of these studies were conducted over the relatively short period of 12 weeks.
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