Zonisamide Improves Parkinsonism in Dementia with Lewy Bodies

Linda Hershey, MD, PhD, from the Department of Neurology at the University of Oklahoma Health Sciences Center

Linda Hershey, MD, PhD

Zonisamide, an early antiepileptic, improved parkinsonism as an adjunct to levodopa in patients with dementia with Lewy bodies (DLB) in a phase 3 trial conducted in Japan, where it has been used as an anti-Parkinson drug.

In commentary that accompanied the recent publication of the phase 2 zonisamide trial, Linda Hershey, MD, PhD, from the Department of Neurology at the University of Oklahoma Health Sciences Center, and David Irwin, MD, from the Department of Neurology at the University of Pennsylvania’s Perelman School of Medicine, welcomed the investigation in patients with DLB, noting that this second most common type of dementia after Alzheimer disease is often distinguished by the manifestation of parkinsonism.¹

"This is important since few randomized placebo-controlled trials have been done in patients with DLB, even though it is a relatively common form of dementia," Hershey and Irwin indicated. "The successful execution of this [phase 2] trial is a major accomplishment and provides evidence of feasibility for future trials that are urgently needed to develop new therapeutics for DLB."

A similarly successful phase 3 trial with a larger cohort, conducted by Miho Murata, MD, PhD, from the National Center of Neurology and Psychiatry, in Tokyo, Japan, and colleagues, appears to have increased the feasibility of this treatment strategy for patients with DLB. The trial was described at the International Congress of Parkinson's Disease and Movement Disorders, in Hong Kong.²

The subjects were aged 20 to 84 years (mean, 77.2 years), were diagnosed with probable DLB (mean duration of dementia, 3.6 years; motor dysfunction, 2.7 years), had a baseline total score on the Unified Parkinson's Disease Rating Scale part 3 ≥10 (UPDRS3; mean, 31.2), and were on a stable regimen of levodopa/dedecarboxylase inhibitor. In total, 351 subjects were randomized to receive 12 weeks of zonisamide 25 or 50 mg/day or placebo in double-blind format. A 40-week, open-label extension with active medication was completed by 230 of the subjects.

The primary endpoint was improvement in UPDRS3 score from baseline to week 12. Additional measures throughout the trial included the Mini-Mental State Examination (MMSE), the Neuropsychiatry Inventory-10 (NPI-10). Drug safety monitoring included laboratory test values, vital signs and body weight at each visit, and 12-lead ECG at rest was measured at screening, baseline and weeks 4 and 12.

Murata and colleagues reported that there was an improvement (reduction) in UPDRS3 score in all groups at week 12, but the reduction with both zonisamide 25 mg (-4.1±0.6) and 50 mg (-4.0±0.7) were statistically significantly greater than with placebo (-1.4±0.6). The scores were further reduced with active medication by week 24 to 28 (-5.1 to -6.3), and then remained almost constant through week 52.

Although there was a greater score reduction in MMSE at week 12 with 50-mg zonisamide than placebo, there was no long-term effect evident on either the MMSE or the NPI-10. The investigators indicated that there were no remarkable adverse events. They also reported that adverse events were quantitatively and qualitatively similar to those observed in the phase 2 study, with no worsening of cognitive function, behavioral and psychological symptoms of dementia, or caregiver burden.

"Zonisamide improves DLB parkinsonism and is well tolerated," Murata and colleagues concluded.

REFERENCES

1. Hershey LA, Irwin DJ. Zonisamide for DLB parkinsonism: An old drug used in a new context. Neurology. 2018; 90:349-350.

2. Murata M, Odawara T, Hasegawa K, et al. Zonisamide improves parkinsonism in DLB patients: A randomized phase 3 trial [abstract]. Mov Disord. 2017; 32 (suppl 2). mdsabstracts.org/abstract/zonisamide-improves-parkinsonism-in-dlb-patients-a-randomized-phase-3-trial. Accessed October 25, 2018.