Zonisamide with Levodopa May Reduce Risk of Dementia, Other Parkinson’s-related Symptoms, Japanese Study Suggests

Zonisamide, Parkinson's

Japanese researchers have reported that zonisamide — an antiparkinsonian medicine approved in Japan as a combination therapy with levodopa — may be associated with a lower risk of dementia, insomnia, and gastric ulcers in Parkinson’s disease, compared with other non-levodopa medicines.

Their research was published in the study “Comparison of zonisamide with non-levodopa, anti-Parkinson’s disease drugs in the incidence of Parkinson’s disease-relevant symptoms,” in the Journal of the Neurological Sciences.

Marketed under the name Zonegran in the U.S. for adjunctive therapy in the treatment of partial seizures in adults with epilepsy since 2000, zonisamide has been approved in Japan (where it’s called Trerief) as an antiparkinsonian agent to be used in combination with levodopa therapy.

Parkinson’s patients have low levels of the chemical messenger dopamine in their brains due to disease-specific death of dopaminergic (meaning “dopamine-producing”) neurons. Among other brain functions, sleep, memory, and movement are all affected by the lack of dopamine and, as such, patients often develop insomnia and dementia, along with the hallmark motor symptoms of Parkinson’s disease.

Levodopa (L-DOPA) is the first choice when it comes to effective Parkinson’s motor symptom control, and as the disease progresses, patients typically need to gradually increase their treatment dose for maximum benefit. After that, they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy. Because of this, most patients will require combination therapy at some point.

Although zonisamide’s mechanism of action is not yet fully understood, studies indicate the compound acts by preventing the breakdown of dopamine, increasing its levels in the brain, and relieving Parkinson’s symptoms. Evidence also suggests that the medicine may have neuroprotective effects.

Clinical trials have shown zonisamide significantly alleviates Parkinson’s motor and non-motor symptoms. “However, partly because zonisamide is off-label for PD [Parkinson’s disease] except for in Japan, situations in which it is more suitable than other drugs have not been sufficiently elucidated,” the researchers noted.

For the study, investigators from Ehime University Graduate School of Medicine in Japan sought to evaluate if zonisamide use in Parkinson’s patients, 40 years or older, was associated with the time of onset of Parkinson’s disease-relevant symptoms, mainly mental, autonomic nervous system, movement, and gastric symptoms.

The results were compared to seven other non-levodopa drug classes that are often used when primary therapy is not fully effective (also referred to as second-line therapy).

For this analysis, levodopa was not considered as a comparison drug to zonisamide, as the majority of study participants were taking levodopa together with zonisamide or another second-line medicine.

Patients had to be on levodopa or other antiparkinsonian medicine without having switched to or recently combined use with other drug classes.

Using a set of statistical approaches, the researchers investigated the time it took for a given symptom of interest to occur while participants were on zonisamide, compared with other non-levodopa medications indicated for Parkinson’s disease.

Of the 9,157 studied subjects, those who were on COMT inhibitors, anticholinergics, or amantadine were two to nearly five times more likely to develop dementia. In addition, zonisamide use was found to be associated with a lower risk of developing insomnia and gastric ulcers, compared with three other non-levodopa medicines.

An increased prevalence of gastric ulcers has long been associated with Parkinson’s disease, and they are generally accepted as a symptom experienced by patients.

“Zonisamide also showed significant lower risk in the incidence of orthostatic hypotension, constipation, and limb fracture,” the researchers wrote, adding that the treatment was, however, also associated with a higher risk “in the incidence of depression and aspiration pneumonia than at least one of the other drug classes.”

Compared with three other classes of medications, zonisamide appears to be associated with a lower risk of developing dementia, insomnia, and gastric ulcers in Parkinson’s disease. However, it was not always the same three-treatment set that was found to be somehow associated with the lowest risk for a given symptom.

Nonetheless, “[t]here may be a potential clinical impact of zonisamide on some of the [Parkinson’s disease]-relevant symptoms,” the authors concluded.

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Add-on Azilect Safe and Effective in Levodopa-treated PD Patients, Phase 3 Trial in Japan Shows

Azilect, levodopa

Using Azilect (rasagiline) as an add-on therapy to levodopa was safe and improved motor function over one year in Parkinson’s patients with off periods, according to a Phase 3 trial in Japan.

The study, “Long-term safety and efficacy of adjunctive rasagiline in levodopa-treated Japanese patients with Parkinson’s disease,” was published in the Journal of Neural Transmission.

Progressive loss of dopamine-producing neurons in a brain area called substantia nigra and subsequent reduction of dopamine levels are hallmarks of Parkinson’s disease. As a result, most pharmacological Parkinson’s treatments aim to ease symptoms by boosting the amount of dopamine in the brain.

Long-term use of levodopa, the standard Parkinson’s medication, may lead to the resurgence of symptoms by a gradual decline in levodopa’s efficacy, known as off periods. In such cases, Japanese and international guidelines recommend adjusting levodopa’s dose and/or formulation, or using add-on treatments such as inhibitors of monoamine oxidase-B (MAO-B), an enzyme that breaks down dopamine.

Azilect, a selective MAO-B inhibitor, is currently indicated outside Japan as an adjunctive therapy for people with Parkinson’s.

In prior studies conducted by a team of Japanese researchers, adding Azilect to levodopa reduced the duration of mean daily off periods, eased Parkinson’s symptoms — as assessed with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) — and improved the quality of life of Japanese patients up to 26 weeks.

To provide insights for clinical practice, the same team now evaluated the long-term (up to 52 weeks) safety and efficacy of combining 1 mg/day Azilect with levodopa in patients with Parkinson’s.

In the multi-center, open-label Phase 3 trial (NCT02337764) — sponsored by Takeda, which obtained a license to market Azilect in Japan from Teva Pharmaceutical Industries — a total of 222 participants (mean age 68) recorded their off periods, on periods (motor symptoms under control) with or without troublesome dyskinesia — involuntary, jerky movements — and sleeping time in 30-minute intervals over 24 hours during the seven days prior to visits at weeks 0, 6, 10, 18, 26, 34, 42, and 52.

All included patients (mean Parkinson’s duration nearly seven years) were experiencing wearing-off or weakened effects of levodopa. The primary goal was the incidence of treatment-emergent adverse events (TEAEs).

Secondary goals included the MDS-UPDRS Part II (motor aspects of daily living) and Part III (motor examination), total scores during on periods, and mean daily off-time for patients with wearing-off periods at the start of the study. Assessments of quality of life and non-motor aspects of daily living were also conducted.

At baseline, 77.8% of patients required a dose of levodopa above 300 mg/day. The mean duration of levodopa treatment was approximately 4.6 years. Also, 116 patients (52.3%) had wearing-off periods, with a mean duration of nearly three years. Dopamine agonists were the most frequently used concomitant therapy for Parkinson’s (163 patients, or 73.4%).

A total of 599 TEAEs were reported by 185 patients, most (586) being mild or moderate. Forty-seven patients (21.2%) discontinued treatment because of TEAEs. The most common TEAEs were fall (16.7%), nasopharyngitis — inflammation of the pharynx and nasal cavities — (14%), and dyskinesia (10.8%).

The incidence of TEAEs was higher (52.3%) during days 1–83 after starting Azilect, subsequently decreasing over time. No new safety concerns were found.

Forty-seven serious TEAEs were reported in 39 patients, 22 of which led to study discontinuation and 24 were considered treatment-related. No deaths occurred.

Combining Azilect with levodopa improved patients’ on state throughout the study, with a clinically meaningful mean change of -7.6 MDS-UPDRS Part III points from baseline to week 52. Among patients with wearing-off periods, Azilect led to a nearly one-hour reduction in daily off periods after six weeks, which was maintained throughout the study.

Using Azilect with levodopa also improved quality of life. This was most evident in mobility, activities of daily living, stigma, and bodily discomfort domains.

Overall, “mean changes in MDS-UPDRS scores and daily OFF-time suggested that adjunctive rasagiline (azilect) treatment with levodopa was efficacious, with efficacy maintained for at least 52 weeks,” scientists stated.

They cautioned that the absence of a placebo group complicates the assessment of the combination therapy’s benefits. However, the fact that the results were similar to the investigators’ prior findings suggests that these benefits were treatment-related, they said. Studies beyond 52 weeks may be needed, they said.

Three of the study’s authors are employees of Takeda, four served on advisory boards for Takeda, and two conducted Takeda-sponsored research.

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