Phase 1/2 Trial Supports Ketamine for Levodopa-induced Dyskinesia
Low-dose ketamine safe, well-tolerated — and reduces dyskinesia for 3 months
New trial data suggest that low-dose ketamine — which does not induce anesthesia — may be a potential treatment for levodopa-induced dyskinesia, or involuntary movements, in Parkinson’s disease.
“Ketamine was safe [and] well-tolerated with 100% of patients treated with ketamine demonstrating reduction in dyskinesias,” PharmaTher Holdings, the Canadian-based company developing the therapy candidate, said in a press release announcing the results of a Phase 1/2 clinical trial.
According to PharmaTher, which specializes in ketamine pharmaceuticals, plans are in the works for further clinical trials.
“Data from the Phase 1/2 study of ketamine [demonstrates] ketamine’s safety and tolerability with clinically meaningful efficacy that supports further investigation in a proposed Phase 3 clinical study as a potential new treatment for levodopa-induced dyskinesia in Parkinson’s disease patients,” said Fabio Chianelli, CEO of PharmaTher.
A presentation of the trial’s results, titled “Subanesthetic infusion of ketamine produces long-term reduction in levodopa-induced dyskinesia,” was displayed at the Movement Disorder Society (MDS) International Congress of Parkinson’s Disease and Movement Disorders, held in Madrid, Spain, Sept. 15–18.
Levodopa, a standard Parkinson’s therapy, is a precursor molecule that is converted to dopamine in the brain. It is well-known for controlling Parkinson’s disease symptoms such as rigidity and slowness of movement.
However, prolonged use of levodopa may result in spontaneous involuntary movements — a condition called dyskinesia.
PharmaTher recently received a U.S. Notice of Allowance on its patent application for ketamine as a potential treatment for Parkinson’s disease and other motor disorders.
Ketamine (sold as Ketarx) is approved by the U.S. Food and Drug Administration (FDA) as an anesthetic and pain reliever.
Investigating Ketamine for Parkinson’s dyskinesia
In Parkinson’s disease, the results of a previous Phase 2 trial (NCT04912115) indicated that low-dose ketamine — which, unlike higher doses, does not induce anesthesia — reduced dyskinesia in patients with the neurodegenerative disorder.
Now, results from the Phase 1/2 clinical trial confirmed that ketamine is safe and well-tolerated. The medication also was found to promote a reduction of dyskinesia in treated patients for at least three months.
The trial was an open-label study to test the safety, tolerability, and pharmacokinetics — i.e., the process of absorption, distribution, metabolism, and excretion of a compound — of low-dose ketamine as a treatment for dyskinesia induced by levodopa. The study also aimed to find the effective dose to use in patients.
A total of 10 people with moderate to advanced Parkinson’s were enrolled in the study. The participants received two ketamine intravenous (into-the-vein) infusions within one week. The dose used was 0.30 mg/kg/hour, for five hours per infusion. Nine patients completed the infusion schedule.
Results showed that the maximum tolerated ketamine infusion rate was 0.20-0.30 mg/kg/hr. These doses were not associated with discomfort due to hypertension, also called high blood pressure, or dissociation. Dissociation is a common side effect of ketamine in which patients enter a mental state where they are less aware of their surroundings and start to feel disconnected from the body.
Dyskinesia decreased 51% during ketamine administration, 49% at three weeks after treatment, and 41% at three months. This effect was measured by the Unified Dyskinesia Rating Scale (UDysRS), a scale developed to evaluate involuntary movements.
Ketamine also had effects on Parkinson’s symptoms as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS). The UPDRS is the most widely applied rating scale to assess Parkinson’s severity and progression.
During ketamine infusion, UPDRS was reduced by 27%. The reduction at three weeks was 28%, and at three months after treatment it was 5%.
No adverse events after the treatment were reported.
“Our results provide further support for the repurposing of sub-anesthetic ketamine for individuals with [levodopa-induced dyskinesia],” the researchers wrote.
Based on these data, PharmaTher is planning a Phase 3 clinical trial to allow Ketarx approval by the FDA for Parkinson’s treatment under the 505(b)(2) regulatory pathway. This procedure is a new compound application based partially on previous studies, and offers a faster route for approval compared with traditional regulatory pathways.
“We are now focused on obtaining an agreement with the FDA to pursue approval under 505(b)(2) regulatory pathway with a potential Phase 3 clinical study for ketamine in the treatment of levodopa-induced dyskinesia in patients with Parkinson’s disease,” Chianelli said.
Ketamine also is believed to have a positive impact in pain relief and to offer additional benefits in easing depression, another frequent symptom in Parkinson’s patients.