#AANAM – SEP‑363856 Shows Promise in Easing Parkinson’s Psychosis

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The investigational medication SEP-363856 might ease symptoms of Parkinson’s disease psychosis, according to data from a small clinical trial.

“In this proof-of-concept study, improvements across several scales without worsening motor parkinsonism suggest that SEP-363856 may provide a novel … treatment for [Parkinson’s disease psychosis], particularly for patients with cognitive impairment,” the researchers wrote.

The findings support further testing of SEP-363856 for treating Parkinson’s psychosis, according to the investigators.

The results were presented at this year’s annual meeting of the American Academy of Neurology (AAN), in a talk titled “Efficacy and Safety of SEP‑363856, a Non–D2-Receptor Binding Drug With Antipsychotic Activity, in Patients With Parkinson’s Disease Psychosis.” The 2021 virtual AAN is being held online April 17-22.

Parkinson’s psychosis is a non-motor symptom of the neurodegenerative disease in which people can experience hallucinations, in which they see, hear, or feel something that does not exist. Patients also can have delusions, or illogical or irrational beliefs that are not based on reality.

Most currently available treatments for psychosis — known as antipsychotics — are believed to work by activating specific protein receptors in the brain, particularly dopamine 2 (D2) receptors. This can pose a problem in Parkinson’s, as D2 receptors are impaired in the brains of people with the disease, such that targeting these receptors may worsen some symptoms.

SEP-363856 is being developed by Sunovion as a treatment for Parkinson’s psychosis and schizophrenia. The medication is believed to work through D2-independent mechanisms. Specifically, SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1), a protein that is involved in the regulation of certain brain signaling molecules, and that has emerged as a possible target for psychiatric conditions in recent years.

Sunovion sponsored a small Phase 2 clinical trial (NCT02969369) to test SEP-363856 in people with Parkinson’s psychosis.

“We sought out, in this trial, to use a proof-of-principle study to evaluate the efficacy and safety of SEP-363856 in patients with Parkinson’s disease psychosis,” said Stuart Isaacson, MD, medical director of the Parkinson’s Research and Education Foundation, who presented the trial’s results at AAN.

The trial enrolled 39 adults with Parkinson’s psychosis, who were randomly assigned to receive SEP-363856 (flexibly dosed at 25, 50, or 75 mg/day), or a placebo, for six weeks. On average, the participants had been living with Parkinson’s for about nine years, and had experienced Parkinson’s psychosis for about two years.

Of the enrolled participants, 26 — 11 given a placebo and 15 given SEP-363856 — completed the trial. The most common reasons for discontinuation in both groups were adverse events (side effects) and the patient’s individual decision.

The study’s main goal was to determine the effect of treatment on the Scale for Assessment of Positive Symptoms–Parkinson’s Disease scores. This scale, known as SAPS-PD, is a standardized assessment of the severity of hallucinations and delusions that can occur in Parkinson’s. SAPS-PD scores can range from 0 to 45, and higher scores indicate more severe symptoms.

At the start of the trial, the mean SAPS-PD total score was 14.6 points. Over the course of the six-week trial, participants given SEP-363856 experienced an average decrease of 2.5 points on the SAPS-PD. By comparison, those given a placebo experienced an average decrease of 1.4 points. The difference between the groups was not statistically significant — meaning that, mathematically, there is a non-negligible likelihood that the difference between the groups could be due to random chance, not the effect of treatment.

“There did appear to be improvement [in psychosis symptoms] with this medication … but there was also placebo improvement,” said Isaacson, suggesting that a placebo effect could explain the lack of a statistically significant difference in this small study.

Although improvements were seen in both hallucinations and delusions, they appeared to be more pronounced in hallucinations, Isaacson noted.

One in four of the trial participants treated with SEP-363856 were in complete remission after six weeks — meaning they had a score of zero on the SAPS-PD, or no symptoms of psychosis. By contrast, none of the participants given the placebo were in remission at the end of the trial. Rates of partial remission also were higher with SEP-363856 than the placebo.

The results give “hope that [SEP-363856] does indeed have antipsychotic activity in Parkinson’s disease psychosis,” Isaacson said.

The researchers noted that SAPS-PD improvements were generally more pronounced among participants with greater cognitive impairment, as evidenced by lower scores on the Mini-Mental State Examination, or MMSE.

Notably, scores on the MMSE did not differ significantly between the SEP-363856 and placebo groups at the end of the trial, nor did assessments of motor symptom severity of sleepiness.

Based on these findings, SEP-363856 “does appear to be a novel antipsychotic that does not worsen Parkinsonism [Parkinson’s-like symptoms],” Isaacson said.

Treatment with SEP-363856 was generally well-tolerated by trial participants. Common adverse events included hallucinations, confusion, falls, and dizziness. The researchers noted that psychiatric adverse events were more common with higher doses of the medication.

According to Isaacson, this study serves as a proof-of-principle for further investigation of SEP-363856 in Parkinson’s psychosis.

“Hopefully, [more, larger] studies will be performed to further identify and determine the efficacy, safety, and tolerability of SEP-363856 in Parkinson’s psychosis,” Isaacson concluded.