First-in-Class Med Safe, Effective for PD Motor Fluctuations

SEOUL, South Korea — The novel GPR6 inhibitor solengepras was both safe and effective for improving motor fluctuations related to Parkinson’s disease (PD).Phase 3 data from the ARISE trial, a multicenter study involving more than 300 participants, met its primary endpoint, showing a significantly greater reduction in average daily OFF time from baseline to week 12 with once-daily oral solengepras (150 mg) compared with placebo. Treatment benefits were evident as early as week 2.Safety and tolerability analyses showed an overall completion rate of 91%, with more participants discontinuing in the placebo group than in the active treatment group. A serious treatment-emergent adverse event ( TEAE) was reported in one participant in the placebo group vs none in the active treatment group.“The takeaway message is that this is a novel, nondopaminergic mechanism that, in this phase 3 study, demonstrated safety and efficacy. So the company will be engaging in discussions with the FDA about approval,” said study investigator Robert Hauser, MD, professor of neurology and director of the Parkinson’s Disease and Movement Disorder Center at the University of South Florida in Tampa, Florida.He added that while meeting the primary endpoint was an important outcome, he was also pleased to see improvements in ON time without troublesome dyskinesia and in daily functioning.The findings were presented on October 7 at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2026.A New Therapeutic TargetUnlike conventional dopaminergic therapies, which increase or mimic dopamine activity, solengepras targets a different pathway involved in regulating movement. According to the drug’s manufacturer, this targeted approach could potentially offer a new treatment option for PD while potentially reducing unwanted effects on other cell types.The multicenter international phase 3 ARISE trial was double-blinded, placebo-controlled, and it included 341 patients aged 30 years or older (mean age, 65.5 years; 69.2% men) enrolled at sites in the US (60.2%), Poland, Australia, Czech Republic, Italy, Spain, France, and the UK. All patients had experienced at least 3 hours of average daily OFF time (mean, 5.6-5.7 hours).Participants were randomly assigned to receive solengepras 150 mg (n = 113) or 75 mg (n = 114) or matching placebo (n = 114) for 12 weeks. They also received their usual levodopa at stables doses either alone (45.5%) or with a dopamine agonist (DA, 23.2%), with a monoamine oxidase inhibitor (MOI, 16.7%), or with both a DA and an MOI (14.7%).Among the 341 patients randomized, 91% completed the study. Of the 30 dropouts, 10.5% were from the placebo group, and 8.0% and 7.9% were from the solengepras 150 mg and 75 mg groups, respectively.Motor, Nonmotor BenefitsThe primary outcome measure was the change at 12 weeks in average daily OFF time on motor diaries for 150 mg compared with placebo. Results showed significant OFF-time reduction during this time for solengepras 150 mg (-1.56 h/d) compared to placebo (-0.95 h/d; P = .035).Key secondary endpoints included changes in ON time “without troublesome dyskinesias” and changes on the Motor Experiences of Daily Living in Parkinson’s disease Part II (MDS-UPDRS II), the Clinical Global Impression of Severity (CGI-S), the Epworth Sleepiness Scale (ESS), and the Parkinson’s Disease Questionnaire 39 (PDQ-39).The increase in ON time was significantly greater in the higher-dose group than in the placebo group (1.58 vs 0.98 h/d; P < .05), as was improvement in daily function on the MDS-UPDRS II (-2.05 vs -0.14 points; P = .0008). Several individual components of the MDS-UPDRS II, including saliva and drooling (P = .0001), dressing (P = .02), and walking/balance (P = .03), also showed improvement.The higher-dose group did not show greater improvement than the placebo group on the CGI-S. Although solengepras 150 mg was associated with greater reduction in daytime sleepiness on the ESS compared to placebo (-1.39 vs -0.41; P = .009) and greater change on the PDQ-39 (-3.73 vs -0.86; P = .01), these results were considered to be “nominally significant” because the ESS and PDQ-39 came below the CGI-S in the study’s prespecified hierarchy.Still, the drug showed benefits for both motor and nonmotor function, said Hauser.“OFF time has long been the main way we assess add-on therapies, but it captures only one aspect of the disease. Looking at these measures together may give a fuller picture of a treatment’s potential benefits for patients,” he added in a release.Three participants in the 150 mg group and three in the placebo group had an adverse event that was classified as severe.Any serious TEAE was reported by one participant in the placebo group and none in the solengepras 150 mg group. The rate of early discontinuation because of a TEAE was 3.5% in both groups.The most common TEAEs in the 150 mg group were urinary tract infections (8% vs 6.1% in the placebo group), headache (8% vs 3.5%), nausea (6.2% vs 1.8%), and insomnia (6.2% vs 0.9%). Dyskinesia, though less common, was reported in 4.4% of the 150 mg group vs 1.8% of the placebo group.Overall, the percent of patients with at least one TEAE was 61.1% for the higher-dosage group vs 52.6% for the placebo group, which Hauser noted was “lower than typically seen with dopaminergic Parkinson’s medications.”He added that discussions with the FDA regarding a path to New Drug Application filing for the novel drug is scheduled for Q4 of this year.A Novel Approach, but Questions RemainAlthough the study’s findings are promising, questions remain about how the drug would fit into the existing PD treatment landscape.Session co-moderator and past president of the MDS Victor Fung, MD, professor of neurology and motor control at Sydney Medical School and director of the Movement Disorders Unit at Westmead Hospital in Sydney, Australia, said the research was particularly interesting because of the drug’s novel mechanism of action.Fung, who was not involved in the study, told Medscape Medical News he would like to see whether solengepras provides additional benefit when combined with other treatments, including deep brain stimulation. He also said he is interested to see more detailed results, particularly additional quality-of-life data.The study was funded by Cerevance. Hauser reported having numerous disclosures with several companies, which include consulting fees from Cerevance. Fung reported no relevant financial disclosures. He noted that although his center participated in the ARISE trial, he was not involved.