Phase 3 ARISE Trial of Parkinson Therapy Solengepras Begins Dosing

Craig Thompson

According to an announcement, Cerevance’s phase 3 ARISE pivotal trial (NCT06553027) assessing its investigational agent solengepras as a potential adjunctive therapy for Parkinson disease (PD) has begun dosing. The global, placebo-controlled, 12-week trial plans to enroll 330 patients with the disease, with topline data expected in the first half of 2026.¹

Eligible participants for this study include individuals diagnosed with PD meeting UK Brain Bank and MDS Research Criteria, displaying bradykinesia, motor asymmetry, or rest tremor, and a prominent response to levodopa. The double-blind study will use change in the total daily OFF time over the 12-week period as the primary end point. Solengepras, also known as CVN424, is designed to selectively address the indirect dopamine pathway by modulating the GPR6 receptor.

ARISE will test the effects of the therapy in 2 doses (75 mg, 150 mg) against placebo over the treatment period. In addition to its primary end point, the study will also include several secondary outcomes, such as change in ON time without troublesome dyskinesia, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II scores, patient and clinician global scales, Epworth Sleepiness Scale, and Cogstate digital cognitive battery, among others.

"Parkinson disease is the fastest growing neurological disorder globally, highlighting a significant need for more improved and effective therapies," Craig Thompson, chief executive officer at Cerevance, said in a statement.¹ "Unlike traditional Parkinson treatments that aim to restore dopamine levels, solengepras is designed to selectively target and modulate the specific brain circuits responsible for controlling movement and non-motor functions, without relying directly on dopamine pathways."

He added, "This novel mechanism of action is designed to reduce motor complications such as dyskinesia and OFF periods, which we believe may offer potentially improved tolerability and potential impact on non-motor symptoms for individuals with Parkinson’s disease."

Additional inclusion criteria for the study state that participants must have a BMI between 18.0 and 35.0 kg/m², a Modified Hoehn and Yahr Stage of at least 3 in the ON state, and be freely ambulatory (with or without assistive devices). Cognitive function should be adequate (MoCA ≥ 24), PD medications stable, and participants must accurately complete ON/OFF diaries. Additionally, they must meet contraceptive requirements and be approved by the Enrollment Authorization Committee.

Patients are excluded study if they have secondary or atypical parkinsonism, severe dyskinesias or OFF periods that could hinder study participation, or prior surgical or therapeutic interventions such as deep brain stimulation or Duopa. Other exclusions include clinically significant orthostatic hypotension, hallucinations requiring antipsychotics, or routine use of certain medications like strong CYP3A4/5 inhibitors or dopamine antagonists. Individuals with significant cardiac, psychiatric, or laboratory abnormalities, prolonged QTc intervals, active depression, substance use disorders, recent suicidality, or malignancy concerns will also be excluded. Additionally, abnormal liver enzymes, significant renal impairment, or a history of specific cardiac conditions will disqualify participants.

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"The initiation of ARISE builds on the encouraging Phase 2 data we have generated and represents an exciting chapter in Cerevance’s journey to address the unmet needs of individuals with Parkinson disease," Sagar Vaidya, MD, PhD, chief medical officer at Cerevance, said in a statement.¹ "We look forward to advancing solengepras through this pivotal trial and moving closer to potentially bringing a new, non-dopaminergic therapy to the Parkinson community."

Prior to ARISE, solengepras demonstrated efficacy and safety in a phase 2, randomized, double-blind, placebo-controlled study (NCT04191577), published in The Lancet Discovery Science Suite. The study met its key efficacy end point and demonstrated a reduction in average daily OFF time from baseline at day 27, as recorded over 2 days using a self-reported patient motor diary. Overall, the solengepras 150 mg dose cohort demonstrated a statistically significant reduction of 1.3 hours (P = .02) in average daily OFF time versus placebo, representing a 1.6-hour (P <.0001) improvement from baseline.²

In the study, decreases in OFF time were accompanied by trends towards increased total daily ON time without troublesome dyskinesia. Specifically, the placebo-adjusted least squares mean treatment difference for good ON time was +0.67 (P = .27) with solengepras 150 mg dose. In the supplementary post-hoc analysis, treatment with higher doses of the agent reduced OFF time by –1.78 hours (P = .0045) compared with placebo and increased good ON time by +1.3 hours (P = .04). On a secondary outcome, patients in the solengepras 150 mg group showed an improved ESS score of –1.35 (±0.68) compared with placebo (P = .049).

In terms of safety, the therapy was generally well-tolerated with few adverse events (AEs) and low rates of dopaminergic AEs across both dose cohorts. No treatment-emergent AEs were reported, as well as no notable changes in laboratory parameters, physical examinations, ECGs, and BDI scores during the study. In addition, there were no clinically relevant changes in blood pressure or pulse rate.

REFERENCES
1. Cerevance doses first patient in pivotal phase 3 ARISE trial of solengepras for treatment of Parkinson’s disease. News release. Cerevance. November 18, 2024. Accessed November 18, 2024. https://www.globenewswire.com/news-release/2024/11/18/2982801/0/en/Cerevance-Doses-First-Patient-in-Pivotal-Phase-3-ARISE-Trial-of-Solengepras-for-Treatment-of-Parkinson-s-Disease.html
2. Brice NL, Carlton M, Margolin DH, et al. CVN424, a GPR6 inverse agonist, for Parkinson’s disease and motor fluctuations: a double-blind, randomized, phase 2 trial. eClinicalMedicine. 2024;77:102882. doi:10.1016/j.eclinm.2024.102882