Cerevance's Solengepras Fails Primary Endpoint in Phase II Parkinson's Trial, Shows Promise for Non-Motor Symptoms
核心洞察
Cerevance (搜索)'s GPR6 (搜索) antagonist solengepras failed to meet its primary endpoint in the Phase II ASCEND trial as a monotherapy for early, untreated Parkinson's disease (搜索) patients, showing only a small, non-significant improvement versus placebo.
Despite missing the primary endpoint, solengepras demonstrated promising trends in improving non-motor symptoms and functional impairments, with fewer adverse events related to non-motor symptoms reported in the treatment arm.
The company is advancing solengepras in the pivotal Phase III ARISE trial as an adjunctive therapy to levodopa for Parkinson's patients with motor fluctuations, with topline data expected in the first half of 2026.
Cerevance (搜索) announced disappointing results for its investigational Parkinson's disease (搜索) treatment solengepras at the AD/PD 2025 International Conference on Alzheimer's and Parkinson's Disease on April 2. The potential first-in-class G-protein coupled receptor 6 (GPR6 (搜索)) antagonist failed to meet its primary endpoint in the Phase II ASCEND trial when used as a monotherapy in early Parkinson's disease.
The 12-week ASCEND trial evaluated 64 patients aged 30 and older with early, untreated Parkinson's disease (搜索) who were randomized to receive either 150mg solengepras daily or placebo. The primary endpoint measured change from baseline on the Movement Disorder Society – Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III combined score.
Patients treated with solengepras showed only a small, non-statistically significant improvement compared to placebo (-2.5 for solengepras versus -2.1 for placebo). According to Cerevance (搜索), the results missed statistical significance primarily due to lack of differentiation between solengepras and placebo in the Part III physician-administered neurological exam.
Promising Signals in Non-Motor Symptoms
Despite missing the primary endpoint, the company highlighted several positive trends in patient-reported measures. These included improvements in non-motor symptoms (-1.38 on the MDS-UPDRS Part I, p=0.12), daily function (-0.4 on MDS-UPDRS Part II, p=0.62), overall non-motor symptom burden (-1.7 on the Non-Motor Symptoms Scale, p=0.59), and daytime sleepiness (-0.3 on the Epworth Sleepiness Scale, p=0.62).
"For people with Parkinson's disease (搜索), dopaminergic therapies are the standard of care as they reduce tremors, stiffness, slowed movement, and other symptoms. However, there are crucial treatment gaps in addressing functional impairments and non-motor symptoms," said Dr. Aaron L. Ellenbogen, primary investigator of the ASCEND trial and assistant professor of medicine at Oakland University William Beaumont School of Medicine.
"The improvements in functional and non-motor symptoms observed in the patient-reported measures of the ASCEND trial suggest that solengepras could be a promising option for managing non-motor symptoms without the distressing side effects associated with conventional dopaminergic therapies," Dr. Ellenbogen added.
Favorable Safety Profile
Solengepras demonstrated a favorable safety profile as a monotherapy, with all subjects completing the 12-week trial period and no serious adverse events reported. Only 25% of participants receiving solengepras experienced any treatment-emergent adverse events (TEAEs). The most common TEAEs, occurring in more than 5% of patients, were COVID-19, dizziness, headache, insomnia, and orthostatic hypertension.
Notably, fewer adverse events related to non-motor symptoms were reported in the treatment arm compared to the placebo arm, suggesting potential advantages in managing these aspects of Parkinson's disease (搜索).
Novel Mechanism of Action
Unlike traditional Parkinson's treatments that focus on dopaminergic pathways, solengepras works through a novel mechanism as a GPR6 (搜索) antagonist. It is designed to decrease inhibitory signaling in indirect medium spiny neurons (MSNs) without directly affecting dopaminergic pathways.
This non-dopaminergic approach aims to restore both motor and non-motor function by improving the relative balance between direct and indirect pathways in the brain, potentially reducing the risk of common side effects associated with dopaminergic therapies, such as dyskinesias and motor fluctuations.
Craig Thompson, Chief Executive Officer of Cerevance (搜索), stated, "We are encouraged by the results of the Phase 2 ASCEND trial of solengepras as a monotherapy, which align with findings from our Phase 2 trial of solengepras as an adjunctive therapy, with both demonstrating benefits on patient-reported measures."
Future Development Path
Despite the ASCEND trial setback, solengepras has previously shown promise as an adjunctive therapy. In an earlier Phase II trial in Parkinson's patients with motor fluctuations (NCT04191577), the drug achieved a clinically meaningful reduction in OFF-time with minimal dopaminergic side effects.
Cerevance (搜索) is now focusing on the pivotal Phase III ARISE trial (NCT06553027), which is evaluating solengepras as an adjunctive therapy to levodopa and other background Parkinson's disease (搜索) medications. The ARISE trial targets a different patient population than ASCEND, specifically studying Parkinson's patients with motor fluctuations who experience more than three hours of OFF time per day. Approximately 330 patients are being enrolled globally, with topline data expected in the first half of 2026.
Market Positioning and Competition
As a monotherapy, solengepras would face significant competition from well-established treatments for core Parkinson's disease (搜索) symptoms, including levodopa, dopamine agonists, and monoamine oxidase B inhibitors (搜索). Many of these competitors are available as generics across major pharmaceutical markets.
However, as an adjunctive therapy, solengepras could potentially fill an important niche. Key opinion leaders have noted that dopamine agonists are no longer the preferred adjunctive therapies for Parkinson's disease (搜索) due to side effects such as hallucinations, delusions, and compulsive behavior.
With its novel, non-dopaminergic mechanism, solengepras could differentiate itself from competitors in the adjunctive treatment space, which includes MAO-B inhibitors, catechol-O-methyltransferase (COMT) inhibitors, and adenosine receptor antagonists (搜索). However, Cerevance (搜索) will need to demonstrate superior efficacy and safety over these marketed adjunctive therapies in large Phase III clinical trials to secure a meaningful market position.
The company's focus on addressing both motor and non-motor symptoms of Parkinson's disease (搜索) aligns with growing recognition of the importance of comprehensive symptom management in improving quality of life for patients with this progressive neurodegenerative disorder, which affects more than 10 million people worldwide and approximately 1 million in the United States.