On 2 April, at the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Disease, Cerevance announced that solengepras failed to meet its primary endpoint—change from baseline to week 12 on the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II + Part III—in its Phase II ASCEND trial (NCT06006247). The ASCEND trial sought to evaluate solengepras as a monotherapy in early Parkinson’s disease (PD). Solengepras is a potential first-in-class G-protein coupled receptor 6 (GPR6) antagonist that is designed to decrease inhibitory signalling in indirect medium spiny neurons (MSNs) without directly affecting dopaminergic pathways. Solengepras is under investigation as a once-daily treatment for PD.
The ASCEND trial evaluated the safety, tolerability, and efficacy of solengepras and aimed to establish its potential to improve motor and non-motor functions in participants with early PD who are not taking dopaminergic or anti-PD therapies. ASCEND included 64 patients ages 30 years and older with early, untreated PD, who are not yet experiencing motor fluctuations/OFF time. Participants were randomized to receive either 150mg solengepras daily or placebo for 12 weeks. The drug failed to meet its primary endpoint, as patients treated with solengepras experienced a small, non-statistically significant improvement from baseline compared to placebo in the MDS-UPDRS Parts II and III combined score at week 12 (-2.5 for solengepras versus -2.1 for placebo). According to Cerevance, the results missed the statistical bar primarily because of the lack of differentiation between solengepras and placebo in the Part III physician-administered neurological exam. Despite missing the primary endpoint, Cerevance said the trial saw trends in improvement on other patient-reported measures. These included benefits 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). Solengepras was well-tolerated as a monotherapy, with all subjects completing the 12-week trial period and no serious adverse events (AEs) being reported. Only 25% of the participants who received solengepras experienced any treatment emergent adverse events (TEAEs). The most common TEAEs (emerging in more than 5% of patients) were Covid-19, dizziness, headache, insomnia, and orthostatic hypertension.
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Despite the failure of the ASCEND trial, solengepras has shown promise as an adjunctive therapy. Solengepras has achieved a clinically meaningful reduction in OFF-time with minimal dopaminergic side effects in a Phase II trial in PD patients with motor fluctuations (NCT04191577). Moreover, Cerevance is moving forward with its pivotal Phase III ARISE trial (NCT06553027), which is evaluating solengepras as an adjunctive therapy to levodopa and other background PD medications in a different patient population than ASCEND. Specifically, ARISE is studying PD patients with motor fluctuations who have more than three hours of OFF time per day. Topline data from this trial is expected in H1 2026.
Clinical data indicates that solengepras may have a future as an adjunctive therapy to dopaminergic or anti-PD therapies. As a monotherapy, solengepras’s commercial positioning would be a cause for concern, as it would face competition from well-established therapies for the treatment of core PD symptoms, such as levodopa, dopamine agonists (DAs), and monoamine oxidase B inhibitors (MAO-Bs). According to GlobalData’s Drugs Database, six dopamine agonists are currently marketed across the seven major pharmaceutical markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan), many of which are available as generics. Additionally, AbbVie’s tavapadon is another DA that is in Phase III development. Given the crowded market, it will be difficult for solengepras to compete directly with the other DAs already on the market as a monotherapy, so entering the market as an adjunctive therapy would be the most likely route to success. Key opinion leaders (KOLs) previously interviewed by GlobalData have noted that dopamine agonists are no longer the preferred adjunctive therapies for PD due to side effects such as hallucinations, delusions, and compulsive behaviour. Therefore, solengepras could occupy a niche in the market. As a GPR6 antagonist, it has a novel, potentially first-in-class, non-dopaminergic mechanism, which differentiates it from competitors. However, the adjunctive treatment space is also competitive with MAO-B inhibitors, catechol-O-methyltransferase (COMT) inhibitors, and adenosine receptor antagonists, which can all be prescribed with levodopa. Cerevance will need to demonstrate that solengepras can show superior efficacy and safety over marketed adjunctive therapies in large Phase III clinical trials or engage in head-to-head studies for direct comparisons.
Although solengepras failed to meet its primary endpoint in the Phase II ASCEND trial as a monotherapy for early PD, the drug demonstrated promising trends in improving non-motor symptoms and functional impairments. Furthermore, its favourable safety profile, novel mechanism of action, and promising data when investigated as an adjunctive treatment (NCT04191577) have indicated that it is a potentially valuable adjunctive therapy. Pending the results of the Phase III ARISE trial, solengepras could be an option as an adjunctive therapy for PD patients with motor function.
