Solengepras reduces OFF time in Phase 3 Parkinson’s trial

A new Parkinson’s drug has produced positive results in a large Phase 3 clinical trial, reducing the amount of time people spent in the “OFF” state and also showing improvements in everyday activities, daytime sleepiness and quality of life. The drug, called solengepras, is being developed by Cerevance as an add-on treatment for people with Parkinson’s who already take levodopa or other Parkinson’s medicines but continue to experience motor fluctuations. The results are important because solengepras works differently from most current Parkinson’s medicines. Rather than directly increasing or replacing dopamine, it targets a brain receptor called GPR6, which is involved in the brain circuits that control movement. The problem with “OFF” time As Parkinson’s progresses, levodopa can become less predictable. A person may take their medication and experience a period when it works well, known as “ON” time. Later, its effect may wear off and Parkinson’s symptoms such as stiffness, slowness and tremor return. This is known as “OFF” time. For some people, these fluctuations can take up several hours of the day and make everyday life difficult. The Phase 3 ARISE trial specifically recruited people who were already experiencing motor fluctuations. The 341 participants had an average of 5.65 hours of OFF time every day despite their usual Parkinson’s medication. They continued taking their existing medication during the trial. Participants were randomly given either 75 mg of solengepras, 150 mg of solengepras, or a placebo once a day for 12 weeks. The main question was whether the 150 mg dose could reduce daily OFF time compared with placebo. Less OFF time with the higher dose The answer was yes. After 12 weeks, people taking 150 mg of solengepras had reduced their daily OFF time by 1.56 hours from the beginning of the trial. The placebo group also improved, reducing OFF time by 0.95 hours. That means the difference between solengepras and placebo was 0.61 hours, or about 37 minutes per day. This was statistically significant, meaning the result was unlikely to have happened simply by chance. The difference was already visible at the first assessment, two weeks after treatment began, and remained present at the later assessments through week 12. The drug also increased the amount of “ON” time without troublesome dyskinesia by about 36 minutes per day compared with placebo. Dyskinesia refers to involuntary movements that can occur as a complication of Parkinson’s treatment, particularly long-term levodopa treatment. These numbers are worth looking at carefully. A reduction of 37 minutes of OFF time per day is meaningful, particularly for someone who experiences several hours of OFF time. But it is not a dramatic disappearance of motor fluctuations. The placebo group also improved considerably, which is common in Parkinson’s clinical trials. The results were not limited to OFF time One of the more interesting parts of the trial is that the researchers looked beyond the traditional measurement of OFF time. People taking the 150 mg dose showed a statistically significant improvement in motor experiences of daily living, measured using part II of the MDS-UPDRS. This scale includes everyday activities affected by Parkinson’s, such as getting dressed, eating, moving around and carrying out other daily tasks. The difference between solengepras and placebo was 1.91 points on this measure. There were also improvements in some non-motor measures. Daytime sleepiness improved by 0.98 points compared with placebo on the Epworth Sleepiness Scale. Quality of life also improved on the PDQ-39, although this was an exploratory measure rather than one of the main confirmatory endpoints of the trial. This is potentially interesting because Parkinson’s is much more than a movement disorder. Sleepiness, fatigue, mood, cognition and other non-motor symptoms can have a major effect on daily life. However, these results should still be interpreted cautiously. The study was primarily designed to establish the effect on OFF time, and the company describes the quality-of-life result as exploratory. A different approach to Parkinson’s treatment The mechanism behind solengepras is perhaps the most interesting part of the story. Most established Parkinson’s medicines work by increasing dopamine activity in some way. Levodopa, for example, is converted into dopamine in the brain. Other medicines stimulate dopamine receptors or slow the breakdown of dopamine. Solengepras takes a different approach. It targets GPR6, a receptor found mainly in cells belonging to the brain’s indirect movement pathway. This pathway acts partly like a brake on movement. When dopamine is lost in Parkinson’s, the balance between the brain circuits that promote and inhibit movement becomes disrupted. The idea behind solengepras is to reduce some of this excessive braking without directly increasing dopamine. That makes solengepras particularly interesting as a potential new type of Parkinson’s treatment. It is not simply another way of delivering more dopamine. But it is important to remember that this is still an investigational medicine. The Phase 3 results show that targeting this pathway can produce a measurable clinical effect. They do not yet prove that the drug will change the underlying progression of Parkinson’s disease. What about side effects? The safety results were also encouraging. About 3.5% of participants stopped treatment because of an adverse event, and this was the same in the placebo group. No serious adverse events were reported in the 150 mg group. The most commonly reported side effects with 150 mg were headache and urinary tract infection, each occurring in 8% of participants. Insomnia and nausea were each reported in 6.2%. Dyskinesia was reported in 4.4% of people taking 150 mg compared with 1.8% taking placebo. The relatively low rate of treatment discontinuation is encouraging, especially for an add-on Parkinson’s treatment. However, the trial lasted only 12 weeks, so longer-term safety will still need to be established. What happens next? The ARISE trial has achieved its primary endpoint, which is an important milestone in drug development. Cerevance now plans to discuss the results with the US Food and Drug Administration and determine the requirements for a potential application for approval. Solengepras is therefore not yet an approved Parkinson’s treatment. More regulatory review is required before it could become available as a standard treatment. The Phase 3 results nevertheless provide stronger evidence than the earlier studies that this approach can help people with Parkinson’s who experience motor fluctuations. The most interesting question now is not simply whether solengepras works. It is how useful the benefit will be in everyday life, how well it performs over longer periods, and where it could fit alongside existing Parkinson’s treatments. For people who are spending several hours a day in the OFF state, gaining roughly half an hour or more of additional useful time could be valuable. At the same time, the results do not suggest that solengepras eliminates OFF periods or replaces levodopa. What makes the trial significant is the combination of a measurable reduction in OFF time, improvements in daily function and encouraging tolerability, together with a mechanism that does not directly target dopamine. If these findings are confirmed through regulatory review and longer-term use, solengepras could add a genuinely different option to the Parkinson’s treatment toolbox.