SYN120 Fails to Show Efficacy Against Parkinson Dementia in Phase 2a SYNAPSE Trial

SYN120, a dual 5-HT6/5-HT2A antagonist, did not improve cognition during 16 weeks of the placebo-controlled phase 2a SYNAPSE trial of patients with Parkinson disease (PD) dementia. The disappointing results from the much-anticipated trial were announced in a platform presentation May 5 at the American Academy of Neurology’s 2019 annual meeting.

“Despite the promising ‘pedigree’ that this drug had from years of experience in animal models and patients, it did not deliver in a rigorous clinical trial,” says neurologist Hubert Fernandez, MD, Director of Cleveland Clinic’s Center for Neurological Restoration and principal investigator of the SYNAPSE trial. “The outcome from SYNAPSE illustrates how challenging it is to find a drug to treat this difficult condition.”

Background: New dual-activity molecule

SYN120 is a dual antagonist of serotonin, blocking two receptors shown to improve cognition and symptoms of dementia in preclinical models:

• The 5-HT6 receptor, which modulates neurotransmitters related to learning and memory
• The 5-HT2A receptor, which mediates psychiatric symptoms, including depression, apathy and psychosis

Currently, the only FDA-approved treatment for PD dementia is the acetylcholinesterase inhibitor rivastigmine.

Many indicators assessed safety and efficacy

SYNAPSE was a randomized, double-blind, placebo-controlled study of 82 patients with PD dementia at 20 Parkinson Study Group sites; all were already taking rivastigmine. Seventy-seven patients completed the study and were included in the analysis — 36 taking SYN120 100 mg daily and 41 taking placebo.

Efficacy was assessed from baseline to week 16 using a variety of cognitive scales. Difference estimates, none of which reached statistical significance between the SYN120 and placebo arms, were as follows:

• Computerized Drug Research Cognition Battery (CDR) Continuity of Attention (sustained attention): –4.0; P = 0.13
• CDR Quality of Episodic Memory: 7.49; P = 0.52
• Alzheimer’s Disease Assessment Scale – Cognitive Subscale: –0.36; P = 0.82
• Alzheimer’s Disease Cooperative Study – Clinician’s Global Impression of Change: –0.43; P = 0.07

Safety and tolerability were also evaluated by multiple measures:

• Interestingly, motor symptoms, assessed with the Unified Parkinson’s Disease Rating Scale Part III, worsened in the SYN120 group versus the placebo group (difference estimate = 4.81; P = 0.01).
• Adverse events were reported at comparable rates in the two groups — by 74% of patients taking SYN 120 and 77% of those taking placebo.
• Adverse events led to treatment discontinuation in 16% of SYN120 recipients versus 14% of placebo recipients.
• Nausea, vomiting and visual hallucinations — although infrequent — occurred twice as often in the SYN120 group.

A separate analysis of secondary outcomes in the same trial population, presented at the 2018 International Congress of the International Parkinson and Movement Disorder Society, found statistically significant improvement in apathy scores in the SYN120 arm, as well as numerical improvements in sleep, anxiety and irritability, although the latter did not reach statistical significance (Mov Disord. 2018;33[suppl 2]).

Takeaways: The challenges of PD dementia research

According to Dr. Fernandez, who serves as co-chair of the Parkinson Study Group — the largest nonprofit scientific network of Parkinson centers in North America and the group that conducted the SYNAPSE study — the results of this trial highlight at least three difficulties of conducting research in PD dementia:

• Performing extensive cognitive testing in patients with combined dementia and motor limitations is extremely challenging, as few qualified candidates are willing or able to participate. For instance, 20 sites were needed to enroll 82 patients in this study.
• Designing a trial to elicit clear differences in cognitive outcomes presents its own potential pitfalls. While the SYNAPSE trial found no SYN120-associated improvement in direct cognitive measures, some improvement was found in measures that only indirectly involve cognition, such as ability to perform activities of daily living. These mixed findings are difficult to explain, Dr. Fernandez notes.
• Despite consistent evidence of the potential benefits of a novel compound, clinical trials may not have the expected results.

“Addressing dementia remains one of the most important unmet needs in Parkinson disease and continues to be the area with the deepest knowledge gaps,” Dr. Fernandez observes. “This challenges the field to keep trying to develop novel compounds as well as creative clinical trial designs.”

The SYNAPSE study was sponsored by the Michael J. Fox Foundation for Parkinson’s Research and Acorda Therapeutics.

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