About Alzheimer’s disease and other cognitive disorders
Alzheimer’s disease is characterized by a progressive, irreversible decline in memory and cognitive function. Symptoms typically start to appear after the age of 60, but it can arise in younger individuals. Ultimately the continued loss of function significantly interferes with a person’s daily life and activities (e.g. washing, feeding, walking) until they require constant nursing care.
Alzheimer’s disease represents a large and growing economic and social burden to society. Currently it is estimated that there are 11 million patients in the US and 5MEU countries. As the risk of developing Alzheimer’s increases with age, the number of patients in the US and Europe is expected to double by 2040.
Alzheimer’s disease is associated with changes in the brain including amyloid plaques, tangles and loss of neurons. The cause of the neuronal loss and the underlying cause of cognitive deficits are not well understood, though several neurotransmitters have been shown to have positive effects on cognitive capabilities, specifically acetylcholine and glutamate.
Currently there are no therapies that can cure this disease. Existing therapies are targeted at symptomatic improvement of cognitive function. The acetylcholinesterase inhibitors (that increase concentrations of acetylcholine in the brain) represent the main therapeutic class available today, but the efficacy displayed is limited, and has a slow onset since all require careful dose titration (gradual increase in dose to the efficacious level) because of GI and other side effects.
In addition to Alzheimer’s disease, cognitive deficits are frequently associated with other disorders of the central nervous system. For example, cognitive impairment is a common feature of schizophrenia, and it has been reported that up to 80% of patients with schizophrenia show significant cognitive impairment. Cognitive deficits are also common in neurogenerative disorders such as Parkinson’s disease, where long-term follow-up studies have suggested that 50 to 80% of patients with Parkinson’s disease may experience dementia.
SYN120 Product profile
SYN120 is an oral, dual antagonist of the 5-HT6 and 5-HT2A receptors. These two distinct properties could result in a unique therapeutic profile for SYN120 combining pro-cognitive and antipsychotic activities in neuro-degenerative diseases, such as Parkinson's disease and Alzheimer's disease. 5-HT6 receptors are located exclusively in the brain and antagonizing them results in increased concentrations of acetylcholine and glutamate, two known pro-cognitive neurotransmitters. The localization of the 5-HT6 receptors in the brain therefore avoids stimulation of peripheral cholinergic neurotransmission and the subsequent adverse effects. The 5-HT2A receptor, on the other hand, is expressed widely through the central nervous system and is believed to play a role in the antipsychotic action of many neuroleptics.
SYN120 has completed single and multiple ascending dose Phase 1 clinical studies and a Phase 1 positron emission tomography imaging study to determine therapeutic dose for subsequent Phase 2 studies. In these trials, doses well above the anticipated therapeutic dose were well tolerated.
Clinical Trial Status
SYN120 has earlier been studied in two placebo-controlled trials in which volunteers received SYN120 at doses more than 10-fold the anticipated therapeutic dose for up to 14 days In these studies, SYN120 was well tolerated and there were no observations precluding further development, such as clinically relevant effects on QTc, which has been an issue with other compounds targeting this pathway. A PET imaging study completed in 2012 demonstrated that target levels of receptor occupancy expected for efficacy can be achieved with SYN120 doses that are an order of magnitude lower than those that have previously been shown to be safe and well tolerated for up to two weeks in healthy older volunteers.
SYN120 was advanced into Phase 2 development in December 2014 with the start of a Phase 2a clinical study in patients with Parkinson's disease dementia (PDD). The SYNAPSE study is an 80 patient, randomized, double-blind, multi-center, placebo-controlled trial. Patients are randomized 1:1 to placebo or SYN120 dosed once daily over a 16 week treatment period. In addition to assessing safety and tolerability, the main focus of the study is to establish efficacy of SYN120 on cognition using the Cognitive Drug Research (CDR) Computerized Cognition Battery as the primary efficacy endpoint. The study is primarily funded by The Michael J. Fox Foundation (MJFF) and is being conducted by the Parkinson Study Group (PSG) at approximately 12 sites in the United States specializing in cognitive dysfunction in Parkinson's disease. Biotie and the PSG share responsibility for the design and execution of the study. Top-line results of the study are expected in the second half of 2017.
Biotie has exclusive worldwide rights to develop and commercialize SYN120 under a license agreement with Roche and will be able to use data from the MJFF-funded study for any future regulatory submission for SYN120, including Alzheimer's disease, although further clinical development plans in such indications will depend on the availability of funding.
Synosia licensed SYN120 from Roche in March 2009. Biotie also licensed a second 5-HT6 antagonist from Roche, SYN114, which is a backup to SYN120. This product has completed Phase 1 single and multiple ascending dose studies.
Scientific literature related to the project
Upton, N., Chuang, T. T., Hunter, A, J., & Virley, D. J. (2008). 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics, 5(3), 458-469.
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