SYN120 for the treatment of Alzheimer’s disease and other cognitive disorders
Alzheimer’s disease is the leading cause of dementia in the ageing population and represents a huge social and economic burden. Currently there are few options for patients and the efficacy of products commonly used today is hindered by their unfavorable side effect profile. SYN120 specifically targets a class of receptors in the brain that are involved in cognition. This specificity could help reduce the risk of peripheral side effects, potentially giving SYN120 a broader therapeutic window than current therapies through which to reduce the debilitating symptoms of this disease.
About Alzheimer’s disease
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.
SYN120 Product profile
SYN120 is an orally administered, potent and selective antagonist of the 5-HT6 receptor that is in development for the treatment of Alzheimer’s disease and other cognitive disorders, including schizophrenia. 5-HT6 receptors are located exclusively in the brain and blocking them results in increased concentrations of acetylcholine and glutamate, two known pro-cognitive neurotransmitters. SYN120 is a third generation 5-HT6 antagonist that has been designed to be devoid of some of the cardiovascular side effects that have impacted this class of drugs. Moreover, the selective expression of 5-HT6 receptors in areas of the brain important in cognition is expected to improve the efficacy and safety profile of SYN120 versus currently available therapies.
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.
In July 2011, Biotie commenced a PET study to determine the dose required to occupy the 5-HT6 receptor in the brain and to establish therapeutic dose. Top-line results for the PET study were announced in March 2012. The study was conducted at the Johns Hopkins University School of Medicine in the United States and enrolled nine healthy volunteers who were treated with different doses of SYN120. The results demonstrate 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.
Collaboration partner
Synosia licensed SYN120 from Roche in March 2009 and Roche has a onetime option to take back rights for development and commercialization of SYN120 following the PET study. Biotie will provide Roche with an extensive package of preclinical and clinical data to facilitate their decision. If Roche exercises their option to opt-in they will make a pre-negotiated milestone payment to Biotie and will take over all development and commercialization. In return, Biotie will receive development and commercialization milestones, and will be eligible to receive royalties on sales. If Roche does not exercise their option, then Biotie will seek an alternative partner for the further development of SYN120 in Alzheimer’s disease.
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.
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Updated March 8, 2012