PDE10: Novel target demonstrates promise in schizophrenia
About schizophrenia
Schizophrenia is a chronic, severe and disabling mental disease that affects around 1% of the population. The disease often presents itself during early adulthood and consequently can have a severe impact, not only on the education and career of the patient, but also on the quality of life of their families and caregivers.
Schizophrenia is characterized by a range of symptoms that fall into three main categories – positive (e.g. hallucinations, grandiose delusions), negative (e.g. social withdrawal, low motivation) and cognitive (e.g. poor execution of day-to-day tasks and memory problems). There are several types of products on the market to treat schizophrenia, classifi ed as typical (fi rst generation) and atypical (second generation) anti-psychotics. These products have various mechanisms of action, including modulation of neurotransmitter signaling in the brain of the patient, and tend to reduce positive symptoms of the disease better than negative and cognitive symptoms. Moreover, these products are frequently associated with undesirable side effects, including weight gain, movement disorders and cardiovascular problems.
Product profile
Biotie and partner Pfi zer (formerly Wyeth) are focused on the development of a new class of products that inhibit a novel target called phosphodiesterase 10 (PDE 10). PDE 10 is an enzyme that is predominantly expressed in the brain and is responsible for deactivating cellular signaling molecules known as cyclic nucleotides (specifi cally cAMP, cGMP). Growing evidence suggests that abnormally low levels of cyclic nucleotides play a role in various neurological conditions, including schizophrenia. PDE10 inhibitors have the ability to increase the level of cyclic nucleotides in the brain and therefore restore balance to important neurological pathways. Early pre-clinical data indicates that PDE10 inhibitors could have a broader range of activity than existing agents, by treating not only the positive symptoms of the disease, but also, the negative and cognitive symptoms. In addition, by working through a unique pathway, PDE10 inhibitors may have an improved safety profile versus existing agents, allowing therapeutic doses to be reached that can better manage poorly controlled positive symptoms, such as grandiose delusions.
Development status
Pre-clinical data from our studies presented during 2009 at the American Chemical Society Fall Meeting in Washington D.C. and the Society for Neuroscience in Chicago, showed that initial compounds in the PDE10 inhibitor program display promising antipsychotic activity in animal models. Importantly, the activity seen spans the positive, negative and cognitive symptom groups of the disease, without the same signal of side effects that is characteristic of current therapies such as movement disorders or prolactin elevation.
In August 2009, Biotie reached a development milestone in its collaboration with Pfi zer, resulting in a USD 1 million payment. The research phase of the collaboration with Pfi zer for the development of PDE10 (phosphodiesterase 10) inhibitors for schizophrenia is now nearing completion. One compound is currently in preclinical development.
Collaboration partner
Biotie entered into a research collaboration and license agreement with Pfi zer (then Wyeth) in December 2006 for the development of PDE10 inhibitors for schizophrenia. Under the terms of the agreement, Biotie is eligible to receive up to USD 110 million from Pfi zer, comprised of signing fees, research funding and milestone payments. Biotie will also be eligible for royalties on sales of products arising from this partnership.
The discovery phase of the Research Collaboration and License Agreement between Biotie and Pfizer regarding the development of PDE10 (phosphodiesterase 10) inhibitors for schizophrenia will end in June 2010. Under the terms of the agreement, Pfizer has been funding Biotie's research activities on the PDE10 inhibitor program since its initiation at the end of 2006 and has the sole authority with respect to developing discovered compounds. To date, the program has advanced one compound into preclinical development.
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Updated March, 2010