PF-05251749 is an experimental oral therapy for “sundowning” in Alzheimer’s disease and irregular sleep-wake rhythm disorder (ISWRD) in Parkinson’s disease. Originally developed by Pfizer, PF-05251749 is in the process of being acquired by Biogen.

How PF-05251749 works

Parkinson’s disease is a neurological disorder characterized by progressive loss of nerve cells in the brain that mainly control balance and movement. Many patients with Parkinson’s disease also experience non-motor symptoms such as difficulty sleeping, and have nightmares and restless sleep. This disorder is called ISWRD.

As the disease progresses, the frequency and severity of ISWRD increase for many patients. ISWRD is thought to be caused by alterations in patients’ circadian clock, which controls circadian rhythms regulating the sleep-wake cycle, such as feeling sleepier when the sun goes down or getting hungry at roughly the same time every day.

The circadian clock is controlled by a small region of the brain called the suprachiasmatic nucleus (SCN). Within the SCN, a key enzyme involved in regulating circadian rhythms is casein kinase 1E (CK1E). CK1E regulates the activity of two clock proteins, which are most active during the day and are required for the production of additional components most active at night. So, the circadian cycle is an on-off cycle of many components, where the activity of “daytime” proteins promotes the production of “nighttime” proteins, which in turn repress the “daytime” proteins.

This cycle is thought to be dysregulated in Parkinson’s disease.

PF-05251749 is a small molecule that can cross the blood-brain barrier and inhibit CK1E, thereby preventing “nighttime” proteins from being produced during the day. Preclinical studies have indicated that CK1E inhibitors can be used to “entrain” normal sleep-wake cycles in animal models of neurological disorders.

The precise oral dosing of PF-05251749 that’s necessary to show efficacy in Parkinson’s disease patients has not yet been established.

PF-05251749 in clinical trials

Two Phase 1 clinical trials in healthy volunteers, ages 18 to 55 (NCT02443740) and ages 18 to 85 (NCT02691702), were conducted to assess the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of PF-05251749. These studies also determined how much of the compound reaches the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord).

Data from these trials indicated that PF-05251749 has an acceptable safety profile. Biogen is planning to begin a Phase 1b clinical trial towards the end of 2020.

 

Last updated: Jan. 23, 2020

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Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

Emily holds a Ph.D. in Biochemistry from the University of Iowa and is currently a postdoctoral scholar at the University of Wisconsin-Madison. She graduated with a Masters in Chemistry from the Georgia Institute of Technology and holds a Bachelors in Biology and Chemistry from the University of Central Arkansas. Emily is passionate about science communication, and, in her free time, writes and illustrates children’s stories.
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Özge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.
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Emily holds a Ph.D. in Biochemistry from the University of Iowa and is currently a postdoctoral scholar at the University of Wisconsin-Madison. She graduated with a Masters in Chemistry from the Georgia Institute of Technology and holds a Bachelors in Biology and Chemistry from the University of Central Arkansas. Emily is passionate about science communication, and, in her free time, writes and illustrates children’s stories.
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