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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