Non-motor symptoms associated with Parkinson’s disease include alterations in patients’ circadian rhythm, or the body’s inner clock, which is synchronized by natural light-dark patterns. This clock also controls key body features, including wake/sleep cycles, body temperature, digestion, hormonal cycles, and behavior patterns.
Parkinson’s patients often show difficulties in sleeping, such as insomnia, nightmares, and restless sleep, a condition collectively called irregular sleep wake rhythm disorder (ISWRD). ISWRD’s frequency increases over the course of the disease and with disability progression.
The circadian clock also plays a role in sundowning — a sudden worsening of confusion, agitation and aggression occurring in the late afternoon and spanning into the night — experienced by at least 20% of Alzheimer’s patients.
In mammals, a tiny region within the brain’s hypothalamus is responsible for controlling circadian rhythms, and an enzyme called casein kinase 1 (CK1), which exists in two forms, is a key regulator of this clock.
PF-05251749 is an oral, brain-penetrable, highly selective, inhibitor of both forms of CK1 that can alter circadian rhythms significantly. Inhibiting CK1 disrupts the function of two genes, CLOCK and BMAL1, which are thought to influence the regulation of circadian rhythms.
Two Phase 1 trials in healthy adults ages 18–55 (NCT02443740) and an older group ages 18–85 (NCT02691702) have assessed the compound’s safety, pharmacokinetics and pharmacodynamics (essentially how a compound behaves inside the body and how the body affects it) and exposure in cerebral spinal fluid (that which surrounds the brain and spinal cord). In these trials, PF-05251749 showed an acceptable safety profile.
“This asset is highly complementary to our existing pipeline of potential disease-modifying therapies in Alzheimer’s and Parkinson’s diseases,” Alfred Sandrock Jr., MD, PhD, executive vice president, research and development and chief medical officer at Biogen, said in a press release.
“Many patients with Alzheimer’s and Parkinson’s suffer from debilitating sleep disorders and agitation, and we believe that the regulation of the circadian rhythm may hold promise in addressing these challenging behavioral and neurological symptoms,” he said.
Pfizer will receive an upfront payment of $75 million for PF-05251749. Additional milestone payments may reach $635 million.
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