PET Imaging Biomarker Collaboration Established for Investigational BACE Inhibitor Clinical Development Program

Merck (Whitehouse Station, NJ, USA), known as MSD outside the United States and Canada), and GE Healthcare (Chalfont St. Giles, UK) have initiated a clinical study collaboration, license, and supply agreement for use of [18F]flutemetamol, an investigational positron emission tomography (PET) imaging agent, to support Merck’s development of MK-8931, a unique oral beta amyloid precursor protein site cleaving enzyme (BACE) inhibitor and Merck’s chief investigational candidate for Alzheimer’s disease (AD).

Accumulation of beta amyloid in the brain is a pathologic characteristic related to Alzheimer’s disease. Currently, AD is diagnosed by clinical examination (i.e., physical, medical history neurologic, psychiatric, and neuropsychologic exams, laboratory tests and magnetic resonance imaging [MRI] or computed tomography [CT] scan). An AD diagnosis can only be validated through histopathologic identification of characteristic features, including beta amyloid plaques, in postmortem brain samples.

“There is a serious unmet need for a reliable method for measuring beta amyloid deposits to help physicians diagnose Alzheimer’s disease at its different stages and study its progression,” said Darryle Schoepp, PhD, senior vice president, head of neuroscience and ophthalmology, Merck Research Laboratories. “This agreement will allow us to employ an investigational imaging agent to help identify patients who might benefit from an antiamyloid therapy and enable clinical evaluation of our lead BACE inhibitor candidate for Alzheimer’s disease, MK-8931.”

Under the agreement, GE Healthcare will supply [18F]flutemetamol to help select patients for clinical trials and evaluate this investigational agent as a companion diagnostic tool. A joint Merck and GE Healthcare imaging advisory committee will oversee the planned imaging studies.

“In clinical trials, [18F]flutemetamol demonstrated consistent performance in the visual detection of beta amyloid in the brain when compared with histopathology data,” said Jonathan Allis, general manager, PET, GE Healthcare medical diagnostics. “[18F]flutemetamol imaging has the potential to be part of a larger diagnostic workup that may help doctors rule out Alzheimer’s disease by reliably showing the absence of amyloid deposits in patients with unexplained loss of cognitive function.”

Merck is advancing several novel programs involved in AD research, including candidates designed to modify disease progression as well as improve symptom control. Merck’s lead candidate in disease modification is MK-8931, an investigational oral BACE inhibitor.

Results of phase I clinical studies demonstrated that MK-8931 can reduce cerebral spinal fluid (CSF) beta amyloid by greater than 90% in healthy study participants without dose-limiting side effects. Based on these findings, Merck has established a global, multicenter phase II/III clinical trial, called EPOCH (please see Related Links below), to evaluate the safety and effectiveness of MK-8931 versus placebo in patients with mild-to-moderate AD.

[18F]flutemetamol is an investigational PET imaging agent being developed by GE Healthcare for the detection of beta amyloid deposits in the brain. Pooled results from phase III brain autopsy and biopsy studies showed a strong concordance between [18F]flutemetamol images and AD-associated beta amyloid brain pathology. Phase III studies demonstrated [18F]flutemetamol visual identification of beta amyloid with a majority read sensitivity of 86% and specificity of 92%.

AD is a debilitating and ultimately fatal disease that progressively destroys neurons in the brain, leading to a deterioration of cognitive function. The symptoms include loss of memory that advances into behavioral alterations, changes in thinking and reasoning skills that have an effect in daily activities, and dementia. AD is the most common cause of dementia, accounting for approximately 50%–75% of the estimated 35-million dementia cases worldwide.

Whereas the precise cause of AD remains unknown, a current predominant hypothesis ascertains that AD occurs due to the accumulation of beta amyloid proteins in the brain. Beta amyloid precursor protein site cleaving enzyme (BACE) is believed to be a major enzyme in the production of beta amyloid peptide. Study findings suggest that suppressing BACE decreases the generation of beta amyloid and may therefore decrease amyloid plaque formation and alter the course of disease progression.

Related Links:
Merck
EPOCH Trial
GE Healthcare