Innovation in a Leading Disease Target: Alzheimer's - Pharmaceutical Technology

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Innovation in a Leading Disease Target: Alzheimer's
An interview with Eric M. Parker, Ph.D., Executive Director and Neuroscience Site Lead, Merck Research Laboratories, about the Merck BACE team's winning research.

Pharmaceutical Technology
Volume 36, Issue 12

An overarching goal of our industry is to improve people's quality of life in terms of better health, and delaying onset of AD for as long as possible would help to contribute to that goal.

PharmTech: The industry, including Merck, has been focused on the amyloid hypothesis for more than 10 years. Do you think this is still the route to follow, and why? What other comparable possibilities do you think are worth pursuing?

Parker (Merck): While the exact cause of AD remains unknown, the amyloid hypothesis is currently the most widely accepted explanation. The hypothesis states that AD is caused by the accumulation in the brain of beta-amyloid (Aβ) protein fragments, which are formed when BACE and γ-secretase enzymes process the amyloid precursor protein. These Aß proteins are sticky and clump together into aggregates such as amyloid plaques that can have toxic effects in the brain. There is a substantial amount of evidence supporting the amyloid hypothesis, including an overwhelming amount of human genetic data that implicates the A peptides as being involved in the etiology of AD.

The amyloid hypothesis suggests that one of the ways to alter the molecular cause of AD is to inhibit the activity of BACE. With these so-called BACE inhibitors, the production of Aß proteins would be stalled, thus possibly impacting the onset of AD.

Despite several investigational compounds and monoclonal antibodies that have tested the amyloid hypothesis with little if any success, we believe that BACE inhibition represents a hopeful approach for AD patients. We have shown that BACE inhibition reduces levels of the A peptides to a greater degree than other treatments that have been tested. Therefore, BACE inhibitors are a promising means for testing the amyloid hypothesis.

That said, however, we are equally dedicated to finding non-amyloid approaches and symptomatic therapies for AD, and are continuing our research in those areas.

PharmTech: Clinical-trial results thus far evaluating the safety and tolerability of the Merck BACE team's MK-8931 in 40 healthy adults aged 18 to 45 has associated single doses of MK-8931 with marked reductions in amyloid beta peptide concentration levels. Can you provide a brief background on this compound? Why is this finding important? What are the next steps and timeframe planned for Phase II and/or III studies?

Parker (Merck): Merck is currently focused on advancing our most promising BACE inhibitor, MK-8931 – an investigational compound designed to inhibit A production as well as reduce existing amyloid plaques in the brain – as a new approach to treating AD. We believe that this compound would be the first to modify the underlying cause of AD, as per the amyloid hypothesis.

The development of small molecule BACE inhibitors with drug-like properties, i.e. inhibitors that are orally available, can cross the blood-brain barrier and bind to the target, has been a significant challenge for pharmaceutical researchers. However, our internal research has overcome this challenge with the development of MK-8931. MK-8931 has been shown in Phase I human testing to suppress A formation and was generally well tolerated in healthy subjects.

Based on these Phase 1 results, Merck is moving forward with the next phase of clinical development in mild to moderate AD patients. Given that BACE inhibitors work at what is thought to be an early stage of the disease process (production of Aß), we are also planning to test MK-8931 in patients at the earliest detectable stage of the disease (so-called prodromal AD patients).

PharmTech: Looking ahead 15 to 20 years, where do you expect the industry will be with Alzheimer's R&D? Do you foresee any major changes or breakthroughs within this time period?

Parker (Merck): There are many researchers pursing a number of different approaches to treating AD, and we are very hopeful that the next few years will yield some answers to what is really a difficult scientific problem and a terrible human condition. There is also an unprecedented degree of communication and collaboration between pharmaceutical companies and with regulatory authorities to find better and more efficient ways to bring treatments to Alzheimer's patients. We still have a long way to go as an industry, but we believe we are going down the right path.


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