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

PharmTech: The PhRMA Research & Hope Awards go beyond solely scientific awards to include honorees for patient advocacy and volunteer work. Why do you think this broader scope is important?

Parker (Merck): The awards honor people who have gone to tremendous lengths to improve the lives of patients suffering from various diseases, with the focus of the 2012 awards being Alzheimer's disease. It's important to recognize not just medical advances and research but also the people who are working to alleviate suffering through caring directly for patients. These people are very often family members and loved ones. It's through collaborative efforts among many stakeholders that we can best hope to achieve the goal that we all have–to help stop the suffering caused by Alzheimer's disease.

PharmTech: Along these lines, in your experience, what major two or three challenges do researchers face in finding a drug to prevent and/or treat Alzheimer's?

Parker (Merck): All neurological diseases are complicated and AD is no different in that regard. We are still working to increase our overall understanding of AD and to identify approaches through which we can help to modify its course and/or provide symptom relief.

That said, there are many challenges that we've faced and continue to face in our research. Many of the latest setbacks that we've seen in the recent studies that have not met their primary endpoints can be attributed to at least two factors. First, the treatments being tested had significant side effects that limited the doses that could be administered, which may have also limited their effectiveness. Second, these studies have reinforced a collective opinion in the field that we may need to start treatment years before patients begin to show symptoms. However, that means being able to identify people who are at risk for developing AD in the first place, and that research is still ongoing.

PharmTech: Because Alzheimer's is so complicated and because of certain R&D/clinical study setbacks in recent months, some reports have stated that people are giving up hope, as well as research funds, toward curing Alzheimer's. What might be your argument or response to these reports?

Parker (Merck): AD is one of the most challenging and devastating diseases of our time, causing untold physical, emotional and financial suffering to patients and their caregivers. We are trying to find new therapies that can help to prevent or slow its onset and that may help to alleviate the disease symptoms. We cannot let ourselves lose sight of the fact that this disease has tremendous human and economic costs.

Yes, there have been many setbacks, but with each setback we can learn new information, draw new conclusions and move the field forward. From this perspective, we don't consider them "failures," per se, but rather, stepping stones.

We know that finding new therapies to help Alzheimer's patients will not be easy, but AD research remains a top priority for Merck. We will continue to make strides and believe that we are already on our way.

PharmTech: A report from PhRMA and the Alzheimer's Foundation talks about delaying the onset of Alzheimer's Disease, and specifically how even just a 5-year delay in onset can save millions of healthcare and medical dollars. What's your perspective on delaying the onset versus preventing the disease altogether? What are the benefits of disease modification in Alzheimer's patients?

Parker (Merck): There are currently no treatments on the market that can slow the progression of AD and few treatments to control some of the symptoms. Of course, preventing the disease altogether is the ultimate goal, but delaying the onset has not only tremendous financial benefits, but significant personal benefits for those dealing with the disease every day. Currently, patients and their families are grateful for even the very modest improvement in symptoms that current treatments afford. Until a cure or prevention is found, delaying the onset of this disease for as long as possible would be a "win" for all concerned.

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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