While the “War on Cancer” has made significant progress, the “War on Alzheimer’s” has proven to be a seemingly implacable foe. The societal costs of neurodegenerative diseases are enormous – Alzheimer’s disease is the most common cognitive dementia, affecting one of every ten people over age 65 and nearly 35% over age 85. This translates into more than 5.4 million Alzheimer’s patients in the US alone, a number expected to reach 9 million by 2030 and 16 million by 2050 as the US population ages. Alzheimer’s is the sixth leading cause of death in the US and is the only leading cause of death currently without a way to prevent, cure or slow the disease (of the top 10 leading causes). As many as 25 million people worldwide are afflicted with less severe memory impairment known as mild cognitive impairment (MCI), which manifests several years before an actual clinical diagnosis of Alzheimer’s can be made. Patients suffering in the later stages of this disease require nearly full-time care; in the US alone, the economic burden of Alzheimer’s is currently estimated to be in excess of $110 billion annually.

A “committed warrior in this war,” Pittsburgh-based Cognition Therapeutics, Inc. is focused on the discovery and development of small molecule therapeutics targeting protein and membrane trafficking dysfunction and the toxic proteins that cause the cognitive decline associated with Alzheimer’s.  There are currently no therapeutics available to prevent toxic protein accumulation or block its destructive effects.

Leading Cognition Therapeutics is president and CEO Kenneth Moch, who has broad expertise building, financing and leading private and public life science companies from start-up through commercialization. Moch previously served as president and CEO of four other life science companies: Chimerix, Inc., an antiviral therapeutics company; BioMedical Enterprises, a manufacturer and marketer of nitinol orthopedic implants; Alteon, Inc., a developer of small molecule therapeutics for cardiovascular aging and diabetic complications; and Biocyte Corporation, the pioneer in cord blood stem cell collection and storage. He has also been a managing partner of The Salutramed Group, LLC, a managing director of Healthcare Investment Banking at ThinkEquity Partners, and a management consultant with McKinsey & Company, Inc.

Building on his longstanding interest in health policy, Moch has served for over a decade on the Board of the Biotechnology Innovation Organization (BIO), where he co-chairs a committee focused on the complexities of developing new medicines for highly prevalent chronic diseases. He is also a founding member of the NYU Working Group on Compassionate Use and Pre-Approval Access. Moch holds an A.B. in biochemistry with a minor in health policy from Princeton University and an MBA from the Stanford University.

As part of a new Alzheimer’s industry series, WuXi AppTec Communications spoke with Moch about how Cognition’s technology can be utilized to bring new therapies to patients who have no effective treatments for this stubborn and still not well understood disease.

WuXi: What are the causes of Alzheimer’s disease? Are they genetic or environmental? Or is it a combination of the two?

Kenneth Moch: The etiology of diseases of the brain is poorly understood, no more so than in Alzheimer’s disease.

This question is one of intense focus within the scientific community, and while much is known there is an extraordinary amount more to learn. The speculation is that the causes will likely be multifactorial – genetic predisposition, environmental triggers, perhaps infections or other insults to neurological processes – but the evidence is still early and evolving.

What we know with certainty is that there is a significant unmet medical need for disease-modifying therapies that can slow or prevent the progression of Alzheimer’s, delay its onset or, for those already suffering from the disease, potentially reverse the neuronal damage, protect synapses and restore synaptic function. It is the recognition of this fact – that without new medicines and innovative approaches we face a societal and economic tsunami from the devastating impact of Alzheimer’s disease – that is spurring the dramatic increase in the funding of Alzheimer’s disease research through the National Institute on Aging.

WuXi: How has the R&D for Alzheimer’s drug discovery evolved over the past five years? What have been some of the major scientific breakthroughs?

Kenneth Moch: The progress in research needs to be separated from the complexities of Development. There has been and continues to be a significant increase in research activities focused on the mechanisms and pathways of neurological activity and dysfunction in general and on Alzheimer’s disease in particular – 30,000 people attended the recent Society of Neuroscience meeting this past November. A number of these efforts have led to potential new therapeutic pathways, and the efforts to translate these scientific advances into experimental medicines has led to an increase in the number of compounds in preclinical and early clinical development.

Thus far none of this work has risen to the level of major scientific breakthroughs – a discovery that meaningfully changes the trajectory of the disease.  But there is clear hope that this will be the outcome of all of the efforts.

On the development front, one could say the exact opposite: that over the past five-to-10 years the results of late stage clinical trials have served, instead, to rule out therapeutic concepts and reduce the developmental pathways. With a historical failure rate of close to 100%, the hurdles of trying to develop a new medicine for Alzheimer’s disease could not be higher.

WuXi: What is your company’s approach to treating Alzheimer’s disease?

Kenneth Moch: Cognition Therapeutics is a privately held biopharmaceutical company focused on the creation and clinical development of a pipeline of disease-modifying small molecule drug candidates that restore and preserve the building blocks of brain health and function: the synapse.

Synapses are the smallest (‘elemental’) unit of brain function and literally represent ’cognitive real estate.’ The organization of synapses in the brain defines the very essence of who we are, how we act and perceive ourselves, and how we learn and evolve. Simply put, unlike any other organ system or tissue in the human body, the brain’s function is inextricably linked to its underlying synaptic architecture. The number of synapses in the brain is the measure most highly correlated with memory ability and cognitive performance. The loss of synapses in the brain is analogous to end organ damage in other organ systems.

Cognition’s lead candidate, Elayta™ (CT1812), was developed internally by Cognition’s scientific team, led by Founder and Chief Science Officer Susan Catalano, specifically to impact the progression of Alzheimer’s disease by protecting and potentially restoring synaptic function. A proprietary first-in-class, orally dosed and highly brain penetrant small molecule, Elayta was designed to displace the most toxic form of amyloid beta (Aβ), Aβ oligomers, from brain cell synapses and clear these Aβ oligomers out of the brain into the cerebrospinal fluid (CSF).

WuXi: How does it differ from other companies?

Kenneth Moch: Elayta utilizes a new and completely novel mechanism of action to displace Aβ oligomers bound to neuronal receptors at synapses.  The evolving evidence from our pre-clinical and clinical work is that, through this MoA, Elayta impacts membrane/protein trafficking dysfunction by mediating the pathological impact of Aβ oligomers.

Specifically, Elayta allosterically modulates (changing the conformation of) a key multiprotein regulator of oligomer receptors, the sigma-2 receptor complex. This destabilizes the Aβ oligomer binding site, increasing the off-rate and thereby displacing bound Aβ oligomers, and facilitating their rapid clearance into the CSF.  Think of Newton’s Cradle, where a metal ball hits one ball and causes a ball on the other side to move.  This is analogous to the way that Elayta displaces Aβ oligomers from their synaptic binding sites.

As a result, Elayta has shown the potential to protect the synapses and facilitate the restoration of synapse number and cognitive performance to normal. These results have been observed in our preclinical Alzheimer’s mouse models and our initial studies in individuals with mild to moderate Alzheimer’s disease, and are being further tested in ongoing Phase 2 clinical studies.

This focus on synaptic protection and restoration has been at the core of Cognition’s scientific efforts since our founding. We believe that through its unique disease-modifying mechanism of action, Elayta will protect synapses from further damage and facilitate restoration of normal synaptic function including new memory formation.

WuXi: What are the major challenges in treating Alzheimer’s disease?

Kenneth Moch: As discussed throughout my answers, this is a war on a specific disease. To succeed will require a coordinated effort to identify the causes, fund the translational research, approve the new medicines and provide access to the millions of individuals who are being impacted by this devastating disease.

WuXi: What are the major regulatory challenges in clinical development? Are changes in clinical trial design needed?

Kenneth Moch: This can be looked at as a question of the barriers to success to the development of new medicines.

The answer is that there will likely be multiple levers that will need to be altered to increase the probability of success of future experimental medicines. Given the nature of the Alzheimer’s disease population – generally elderly individuals with a spouse of a similar age or a child who is serving as a caretaker – the ability of these individuals to successfully participate in long-term clinical trials is an issue; this conflicts with the evolving trend to run longer term trials to get an ‘event rate’ difference between treated and placebo patients.

Overall, there is a need for new endpoints for Alzheimer’s – which, looking externally, may be based on new digital tools or, looking internally, may be based on a more precise understanding of the components of learning and memory such as synaptic number, which as noted above is believed to be one of the closest correlates of cognitive function.  To further evaluate this, Cognition has formed what we call the Synaptic Health Endpoints Working Group, composed of a broad range of thought leaders, to explore and evaluate synaptic number as a potential endpoint for new Alzheimer’s disease medicines.

WuXi: Why are we seeing so many failures in the late stages of clinical development?

Kenneth Moch: From the standpoint of the development of new medicines, this field is clearly one of the most difficult and complex. It is currently characterized by a heterogeneous patient population being tested with subjective and imprecise clinical endpoints.  Clearly, we need to better understand the factors causing Alzheimer’s disease, and at the same time we need to better understand the potential measurement tools for this disease.

At Cognition, we hope that preventing the loss of synapses or, in the best case, restoring synaptic number can be an approvable endpoint for Elayta. We also hope that some of the new and evolving digital tools will provide ways to measure how individuals with Alzheimer’s disease feel and function. These quality of life measurements will hopefully yield approval endpoints based on improved quality of life for individuals whose quality of life is rapidly declining.

WuXi: What more can government contribute to support R&D?

Kenneth Moch: The ’war on Alzheimer’s disease’ is different from, but akin to, the war on cancer and the efforts during the AIDS crisis. There is now superordinate funding for Alzheimer’s disease research and clinical development, particularly though the significant support of Congress and the efforts of the National Institute on Aging.  In addition to supporting what is known at an increasing level, they are also helping to support the work of scientists who are seeking to identify what is unknown. One can always hope for more money, or for a significant breakthrough which spurs accelerating investment, but at this time it is support in building the ’anti-Alzheimer’s disease‘ infrastructure that is most valuable.

WuXi: How will Alzheimer’s drug development evolve over the next five-to-10 years? What are the best treatment modalities for Alzheimer’s disease? Will combinations of modalities be necessary?

Kenneth Moch: I am hopeful that our understanding of Alzheimer’s disease will evolve in a manner that is not dissimilar to the evolution of therapies for cancer.  Over the course of several decades, the understanding of genetic factors underpinning various forms of cancer has led to smaller, targeted and thus much more efficient clinical trial and subsequently to the approval of many targeted therapies.

I anticipate that the treatment of Alzheimer’s disease will be through drug combinations – polypharmacy – but that crystal ball is still cloudy.

WuXi: Is a cure possible? What scientific advances are needed to find a cure?

Kenneth Moch: One can hope. I can only speculate on the needed scientific advances, but they will likely focus on the bio/electrochemical and immunological pathways and processes of the brain, and the processes of learning and memory.

A key early step will also be the identification of biomarkers and genetic markers of AD susceptibility, which will have a meaningful impact on the ability to undertake the development of new medicines for Alzheimer’s disease.

It is important in answering this question to build on my prior answers, and take a moment to praise the US Congress for providing significantly increased funding to the National Institute on Aging (NIA) for Alzheimer’s disease research, and to further praise the NIA for the way in which they have allocated this funding to increase efforts to identify the cause/causes of Alzheimer’s and to explore potential cures for this disease.  Without such efforts, scientific efforts would be severely limited and companies such as Cognition would not be able to test the potential of their experimental medicines.