Newsletters
2/3
Q1 2021
Michael Fossel, MD, PhD
The foremost obstacle to curing Alzheimer's disease has been a lack of understanding of the disease. Understanding per se was a sufficient obstacle, but getting investors to both understand and then support an effective clinical intervention has taken years and perhaps the patience of a saint. In 2021, we see the "proper time and place" for that intervention is upon our horizon. The fundamental mechanisms involved have been clearly delineated in the literature. Our investment partners are now ready to move ahead as we push forward to human trials. Over the past year, we have not only published a clear explanation of the model – and how we can intervene effectively – we have also added gravitas and credibility to our program through those we have brought onto our scientific and clinical advisory boards.

Nor are those the only current changes.

We have engaged Kim Gannon, PhD, whose expertise in biotechnology, gene therapy, clinical trials, and Alzheimer's disease make her a valuable addition to our team. We are delighted to have Kim's support and her hands-on knowledge behind our vision as we move ahead. We have also engaged two other globally-known experts. Both have demonstrated success in gene therapy, encompassing manufacturing, preclinical studies, regulatory submissions and clinical trials. Together, these new additions to our team, along with the rest of us at Telocyte, are working toward a rigorously verified treatment for Alzheimer's disease.

Our first animal study later this year will give us a chance to not only refine the technical aspects of our therapy, but will help ensure we have the safest and most effective intervention for our planned human trial. In addition, this study will help gather the data we need to obtain proof of concept in a large animal model, demonstrate widespread brain distribution of our therapeutic, and help guide dose selection for future studies, including the clinical trial. Data from this study will solidify our intellectual property position, generate excitement for and confirmation of our approach and facilitate additional funding necessary for successful human trials.

If you would like to understand more about our approach, we will be improving our website in the next month or so, including videos such as this 3-minute animation, which explains how Alzheimer's works and how we can intervene clinically. If you prefer a longer (35 minute) presentation, you may want to view this lecture, given at a recent neurology conference. Our primary mission, however, resides in neither a website nor a video. Our mission remains a more critical, practical, and difficult goal, driven by compassion: we intend to cure Alzheimer's disease.

We see the "proper time and place" as within the reach of here and now.
2/3
Q4 2020
Michael Fossel, MD, PhD
We all share the disruption of our world due to the ongoing pandemic. For many the disruption has been life-changing, for some it has been a problem, for a few it has been fatal. The pandemic is a universal experience that has been felt in the biotech and gene therapy world as well. The impact upon clinical trials has been unprecedented and will echo for years. Funding has been disrupted for many in the field, although perhaps less so than predicted. Regardless, the pandemic has affected all of us.

Telocyte has been lucky. Our clinical trials have not yet begun and our investors have pulled back. We continued our plans, continued our work, and continued our investor discussions. We have lost very little, while (perhaps unexpectedly) gaining in efficiency.

Ironically, our approach might help treat Covid infections. The greatest single COVID risk factor is age, but the underlying risk is cell aging, which is precisely what Telocyte will target in our FDA trials. Our intervention should have a profound effect upon Alzheimer's and other age-related diseases, as we reset cell aging at its most fundamental level. If we reset cell aging in the immune system, then the risk of Covid mortality might fall to that seen in younger patients.

In aging disease, the question is not the chronologic age, nor is the key issue any of the dozens of biomarkers which we associate with aging: the key issue is cell aging itself. The single most important risk factor for age-related disease (and that includes Covid infections which have higher risk in the elderly) is not any set of symptoms or biomarkers, but the cellular age of those cells involved in the disease. If we were to list all of the biomarkers of aging or of any age-related disease, such as Alzheimer's disease, we would not be one whit closer to an effective therapy. Biomarkers are not diseases, nor do they contribute to our understanding of disease. Understanding a disease – and our ability to cure a disease – require that we actually understand the system itself. Only then can we intervene. We at Telocyte are focused on that understanding. Rather than focus on genes, beta amyloid, tau tangles, or other biomarkers – that are, frankly, misleading – we focus on the fundamental disease process itself, weaving a complete and complex understanding of Alzheimer's that encompasses all of the known risk factors, all of the known biomarkers, and all of the clinical data, with the result that we understand the disease and the key point of intervention to cure and prevent Alzheimer's. We intend to test that point of intervention in rigorous and carefully executed clinical trials. This can best be accomplished through accepted regulatory channels, such as the FDA and the EMA, in order to ensure patient safety, clinical efficacy, and global credibility.

With that in mind, we have moved carefully, selecting individuals for our SAB (scientific advisory board) and CAB (clinical advisory board). Our website shows many of these board members, but we have new members as well. These include Richard Mohs PhD (of the Global Alzheimer's Platform Foundation) and Kurt Whittemore PhD (at Harvard's Boston Children's Hospital) who have both joined our Scientific Advisory Board. Our Clinical Advisory Board now includes not only Russell Swerdlow, MD (Co-Director of the KUMC Alzheimer's Disease Center, who moved to our clinical board), but Mario Masellis, MD (of Sunnybrook Research Institute in Toronto), Lon Schneider, MD (of the Keck School of Medicine at USC), Steven Arnold, MD (Professor of Neurology at Harvard Medical School) with another globally known Alzheimer's researcher likely to join soon. In addition, we have contracted with Worldwide Clinical Trials to help us in our FDA hearings and help with our human trials.

Finally, our lead investor group has issued the following public statement supporting Telocyte and our program as "A Vote of Confidence in Telocyte":

Pharma Capital Partners is a private equity drug development firm that invests exclusively in companies with promising late-preclinical or IND-stage therapeutic assets. An area of major interest for us is neurodegenerative diseases, including Alzheimer's dementia. Disappointingly, every therapeutic candidate to reverse or arrest progression of this dementia to date has failed in late-stage clinical trials. A number of interesting new drug candidates in that space have come to our attention but none has bolstered our hope for a cure as much as the novel gene therapy proposed by Telocyte. We are engaged in extensive due diligence regarding their approach, and we are very supportive of their plans. Importantly, their proposed gene therapy has been validated in an animal model of aging brain that seems as translational as any other so-called model of Alzheimer's dementia. The safety of the viral vector Telocyte intends to use to deliver the therapeutic gene directly into the central nervous system, moreover, has been demonstrated in clinical investigations of other neurodegenerative conditions, such as Parkinson's disease, so we are comfortable with that route of administration. Telocyte will undertake its clinical trials in accordance with best practices and FDA Guidance. It is high time for a systems approach to the devastating disease Alzheimer's dementia, and Telocyte is the first to undertake such an approach in the right way. Pharma Capital Partners affirms its confidence in the outcome and looks forward to collaborating with Telocyte in implementing its well-conceived development plan.
2/3
Q3 2020
Michael Fossel, MD, PhD
It is disturbing when otherwise intelligent and even well-educated people routinely make the same errors that have echoed throughout scientific and medical history. We repeat the mistakes of the past blithely and with an arrogant ignorance.

In respect to age-related disease generally and Alzheimer's disease specifically, we routinely confuse the disease with the symptoms. We persist in focusing on measurements, definitions, descriptions, symptoms, signs, components, hallmarks, and biomarkers, while ignoring the underlying disease itself. Dr. Leonard Hayflick (the discover of cell aging) and I were talking a few months ago when he pointed out that "The cause of aging is ignored by the same people who argue that aging is the greatest risk factor for their favorite disease." He is correct: physicians and researchers universally and correctly cite aging as the single most predictive risk factor for agerelated diseases – it is far-and-away the best predictive risk factor for Alzheimer's disease – yet then immediately go on to focus on other aspects and entirely ignore the aging process itself. They pay lip service to aging, but then address more superficial and less difficult aspects of dementia. In getting caught up in details, they confuse details with understanding. Having a firm grasp of thousands of details, no matter how important those details may be, is not the same as understanding disease or understanding aging. Knowing details is not the same as understanding how those details work.

Symptoms are not a disease, but are merely the outcomes of a disease.

Two thousand years ago, Galen – one of the greatest of the classical physicians – gave a perfect description of the Antonine plague, yet he had no concept of microbes, viral illness, and infectious disease, nor could he prevent or cure the plague. Descriptions are not the same as understanding.

It's axiomatic that "if you can't measure it, then it's not science", but we need to go beyond mere measurement. You can measure precisely and extensively, but if you don't understand what the measurements mean, then it's still not science. Five hundred years ago, Vatican astronomers had superb measurements of planetary motion but, convinced that the earth was the center of the universe, they had no understanding of celestial mechanics. Measurements are not the same as understanding.

In 1895, Lord Kelvin – great physicist though he was – stated that "Heavier-than-air flying machines are impossible", some eight years before the Wright brothers proved him wrong at Kitty Hawk. Lord Kelvin had excellent definitions of weight and air pressure, but no understanding of aerodynamics. Definitions are not the same as understanding.

Less than a decade ago, when Ebola virus was a west-African epidemic, we could accurately list the dozens of symptoms of the disease, but Ebola virus is not merely symptoms, but a complex pathological interaction between a virus and a human host. The disease is the process, not the symptoms. Knowing the symptoms is not the same as understanding.

Currently, most institutions that purport to fund cures for Alzheimer's and other dementias make the same mistake: they focus on components, hallmarks, biomarkers, measurements, and definitions, but they fail to examine their assumptions about the processes underlying the dementias. Until now, we have seen an institutional bias against innovation or effective therapeutic trials. Ironically, despite the claims of those purportedly interested in innovation, ground-breaking approaches, and tomorrow's medical breakthroughs, the most strident claims are made by precisely the same firms that continue to invest in and to perfect yesterday's technology. Were it now 1903, they would be investing in the "latest" technological advances in gas-filled balloons, yet would not recognize the importance of what the Wright brothers were doing at Kitty Hawk. They don't invest in innovation, they perfect technologies that are about to be superseded by the unexpected and revolutionary.

The major global pharmaceutical firms invest in trials that not only fail, but that lack any scientific support for their approach. Their models are based on biomarkers (such as amyloid plaques), not on fundamental mechanisms of disease (such as cell senescence). By mid-2019, Biogen Eisai spent more than $750 million on its failed trials, more than 20 times the amount for which we could easily demonstrate an effective cure for Alzheimer's disease if were to target fundamental mechanisms rather than superficial biomarkers.

Investors do much the same thing. One large group of investors for alumni of major US universities brags about its funding for age-related diseases, but they fund approaches that have no scientific rationale, that are contradicted by their own published data (e.g., senolytics companies), and that focus on hallmarks, biomarkers, definitions, components, and symptoms, rather than considering the systems process that underlies and causes these tragic diseases. These companies and their investors confuse the components with the process, mistakenly thinking that if we can list hallmarks and biomarkers, then we have understood the process. We have not: hallmarks and biomarkers are not disease processes and are not effective clinical targets. You cannot cure Covid-19 using cough medicine; you cannot cure age-related disease by using small molecular approaches.

Peter Diamandis, a known investor in the longevity market, touts the "key technologies" of what he calls a "trillion-dollar industry", but then gets lost in the components of aging but without any understanding of aging itself. For interventions, he focuses on the latest techniques (stem cells, CRISPR and senolytics, for example) and cites miniscule components of the aging process (the Wnt pathway, for example), but without any fundamental understanding of aging as a fundamental process. The latest fads, the latest techniques, and the latest investments are not the same as understanding the aging process. Aubrey de Grey, touted as an author and would-be scientist, leads panels on "hallmarks of aging", but has no understanding of the fundamental aging process itself. Hallmarks and biomarkers are not aging anymore than symptoms are a disease.

Consider an analogy, that of a common infectious disease in the centuries prior to our understanding that such diseases had microbial etiologies. We now recognize that classic plague is the result of an infection of Yersinia pestis, yet in the middle ages it was often described in a multitude of ways and occasionally diagnosed as being entirely different and unrelated forms of plague. Nor was this necessarily an error, as even now for example we recognize several types of Yersinia pestis infection which, while sharing precisely the same bacterial etiology, differ in their clinical presentation and course depending upon the initial site of entry and tissue spread of the bacterial invasion. Pneumonic plague, bubonic plague, and septicemic plague all differ in their clinical presentation, in their course, and even in their mortality rates, yet each of these is fundamentally the same disease, caused by the same bacteria. Diagnosing each as a separate clinical syndrome is warranted, despite the shared underlying cause, that of Yersinia pestis infection. The fact that 1) pneumonic plague has a pulmonary focus, 2) bubonic plague has a focus in the lymphatics, and 3) septicemic plague occurs predominantly in the vascular system may confuse the novice physician (let alone the medieval healer with no knowledge of bacteria), yet they still share a fundamental and unified etiology: the Yersinia pestis bacillus.

Whether we consider plague to be three diseases or one disease might be a matter of judgement, but to simply assume that the three clinical presentations represent independent etiologies due to completely different causes avoids the fundamental insight as to the commonality of basic cause. They may present differently, but we cannot understand (or treat) plague unless we understand not merely the syndromes, but microbial disease generally, Yersinia pestis specifically, and the role it plays in those three different presentations. Moreover, effective intervention requires that we understand not merely the syndromes, but the unified underlying microbial etiology that lies beneath these syndromes. Only when we understand the disease process, can we cure the disease.

A parallel observation applies to age-related human dementias. Understanding of the shared, common, and fundamental etiology, at the cellular or epigenetic levels, explains the multitude of clinical presentations and offers an effective point of intervention. Until we understand the fundamental, unified etiology, we can never cure the dementias.

To construct such a unified model, we need to distinguish between systems models and mere components. For example, at the macro-level, a number of clinical findings are typical of aging human beings, including grey hair, memory loss, sarcopenia, osteoporosis, osteoarthritis, declining GFR (glomerular filtration rate), arterial disease, skin aging, poor healing, immunosenescence, etc. Although these are typical "components" of aging, they are not aging per se and they certainly are not a systems model of aging. Rather, they are simply the component outcomes of a more fundamental process that expresses itself in these macro-level findings. At the microlevel, we also see innumerable component findings that are typical of aging human beings, including inflammation, declining DNA repair rates, increased mutations, lipofuscin deposits, a declining ATP/ROS ratio (adenosine triphosphate/reactive oxygen species), methylation changes, acetylation changes, telomere shortening, and thousand of other arcane alterations in cell function. Nevertheless, important, or even defining as these various changes may be, they are not themselves the aging process, but are merely the component outcomes of a more fundamental process that expresses itself in these micro-level findings. Aging is the process, not the biomarkers that we observe as we age. We should never confuse biomarkers (or components, hallmarks, signs, symptoms, etc.) with the process that drives such biomarkers: to do so is to make a fundamental conceptual error. Aging is the system process; the clinical findings are the components. This is true throughout clinical medicine: a disease process is not just a list of symptoms.

Much the same confusion occurs when we consider the human dementias. We see large global pharmaceutical firms and individual academic researchers alike conflate specific dementia syndromes with their correlated histology. But just as Alzheimer's disease is not merely beta amyloid plaque, tau tangles, or inflammation, the same is equally true of any of the age-related dementias. Dementias are not merely a list of common findings, such as mitochondrial dysfunction, inflammatory changes, glial activation, alpha synuclein deposits, disruption of the blood-brain-barrier, glymphatic alterations, and so forth. These may serve as clinical guideposts to disease, yet none of these are the disease process itself. They are outcomes, not causes. A process is not its components, a disease is not its symptoms.

We must understand fundamental causation rather than exploring the superficial biomarkers that lie downstream of the basic disease process. Why do beta amyloid plaques form in Alzheimer's disease? Why do alpha synuclein deposits form in Parkinson's disease? Why do hypertension and hyperglycemia appear to trigger vascular dementia? To merely wave one's hands and ascribe the more fundamental process to genes, aging, or ''vascular changes" avoids the fundamental question raised here. Genes (the ApoE4 allele, for example) play a role, but we see patients with double ApoE4 alleles and no disease, and we see patients with Alzheimer's and no apparent genetic risks. Genes are associated with disease, but they are not the disease itself and certainly do not provide a fundamental model nor an explanation. Likewise, age itself is no explanation unless we can explain why some 50-year-old develop dementia, while some centenarians do not.

We offer an effective systems modeli that accounts everything we know of agerelated dementia, successfully predicts the universal failure of prior clinical trials, explains the cognitive decline seen in other species (and why their histology and physiology differ from the human counterparts), and – most importantly – offers an innovative an effective point of intervention. No other model, no other biotech company can do so.

We simply need to take it to human trial.
2/3
Q2 2020
Michael Fossel, MD, PhD
Our world has changed.

Over the past few weeks, our lives have changed unexpectedly and, for most of us, dramatically. The Coronavirus pandemic has not only changed our personal lives, but our professional lives as well.

Telocyte is no exception. Many biotech and pharmaceutical firms have had their clinical trials disrupted, their production shifted, their employees working from home, and their finances put at risk. Most companies and most employees have willingly shouldered the risk, determined to do everything possible to help others. While any company has an obligation to provide a return to those who invested their money – often their own personal pensions – in such companies, most biotech and pharmaceutical firms also have a mission to improve human health and the quality of human life. That such companies remember this latter mission speaks volumes about the compassion and dedication of those working in this industry.

At Telocyte, the impact has been largely personal, as we are still moving toward human trials, rather than being in the middle of such trials. While many of our investors and potential investors have had to delay working with us, other investors are becoming even more eager to move ahead, as the Coronavirus has made their interest in biotechnology all the more poignant and critical to them, both personally and professionally.

We continue to move ahead with our work at Telocyte, but like most of you, we find ourselves working to keep up with and address the needs of our families, our neighbors, and others who share the global risks at this time. I now lead a weekly global Zoom call on Covid-19 (here is the March 25 call), while working full time for Telocyte. All of us at Telocyte, and probably an increasing number of you who are reading this, know people who have Covid-19. These are troubling times. Not only are there personal medical risks, but our society – locally and globally – is changing around us. While we will continue to focus on curing Alzheimer's disease, we want each of you to know that we share the same concerns we all face as the world changes.

Be safe, be healthy, and please be careful
2/3
Q1 2020
Michael Fossel, MD, PhD
For those of you who might like to understand our approach, I suggest you may want to read a paper that will be published on Wednesday January 8th in Alzheimer's & Dementia, the premier global journal on Alzheimer's disease, and published by the Alzheimer's Association.

I gave an invited talk in Washington for the association last year and was then asked to write the paper. In the talk, I pointed out that while we have a number of "targets" (such as beta amyloid and tau tangles) and a number of sophisticated techniques (such as monoclonal antibodies), what we completely lack is an overall "systems" model that explains how the risk factors are related to the clinical findings.

For example, we know that closed head injuries, infections, radiation exposure, toxins, and dozens of genes increase the risk of beta amyloid deposits and tau tangles, but we don't have a unified model that explains WHY those risk factors cause those deposits and tangles, along with the clinical findings of Alzheimer's disease. We need a single, overarching model to explain not only Alzheimer's, but other age-related dementias (including Parkinson's, FTD, EOAD, Lewy body disease, vascular dementia, mixed dementias, and others). Such a model should also explain why animals suffer from cognitive decline as they age. Most importantly, we know that the single major risk factor for Alzheimer's disease is age, but exactly how does aging cause human dementias?

Our model ("A Unified Model of Dementias and Age-Related Neurodegeneration") explains how and why age-related dementias occur, why animal models fail to work in humans, why all prior human trials have failed, and presents the rationale for the novel target that we will use in our FDA human trials. It also answers ten key questions that have bothered other researchers in this field.

If you'd like to understand why Alzheimer's occurs and why we expect to succeed in our human trials, let us know and we'll send a copy to you. The paper is not for the faint-of-heart: it's not only quite technical, but it's also a long paper (17k words, 269 references, and 8 figures, even before the appendix was added). The paper had eight reviewers who were remarkably complimentary. Most of the reviewers wished the paper were shorter, but then also asked me to add more information about issues that were specific to individual reviewers. Given this interest from the reviewers, the editors requested an appendix, making the paper even longer but giving readers a feel for the dialogue between the eight reviewers and myself.

The editor-in-chief was impressed enough with the model that he joined our Scientific Advisory Board. The paper promises to be a watershed for the Alzheimer's field, as well as offering insight to our investors as they try to understand how Telocyte will succeed where others have not. We welcome anyone who would like a copy of the paper. Just email us and ask.

Several people have asked about a company that is trying a similar approach, although they are doing so without FDA oversight, in an "offshore" location, and at a substantial financial cost to patients. We can understand the need for haste, but we have grave concerns about their approach. Our ethics require us to go through the FDA, use an academic setting for our trial, get the approval of an institutional review board, and provide our therapy free-of-charge to patients in our phase 1 human trial. Our concerns revolve around three issues that define Telocyte: credibility, safety, and efficacy.

We realize that any trial – regardless of where it is done or under whose auspices – will have a difficult time gaining credibility if there are positive results in treating Alzheimer's patients. There have been more than 400 registered Alzheimer's trials, all of which have, by global consensus, had negative results. Any trial that suggests an effective intervention (or even a marginal delay in disease, as with the Biogen results presented when I was at the recent CTAD conference in San Diego in early December) will automatically generate professional eye-rolling and a degree of understandable disbelief. That disbelief is clear enough when the studies are done by well-known pharmaceutical firms and biotech companies with careful oversight by the FDA, but to expect any scientific or public confidence when a human trial is done in a more lackadaisical manner is impossible.

We are also profoundly concerned about safety and efficacy. I just returned from a major conference on gene therapy in neurological disease (GTxN). While there is enormous potential for the use of gene therapy in medicine, there are also major pitfalls and difficult technical issues whose dangers escape the unwary. At Telocyte, we have been working on our human protocols for three years and yet we still see potential safety risks and uncertainties that have us talking to gene therapy experts, combing the literature, and tweaking our approach to increase safety and ensure efficacy. While there is enormous potential, there are also enormous dangers and difficulties; dangers which we are aware of and which we know how to mitigate, difficulties which we understand and know how to avoid.

We intend to cure Alzheimer's. We do not intend to cure Alzheimer's by taking shortcuts with people's lives or by using an approach that is likely to fail. We are in this not only for the long run, but for the needs of those we hope to cure. We are fully committed to curing Alzheimer' credibly, safely, and effectively.
2/3
Q4 2019
Michael Fossel, MD, PhD
Our video, "Introducing Telocyte", can be seen on the media page of Telocyte.com, offering insight into why we founded Telocyte, how our approach works, and the program for our FDA human trials. I hope that you will find it both intriguing and educational. Feel free to email us for additional information or any questions that arise. You may also find this talk by Maria Blasco, our chief collaborator, to be informative as she discusses the scientific data that supports our approach.

Over the past few years we have found that, in addition to technical and clinical questions regarding Telocyte, certain questions have come up repeatedly. These questions often focus on ethical issues or issues regarding the policies that we live by at Telocyte. As we move ahead to clinical trials in the next year or so, the potential implications are important to us, to those working with us, and to the patients we intend to help.

Our primary aim is to cure Alzheimer's disease, as well as many other agerelated diseases that afflict millions of people: the clinical implications are clear, but the ethical implications – how we do it – are equally important to all of us. In addition, Telocyte lives by a set of business principles that are part of our internal culture, principles that drive us and direct us as we find ways to cure disease and improve human lives.

One initial observation deserves to be made. Looking back over the past several hundred years of human medicine, the advances that have done the most to improve human lives have not been technical advances, but conceptual advances. Human lives have improved far more – and more lives have been saved – as a result of the concept of microbial disease, than they have from organ transplants, robotic surgery, or statins. This is not to denigrate technical advances, but to recognize the far greater value of reassessing how disease occurs and finding innovative (rather than incremental) ways of treating and preventing disease. The best of modern medicine derives far more from revolutionary concepts such as microbial disease (with the associated advances in aseptic surgery, antibiotics, and immunizations) than to incremental changes in medical care. Moreover, while incremental advances have raised the cost of healthcare (and not always with a parallel increase in the value of healthcare), conceptual advances have reliably lowered the costs of healthcare. In 1950, for example, the standard of care for polio was braces, rehabilitation therapy, iron lungs, and other treatments which did nothing to cure or prevent polio. These costs were estimated to result in a bankrupt medical care system by the year 2000, but the reality was remarkably different thanks to innovative therapy – polio vaccines – that not only saved lives, but drastically lowered the costs of polio care; with current costs running approximately ten cents per patient globally. Innovative care improves human lives and lowers social costs; incremental care has limited impact on the quality of life while raising those costs.

At Telocyte, we are dealing with a conceptual revolution in healthcare, one that promises to not only dramatically improve the quality of care, but to lower the cost of care. We intend to improve human lives, individually and personally, of real people with real problems.

Our primary ethical principle is simple: to treat others as we would want to be treated. Putting it even more succinctly, we should treat people like human beings. We all have compassion for children, as we were all once children ourselves. The same should be as true at the other end of the lifespan: age itself is never an excuse to withhold compassion. Our goal is to improve the lives of all of us, not simply those who are young. If we withhold medical care for those beyond a certain age, society is in danger of losing its humanity and it's compassion. Medical care – and caring for one another – cannot be limited by age or age-related disease. Compassion has no age limit.

Our primary focus is Alzheimer's disease, with other age-related diseases as our next priorities. We intend to make our treatment available on a global basis and will meet accepted regulatory standards – such as those of the FDA or EMA -- for human clinical use. Participants in our trials will be selected on the basis of our clinical protocols and relevant clinical criteria. Preference or priority will not be based on gender, race, ethnicity, relationship, financial investment, or other non-clinical considerations.

Our business practices – like our human trials – will be in line with accepted business standards and practices. Investment funding will be utilized in the most costefficient manner to achieve our business goals. Our Scientific Advisory Board was chosen to aid and advise the executive team on all aspects of medicine, science, and regulatory compliance. We chose our SAB members for their practical experience in directing human trials, biotechnology companies, and global institutes.

Our ethical standards, like our business practices, have a common goal: to improve the quality of life of those we love, those we live among, and those we share our world with. It requires innovation, investment, and imagination.

It can be done.
2/3
Q3 2019
Michael Fossel, MD, PhD
In our Q1 2017 newsletter, as CEO, I wrote about the reasons why I co-founded Telocyte with Michael; today I reflect on our progress, learning and challenges over the last 2 years. Back then, we contributed and participated in the very first Advanced Therapy Medicinal Products (ATMP) conference in London, UK. It was our first presentation as Telocyte, introducing our telomerase gene therapy which resulted in our contribution to the Advanced Therapies Investment Report 2017.

For me, it was an opportunity to access this emergent advanced therapy sector and industry in terms of its maturity and acceptance. Unsurprisingly, it was characterised predominantly by small, young biotechnology companies developing therapeutic agents and peripheral technologies, supported largely by academic and publicly funded basic and translational research efforts.

There were a few of the large pharmaceutical folks but the subsequent discussion panels were largely downbeat focusing predominantly on the manufacturing commercial operations and supply chain challenges; as well as building value for Cell and Gene Therapies and establishing Market Access pathways. The Editor's opening paragraph of the report nicely summarised the arc of medical successes but pointed to the elephant in the room (my emphasis).

The past 60 years have seen globally significant advances in medical technology which have drastically increased both quality and expectancy of life across the globe. Made possible through advancements in antibiotics, vaccinations, small molecule drugs, and biologics, the developed world now expects to live long and healthy lives. Successes in medical science have supressed the incidence of predominantly acute external pathologies, altering the clinical landscape to place chronic internal failures of the body firmly in the foreground. 80% of 2012 EU deaths were a result of non-communicable diseases. Despite on-going and partially successful efforts from existing treatment modalities, heart failure and cancer together account for over a million deaths every year in the US, and in the EU, there are an estimated 1.3 million annual deaths from cancer alone. Progress in cancer treatment has been slow; treatment approaches have remained largely unchanged since chemotherapy became commonplace in the 1940s, and often, cancer treatment side effects can be as damaging as the disease itself.

What was most shocking to me about this statement was that deaths from Alzheimer's Disease were not even mentioned or on the radar screen. In November 2017, the news broke: "Dementia now Britain's biggest killer overtaking heart disease for the first time" with dire predictions suggesting that 1.2 million people would be living with dementia by 2040. According to the Alzheimer's Association 2018 Alzheimer's Disease Facts and Figures report, an estimated 5.7 million Americans of all ages were living with Alzheimer's dementia. They went on to say:

By 2025, the number of people age 65 and older with Alzheimer's dementia is projected to reach 7.1 million — almost a 29 percent increase from the 5.5 million age 65 and older affected in 2018. By 2050, the number of people age 65 and older with Alzheimer's dementia may grow from 5.5 million to a projected 13.8 million, barring the development of medical breakthroughs to prevent, slow, or cure Alzheimer's disease.

As 2017 progressed, it was clear Telocyte would need to establish a detailed program plan and clinical protocol for our telomerase gene therapy approach to treating Alzheimer's Disease, a plan that we could confidently share with potential investors and of course the FDA, detailing budgets, manufacturing and quality compliance, toxicity study and clinical protocols. Our first investor has allowed us to do just that by working with our excellent Scientific Advisory Board, PPD (our CRO), and Cooley LLP (our legal team). This was a non-trivial effort, but I can report we are now ready to move forward into our Phase 1 program.

From day one, Telocyte has been a company with a global outlook. One of our first actions was to establish a website to provide information to both those families with Alzheimer's Disease to understand our approach and our progress but also to investors who wanted to know more about Telocyte and the team.

This has attracted attention from around the world and we are today in discussions with investor groups from the US, EU and China. Selecting and working with the right investor is critically important to us and so education and due diligence discussions on both sides are taking up a lot of our time. When asked by families of Alzheimer's patients why it is taking so long to for us to commence clinical trials, this is a large part of the reason.

Another frequent question we get asked is; why are there no treatments, after all the research time and billions of dollars expended by charities and large pharmaceutical companies? Telocyte has chosen large molecule biologics to address Alzheimer's disease using a therapeutic gene. Previous attempts from pharmaceutical biotech companies to provide an effective clinical intervention for Alzheimer's have failed because these companies chose the wrong technology and targeted disease symptoms, rather than the root cause, using a classical small molecule, chemical approach. The halting of late stage drug trials by Roche and Biogen/ESAI are the most recent examples of this failed approach.

Since 2017, our experience has been that a number of investors and academics believed that biologics (and Telocyte) were not relevant, as there were several major pharmaceutical companies that were already progressing with drug trials to address Alzheimer's. They felt that such trials were making good progress and were clearly going to result in an effective clinical intervention. The science emanating from major universities and research laboratories agreed that the only viable drug targets – using small molecular drugs – were beta amyloid or tau tangles. This was an accepted consensus.

Large pharmaceutical companies are fully geared up to engineer small molecule chemical structures that can be deployed and then biologically evaluated for efficacy and safety. It is a time-consuming and very expensive process, consuming hundreds of millions of dollars over many years. Unfortunately for them (and for those with Alzheimer's disease) they failed. We predicted exactly that, although we take no pleasure being proven right. Time, money, and lives have been needlessly wasted. As Albert Einstein was said to have commented, "Insanity: doing the same thing over and over again and expecting different results."

If you have been following our quarterly newsletters, you will have seen that we have a very different view regarding the pathology of Alzheimer's based on the work of Dr Michael Fossel, my colleague and co-founder. Our position for taking a biologics approach is clear:

"The cell senescence model of age-related disease provides a single framework for understanding many age-related diseases, specifically including the dementias, such as Alzheimer's disease. It further suggests that such diseases may be both prevented and effectively treated through a gene-therapy intervention that is currently feasible and that would effectively test the cell senescence model"

Reality is the forcing function for change. The twenty-first century is facing new realities on many fronts; from coping with science technology developments arriving at exponential speed, to dealing with global plastic pollution and temperature rise with subsequent climate changes and (of course) the rapidly expanding incidence of age-related diseases like Alzheimer's. Telocyte is responding to that exponential growth in age-related disease, as we live longer and more of us age. When looking at our 'Healthspan' as opposed to our 'Lifespan' we see that our last decades are blighted, as we suffer the insults of aging. Unsurprisingly, this outcome has been universally accepted as natural and, despite various claims for clinical interventions, the care and support to mitigate aging and age-related disease has been disappointing.

Telocyte has a different approach, based on deeper insight and a recognition of a new horizon for healthcare. This week, we could not agree more with the announcements coming from Cambridge University, at the Health Horizons Future Healthcare Forum:

"Over the previous 20 years we have seen a significant change in the healthcare industry. Small molecules have been pushed out of the blockbuster limelight by biologics. Decreasing sequencing cost has allowed more targeted R&D and the use of increasingly interdisciplinary data to influence prognosis has become standard practice."

As I said in 2017, Telocyte was founded to rapidly bring telomerase gene therapy to first clinical human trials for Alzheimer's Disease. Our strategic objectives remain clear:

• We will measure our success by curing patients.
• We will provide proven clinical interventions.
• We will provide cures for age-related diseases.

At Telocyte, we are contrarians, swimming against a consensus view, but we have good reasons, good data, and a clear view of the real point of intervention in the cascade of pathology that is age-related disease. Our focus is on the generation suffering today with Alzheimer's Disease, not 20 years from now. We are looking forward to an exciting future for them and for us!
2/3
Q2 2019
Michael Fossel, MD, PhD
The number of people dying from age-related dementias continues to climb. Why? Within the US alone, the CDC points out that the incidence of death from dementias has more than doubled since the turn of the century and now accounts for almost half of all deaths. This is partly due to the gradual improvement in survival from other age-related causes of death – largely cardiovascular disease and cancer – with the result that more of us now live long enough to succumb to dementia, rather than, for example, heart attacks or breast cancer. We live longer, but our risk of dementia rises with our life expectancy. This increase in dementia includes not only Alzheimer's disease, but vascular dementia as well as other unspecified dementias, all of which are age-related. The older we get, the higher our chances of having dementia.

It might be easy to simply shrug our shoulders and leave it at that, with the pessimistic view that we all age and that dementia is inescapable, but it that true? While it's true that the older we are (and as we survive other causes of death), the more likely we are to get Alzheimer's disease, but why can't we intervene? After all, we once thought of other diseases as inevitable as well, yet few of us now die of infectious diseases that were once "inescapable". As we came to understand that microbes caused such diseases, we finally began to cure them. If we come to understand the causes of dementia, can we cure Alzheimer's?

The first problem lies in not having a single viable model for Alzheimer's. Putting it bluntly, most researchers, most pharmaceutical companies, most biotechnology companies, and almost everyone else admits that they don't actually know what causes Alzheimer's disease or, if they do know, then everyone else disagrees with them. We know what it does, but not why it happens. A few months ago, I gave a talk at an Alzheimer's Association meeting in Washington, in which I pointed out that in order to move ahead, we need a single, comprehensive model that explains not only Alzheimer's dementia , but all of the other age-related dementias (including Parkinson's). Moreover, as I noted in my talk, the standard complaint is that "everything works in mice, but nothing works in humans". Any model that can explain human dementias must also be able to explain the same sort of problems that occur in aging animals. In short, we need a systematic model that can consistently explain the age-related cognitive decline seen in humans and animals, Alzheimer's and Parkinson's, those with genetic risks and those without, and a lot more. After the meeting, the audience was in enthusiastic agreement. The Editor-in-Chief of the journal Alzheimer's & Dementia asked me to publish such a model and promptly joined our Scientific Advisory Board (see below).

While the absence of a rational and comprehensive model is the first problem, the second stumbling block lies in the inability of investors and others to accept innovation. While almost all venture capital groups, pharmaceutical companies, and entrepreneurs proclaim their interest in innovation, revolutionary technology, and bold new ideas, the reality is that they trudge along in the worn-out path of any previous innovation; they support incremental advances (a marginally improved hot air balloon), but seldom support innovative advances (the Wright brothers). Even when they see the first flight at Kitty Hawk as revolutionary and innovative, they get bogged down in that particular innovation and are unable to go further. It's as though they were awed by the achievement of the Wright brothers and, loudly proclaiming their support for "innovation", they try to perfect a better kind of wood frame, a tougher kind of cloth, a lighter bicycle chain transmission, and a "more advanced" 12 horsepower engine – a 14 horsepower engine? This might make for a longer flight at Kitty Hawk, but it won't result in international passenger jets that carry hundreds of passengers across the Pacific Ocean in a few hours. Incremental improvements are not innovation. Tweaking of existing molecules is not a revolutionary therapy.

For Alzheimer's disease, the result is that not only do we lack an accepted comprehensive model, but most investors are zealously averse to innovation. They prefer spruce wood and bicycle chains to jet engines. The result is the consistent failure of human AD trials as well as useless and exorbitant expense. Biogen alone, in its recent failure with aducanumab, spent more than three quarters of a billion dollars – without a viable intervention or any clear pathway forward. Sailing into the unknown without a map is both heartbreaking and expensive.

To some extent, although far less than you might imagine, the FDA itself has dragged its heels with respect to innovation. Ironically, compared to many researchers or to institutional investors, the FDA has actually tried very hard to keep up with the pace of technology – for example, gene therapy – and to foster true innovation. That's not to say that any regulatory system is perfect, but the FDA is an example of a government agency that has shown an honest and largely effective interest in moving ahead with safer, cheaper, and more effective clinical interventions. As Scott Gottlieb, the recent head of the FDA put it, "Without a more agile clinical research enterprise capable of testing more therapies or combinations of therapies … more efficiently and at lower total cost, important therapeutic opportunities may be delayed or discarded because we can't afford to run trials needed to validate them."

Exactly.

Meet our Scientific Advisory Board:

We'd like to welcome our newest board member, Zaven Khachaturian, and to introduce you to this remarkable and well-known researcher in the field of Alzheimer's disease. Dr. Khachaturian is the Editor-in-Chief of Alzheimer's & Dementia, as well as a neurophysiologist with a life-long interest in understanding the causes of dementia.

Dr. Zaven Khachaturian is the Senior Science Advisor to the Alzheimer's Association, Editor-in-Chief of Alzheimer's & Dementia (the journal of the Alzheimer's Association) as well as President of The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020). He was the chief architect of the extramural research programs on "Brain aging and Alzheimer's Disease" supported by the NIA/NIH from 1977-1995, then worked with national and international advocacy organizations, governments, and universities on strategic planning, development, and financing signature research programs on brain aging and dementia. His primary scientific contributions include a broad-spectrum approach to integrate basic research, public health research, public policy formulation and bioinformatics to solve the diseases associated with brain aging. As a planner and developer of research programs, he has identified the most important scientific challenges confronting the field, assembled the best research teams to solve these problems, and has developed innovative solutions and resources to enable for rapid breakthroughs. He is the best recruiter of scientific talent for the field of Alzheimer's research and has mentored countless investigators worldwide including many of key opinion leaders in aging-dementia research. He continues to coordinate researchers from a wide spectrum of approaches. His major scientific achievements also include the earliest diagnostic criteria for Alzheimer's disease and the calcium hypothesis. He trained in neurophysiology at Yale (BA), Case Western (PhD) and Columbia (Postdoc).
2/3
Q1 2019
Michael Fossel, MD, PhD
Telocyte focuses on Alzheimer's disease. Once we have engaged in our phase 1 FDA trial, currently slated for 2020, we plan to engage with other age-related diseases, including other dementias as well as cardiovascular disease, osteoarthritis, etc. At the most fundamental level, all of the diseases that we target share one coming feature: aging. Aging is no mere chronological measure, but an underlying process that occurs at the genetic – and epigenetic – level. Realistically, the only way we can cure age-related disease is by intervening in the aging process. One might say that we can only reverse age-related diseases by reversing aging itself.

Why then is Telocyte narrowly focused on disease and not on longevity?

Some twenty years ago, the FDA circulated a private white paper on the issue of age-related disease. Shorn of the explanations and the data, the outcome was simple: they would take the stance that they would not consider any interventions aimed at "aging", but they WOULD consider interventions aimed at age-related diseases. Frankly, both then and now, I agree with that stance. After all, it is not the years that bother us but the discomforts. The measure of importance is, after all, the loss of ease or the "dis-ease" that accompanies aging. Putting it differently, the practical measure of any intervention aimed at aging must be its ability to prevent and cure the diseases of aging.

Longevity, for example, is not the measure of success. In Greek mythology, it was Tithonus (Τιθωνός) who received the "gift" of eternal life without eternal youth: he had longevity without health. Pure length of life – longevity – is neither attainable without health nor is it desirable. The measure of our lives, from the medical if not the philosophical standpoint, is how healthy we are, not how long we can prolong unhealthy lives.

As a result, we believe that our critical focus must lie with improving health, not with extending lives. We have nothing against longevity – far from it – but that longevity must be secondary to optimal health, not to years that are merely long, perhaps even all-too-long. When Telocyte focuses on age-related disease, it is not really the diseases we focus on, but the agerelated health that we create by curing and preventing those diseases

One result of this keen desire to ensure health is that we avoid discussions, meetings, conferences, and presentations that focus on longevity or age reversal. With prejudice to none, our goal is not longevity, but health; our goal is not age reversal, but the cure of the diseases of aging. Our concerns are not cosmetic, but more lie with more a fundamental issue.

We intend to create healthier lives by curing and preventing age-related disease, starting with Alzheimer's disease.

How Alzheimer's works

Why do we get Alzheimer's or any other dementia? And why do some of us get it so early, while others do not? What causes Alzheimer's and other dementias?

Alzheimer's occurs when the neurons of the brain become dysfunctional and are lost. The neurons, however, depend upon the health and function of the surrounding glial cells, cells that take care of the metabolic and physiological needs of those critical neurons. In some sense, the neurons are merely the "innocent bystanders" as the glial cells fail. In all of the various types of Alzheimer's dementia (sporadic, familial, etc.) and indeed in all of the age-related dementias (Lewy Body, Frontotemporal, Parkinson's, etc.) it is the glial cells that are the single common denominator. The glial cells fail as, having divided repeatedly over your lifetime, their telomeres shorten, and their pattern of gene expression becomes abnormal, insufficient, and pathological. The process is remarkably complex and affects a myriad of processes – including beta amyloid and tau tangles – but the fact that telomere shortening is always central to the pathology is what allows us to target telomeres in our goal of curing and preventing Alzheimer's and other age-related dementias.

Yet we know that a number of variables seem to play a role in the onset of Alzheimer's disease. One person shows symptoms at age 50, another at age 80. One person, with a history of head injuries (e.g., football players), or a history of infections, or a history of chemotherapy, comes down with a dementia far earlier than another person. Not only does age itself play a role, but so do our genes (e.g., a double ApoE4 allele), and your life-long medical history. Why do so many things appear to play a role in our risk of dementia? The reason is that these are variables that accelerate glial cell loss and replacement, thereby accelerating aging and agerelated disease. The result is dementia. Upstream, we have all the various risk factors – each of which determines the rate at which our glial cells divide and age – and downstream we have all the classic findings of dementia – including beta amyloid plaques, tau tangles, and a host of other findings.

The one oddball, perhaps, is vascular dementia, but even here we find that there are cells that show the same process of telomere shortening and cell failure. In the case of vascular dementia, the problem lies not with the glial cells, but the cells that line the blood vessels of the brain: the vascular endothelial cells. While the cells are different – glial or endothelial cells – the outcome is the same: the cells divide, telomeres shorten, gene expression changes, the cells cease to work normally, and the result is the failure and death of neurons. More importantly, the result is the loss of those we love.

In all cases, however, whatever the type of dementia, the key is that we can prevent or cure such dementias not by dealing with the dozens of risk factors that lie upstream, nor by trying to repair the dozens of findings that lie downstream, but by intervening in a single, critical point: the telomere.
2/3
Q4 2018
Michael Fossel, MD, PhD
The field of Alzheimer's research remains frustratingly unchanged, characterized by frequent claims of research breakthroughs, followed by predictable clinical failures. Results of the recent Biogen/Eisai study, announced at the Alzheimer's Association International Conference (the AAIC) in Chicago in July were, despite hopes and despite considerable "spin", unimpressive in any of the current clinical trials. Similar hopeful, but unimpressive results have surfaced from any number of global laboratories, academic centers, and pharmaceutical firms over the past decade. Media stories proliferate, averaging once a week, and announce a "breakthrough", but the details are scarcely worth enthusiasm. In every announcement, the claims are optimistic; the data is not. Whether looking at monoclonal antibodies against beta amyloid, attacks on tau protein, mitochondrial small molecular compounds, or senolytics, none of the data supports the current claims that we can slow the course of Alzheimer's, let alone that we might be able to stop or reverse the personal tragedies that make up Alzheimer's disease.

Our Scientific Advisory Board members met at the AAIC in July and, while we are eager to move ahead with our FDA study and human trials using telomerase gene therapy, we were pessimistic about other current trials, both those announced at the AAIC meeting and those still in progress. Despite a recent poll noting that most Alzheimer's researchers still pin their hopes on beta amyloid as the best place to intervene, there has never been any evidence that targeting beta Amyloid is even marginally effective. In short, most researchers continue to invest their time and their investor's money in a consistently-failing model. Oddly enough, even Dr. Alois Alzheimer, for whom the disease was named, warned against this 110 years ago, pointing out that amyloid plaques were a result, not a cause, of the disease.

Similar misplaced optimism is fashionable for the use of senolytics. These are drugs that are intended to kill senescent cells, thereby improving the cellular "neighborhood" for the remaining, non-senescent cells. The problem is that removing senescent cells hastens the process of senescence in the remaining cells, which must divide and replace the cells that have been removed. While we would expect a transient improvement, we would also expect that the pathology would then accelerate. Not surprisingly, the published data show just such an outcome: there is an acceleration in the course of disease. Senolytic therapy, like beta amyloid and other narrow approaches, fail on both theoretical grounds and in the face of animal data. Ironically, both the media and investors remain fascinated, despite the fact that "the emperor has no clothes."

Telocyte's approach is not only consistent with all clinical and animal data, as well as having proven predictively valid in predicting the results of clinical trials but telomerase gene therapy has consistently lived up to expectations when used in animal models. Aged animals with poor memory, poor learning ability, and other poor behavioral measures, consistently improve in all respects.

The next step remains clear: approval for a phase 1 FDA human trial.

Meet our Scientific Advisory Board:

Last quarter, we featured Dr. Russell Swerdlow, a neurologist who has been the primary investigator on numerous FDA human Alzheimer's disease trials, and who is the director of the Alzheimer's Disease Center at the University of Kansas. This quarter, we introduce Dr. Joseph Araujo.

Joseph Araujo is the President and CEO of InterVivo Solutions, which is focused on optimizing translational services to facilitate the development and approval of novel CNS drugs. His scientific background includes graduate training in pharmacology at the University of Toronto, more than 35 refereed publications and several invited presentations, which focus on natural aged canine models of human disease. Joseph has co-founded, held executive level positions and consulted for life science companies including CanCog Technologies, Vivocore, Karyopharm Therapeutics, NPM Pharma, Ketogen, and Epione Animal Health.

InterVivo Solutions is a preclinical in vivo CRO providing research services using translational animal models for efficacy, pharmacokinetics, early safety and toxicology, including bioanalytical and imaging support. InterVivo's core expertise is in CNS diseases and is unique in its focus on providing predictive animal models in appropriate species to improve the successful transition of new pharmaceuticals to the clinic, which include the canine model of Alzheimer's and knock-out rat models of Parkinson's disease.
2/3
Q3 2018
Michael Fossel, MD, PhD
The major problem with innovation is that it is innovative. Incremental approaches to Alzheimer's intervention have – without exception – failed to slow disease progression. The field is ready for innovation, yet few people are able to evaluate innovative approaches with a clear eye toward the data, without preconceptions and without the conceptual blinders imposed by unexamined assumptions.

Everyone favors innovation, unless you are innovative.

Over the past two years, a number of pharmaceutical firms (and biotechnology companies) have not only encountered failure in their clinical trials but have decided to capitulate and abandon the search for an effective intervention for Alzheimer's disease. On the one hand, their pessimism is warranted: there have been more than 400 registered interventional Alzheimer's trials and no positive results. By itself, of course, this is surprising as statistical chance alone would be expected to result in better results than these, yet there it is. While poor clinical trial design may underlie many of the negative results, the primary problem is that these attempts are poorly aimed. Putting it bluntly, given that they have misunderstood the target, it is small wonder when they fail to hit it.

To adapt Coco Chanel's pithy advice – "Don't spend time beating on a wall, hoping to transform it into a door". To date, AD trials have made the classic blunder of beating their heads against the wall, rather than using the door.

The error lies in the unwillingness to reexamine their assumptions. Alois Alzheimer, for whom the disease was named more than a century ago, warned against the assumption that dementia was caused by the amyloid plaques and the other histological changes seen at autopsy. Despite his prescient advice, almost all trials have targeted amyloid, tau tangles, and other histological findings, never going deeper into the causes that underlie these findings. This is much like treating a fatal viral infection by treating pain, fever, hypotension, and other clinical findings rather than treating the virus itself. Every disease has its own signs and symptoms, but signs and symptoms are not a disease. Amyloid plaques, tau tangles, and mitochondrial dysfunction are outcomes, not causes. They are signs of the disease, even defining markers of the disease, but they are not underlying causes. So far, all clinical trials to date have only targeted disease markers.

Telocyte has a better idea.

Where we stand and where we are going

We have been offered the full support of a major global pharmaceutical investment firm. This investment will enable our phase 1 and phase 2 FDA human trials. We are now ready to apply to the FDA, to ensure that our protocols and production quality will meet the FDA expectations and requirements. In the next few months, we will finalize contracts for FDA consulting and for production of our telomerase gene therapy, TEL-01. Our timing now depends upon our ability to produce TEL-01 in sufficient quantity and quality to meet the needs of our patients in the upcoming human trials. We have a growing patient registry of more than 100 volunteers for our FDA phase 1 human trial, currently scheduled to begin within the next two years.

We intend to ensure that TEL-01 is effective, safe, and credible.


Meet our Scientific Advisory Board:

Last quarter, we featured Dr. Mimoun Azzouz, one of our two world-renown specialists in gene therapy. We'd now like to introduce you an equally eminent neurologist and specialist in running Alzheimer's disease trials: Dr. Russell Swerdlow. Dr. Swerdlow has extensive experience in clinical medicine, human clinical trial design and execution, and FDA regulatory interactions in human Alzheimer's disease trials. In addition, we anticipate that Dr. Swerdlow will be our lead investigator for our FDA human trials.

Dr. Russell Swerdlow is the Director of the University of Kansas Alzheimer's Disease Center and the KUMC Neurodegenerative Disorders Program. Dr. Swerdlow is a Professor in the Departments of Neurology, Molecular and Integrative Physiology, and Biochemistry and Molecular Biology at the University of Kansas School of Medicine. After receiving his undergraduate and Doctor of Medicine degrees from New York University, he trained as a neurologist and cognitive disorders subspecialist at the University of Virginia. Dr. Swerdlow is a laboratory-based neuroscientist who is internationally known for his work on mitochondrial dysfunction in neurodegenerative diseases. National level recognition includes the S. Weir Mitchell Award from the American Academy of Neurology, a Cotzias Fellowship from the American Parkinson's Disease Association, research grants from the National Institutes of Health, and membership on NIH and Veteran's Administration Study Sections. Before joining KUMC in 2007, Dr. Swerdlow chaired the Alzheimer's Disease and Related Disorders Commission of the Commonwealth of Virginia, and from 2005-2010 he served as the Research Committee Chair for the CurePSP Foundation. His more than 200 scientific articles, focusing on Alzheimer's disease and mitochondrial function, have been published in JAD (Journal of Alzheimer's Disease), Journal of Neurochemistry, Current Pharmaceutical Design, Biochim Biophys Acta, Human Molecular Genetics, PLoS ONE, Neurology, Experimental Neurology, and other respected academic journals.
2/3
Q2 2018
Michael Fossel, MD, PhD
Alzheimer's disease has been with human beings as long as we've been human. Few of us grew old enough to suffer from "senile dementia"; many of us died as children, during childbirth, or from trauma, infection, and the host of diseases that we are still prey to. And yet, some of us, even thousands of years ago, succumbed to Alzheimer's.

Alzheimer's disease was first named more than a century ago. Essentially, it's been around as "Alzheimer's disease" for about as long as modern medicine began to become modern. We knew about the "shrunken brain", the amyloid plaques, the dying neurons, and even the tau tangles for a century or so. And yet, modern medicine or not, we succumbed to dementia.

Alzheimer's disease trials, more than 400 of them, even if we only count those registered on the clinical trials website, have been trying to prevent, cure, or stop the disease for several decades. More recently, those trials have moved toward the more fatalistic goal of merely hoping to slow it down, and even then, only statistically. And yet, even after hundreds of trials, we succumb to Alzheimer's.

Alzheimer's disease as caused by cell aging, was first suggested twenty years ago and that same paper suggested that we might be able to use cell aging as a therapeutic target. That notion, that cell aging not only caused Alzheimer's disease and a host of other age-related diseases but could be an effective point of intervention was consistent with everything we know about Alzheimer's disease, everything we know about those failed clinical trials – and why they failed, and everything we know about human aging itself. And yet, even after twenty years, we succumb to Alzheimer's.

Alzheimer's disease became the target for our human trials two years ago. We have put our time, our resources, and our very lives into moving ahead, into getting to human trials, into finding a way to save human lives. We have flown around the world, we have spoken at conferences, we have met with investors. We have found others to join us, we have designed protocols, we have niggled over the best way to deliver a cure in real, suffering human patients whose souls are dayby-day disappearing to Alzheimer's disease. And yet, even after two years, the people we most want to help still we succumb to Alzheimer's.

Alzheimer's disease is hard for most people to understand. Researchers, clinicians, investors, regulatory agencies all struggle to understand the disease. Most people, once they overcome their assumptions and look carefully at the disease with a fresh eye, realize that we not only have the ability to understand Alzheimer's, we have the ability to cure it. To cure it takes several things. It requires that we understand the disease itself and that we have the right tools to fix the fundamental problem: the changes in gene expression that drive all of the other findings that we mistake for the disease itself are no more than symptoms and outcomes, rather than the cause. It also takes the ability to move from merely having the understanding and the tools to the clinic itself. We now have the understanding and the tools. We need only move to the clinic.

To get there, requires very little else. We need the funding and we need regulatory approval. We are on the edge of both as we quiver on the brink of a cure for Alzheimer's. And yet, even now, those we could cure still succumb to Alzheimer's.

We need to finish a job that began when we first became human.

Where we stand and where we are going

As we finish the first quarter of 2018, we are confident that we can not only prevent and cure Alzheimer's disease – and other age-related dementias – but most other age-related diseases. We are still scheduled to begin our human trials next year and we are putting together our formal application for the FDA. In chemistry, one talks about "rate-limiting steps" in any process: those steps that are the funnel, the slowest process, the narrowest point in the path forward. We have three rate-limiting steps: investors, our production schedule, and the FDA. At the moment, our major concern is funding. While we have several interested global investment groups, interest is not sufficient: we need funds to move to human trials. Production of our gene therapy agents lies in the hands of the vendors. Given the current interest in AAV gene therapy and the time it takes to produce high-quality gene therapy vectors, the vendor's ability to provide GMP quality agents adds to the time to human trials. Finally, the FDA will determine when we can finish our animal toxicity study and when we can begin our human trial.

The sooner we finalize funding, the sooner we can move ahead.

Meet our Scientific Advisory Board:

Last quarter, we featured Brian Kaspar, one of our two world-renown specialists in gene therapy. We'd now like to introduce you to the other one: Mimoun Azzouz,

Professor Mimoun Azzouz, formerly Director of Neurobiology at Oxford BioMedica, is currently Chair of Translational Neuroscience at the University of Sheffield. Azzouz is also Deputy Head of Neurology Unit and Director of Research & Innovation at the Neuroscience Department. His translational research productivity is characterised by publications in top ranking scientific journals, including Nature, Nature Medicine, Nature Neuroscience, and STM. Several inventions emerged from his research. One of his major achievements is his involvement in a gene therapy approach designed to achieve dopamine replacement in models of Parkinson's disease. This strategy has yielded significant translational impact having entered into phase I/II human clinical trials since 2008. He is currently driving 2 clinical development programs through regulatory tox, GMP clinical manufacturing and regulatory bodies. He recently won top level EU ad hominem prestigious ERC Advanced Investigator (2011) and ERC Proof-of-Concept (2017) Awards. These awards are acknowledging his pre-eminence in European biomedical research. He is/has been advisor for companies and academic institutions. He is currently a member of scientific Panels/Boards for various funding bodies such as the Medical Research Council (DPFS MRC, UK), the French Muscular Dystrophy Association (AFM), the Health Research Board (HRB) of Ireland and the Neuroscience Panel, Germany. He has been recently named as Board member of the British Society for Gene and Cell Therapy.
2/3
Q1 2018
Michael Fossel, MD, PhD
Gene therapy has made remarkable progress since the death of Jesse Gelsinger, twenty years ago. Since then, gene therapy has gradually climbed back toward clinical success, but the key questions remain those of efficacy, safety, appropriate clinical targets, and cost. There are five different approaches to gene therapy in current trials, each with different clinical applications. The potential applications depend on the pathology, the organs involved, and current technical limitations. Some are appropriate to specific genetic diseases, some to certain cancers, some to infectious disease, and some to age-related (i.e., epigenetic) disease.

The first approach is in vivo gene replacement, which delivers a normal allele to many or all affected cells, to alleviate the effects of an abnormal allele. Such approaches are typically aimed at children with genetic disease, such as the recent successful demonstration (see Brian Kaspar's information below) of gene therapy to treat spinal muscular atrophy (SMA), and a similar recent success in treating hemophilia.

The second approach, in vivo gene editing, actually edits cells genes, rather than replacing them. In a recent trial involving Hunter's syndrome, the patient's own DNA was literally "rewritten" directly in the cells of the patient's body.

The third approach, ex vivo gene editing, removes and alters the patient's cells, which are then returned to the patient's body. This approach is especially promising for refractory leukemias and lymphomas, but may also be applicable to several other cancers.

The fourth approach, in vitro phage editing, alters bacteriophages that are then used to attack bacteria, and may prove effective in treating resistant bacteria rapidly and effectively.

Telocyte exemplifies the fifth approach, in vivo gene therapy to reset aging cells, and offers the most extraordinary potential in geriatric medicine. This approach uses viral vectors to deliver an active human telomerase gene to transiently reset gene expression in aging cells, restoring normal young cell function and reversing age-related pathology. Telomerase therapy has proven effective in human cells, in human tissues, and in animal studies. Human trials will use Alzheimer's disease as the initial clinical target, but with potential for vascular aging, osteoarthritis, osteoporosis, and a host of other age-related diseases.

As the FDA Commissioner recently said, gene therapy is "no longer the stuff of science fiction."

Meet our Scientific Advisory Board:

Last quarter, we featured Suzanne Hendrix, a specialist in the design of Alzheimer's studies. This quarter, we introduce Brian Kaspar, one of our two world-renown specialists in gene therapy.

Dr. Brian K. Kaspar is a principal investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital and Associate Professor in the Department of Pediatrics and Department of Neuroscience at The Ohio State University College of Medicine. In 2013, Dr. Kaspar was named Fellow of the American Association for the Advancement of Science (AAAS). He has published more than 100 scientific articles. He received his PhD in molecular pathology from UC San Diego and did his postdoctoral work on neuroscience and gene therapy at the Salk Institute. Dr. Kaspar founded two biotech companies (Avexis and Milo) working on gene therapy.

In November of 2017, Dr. Kaspar was the senior author of a ground-breaking paper published in NEJM (the New England Journal of Medicine), which described the successful use of AAV9 gene therapy to successfully treat 15 patients with SMA (spinal muscular atrophy).
2/3
Q4 2017
Michael Fossel, MD, PhD
Many biotech firms, particularly those aimed at Alzheimer's disease, find that their major problem is finding the "signal in the noise". They strive to find any statistically positive result over several years of clinical trials and several thousand patients with Alzheimer's disease – so far to no avail, despite the time lost, the money spent, and the patients who fail to benefit. Some large pharmaceutical firms, for example, spend years following thousands of patients (and spending hundreds of millions of dollars), only to find only a marginal, statistically weak result that later proves fruitless and clinically ineffective.

At Telocyte, we have a unique problem.

We expect that our "signal" (cognitive improvement in patients with moderately severe Alzheimer's disease) will be so apparent that we will need only a few months and a dozen patients in order to show unambiguous improvement. Strange as it may appear, that's our problem. Effective clinical results are so unexpected, so far beyond the historical norm, that most people will – predictably – have a difficult time believing those results. Until now, every pharmaceutical company has failed, totally and without exception. When Telocyte succeeds in our phase 1 human trial, it will (and should) prompt questions. How credible are our (incredible) results? We are profoundly concerned not about our ability to achieve results, but our credibility once we achieve such results. Our focus then, is to ensure that when people have questions about what we have done, we have answers. We need to tread carefully and without a misstep as we move into human clinical trials.

There have been far too many claims and, equally, far too many failures.

When a biotechnology company fails to show any effect on Alzheimer's, as every single clinical trial has done to date, no one questions the credibility of that failure: it's an expected outcome. But when a company succeeds, particularly in the face of a history of universal failure, then it can expect doubt and disbelief. At Telocyte, our task is not merely to cure Alzheimer's disease, but to minimize error and maximize our credibility.

To this end, during the last quarter, we have had meetings with the Alzheimer's Association at the global research conference in London, the Alzheimer's Drug Discovery Foundation in their recent New York conference on drug discovery, and with the director of the Dementia Society of America. In every case, we are not seeking support or publicity, but merely that they understand our program and a chance to ensure that they are not blind-sided by our upcoming clinical trials. In addition, we have acquired new internal expertise to be sure that our human trials are done well. To this end, a globally respected expert on statistics and the design of clinical trials, specifically interventional clinical trials in Alzheimer's disease, met with us in London and graciously joined our Scientific Advisory Board to ensure that our clinical trials achieve valid and reliable data. I urge you to look at her biographical notes below, as well as on our website. She is eager to work with us and we, in turn, are more than delighted, and honored, to work with Dr. Hendrix.

As with so many ventures, the path is clear and well-defined at a high-level, but there is a stunning amount of work involved in getting the details right. We continue to move ahead on the completion of full funding for our upcoming animal study and our planned human trial, which is currently scheduled for late 2018. Currently, we are actively and continually reassessing both our animal toxicity protocols and our human protocols, adjusting for new technical advances in diagnosis and delivery systems, optimizing our techniques, and doing everything we can to ensure that we meet with success, both in our meetings with the FDA and, ultimately, in our clinical trials.

It's definitely a labor, but a labor of love.

Meeting our Scientific Advisors:

Over the next several quarters, we'd like to introduce you to the members of our Scientific Advisory Board, members whose expertise underlines our commitment to getting our work done right. This quarter, we introduce the newest member of our SAB, Dr. Suzanne Hendrix.

Suzanne Hendrix has worked for the past 26 years as a biostatistician focusing on clinical trial research in many different indications. She has extensive experience designing clinical trials, writing statistical analysis plans, running analyses, writing statistical reports, interacting with the FDA and preparing manuscripts for publication. She is experienced at communicating statistical concepts in an understandable way, and has helped develop software for graphically understanding large complex datasets. For the past 14 years, she has specialized in statistical issues in Alzheimer's disease such as identifying appropriate outcomes, addressing measurement issues, demonstrating disease modification and optimizing clinical trial design and analysis. She has been on multiple advisory boards and expert panels addressing current issues in Alzheimer's disease, and has interacted with the division of Neurology products at the FDA and with the EMA through scientific advice regarding these issues. She is currently president and owner of Pentara, a company that provides data management and statistical consultation to the pharmaceutical industry, academic groups and non-profit groups, primarily supporting clinical trial design and optimization in Alzheimer's disease. She has researched methods for discerning disease modification of treatments, and has proposed novel approaches to this problem. She is an active researcher in the Alzheimer's disease field with over 100 publications and presentations.
2/3
Q3 2017
Michael Fossel, MD, PhD
I often compare our progress to a three potential outcomes: the pessimistic, the optimistic, and the realistic. The pessimist outcome is failure, the optimistic outcome is miraculous, and the realistic outcome is the mean outcome for most biotech firms that make progress. If these were each placed on a scale from 0-10, then 0 is failure, 10 is a wildly miraculous outcome, and 5 is what happens to most successful biotech firms. Given this scale, we have been steadily progressing as a "6", i.e., better than we any realist would expect.

At the moment, we are in active negotiations with a global funding group that 1) sees and understands our aims and our understanding of age-related disease, 2) is excited about the clinical and commercial prospects, and 3) suggests funding us completely. While we ourselves are delighted, we will have to see what the negotiations bring over the next two months. We continue to talk with several other large investment groups, as well as individual investors. In the past month, I've been in Madrid, New York City, Palo Alto, and Montana, and am scheduled to be in London in a few weeks. The London trip not only includes several committee and personal meetings during the annual global Alzheimer's Association International Conference, but meetings with a member of parliament, a wealthy global investor, and various research groups in the UK.

On the FDA front, we have finalized our toxicity study protocol and are arranging an appointment with the FDA to ensure that this protocol meets their needs, as a prelude to our first human trial next year. While the FDA currently has a prolonged (several month) delay, we plan to begin the animal toxicity study in Q4 of this year, completing it in Q2 of 2018.

As discussed in our Q2 newsletter, while we continue to make contacts, have discussions, and encourage interactions with the FDA, academia, pharmaceutical groups, and other biotechnology firms, particularly those involved with Alzheimer's disease, we generally avoid publicity or headlines. We have given quite a few interviews regarding how Alzheimer's work and the prospects for an effective clinical intervention, but feel that our best "publicity" will be the results of our upcoming human trials, beginning in mid 2018.

The Telocyte patient registry

We often receive questions regarding human trials, currently scheduled for 2018. The location is not yet settled, but it will be held at an academic medical center in the United States, with the most likely suggestion being Kansas City. Treatment will be a one-time injection, with regular follow-up every two months, over a six month period. We will treat at least one dozen volunteers, each with moderately severe Alzheimer's disease and no other unstable medical problems. We currently have a registry of three dozen patients, one third of whom are less than 65 years old. If you would like to be added to the registry, please let us know.

Alzheimer's: a perspective

Many of us see media (as well as academic and biotech) updates on Alzheimer's on a daily basis. I typically find half a dozen come across my emails every day. Some of these stories offer hope, some increase our concern. Recently, Forbes offered an article suggesting that there were perhaps twice as many people with Alzheimer's as we had estimated, nationally and globally. In reality, there are not more people with Alzheimer's, but we've simply gotten a bit better at picking them up earlier (or so we think). With advances in imaging techniques, particularly targeted PET scans, we see earlier and earlier evidence of what will become Alzheimer's disease, often well before it is clinically apparent. Until recently, the diagnosis was made solely on clinical grounds: you were having more and more memory or cognitive problems, you were tested and interviewed, and you were diagnosed with Alzheimer's, solely on clinical grounds Purists continued to maintain that only an autopsy justified a firm diagnosis, but the reality was that clinical diagnosis was acceptable and accepted.

More recently, however, we've begun to use not only CT and MRI scans to detect anatomic changes in the brain, but PET scans, which can focus on actual metabolic function (rather than just anatomy), so we began to see not only which areas of the brain had loss of neurons, but which areas had neurons that were still there, but were already "in trouble". PET scans also allow us to look at even minimal changes in amyloid and tau proteins, changes that predict upcoming neuron failure and clinical Alzheimer's disease.

This is a diagnostic two-edged sword. On the one hand, it offers to tell you that, while you don't yet have Alzheimer's, you soon will. Is this bad news or good news? Is ignorance bliss or a chance to make plans?

This is also a therapeutic two-edged sword. On the one hand, we might be able to "catch it earlier" and begin early therapy. On the other hand, there is no therapy that has yet proven capable of changing the course of the disease, whether you catch it earlier or not.

In short, the recent advances don't really change the human tragedy of AD at all.

We are slightly better at diagnosing AD, but no better at treating it. Most global pharmaceutical firms and most biotech firms are focused on testing their interventions on early Alzheimer's disease and are, frankly, having a hard time finding enough patients. Their rationale for going after early disease is clear: the earlier you start treating it, the better the chance of slowing it down. Unstated, however, is the clear assumption that none of these companies want to treat moderate AD because none of them believe that AD can be stopped, let alone reversed. They are hoping that they can "stop the avalanche before it gets started" or, more realistically, find a way to slow the inevitable downhill course, at least marginally, Stopping AD or curing AD are no longer part of reality for most companies.

Oddly enough, that's precisely where Telocyte comes in. We are the only company that will be treating patients with moderate (rather than early) Alzheimer's. We are also the only company that is confident that we can both prevent and cure (rather than merely slow or postpone) Alzheimer's.

It's a dizzying perspective.
2/3
Q2 2017
Michael Fossel, MD, PhD
We are about to initiate our discussions with the FDA.

Our key activities this quarter will be 1) to confirm our investment funding and 2) to move ahead with our FDA discussions and with the FDA animal study itself.

In regard to our investment funding, we are updating our corporate legal structure, setting our term sheet and stock, and defining our board of directors, to include our current (and future investors). We have recently been joined in this effort by the world's preeminent biotech attorneys, Cooley LLC. Cooley is a global firm, first founded in Silicon Valley and now found globally, who is the number one firm in global biotech and pharmaceutical licensing, as well as number one in life sciences venture capital financing. Cooley is proving to be a remarkable asset in our corporate success and we anticipate using them as our legal partners in the years to come, as we move on to demonstrate our ability to intervene in Alzheimer's and other age-related diseases. We have two major investors who have committed substantial funds to Telocyte, and five other major investors who wish to commit similar amounts.

Our next major step is to begin our FDA toxicity study. We have a kick-off meeting in Madrid with CNIO, our collaborators, in late April. We will review the FDA study protocol, and initiate our management committee. In the next two months, we expect to sign our vendor contracts and then begin the animal toxicity study. The animal toxicity study is required by the FDA and is the prelude to our upcoming human trial, scheduled for 2018.

As the spring progresses, we will also be initiating discussions with the FDA. Our overriding concern is credibility, as seen by both the FDA and by clinical researchers globally. We will ensure that, as we move ahead, our approach, our data, and our credibility are unquestionable. We intend to do it right, ensuring that everything we do meets global and US standards, scientifically and medically, so that our results are seen as both valid and reliable. To that end, we will be working with one of the most credible and well-regarded CRO's (contract research organizations), INC Research.

While credibility is our overriding concern, publicity is not.

In general, we will be continuing to make contacts, to have discussions, and to encourage interactions with the FDA, researchers, and organizations, particularly those involved with Alzheimer's disease, but at the same time, we will not seek out publicity or headlines. We believe that our time and efforts are best spent trying to cure Alzheimer's disease, rather than in public relations efforts. To that end, we will continue to avoid most interviews, while at the same time trying to ensure that no one is blind-sided by the results of our upcoming human trials next year. I have been (and will be) meeting with the Alzheimer's Association, the Dementia Society of America, the Alzheimer's Drug Discovery Foundation, and other researchers at international Alzheimer's conferences, such as the AAIC in July in London. This is a delicate balance: we prefer to avoid major media, while still wanting to have those involved in research, clinical trials, investments, and regulatory agencies have a full and open knowledge of what we are trying about to accomplish.

We want successful patients, not successful publicity.

Who is involved at Telocyte?

There are currently three of us (all otherwise-retired and all without salary) working fulltime at Telocyte. In addition, we have almost a dozen volunteer associates around the world. These include people with long careers in biotechnology, academic research, information processing, investment, law, chemistry, medicine, and other professional areas. They live in San Francisco, Boston, London, Barcelona, Indianapolis, Bethesda, New York, Detroit, Stanford, and elsewhere. They work with us because they believe, as we do, that we will be able to entirely upend global medical care, curing age-related disease and lowering healthcare costs. They work with us because they believe, as we do, that the most effective place to start is to prevent and cure Alzheimer's disease.

In addition to those of us working with us at Telocyte, and the five hundred people who follow our quarterly updates, there are several dozen other people – far more important to all of us – who are involved with Telocyte. These are the several dozen Alzheimer's patients who have asked to join our registry of volunteer for our human trial. While there is no certainty about who will be able to be part of our first human trial in 2018, and no certainty that we will be able to help cure them, one thing remains quite certain: these individuals are the reason Telocyte exists. We have one clear goal: to help those patients overcome Alzheimer's. These individuals, and others with the same disease, are the soul of our company, not because they volunteer or because they help us achieve success, but because they are the reason that we need to achieve success.

Telocyte exists because of and for patients with Alzheimer's disease

How does Alzheimer's happen?

Current research still focuses on amyloid as the cause for dementia, yet every clinical test of amyloid as a point of intervention – every single clinical trial – has failed. Yet even those who know this approach has failed remain unable to step back and reevaluate their approach. Instead of admitting failure, and instead of looking for a deeper, more sophisticated understanding of the Alzheimer's process, they remained devoted to the idea that amyloid causes Alzheimer's disease. Hundreds of failures haven't shaken their faith in this naïve view of how the pathology occurs. Global conferences talk about "reevaluating the role of amyloid" and then talk about how they can find yet another, slightly different way to attack amyloid again. Nor is the major alternative to amyloid, tau protein, faring any better in clinical trials. There have been fewer experimental trials aimed at tau proteins than at beta amyloid, yet neither approach has every had any clinical success whatsoever. It's as though pharmaceutical firms are determined that they can run headlong into a cement wall and fail, yet then hope that – if only they run harder and faster – they will be able to force their way through that same wall. Their only success is to lose money, lose time… and lose lives.

Alzheimer's disease is not caused by amyloid, nor by tau proteins, nor a myriad other things that are common to Alzheimer's disease. If we really wanted to define the cause of Alzheimer's, we need to go upstream and ask ourselves, "why do these patients get amyloid plaques and tau tangles in the first place?" Only be truly understanding how Alzheimer's disease works, can we understand how to treat it.

We know that Alzheimer's begins from dozens of risk factors – head trauma is but one example among dozens – that feed into a common cascade of disease. That cascade includes a set of changes that occur within the glial cells. And as the glial cells change, they begin the slow process that results in amyloid plaques, tau tangles, and the host of other findings that are part of Alzheimer's disease.

Yet even then, the question isn't "what causes Alzheimer's?" The important question, the only question that matters is "where can we intervene?" We know that interventions aimed at one of the many "downstream" targets – such as amyloid or tau proteins – have no effect on the disease. We also know that when we aim "upstream" – using telomerase to reset glial cell function – we see dramatic improvements in every animal we test.

There is no current treatment for Alzheimer's disease and none of the clinical trials, (e.g. Eli Lily, Biogen, and others) have ever shown any effect on Alzheimer's disease. All experimental interventions, even in animal studies, have proven ineffective – except for telomerase. The failures occur because current interventions target the end results (i.e., beta amyloid and tau proteins) rather than targeting the underlying causes of Alzheimer's pathology.

Telocyte uses a novel approach that addresses the fundamental alterations in gene expression that underlie Alzheimer's disease. Our technique resets age-related behavioral decline, using telomerase, to reset gene expression to that found in normal young cells. The intervention is uniformly effective in animal trials and is entirely applicable to human patients. It's time we tried something that not only makes sense, but something that works.

The Telocyte patient registry

We often receive questions regarding human trials, currently scheduled for 2018. The location is not yet settled, but it will be held at an academic medical center in the United States. We are evaluating three potential clinical locations. Treatment will be a one-time injection, with regular follow up every two months, over a six month period. We will treat a dozen volunteers, each with moderately severe Alzheimer's disease and no other unstable medical problems. We currently have a registry of three dozen patients, one third of whom are less than 65 years old. If you would like to be added to the registry, please let us know.

Hello everyone.

I am delighted to be able to contribute to this quarterly newsletter and take the opportunity to introduce myself to you all. I began working as a member of the Telocyte team after my retirement from the software industry in 2014. As a former mechanical engineer, program manager and Chief Customer Officer you might wonder why I would be involved in Telocyte. The answer is very straightforward. Firstly, I was inspired by the vision and mission that our cofounders Peter & Michael have established. Secondly, my career has focused on driving operational excellence and building strategic relationships with partners and customers. These are qualities that will be essential to Telocyte's success as we approach clinical and human trials, achieve FDA approval and work with partners like CNIO in Spain to achieve our goals.

I am excited by the progress we have been making in building our operating plans and establishing strategic relationships with partners and know that I can help to ensure that they deliver the results we expect so that we can achieve Telocyte's vision and mission. It is a privilege to work on such a noble and inspirational cause and I look forward to working and meeting with you all in the future.

Best Regards,

Mark Hodges.
2/3
Q1 2017
Michael Fossel, MD, PhD
As we enter 2017, we find ourselves beginning new collaborations, new endeavors, new prospects, and new hopes for Alzheimer's. Telocyte has now completed our contractual arrangement for our FDA animal toxicity trial and, after working with our regulatory consultants and our collaborators, the protocol for that trial is in final form. Our financing is likewise entering a new phase, as a global investment group negotiates to provide funding for that same FDA toxicity trial.

Yet while we move ahead, the reason we do so remains unchanged: Alzheimer's disease continues to haunt all of us. The Alzheimer's Association estimates that one in three of us will be diagnosed with AD. Alzheimer's has become the leading cause of death in some nations, while the global incidence climbs in every nation as our average lifespans lengthen. Wherever we live, whatever our economy, however our health care is delivered, not only do the human costs of AD grow, but the economic costs (currently one quarter of a trillion dollars annually in the US alone) grow larger as well. At Telocyte, we believe that we can erase those costs, erase those fears, and erase the disease itself.

We hope that a year from now we can begin to take our vision from an old scientific hope to a new clinical reality, as we begin our first human trial.

What are we doing at Telocyte?

Getting to the clinics takes financing, hard work, intelligence, and careful planning. Over the next year or so, we have two goals:

1) To complete our FDA animal toxicity study (the "preclinical study") and
2) To complete our FDA Phase 1 human trial.

The first step, our preclinical study, will begin in the next few months and last a minimum of six months. The primary aim is to provide the animal data that the FDA requires, preliminary to our beginning an FDA-sanctioned human trial. This study includes both young and old mice, as well as human cell studies in the laboratory of our collaborator, CNIO, in Madrid. As that study moves ahead, we will be in discussion with the FDA, to ensure that we have the data they need to grant us an IND (Investigational New Drug) status, so we can begin our phase 1 human trial. The second step, to begin in early 2018, will also last six months. We will treat 12 volunteers, each with confirmed moderate Alzheimer's disease. We anticipate clear cognitive improvements in these dozen human volunteers.

How does Alzheimer's happen?

Alzheimer's is not only the loss of our memory, but also the loss of independence, the loss of our ability to reason, and even – some would say – the loss of our souls. Stepping back from the human cost, however, what causes Alzheimer's in the first place?

For more than a century, we have known that the clearest change in the brains of those with AD is the death of our nerve cells. Neurons die and the results are obvious in autopsy. But going "upstream" a bit, what makes our neurons die? For several decades now, we have seen a fairly good (although not perfect) correlation between neuron death and two findings that are seen under a microscope: deposits of amyloid protein (plaques) and deposits of tau protein (tangles). Reasonably enough, researchers have tried valiantly to prevent or decrease both the plaques and the tangles. The frustrating outcome, however, is that no matter what we do to the plaques or tangles, neurons continue to die and our cognitive decline continues downhill. So far, not a single AD trial has succeeded.

Many researchers have begun to think that the reason is that there is something that lies further "upstream", something that causes not only plaques and tangles, but all of the many other, perhaps less obvious pathological findings. They reason that if you only attack amyloid or only attack tau proteins, the "upstream" problem continues causing all of the other problems. If you only attack one part of the problem, such as amyloid, then the other problems continue, as does neuronal death and cognitive decline. Put differently, no matter what you do to amyloid alone, you haven't changed the overall disease process, so the cognitive decline continues. This is exactly what the human trials show: if all you do is attack one of the many problems, the result is futility and frustration.

The result is Alzheimer's.

Over the past decade or so, however, there has been a growing consensus that AD – and all of those various "upstream" problems such as plaques and tangles – are the result of changes in the glial cells and that aging itself (particularly cell aging) plays a key role. A growing consensus has begun to look not only at targeting the glial cells, but at targeting the way these cells age. This would be merely an interesting theory, except for two facts:

1) All of the data supports the role of the glial cells and
2) We are now capable of reversing glial cell aging in human patients.

Which is exactly what Telocyte is about to do.

Hello everyone,

I would first like to thank all Telocyte Associates who have supported and helped Michael and I throughout 2016. Your dedication and commitment has been an inspiration, as we pursue our goal of developing telomerase therapy to treat Alzheimer's Disease.

If you have read Michael's latest book, The Telomerase Revolution, you will have seen his description of the Parabolic Cliff. That parabola describes the trajectory of our health as we age, the initially flat curve tightens ever quicker as we progress in time and finally pass over the event horizon of this reality.

My core driving inspiration for Telocyte is Iris, my mother who sadly was diagnosed initially with vascular dementia and subsequently also Alzheimer's Disease in 2011. My family and I had the privilege of walking with her along her Parabolic Cliff as she bravely coped and battled with her dementia.

In those early years she asked me to look for a treatment or cure, her career as a nurse had given her a deep faith in science and medicine that sat well along aside her Christian beliefs. On the 23rd November, 2016 she sadly slipped over the edge of her cliff.

She had been delighted to know that Michael and I had teamed up and founded Telocyte. Global awareness of the disease called dementia has escalated rapidly during the 5 years of her illness. This is transforming the understanding of the socioeconomic impact of dementia on patients and their families and friends.

There are now more Dementia care and support organizations and charities becoming established, Also funds being raised and committed by governments for research into the causes and finding treatments. The problem for Iris and others like her is that all this well-meaning effort and focus assumes that treatments and cures are 20 years in the future. So we have a generation of people who created the 20th century for us now sliding over a precipice with no hope.

Humanity has been here before, facing plague, smallpox, polio and most recently Ebola. Our success against these diseases has derived from deep insights into their pathology and biology. It is the same for dementia and other diseases of age. The discovery of Telomerase and the subsequent laboratory research in the last century has lain dormant. Much as has happened in previous centuries when novel phenomena have been identified but not applied or have not been rediscovered until times of crisis change the dynamic and prevailing social agenda.

Telocyte has been founded to rapidly bring Telomerase Therapy to first clinical human trials for Alzheimer's Disease, working closely with our world class science collaborator CNIO and in compliance with FDA regulations.

This year we have made great progress with Amarex, our regulatory consultants, in detailing the program of work required by the FDA. We have also gained the support of key investors to take us through the required first phase of our program.

Telocyte is rapidly accelerating, our strategic objectives are clear:

• We will measure our success by curing patients.
• We will provide proven clinical interventions.
• We will abolish age related diseases

Michael and I are contrarians, swimming against a consensus view, but we have good reasons, good data, and a clear view of the real point of intervention in the cascade of pathology that is age-related disease.

Our focus is on the generation now suffering with Alzheimer's Disease, not 20 years away. We are looking forward to an exciting 2017 for us and for them!

Peter
2/3
Q4 2016
Michael Fossel, MD, PhD
What are we doing at Telocyte?

Our mission is simple: we intend to cure Alzheimer's disease.

As many of you know by now, we are confident that, given what we know about aging and disease, we can both prevent and cure Alzheimer's disease, demonstrating it in FDA trials within the next two years. This is an extraordinary goal, particularly given the uniform failure of every other FDA-tested intervention. All other pharmaceutical firms and biotechnology companies are hoping they can find a way to slow the course of the disease. Their fatalism leads them to hoping that they can diagnose Alzheimer's before it's even apparent clinically, hoping they can intervene "before the pathology occurs." None of them – not a one – believes that they can reverse the pathology.

Nevertheless, our aim is precisely that. We have good reasons – based on both theory and experimental data – to believe that Alzheimer's begins with agerelated changes in our glial cells, the cells that take care of our neurons. Moreover, we know that we can reverse those age-related changes, permitting glial cells to function normally and to take care of our neurons. Luckily, while some neural damage may be beyond repair, much of the damage that occurs in the neurons is reversible. We intend to do exactly that: reset glial cell function, reverse the damage in neurons, and reverse much of the cognitive decline seen in Alzheimer's disease.

In short, we intend to provide not Band-Aids, not symptomatic care, not an expensive drug that might provide a few more months in a nursing home, but a cure. We don't want people to learn how to "live with Alzheimer's", we want people to live without it.

Where are we going at Telocyte?

We need two things: investments and our FDA trials.

In order to do our FDA phase 1 human trial, we need to finish our animal study for the FDA. The animal study will take about 6 months; the human study will take another 6 months. To do both of these will take about five million dollars.

At the moment, we have a significant percentage of that already, and we are currently negotiating with several venture capital firms who like what we're trying to do. We expect to negotiate with them over the next few months, then move ahead with our work.

The first step, the animal study, is needed for the FDA to grant us permission to do the human study. They are mostly concerned not with efficacy, but with safety. Most of our animal protocol, therefore looks at side effects and complications, both in mice and in human cells in the laboratory. So far, we know that our therapy, if anything, makes the mice (and cells) healthier, but we have to demonstrate that in perhaps a hundred animals.

The second step, the initial human trial, generally aims at safety, but we expect to see clinical improvement, even in our small, initial trial. Showing such a result in an Alzheimer's trial would be unprecedented, but will allow us to move faster as we transition from the laboratory to the clinic. Our initial trial will be about a dozen patients. Oddly enough, while all other pharmaceutical firms and biotechnology companies enroll only patients with early Alzheimer's – not believing they can improve the disease and hoping they can slow it – we will be enrolling patients with moderate Alzheimer's.

There are two reasons for this. First, we can't very well improve a patient unless they already have significant problems to improve. You can't fix what isn't broken. Second, we want to be sure that everyone agrees that our patients initial have Alzheimer's. We know that if we show we can reverse the cognitive decline in patients who only started with minimal disease, most people "knowing" you can't cure Alzheimer's, will assume the diagnosis was wrong. In short, when we show people we can fix it, most people will assume it wasn't really broken. So we will treat patients that, without any possible doubt, have significant Alzheimer's.

With luck, our animal trials will begin in the next few months and our human trials a year later.

Thank you for joining us in our endeavor: we want to cure Alzheimer's dementia within the next 2-3 years. Our aim is to ensure that none of us ever have to "live with Alzheimer's". We would rather that all of us live without it. Now let's make it happen.