Targeting Aging Comes Of Age

Posted October 11th, 2018 by Tom Hughes, in From The Trenches, Science & Medicine, Translational research

This blog is written by Tom Hughes, CEO of Navitor Pharma, as part of the From The Trenches feature of LifeSciVC.

We finally are beginning to understand the biological basis of aging and age-related diseases, making the discovery of new therapies actionable for the first time.

Aging and its underlying biological mechanisms are becoming recognized as a catalyst, if not THE central catalyst, for a wide range of poorly treated prevalent diseases.  A recent piece in The Guardian is a great example of how well-recognized this link is becoming, and the emergence of an anti-aging biotech community is described here.  The upshot is that this is a promising new area in science providing actionable insights with potential for tremendous impact on human healthspan.

I have been following the field of the biology of aging since the beginning of my career in science, more than thirty years, while working in targeted ways to find and advance new therapies in the areas of metabolic and cardiovascular disease. Recently, I became the CEO of a biotechnology company, Navitor Pharmaceuticals, that is squarely in this space and focused on leveraging new discoveries to target the activity of mTOR (mechanistic target of rapamycin).  In many ways, the progress in the field has reached a tipping point and has prompted me to reflect on the advancements, starting with this blog.

I’ll cover two topics here – the confluence of chronic conditions of aging that drive the majority of healthcare costs; and the reasons why you should pay attention now to the emergence of biotech companies in this space, particularly those targeting valid and compelling aging mechanisms.

Chronic conditions of aging are THE major cost drivers for healthcare

There are some shocking statistics to be found regarding the cost of chronic conditions affecting our healthcare system.  The multiple chronic conditions chartbook published in 2010 by the Agency for Healthcare Research and Quality at the Department of Health and Human Services is a short and fascinating read.  A few particularly sobering items from their chartbook:

  • 5% of all Americans have multiple chronic conditions.
  • Almost half of all people aged 45-64, and 80% of those 65 and over, have multiple chronic conditions.
  • 71 cents of every US healthcare dollar go to treating people with multiple chronic conditions.
  • People with multiple chronic conditions account for the majority of clinician visits, prescriptions, home health visits and inpatient stays.

Just take a moment to think about that.  First off, this is a huge portion of our healthcare budget.  It’s not cancer.  It’s not rare diseases.  It’s not cosmetic or elective procedures.  It’s chronic illnesses, primarily associated with aging.  Moving past the costs of care, think about the impact that these diseases have on quality of life.  People suffering from life-limiting and chronic diseases are stripped of productive years, miss out on life in so many ways, and otherwise live a life that is punctuated not so much by what they want to experience, but by visits to the doctor, diagnostic procedures, hospital stays, and years spent unhappily in assisted living facilities.

It’s not a surprise that the most prevalent causes of this confluence of diseases include hypertension, heart disease, dyslipidemia, obesity, diabetes, arthritis and mood disorders.  It’s no surprise that these conditions cluster.  For people living with arthritis, for example, 31% also are obese, 47% also have type 2 diabetes, and 49% also have heart disease.   Depression is a major and particularly concerning comorbidity of type 2 diabetes.  Cognitive impairment is a particularly vexing comorbidity of type 2 diabetes as well, as has recently been reported.  The list goes on, but the point is made – if you have one disorder that is commonly associated with aging, chances are you have another or will develop another one.  Basically, it’s tough to get old.  We all know that.  But, now science is leading us to harness some fundamental mechanisms of aging.

Two cornerstone mechanisms of aging are emerging

Two core aging mechanisms appear to have emerged as being accessible to new pharmacological intervention – the mechanistic target of rapamycin, or mTOR  and cellular senescence (which is wrapped up in mTOR as well).  A third – the benefits associated with metformin treatment – a very old, inexpensive, and very safe natural product with a somewhat mysterious mechanism of action, will be very challenging to optimize further, so I won’t dwell on it here.

Cellular senescence – controlled by mTOR but also directly targeted by emerging biopharmaceutical companies

Cellular senescence is a widely covered field of scientific discovery, and is being pursued as a domain for new drug development by several new companies including Unity Biotechnology, Senolytic Therapeutics, and Oisín Biotechnologies.  The thesis behind these companies is that, as we age, our cells increasingly enter a state of senescence in which they stop dividing and secrete inflammatory mediators that contribute to a wide range of disease processes.  Getting rid of these cells, in principle and in mice – leads to rejuvenation and avoidance of age-related deterioration in health.  Drug development approaches using cellular senescence are emerging in early drug development, and they are fascinating and worthy of attention.

mTOR is a common mediator of cellular decline, senescence, and chronic diseases of aging

The cell’s sensing of nutrients and growth factors is at the core of aging and associated diseases. mTORC1 (mechanistic target of rapamycin complex 1) is the primary sensor and integrator of the cell’s response to nutrient availability, and dysregulation of mTORC1 activation is seen at the core of many age-related diseases including diabetes, chronic kidney disease, and even severe genetic forms of aging including progeria.

Within the mTORC1 pathway, amino acids play a specific and critical signaling role, directing the cell either to make proteins and lipids, and to grow (when nutrient levels and growth factors are abundant, activating mTORC1), or to begin a well-controlled and systematic process of autophagy.  Autophagy is a basic housekeeping function of many cells, involving recycling of cellular components (during a scarcity of nutrients when mTORC1 is inactivated), through a process in which cellular proteins are broken down into basic building blocks, including amino acids, to maintain a flow of renewal and recycling materials for cell maintenance and function.  We need mTORC1 to grow in childhood, but mTORC1 becomes a key driver of aging once we reach adulthood by promoting senescence and by blocking the recycling of old proteins and other cell components that otherwise need to be cleaned out.

Humans today are almost always flooded with both nutrients and growth factors.  Typically, we are especially richly bathed in amino acids as a result of a very protein-rich food supply and abundant calories.  If you’re not intentionally eating a low protein diet, chances are mTORC1 activity in your body is floored, pedal to the metal, driving protein synthesis, leading to insulin resistance, weight gain, and an abundance of senescent cells.  Dietary protein is not your friend.  Sorry to put it that way, but that’s the short and true story.

Rapamycin: the mTOR drug and its effects on age-related diseases

The first and still the most consistent pharmacological agent to demonstrate lifespan extension in multiple species—including yeast, worms, flies, and mammals—is rapamycin, a natural product discovered nearly 30 years ago that targets the mTOR signaling pathway.

Rapamycin and various analogs (“rapalogs”) are approved and marketed for a variety of clinical applications, including antifungal, immunosuppression, anticancer; as an anti-proliferative agent in coronary stents; and for use in rare and severe diseases characterized by the genetic dysregulation of mTORC1. In addition to the approved clinical applications, rapamycin and several rapalogs have demonstrated significant efficacy in a range of preclinical models of chronic diseases, including metabolic diseases, neurodegeneration, autoimmune disease, age-related decline in immune function (i.e., immunosenescence), and mitochondrial disease. Many of these diseases can be classified as being directly associated with increasing age.

The effects of rapamycin on longevity and age-related diseases are similar to the impacts of dietary (or caloric) restriction, which include downregulation of mTORC1-mediated signaling at least in part because of reduced dietary protein intake in the setting of caloric restriction.

The benefits of rapamycin and rapalogs on aging and associated diseases are clear and the link to caloric restriction is compelling. Yet, broad clinical use of rapamycin and rapalogs has been limited because currently marketed drugs inhibit both mTORC1 and mTORC2. This lack of selectivity drives undesirable mTORC2-associated side effects with chronic treatment including metabolic dysfunction such as hyperlipemia and hyperglycemia, insulin resistance, immunosuppression, and others. The ability to selectively inhibit mTORC1 activation without affecting the activity or formation of the mTORC2 complex therefore opens important new therapeutic potential for aging-related diseases.

Diseases of aging are actionable – aging itself remains a challenge

Drug development needs to follow a recognizable path.  Indications need to be rational from a regulatory perspective.  Endpoints need to be valid and useful in clinical practice.  Physicians need to know how to identify patients likely to benefit from therapy and to gauge their progress. Payers need to understand the health economics and value created by new drugs.  This means we need to take a bite-sized approach to age-related diseases.  Fortunately, there is no shortage of opportunity.  In osteoarthritis there are clear and objective measures and unmet medical need.  The same applies to kidney disease, heart disease, diabetes and other chronic and prevalent conditions.  There are also a wide range of rare and serious medical conditions that should be responsive to treatments impacting the mechanisms that underlie aging.  Progeria is a very powerful example of a condition – driven in part through hyperactivation of mTORC1 – that has clear and unambiguous medical endpoints and a high need patient population.  There are many other examples, too numerous to mention.  So yes, aging pathway drugs are actionable.

Demonstrating a benefit on health outcomes in aging populations is another matter, and one that is best left to be established for approved drugs, perhaps even generic drugs.  A major effort is ongoing now with metformin – an inexpensive, safe, and well-established treatment for diabetes that shows promise.  It’s appropriate that it is being evaluated in a large population-based trial for outcomes.

Navitor and mTORC1

Let me share how Navitor’s drug development is aspiring to these principles as we discover new drugs for diseases of aging by targeting selective mTORC1 modulators.

In translational science, we are applying the new insights for selectively modulating mTORC1, born from David Sabatini’s decades of scientific leadership in mTOR and his laboratory at the Whitehead Institute. This separation of mTORC1 inhibition from mTORC2 has been sought by teams throughout the industry and is the focus of our drug discovery work.

In drug discovery strategies, our programs have identified chemical strategies both to reduce mTORC1 activity in diseases characterized by increased mTORC1 activity including age-related diseases, and to selectively increase its activity in settings of pathologically reduced mTORC1, such as major depressive disorder and cognitive impairment.

In therapeutic programs, our lead molecule is in the clinic for major depressive disorder, targeting an amino acid sensor, called sestrin, that we came to understand from Sabatini’s sensor discoveries.  mTORC1 responds robustly to our compound in the brain, with a very compelling chain of effects leading to increased synapse formation and improved behaviors in animal models.  By selectively activating mTORC1 in the brain we hope to overcome the effects of impaired protein synthesis capacity and energy utilization in people struggling with severe depression and cognitive impairment.

Our next program, now in the lead optimization phase, has identified a fascinating approach to robustly and selectively inhibit mTORC1 activity without effects on mTORC2, which opens the door for us to broadly explore the full range of effects of mTORC1 inhibition – without needing to restrict drug exposure, as is necessary with rapamycin and rapalogs, in order to preserve needed mTORC2 activity.  These compounds, which are based on a unique chemical modification of the macrocycle scaffold common to rapamycin and rapalogs, have unprecedented selectivity for mTORC1 and represent the kind of breakthrough that we believe offers a new trajectory for treating a wide range of age-related diseases and, potentially, take steps toward bending the cost curve in healthcare.

It’s an exciting time in the aging space.  Hopefully one that yields important new medications capable of reducing the personal, societal, and financial burdens of chronic diseases.





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