Part of our coverage of the 2019 Longevity Therapeutics summit. An index of all articles about the event appears here.
TAMEing aging (Nir Barzilai, Professor & Director, Institute for Aging Research, Albert Einstein College of Medicine)
Longer-lived people stay healthier for longer (i.e., they are younger when they contract their first disease of aging), and they tend to die fairly rapidly rather than after protracted illness. This gives us the concept of the longevity dividend, the idea that extending longevity will return a huge amount of money to the (non-healthcare) economy.
How do we best translate our advances in understanding aging to humans? At FDA and regulatory bodies around the world, aging per se is not considered a disease. Barzilai doesn’t want to classify aging as a disease, but does want regulatory bodies to acknowledge one or more related indications with which companies involved in longevity therapeutics can engage on the same footing as other kinds of drug developers.
We have known for many years that metformin, a first-line treatment for type II diabetes that has been used for 60 years, extends lifespan in model animals. It also decreases mortality in humans and attenuates the biological hallmarks of aging. (Because the hallmarks are all related, an effect on a few ends up yielding benefits in the others, and there is at least an argument to be made that metformin impacts them all.) Beyond mortality, metformin has substantial effects on healthspan (effect size of ~30%): it delays type 2 diabetes and decreases the risk of specific types of cancer.
Based on these findings, Barzilai has proposed the Targeting Aging with Metformin (TAME) study, which in tends to show that a composite of age-related diseases can be prevented by metformin. In order to overcome the regulatory barrier described above, he must obtain a new indication for the delay of age-related morbidities. To this end, he and other scientists met with the FDA and argued that if they were able to show a decrease in the rate of onset of multiple age-related disease, it should be acceptable as an indication for clinical trial. The FDA was receptive.
In terms of specific design, the study would recruit people age 65–80 that were either frail (reflected by a gait speed of 0.4–1 m/sec) or had an age-related disease (VCD, cancer, mild cognitive impairment [MCI]). The clinical endpoint is time to incidence of any major age-related disease: MI, stroke, cancer, CHF, MCI/dementia, or death; the functional endpoint is time to incidence of time to disability, and the biological endpoins are changes in metformin levels and biomarkers of age and age-related disabilities.
To follow 3000 subjects, the total cost will be $40 million. AFAR is securing the funds, and TAME will begin in the next few months. Additional funds are being provided by private donors, including Juvenescence
Innovating R&D for Ageing: A Systematic, Comprehensive & Innovative Approach to The Development of Therapies for Ageing (Sree Kant, Head of Business Development, Life Biosciences)
Life Biosciences is a biotech company devoted to slowing and/or reversing age-related decline. Because fo the unique challenges of the field, conventional paradigms of funding and business development may not work. Pharma has a long time horizon but is risk averse. Moreover, pharma is reactive vs. proactive and has a quarterly perspective. On the other hand, VC has a short horizon and makes smaller investments, but is much more risk tolerant.
So, how do we finance research and development in longevity? What we need is an entity that can think long-term, like a big pharma company, but is able to make somewhat risky investments in a coherent way that allow us to target aging as a single phenomenon. This is the premise of Life Biosciences.
Founded in 2017, Life Biosciences as built a portfolio of patient-centric companies that target all eight components of aging. Thus, LB is targeting all age-related diseases simultaneously, and in the process changing the definition of what aging means. They are committed to making their biomedical breakthroughs accessible and affordable to all, regardless of age or background.
In this unique business model, LB stays at the center of two cycles: in one, emerging scientists create breakthrough science, which generates intellectual property that leads to future innovation. Meanwhile, LB invests in newcos that populate and advance leads through a drug pipeline, resulting in mindset shifts that attract further investment. The fully integrated ecosystem resulting from these connections centralizes resources to maximize efficiencies, whereas the decentralization of daughter companies ensure nimble R&D.
TORC1 Inhibition as an Immunotherapy to Decrease Respiratory Tract Infections in the Elderly (Joan Mannick, CMO, resTORbio)
Multiple biologic processes underlie aging. As the name might imply, resTORbio is developing a potential new class of medicine targeting a protein complex called TORC1. They selected this target becaust here is a great deal of validation evidence in model organisms that inhibiting TORC1 extends lifespan.
TORC1 is an evolutionarily conserved protein complx that regulates aging. In mice, TORC1 inhibitors extend lifespan in mice, even when started late in life and given intermittently.
What explain these effects? TORC1 is one of the main nutrient systems in our cells, and it may become dysregulated and overactive in some aging tissues. Consequently, inhibiting the pathway can improve the function of multiple organs, including the brain, heart, and immune system. resTORbio decided to target the immune system because reversal of aging-related immune dysregulation has the potential to exert beneficial effects throughout the body.
However, mTOR is a component of two complexes, TORC1 and TORC2. Inhibition of TORC1 has all the lifespan extension benefits, whereas inhibition of TORC2 has negative effects. Therefore, resTORbio is focusing on agents that specifically block TORC1 function while leaving TORC2 alone.
Their lead drug candidate, RTB101, improves immune function in elderly people, as evidenced by their improved response to a flu vaccine. mRNA expression profiling revealed that this effect may be mediated by upregulation of a subset of interferon-relate genes involved in the response to viruses. Viral pnemonia is the fourth most common cause of hospitalization among the elderly in the US.
A subsequent phase IIB study revealed that once-daily dosing of RTB110 (intermittently, rather than constantly) was best for preventing respiratory illness. This effect persisted for weeks after the dosing interval.
In questions, Dr. Mannick pointed out that although they are not 100% sure of the target cell in the body, the company’s functional assays suggest that a direct effect on immune cells (rather than a systemic effect) is involved.
Addressing the Challenges of the Aging Population - Taking a Holistic View (Samuel Agus, CMO, Biophytis)
Biophytis is a French company currently advancing two drug candidates into Phase II trials: Sarconeos, a MAS activator, which will be tested in sarcopenia (a key aspect of frailty) and Duchenne muscular dystrophy; and Macuneos, a PPAR activator, which will be tested against dry AMD and Stargardt disease.
The company’s raison d’etre is identification of small molecules that stimulate resilience to stress, selected by reverse pharmacology from a collection of plant secondary metabolites. Thus far, they have found several molecules that slow down the degenerative processes related to aging.
We can look at frailty in several ways: as a nosological entity with distinct pathophysiology; as a syndrome with identified signs and symptoms; as a disease state, indicating the level of severaity and loss of function; and a predictor of outcomes, representing the degree of loss of resilience.
With this in mind, Agus argued that we need to rethink clinical trials, and ask what it is that we are intending to do: Does a drug improve the condition, mitigate a “tipping point” in the disease, or something else? In thinking about these questions, observational data can be used to inform interventional trial design.
Clinical Evaluation & Regulatory Considerations in the Approval of Biopharmaceuticals for Health-Span Indications (Brian Huber, Chief Operations & Scientific Officer, Carolina Longevity Institute LLC [CLI])
Huber described three levels of clinical and regulatory considerations in longevity therapeutics:
treatments of specific diseases associated with aging by targeting the disease process;
those that target the fundamental aging process as the major risk factor; and
those that target the aging process in order to delay it
Maximal lifespan is determined by species-specific genetics, but it may be malleable under the influence of interventions such as caloric restriction or pharmaceuticals targeting various aspects of the aging process.
A dilemma: How do we increase average lifespan and decrease premature death while increasing healthy aging (or healthspan)? If we can do this, it should decrease healthcare cost. However, historical data don’t bear this out: instead, a decrease in mortality tends to increase morbidity (and costs). In the early 1900s, pneumonia was considered the “old man’s friend” because it killed otherwise health people relatively quickly without an extended period of morbidity. Since that time, however, we have extended lifespan at the cost of increasing morbidity: We spend a lot of time in declining health, with correspondingly exploding healthcare costs.
Huber wonders whether sometime later in this century, we will have returned to a situation when most of the lifespan will be synonymous with healthspan, and death will come quickly at the end of the maximum lifespan without extended morbidity.