The biotechnology company PureTech are moving towards human clinical trials with a new therapy that may slow down the aging process and combat age-related disease. The company has licensed two new drug candidates, derivatives of the drug Rapamycin, from pharmaceutical giant Novartis. PureTech have recently announced a joint venture with Novartis called resTORbio and are moving to clinical trials of the new drugs later this year.
The aim of the first test phase is to see if the new drug can rejuvenate the immune system of aged people, a key reason why we lose the ability to resist diseases as we grow older. Novartis already successfully completed two Phase IIa studies, exploring the immune-enhancing potential of mTORC1 inhibitors in elderly patients. resTORbio plans to build on those findings and start a Phase IIb study, with the two licensed candidates later this year.
Excitingly, the firm has also said that it plans to extend the program to other age-related disorders in the future. “mTORC1 inhibitors could lead us to a new paradigm for treating several aging-related conditions,” said Chen Schor, a PureTech senior executive involved in the resTORbio program. “We have a robust clinical development plan for the first indication and plan to explore the program across multiple aging-related diseases.”
PureTech has set aside $15 million to invest in resTORbio, which will give it about a 58% stake in the new venture; it also has the option to invest another $10 million, which would take its holding in resTORbio to 67%. This is a serious amount of money and a sign that things are starting to change in the world of rejuvenation biotechnology.
It’s all about the mTORC1
Rapamycin is a well-known immunosuppressant and is a substance originally discovered in soil bacteria native to Rapa Nui in Easter Island. Rapamycin blocks the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, which regulates both intracellular and extracellular cell signaling and is a central regulator of nutrient sensing, protein synthesis, cell growth, cell proliferation, and cell survival. When mTORC1 signalling is blocked by rapamycin, it pushes the cells into a survival mode which causes them to live longer.
Rapamycin has been the focus of a number of studies due to its consistent ability to increase lifespan in other species including flies, worms, and rodents. Mice given rapamycin see an average increase of twenty-five percent to their maximum lifespan, which is very impressive indeed.
The key point about rapamycin is that these results are consistent and easy to reproduce, a very important thing in research. Numerous studies have shown rapamycin can influence lifespan and whilst there is currently a study underway in Seattle to see if it extends the lifespan of dogs, there have yet to be any studies in people.
Based on Rapamycin
The new drug is a variant of rapamycin, known as a rapalog, and is sold by Novartis under the brand name Afinitor, though it is more commonly known as Everolimus. The first step for resTORbio will be to use the drug to reverse immunosenescence, or what most people describe as the decline of the immune system.
As we age, the immune system becomes increasingly run down and unable to defend against pathogens, which eventually leads to age-related diseases. The decline of the immune system is a big reason why cancer risk soars from age sixty, for example – because there are fewer and fewer immune cells seeking out and destroying cancer cells.
The first human trials are focused on seeing if this age related decline can be reversed, and appear to include restoring populations of T cells whose levels decline in age.
Joe Bolen the PureTech Health CSO said “Consistent with our strategy of addressing the impairments of the brain, gut, and immune systems, targeting the mTORC1 pathway offers us a compelling opportunity to address conditions impacting these adaptive systems.” He further added “Impairment of adaptive and innate immune system robustness underlies age-associated immunosenescence. Inhibition of the mTORC1 pathway has proven to be effective in re-establishing T-cell composition and function, which in turn can revitalize immune homeostasis.”
The reason why anti-aging drugs are traditionally not developed
Historically, no drugs have been developed to target the aging processes; there are a number of reasons for this. Firstly, it is clinically very difficult to prove efficacy of life-extending drugs in humans, as relatively speaking we live for a very long time; it is easy to conduct tests in mice, rats, worms, and yeast, as they live far shorter lives.
Fortunately, the development of increasingly better biomarkers has started to improve this situation. Reasonable projections can be made for potential lifespan increases based on standard survival curves referenced against biological age. The way to solve this problem is to create comprehensive ways of measuring biological age and a number of companies are engaged in exactly that.
Secondly, the field of life extension has traditionally been viewed with extreme skepticism and was (and still is) haunted by quacks and snake oil salesmen hindering the legitimate researchers. It is hard for most people to tell the difference between a charlatan and a real researcher, so this leads many people to consider the entire field as quackery not to be taken seriously.
Thankfully, this has started to change in recent years, as more and more respected researchers have gotten involved and the results have started mounting up to support the idea. Groups like the SENS Research Foundation have existed for over a decade and have been advocating a repair approach to aging, and whilst it has been a slow uphill battle to change perceptions about aging, the tide is starting to turn in the face of ever more promising research.
Thirdly, current regulations mean aging cannot just be generally targeted, as it has various processes and none of them are officially accepted as a disease even though they lead to age-related pathology. This is the biggest problemm and whilst pressure to classify aging as a disease has increased in recent years, it will be some time before such things are potentially accepted. Solving this will be a long and hard slog to convince regulatory authorities combined with mountains of scientific evidence to support it.
Until then, companies are opting to get age-related therapies through the regulatory gauntlet by targeting the aging mechanisms but stating a particular disease condition. This is why resTORbio will focus on immunosenescence, as it is a well-documented phenomenon which can be easily measured to determine efficacy, and can be related to specific diseases.
Until the idea of preventative repair strategies directly targeting the aging processes becomes mainstream, companies will have to continue jumping through regulatory hoops in order to get these new drugs and therapies into practice.
Part of changing established ideas and creating that shift in paradigm is supporting fundamental and breakthrough research through grassroots fundraising. The more scientific evidence to support a repair approach to aging diseases, the sooner established ideas will change.
This is the power of a grassroots movement and what we do now could have huge impact in the years to come. We are hoping to play our part in this at LEAF using the Lifespan.io platform to fundraise for science and taking part in activism and education.
In closing, we are very pleased to hear the news that yet another large, well-funded company is getting involved in the science of longevity, and we can only hope that this encourages others to do the same.