erasing aging, hand written word on blackboard being erased concept
Today we are witnessing a renaissance in aging research in the pharmaceutical and biotechnology industries. From the interactions and experience at Insilico Medicine, four out of the top ten pharmaceutical companies have prioritized aging research for early-stage drug discovery research looking at the problem from different angles. These range from DNA damage and DNA repair, to modulating cellular senescence, senofibrosis, mitochondrial dysfunction, and other biological processes implicated in aging. There is also a plethora of emerging biotechnology companies focused on drug discovery, drug repurposing, and drug development, which include Cambrian Biopharma, Insilico Medicine, Unity Biotechnology, and BioAge.
Many of these companies regularly present at the annual Aging Research and Drug Discovery (ARDD) conference organized by the University of Copenhagen and Columbia University, which was established in 2014 in Basel, Switzerland. The highlight of the 2014 conference were the presentations by Novartis Chairman Dr. Joerg Reinhardt and Dr. Joan Mannick, who presented the concept of targeting the pathways implicated in aging as a way to address not just one, but many diseases predominately affecting the elderly. That year Dr. Joan Mannick presented her results of a clinical study of Everolimus (RAD001), a close analogue of sirolimus (Rapamicin), a TOR pathway inhibitor, for vaccine potentiation in healthy elderly.
The first Aging Forum (now ARDD) at MipTec (now BaselLife), Basel, 2014. Front row: Charlie ... [+]
The following year she spun off a new company called resTORbio and took it public a year later. In 2019, the company announced the results of a Phase 3 clinical trial for another TOR inhibitor, RTB101 (BEZ235), in licensed from Novartis and very different from Rapamycin or RAD001. The clinical trial failed; however, since this was the first trial of this kind and biotechnology is the industry where failures are more common than successes, the ResTORbio story should be celebrated and studied very carefully for future clinical development in aging.
In 2010 when Dr. Mannick joined the New Indications Discovery Unit at Novartis, she wanted to dedicate her work to aging science. Inspired by the existing research – which was scarce at the time – she saw potential in clinical trials targeting aging in human biology. Naturally, there was resistance. Longevity didn’t fit well into the narrative driving biotech companies at the time. The field was underdeveloped and not thoroughly understood, and this called into question the priorities of those who wanted to pursue work in it. Few individuals follow the path of aging science. Fewer are able to create a company out of an idea. Dr. Mannick did both.
Today, Dr. Mannick is a leading mind in the field of aging science and medicine, and continues to expand its frontiers. She helms Research and Development at Life Biosciences and has published a number of papers on improving immune functions in the elderly, and the role of mTOR inhibitors in the biology of aging, to name a few. She has seen from the driver’s seat the journey that aging science has gone to establish its legitimacy, and she can attest that – much like her own parallel journey here – it has not been without difficulties.
In biomedicine, failure is common, and often the scientists who have lived through and learned from the failures in a difficult clinical trial are in higher demand than those who succeeded in a straightforward one. They did earn the black belt of courage.
I truly believe that now is the time to get into aging research. This field can result in a very rewarding and impactful career - both in the academia as well as well in the industry.
Today I decided to ask Dr. Mannick a few questions. I was joined by Dr. Evelyne Bischof, an assistant professor at Shanghai University of Medicine and Health Sciences. Dr. Bischof is a specialist in internal medicine with a research focus on oncology, preventative and precision medicine, and biogerontology.
Joan Mannick, MD - co-founder of ResTORbio, Head of Research and Development at Life Biosciences
Alex: Joan, thank you for agreeing to be interviewed by myself and Dr. Evelyn Bischof for the blog and for the 8th Aging Research & Drug Discovery conference. It would be great if you can start with a short introduction and tell us about yourself and how you got into longevity.
Dr. Joan Mannick: Thank you so much, Alex. It’s great to promote women in the longevity space. I started my career in academic medicine. I trained in infectious disease and ran a basic science lab that studied the regulation of cell signaling. While in my lab, I came across papers by Cynthia Kenyon in which she pointed out that organisms have the potential to live much longer than they normally do because single gene mutations could result in remarkable extension of lifespan. I love things that challenge conventional thinking!
I got really intrigued by aging science and did some preliminary work studying longevity in fruit flies. I eventually ended up at Novartis in a division called New Indications Discovery Unit. The purpose of this unit was to find areas of drug development that didn’t fit into traditional big pharma silos. I proposed working on aging because it fit the mandate of falling outside of pharma silos. Fortunately the CEO of Novartis at the time, Dan Vasella, and the Head of Research, Mark Fishman, also decided that the field of aging science had gotten to a point where it could be translated to humans. So I was given the green light to move forward in this new space.
Alex: That is incredible. So, you basically went into aging very early. At Novartis, you were responsible for the program that later got spun out and was commercialized as resTORbio. It takes a lot of courage to spin off a company out of big pharma. Can you tell us about this process and how it came to be?
Dr. Joan Mannick: When I was given a mandate to do a clinical trial in aging, I decided to start by targeting mTOR because mTOR inhibition is one of the best validated mechanisms that regulates aging in preclinical species. I wanted to see whether there was benefit of inhibiting mTOR in older humans. There was fear about doing this at the time because people thought mTOR inhibitors were too dangerous to use to treat aging in humans. So we designed a trial where we used either very low doses or intermittent doses of mTOR inhibitors that were predicted to be safe. We then had to pick an endpoint for the trial to assess whether mTOR inhibitors improved something about aging in humans. We decided to study whether imTOR inhibitors improved immune function in older adults because we thought the aging immune system was something we could modify in a relatively short period of time. Results of 2 clinical trials showed that very low daily doses or intermittent doses of mTOR inhibitors improved immune function in older adults as assessed by response to influenza vaccination. In addition, older adults treated with mTOR inhibitors had fewer infections.
After the second trial, Novartis decided to spin this program out into its own separate company called resTORbio in part because it did not fit into any particular late stage franchise at Novartis.
Alex: That is very cool! How long did it take you to do that once the decision was made to turn the program into a new company?
Dr. Joan Mannick: It was difficult to spin out the company because it is a challenge to get alignment of the many levels of decision makers in a big organization. You need perseverance and it helps to have an internal champion.
Alex: But how long did it take to spin off the program and turn it into a company?
Dr. Joan Mannick: It took about a year to spin-out the asset.
Alex: Can you tell us a little bit about how you started building resTORbio? What were the first things that you did? And what things did you do wrong or right when you started building it?
Dr. Joan Mannick: We started the company with just two people; a CEO and myself. We had an asset that had already been through Phase 2 trials, so we were ready for Phase 2b trials. We raised the Series A for the company around April 2017 and in May started a 650-patient Phase 2b trial with just 3-4 people in the company. About nine months later in January 2018, we took the company public. So we just sprinted and hired external CROs to help with the work. I think it just goes to show that you don’t need a lot of people in a start-up, you just need hard workers.
Alex: That is super cool. And of course, it ended up in a Phase 3 failure. Can you describe what could have been done better and what went wrong?
Dr. Joan Mannick: In the Phase 2b trial, mTOR inhibition with RTB101 decreased the incidence of laboratory-confirmed respiratory tract infections in older adults, the FDA-specified primary endpoint. However the FDA requested a change of the primary endpoint from the Phase 2b to the Phase 3 trial because they wanted the phase 3 endpoint to reflect how people feel and function. They decided that laboratory-confirmation of an infection was not relevant to how people feel and function. So the FDA requested that the Phase 3 trial endpoint be changed to the incidence of respiratory symptoms irrespective of whether they were due to a laboratory-confirmed infections and the trial failed to meet that endpoint.
I think a mistake we made was not slowing down and repeating a phase 2b trial with the new endpoint rather than moving right into a phase 3 trial. The probability of success of a trial decreases if the primary endpoint is changed from a previously successful trial. In the end, making sure you have the right endpoint to maximize the probability of success of a trial is more important than speed.
Alex: Got it. And did you use any aging bio markers in the study? And if not, why not?
Dr. Joan Mannick: We looked at interferon-induced antiviral gene expression because we had seen that these genes were upregulated in older adults treated with mTOR inhibitors in previous trials. Consistent with the previous trials, type 1 interferon-induced gene expression was significantly upregulated in the whole blood of older adults treated with RTB101 in the Phase 3 trial. This was really interesting because type 1 interferon-induced antiviral responses are a part of the immune system that has been shown to decline in older adults. The type 1 interferon response is also a part of the immune system that plays a critical role in fighting Covid-19 and other respiratory tract infections. So this biomarker may be key to understanding why in multiple clinical trials older adults treated with an mTOR inhibitor have a decrease in the incidence of laboratory-confirmed viral respiratory tract infections. In future trials it might be useful to determine if the benefit of RTB101 is greatest in older adults who have a confirmed deficiency in type 1 interferon-induced antiviral responses at baseline. .
Alex: Got it, thank you. You recently switched gears from resTORbio. Can you tell us a little bit about that?
Dr. Joan Mannick: After the failed Phase 3 trail resTORbio decided to merge with a very promising CAR-T cell company. Since I love aging biology, I decided to move to Life Biosciences as Head of Research and Development. I think Life Biosciences has in-licensed the most exciting science of any company in the aging space.
Alex: That is very cool. Can you tell us about your current role in Life Biosciences?
Dr. Joan Mannick: The company has three platforms targeting aging biology. The first is a small molecule program targeting mitochondria uncoupling which increases the rate at which calories are burned. This has many benefits for obesity related diseases, including NASH. The second is a chaperone-mediated autophagy program spun out of Ana Maria Cuervo’s lab. She recently published really exciting data in Nature and Cell demonstrating that our tool compounds that activate chaperone mediated autophagy rejuvenate the function of aging hematopoietic stem cells and improve neurologic function in models of Alzheimer’s disease. The third platform is an epigenetic reprogramming platform spun out of David Sinclair’s lab. David published a great paper in Nature late last year showing that in mice Yamanaka gene therapy can safety reprogram the epigenome of the retina and restore vision in a mouse model of glaucoma.
Alex: Very, very cool. Dr. Bischof, would you like to ask a couple of questions?
Dr. Evelyne Bischof: Joan, it’s such a pleasure to connect with you. My first question is, was it difficult for you to decide not to pursue the clinical path? Or was it something natural?
Dr. Joan Mannick: Most of my family has had careers in academic medicine. So for 30 years I followed the family path and had a career as a physician/scientist in academic medicine. However when I turned fifty, I started to question whether I wanted to spend the rest of my life in the same career. My father gave me excellent advice and pointed out that age fifty might be one of the last times that I would have the opportunity to try a new career.At the time, I was getting recruited by some biotech companies. I had friends who had left academic medicine for pharma and who loved their new careers. So, I took a leap of faith and took a job in biotech although I actually kept my academic lab for a year in case I didn’t like biotech and wanted to go back to academics.
It turns out I loved biotech. Although academics give biotech and pharma a bad rap, biotech is much more team-oriented than academia and the end goal of the team is to develop drugs that are safe and efficacious and help people. As a physician, I particularly liked that goal.
Dr. Evelyne Bischof: That’s really awesome and inspiring! My next question is, what is your advice to clinicians, academic and practicing physicians who are not familiar with the longevity fields (that are still mostly outside of academia and the hospital)? How can they learn more about the field?
Dr. Joan Mannick: Aging is a cutting-edge field because we now understand that aging is a biology that can be targeted therapeutically and is the biggest risk factor for almost every disease. The most exciting part is that we are now ready to translate this ground-breaking science to humans and this may transform the practice of medicine.
Dr. Evelyne Bischof: I was also wondering about two things. Firstly, did you experience any hurdles over the years on your path because you are female? And secondly, how did you battle them, and what is your message to those people who are your fans and look up to you?
Dr. Joan Mannick: I’d say it’s key for women to have good mentors. I have had some phenomenal mentors but also had one bad mentor who was very unsupportive of women in the lab, particularly working mothers. My mistake, I think, was I spent too much time trying to prove that I was worthy of his support. My advice is to jump ship quickly once you realize that you have an unsupportive mentor. It’s not worth trying to prove yourself to someone like that. When you find a good mentor, stick with him or her because a good mentor and working environment makes your life and career so much more enjoyable.
Dr. Evelyne Bischof: Thank you so much!
Alex: Thank you, Evelyne, and thank you, Joan. Now let’s switch gears to another exciting topic, mTOR inhibitors. I am deeply passionate about the TOR pathway. You’ve written about this pathway for a long while from different angles. What do you think about the potential of TOR inhibitors in aging? What should we expect in the next few years?
Dr. Joan Mannick: This is my favourite pathway. It’s the best validated pathway that regulates aging. I think there’s a huge amount of work to be done to study the benefit of both rapalogs and mTOR kinase inhibitors in aging related conditions. Different mTOR inhibitors are going to have different advantages and disadvantages that may make them more appropriate for some aging related conditions than others. For instance mTOR inhibitors that cross the blood brain barrier are likely to have the greatest benefit for neurodegenerative diseases whereas mTOR inhibitors that have good exposure in muscle may have the greatest benefit for sarcopenia.
Alex: Very interesting. And staying on this topic, so mucositis seems to be the most frequent side effect of raplogs, and specifically Rapamycin. Do you know what percentage of the patients get it, for rapamycin and Everolimus?
Dr. Joan Mannick: I can only talk about our experience with the rapalog everolimus, which is very similar to rapamycin. The incidence of mucositis even with very low doses of everolimus is quite variable and seems to dependent in part on underlying patient characteristics that we don’t fully understand.
Alex: We don’t understand why it happens, right?
Dr. Joan Mannick: Correct. It is possible that some subjects have an epigenetic or genetic predisposition to getting mucositis. There is not always a clear relationship to the dose of everolimus and the incidence of mucositis.
Alex: That’s very interesting. I know a few people who take rapamycin from time to time let’s say, 5mg a week. It looks like for some of them who have been doing this for a while, they get on rapamycin and a week later, they get mucositis and it stays with them for a while and then it goes away. Sometimes,
the same patient will go on rapamycin three months later, after two a month break, and they would not get mucositis.
Dr. Joan Mannick: Yes rapalog-induced mucositis can spontaneously resolve with continued dosing or after a dose interruption.
Alex: So, it doesn’t look like a genetic factor then.
Dr. Joan Mannick: Unless there are compensatory pathways that get up-regulated.
Alex: For other drugs, for example, if people take rapamycin plus metformin, have you seen any evidence that it might reduce the incidence of side effects?
Dr. Joan Mannick: It is an interesting question but we haven’t had enough subjects who took both metformin and everolimus in our trials to be powered to see a treatment effect or safety benefit.
Alex: Got it. It would be great to find some of the listeners or readers who decide to go into this field and try to link the mucositis to something. The genetic evidence or maybe just sheer luck, or maybe the presence of some bacteria, or maybe some lifestyle modification that can be made.
Dr. Joan Mannick: I think the role of the microbiome in the pathogenesis of mucositis is an interesting question that would be worth exploring.
Alex: It does seem like it could be that. And maybe mouthwash could help all the bacteria would go away. At Insilico, I’m collaborating with many pharmaceutical companies, and I would say four out of the top twenty are very strongly committed to aging research, besides Novartis. So, if you were to pinpoint some of the pharmaceutical companies that are more committed to aging research than the others, which ones would you pinpoint?
Dr. Joan Mannick: I don’t know the research priorities of pharma companies other than Novartis and AbbVie who is collaborating with Calico. So, I wouldn’t be able to pinpoint other companies who are moroe committed to aging research.
Alex: It looks like many companies decided to go into this field through senolytics, because senolytics are a hot area. Several start-ups in this field, as well as and many academics, are working in this area. What do you think about this field in general?
Dr. Joan Mannick: I think senolytics are great. I think there are so many ways to tackle aging biology that are valid and are going to have benefit. And each of these targets are probably going to have greater benefit in some people than others and some diseases more than others, and I’m cheering everybody on.
Alex: Great. And finally, what other longevity physicians so to speak, so females with M.D. degrees who are working in longevity, would you be able name? For the follow-up interviews.
Dr. Joan Mannick: Ana Maria Cuervo comes to mind who is an MD doing great aging research and a member of the National Academy of Sciences. There are also some great female geriatricians who are working on translating aging biology to the clinic including Anne Newman at University of Pittsburgh.
Alex: Thank you. That’s what we need. That’s why we started this series, to promote M.D.’s going into longevity. So, for anybody who is going to be exposed to this content, please do consider that pathway, because it’s very scarce. You are going to be a very rare professional.
Alex: Thank you, Joan. I’m very happy to have you as part of the Aging Research & Drug Development longevity medicine workshop. That’s the workshop dedicated specifically to doctors who are interested in longevity medicine; either practicing clinicians or people who are going into clinical trials, so we’ll have the best of both worlds represented. Thank you for being with us today.
Longevity Medicine Workshop at the 8th ARDD conference organized by the University of Copenhagen and ... [+]
The 8th Aging Research and Drug Discovery conference organized by the University of Copenhagen and Columbia University is rapidly approaching and, for the first time, it will feature a workshop on the emerging discipline – Longevity Medicine, and one of the key speakers at the workshop is Dr. Joan Mannick joining her colleagues from Life Biosciences, Dr. David Sinclair and Dr. Nir Barzilai.
