Fight Aging!

Investing in the Age of Longevity was an event held in London earlier this year as a part of the Longevity Week, a chance for Jim Mellon and the rest of the Juvenescence team to present their thesis on the longevity industry to the investor community - that this is an enormous opportunity to both greatly improve the human condition and generate returns on investment. A number of companies were there to present, as examples of the work on slowing and reversing aging presently taking place, and I was graciously invited to discuss the latest developments at Repair Biotechnologies. The presentations from the event have been posted to YouTube, mine among them.

Today I thought I'd focus on Declan Doogan's talk, which you may find interesting for the points on which he chose to focus. Doogan is the Chief Medical Officer of Juvenescence, a position responsible for guiding the clinical development of therapies as they move through the IND process with the FDA and analogous regulators in other parts of the world. Realistically, it is also a position responsible for taking preclinical development companies and shaping them into clinical development companies. These two phases of development are very different from one another, as different as work in a company is from the academic work that preceded it, and require quite the distinct mindset and set of talents to be successful.

Declan Doogan | Investing in the Age of Longevity 2019

Good afternoon, everybody. I'm pleased to be here. I'm a cofounder of Juvenescence, along with Jim Mellon and Greg Bailey. Those two are the ones who put the company together and are raising all of the capital. I'm the one who spends it. We are ambitious: we can have a meaningful impact on health in the context of longevity. As you heard this morning, aging is a disease, and we want to embark on investigating the mechanisms in longevity, learning from what is going on around us, but also looking to solutions - because we're a drug development company. We're raising capital, we've done quite well so far, thanks to Jim and Greg, and thanks to some of the investors in this room. We want to get on with the job.

Now, I'm a physician. I qualified a long time ago, and looking around the room I could be the oldest person here - which is scary. But I'm involved in this because I think it is a huge medical and societal need. What was really of concern to me was when I saw the statistics. Of course we've done well, we're living longer, 30 years longer than a century ago, and that was usually due to public health measures and control of infectious disease, and so on. But longevity is becoming a huge issue because of the number of people living longer. A 60 year old male, if he is doing everything right, can get 13 years more life expectancy than non-healthy people. But we have 10 or 11 years of unhealth at the end of life, which I call disability in this slide. In the US it is about 11.5 years. In the UK and Japan, as you can see here, 10.8 years. As noted this morning, 25% of Medicare costs occur in the last year of life.

So you can see the opportunity here for the research, development, and medical communities do a lot of good. We have done good in terms of managing cardiovascular disease up to now, to a point. But hypertension causes 45% of all cardiovascular deaths, and it is rising. 80% of the elderly have hypertension, and screening is still not good enough, especially outside the US and Europe. We have the drugs: thiazide and ACE inhibitors are particularly good for reducing not just blood pressure, but cardiovascular events and associated mortality. As you know the statins have done pretty well in terms of managing cholesterol and cardiovascular events and mortality.

Now I put up this next slide not to blow a trumpet or anything, but to say that I am a product of two things. Firstly, I went to medical school to learn how to detect and manage disease. Secondly, I entered the drug industry in the small molecule era where we blocked receptors and enzymes because it translated into disease constructs that we could measure. You could drop blood pressure, you could cure bacterial infection, you could treat erectile dysfunction, and also decrease blood cholesterol. So that was terrific at the time, but you also heard this morning about the rise of molecular biology, monoclonal antibodies, and now gene therapy. Where I was is now old school, but it did good, and it is still needed. I've done some other things in terms of small molecules and fatty acids, and the last one is Juvenescence. This is the one thing that will probably be my last hurrah, so to speak, but I'm going to hand off to our wonderful team of young people who are going to take the baton and run with this. They will deliver some of the medicines that we hope we can develop in the not so distant future.

So the first thing I asked myself is this: really, can aging be reversed? I've listened to Aubrey de Grey for a long time, and I'm now persuaded of that. I am also persuaded that aging is a construct that we all, as physicians and drug developers and whomever, should be passionate about fixing. I mean unhealthy aging. There are all these kinds of interventions and technologies that we can access, some of which will be extraordinary, and look like moonshots, while others will be more incremental. As was said this morning, there are other technologies that we need to be participant in: diagnostics, devices, apps, measurement of health management efficiency, and also we need to change our incentives.

In the American healthcare system, where I live, we are activity-based in terms of incentives. We get rewarded for identifying and treating disease. We do not get rewarded for identifying healthy people and keeping them healthy. So we have to change those incentives. Someone might say "where's the money for a drug company in keeping people healthy rather than treating disease?" But we have to migrate to that new model.

There are drugs in development that have been mentioned this morning. I think Reason mentioned the senolytic dasatinib, that has been used and has impact on longevity. A paper from Intervene Immune described the use of growth hormone, DHEA, metformin, and vitamin D to actually increase longevity. And you might say "how do you do that" - well you measure it by the aging clock, the Horvath epigenetic clock. Then Unity Biotechnology is developing a senolytic for osteoarthritis and pulmonary fibrosis. resTORbio is developing a rapalog for the treatment of immunosenescence; our immune system declines in its efficiency as we get older, manifesting in other diseases coming through. What they've done was a very clever thing, they looked at the uptake of flu vaccine in an elderly cohort, there is an antigen response, and showed that it protected more than in the control group in terms of susceptibility to disease. Samumed, working on the Wnt pathway, treating osteoarthritis of the knee. Then we have MitoQ, nicotinamide riboside, and cell therapy with Mike West's AgeX Therapeutics.

But in order to get there, we don't just say "hey, we've got a disease modifier." Or an age-modifier. We actually access it through disease constructs, as Nir Barzilai has for the TAME metformin trial. These are the sorts of areas where I think I can help design programs with the new technologies and measure impact in a biomarker-enabled way. Then we have that dialog with the FDA, and Europeans, and other agencies, to at least get them to buy into the idea that you are doing something that might improve the prospects for patients, that can manifest in a longer but healthier life. My view is that if you can compress that time of disability from even 11 to 10 years, the benefits to society will be massive.

What we're trying to do at Juvenescence is develop these treatments for both prevention and reversal. I wasn't sure that was going to be possible, until I saw some of the preclinical basic data. We really want to build a thriving company; we have a great group of young people - and young to me is something less than 40 - who are embarking on search and diligence, and we've got an emergent drug development team who are expert and experienced in developing drugs in the conventional pharma model. So we know how to deal with regulators and dialog with them, because we've had plenty of experience of what I'll not call misunderstandings, but miscommunication and misalignment of expectations. What we hope to do is to participate with other companies in moving the agenda forward such that the regulators are understanding that we're all trying to do something of merit, and they have got to work with us to regulate in a practicable way.

In the next slide, I think Laura Deming showed the left picture, of middle-aged mice, on how altering the genome can lead to a longer healthy life span and a change in the phenotype of the patient. This on the right is another set of mouse pictures, and this is from a company that we've invested in that actually interacts with the FOXO4-p53 system. And you look, that is an aged mouse, and the treatment perturbed that FOXO4-p53 system, and you do get rejuvenation. So maybe there is one clue to what we might be able to do in humans, and we're developing drugs in that space. I would hope to see that there is at least a modicum of translation from these animal models. Some animal models will not translate, and we'll learn with the passage of time. But these are the experiments that we'll have to do, and we'll learn from one another.

There is another company that we have, Lygenesis, which is probably the most advanced in terms of bringing something to the clinic. This is organ regeneration, a wonderful little company from Pittsburgh. They actually take hepatocytes and inject them into the abdominal lymph nodes. The hepatocytes are engineered and they grow ectopic livers. This has been shown in dogs: it does actually work, and we're preparing to go into the clinic in humans. Why are we doing that? First of all, the number of liver transplants in a year in the US is now about 8,000 and it is about to grow dramatically because of the increased incidence of nonalcoholic steatohepatitis and cirrhosis, and so on. Each transplant costs $700,000. If you multiply that by 8,000, and going up, you have a big price tag that you've got to pay for healthcare. If Lygenesis could mitigate some of those transplants, you will have a benefit that is quite easy to understand. We were showing that this is a company that is barreling along the road to the clinic, and I have to say that they are a fantastic team of people.

Now, just in finishing up, I want to say that we are a drug development company. We have capital, and Jim and Greg are raising more. We see great opportunities. We are, I won't call it agnostic, but we have a very broad purview over technologies that might actually bear fruit. We have a very good search and diligence team, who set a high bar. We don't just take in anything. We have an ecosystem of longevity experts and drug development experts we can bring to bear. When there is a company that we acquire or a technology we acquire, we fill the gaps. So although we've got the capital to invest, we are principally a drug development company.

The other point I mean is that when I was talking about health, in the future we are not talking about patients. I believe that we should be talking about pre-patients. All of you here who don't have a disease, and you want not to get it, there should be some strategy that you adopt for yourselves, and indeed for your family. When do you start? Now is a good time to start managing the parameters that you know predict for ill health. We go to our annual physician checkup - in this country I've been to many of them, and they are not all that good. I think that we really need to up our game in screening. To have broader biomarkers that we actually incorporate into our annual health screening, and which should be personalized. Our genetics are different, so our propensities are different. So a degree of personalized prevention I think is where we should be headed as well, to manage these growing healthcare costs.

Finally, in our company, we are ambitious, we think we can do it. We've got a lot of companies under our purview now, and we're going to acquire more. We'll need more capital and eventually we'll IPO. Thank you very much.