Q&A

Will individual diseases be tracked in TAME or mainly the composite endpoint of time to disease?

• Individual diseases will be tracked and announced, but when we’re looking at an FDA indication, the composite outcome is really important. It is what we know and think about as aging – this larger kind of phenotype that can’t be defined as any one disease or any one marker. And so I think for a typical first trial, like TAME, its goal is to look at this sort of larger and collective endpoint, so that we can begin to define what this should be in the future. That is incredibly important. And to also make that data available for a larger community to use and develop.

What is the ideal dose of Metformin? What did you decide to use in TAME?

• We decided to use 1500 milligrams for the TAME study. The argument on one hand was that it is for aging, therefore maybe we should use more. And then the argument on the other hand was that those are elderly people, maybe you should use less. So we don’t really know, there was no dose response. So we decided to use the dose that was used by most of the clinical studies – 1500 milligrams, that’s what has led us to this decision.

I want my question to sort of look beyond TAME. If it fails, we all get disappointed, what are the prospects for the next better candidate treatment and getting another trial going on with it? And can we even get a second TAME style trial going before the full TAME trial has finished?

• Personally, I’m an optimist. When people have said that we need a six year trial, I felt that four years would be enough. I don’t have any expectation that TAME is not going to work. But I also just presented the fact that if we had enough money, we should do more than TAME study, we should do some other drugs and maybe another TAME all over the world, because we cannot fail in this study. That’s part of the reason why we chose Metformin, we cannot fail in this study. So I don’t know what to tell you. You know, there’s this story of the two frogs that fell into a bucket of milk. And one of them was trying to figure out what’s going on and drowned. And the other one starts rushing around and moving its arms and everything like that. And in the morning, the farmer came and saw a very tired frog sitting on a bucket of butter. I’m very tired, sitting on the bucket with butter. TAME should have happened a long time ago. But I don’t think it’s going to fail. So I cannot bring myself to tell you what if we need something to succeed. It’s like Unity, failing with one of their senolytic – it doesn’t mean the senescence is not a target, it means that we need a better drug, better approach, better indication.

So then the optimistic question is, are you going to work during these six years on starting a new TAME with a different treatment in parallel while shepherding TAME through?

• Well, I’m trying to convince the new large foundations that are coming in to do several efforts. And I think that will modulate the risk. In particular, I think we’ll get a lot of biomarkers from TAME, but some of the biomarkers might be Metformin specific. So even for this reason, we need some other biomarkers.

Are people following up, the unenlightened ones, who just care about cancer or about different diseases, are they following up on this human data for Metformin? And if so, how? And can you include that somehow, can you use that to support the TAME trial? And if not, do you have any idea why not? In short, why do you think these disease associations did not get clinical followup individually (or did they?), even without an aging point of view?

• The simple answer is that we have to show that it works on aging in a clinical trial. And I’m not selling Metformin to anyone because it will kind of ruin the trial. That happened when the Wall Street Journal first talked about this trial. I got, in the next week, 3000 calls and emails from people who wanted to volunteer for this study. And I thought we’re done recruiting for this study. And then I realized that we didn’t leave our name or email there, so the readers of the Wall Street Journal had to get to us and figure out how to reach us. And mainly, they’re not interested in the trial – they are interested in being on Metformin. In fact, there are several emails that said that they are ready to volunteer for the trial as long as they are not in the placebo group. So I have to distance myself from people who are saying “why don’t we take Metformin”? Not because I don’t believe that, but because I want to have enough people out there in 14 different centers that can be recruited, not totally believing that I’m right, but rather that it’s worth testing.

I didn’t mean just random people taking Metformin, I meant to ask whether there are any oncologists for example that are looking into Metformin’s effect on cancer, trying to start a trial for Metformin just for cancer.

• Yes, there are people who are doing it. NIH has multiple grants on Metformin that are interesting, because they are not only on prevention of cancer (in fact, that’s the hardest thing to do), but also on treatment in cancer. I noticed in the last few weeks, I got emails from people with cancers who are doing intermittent fasting and Metformin before chemotherapy, and things like that, in order to kind of upregulate the aging part to fight the cancer better. Also for metastases. So there are studies like that. But remember, we’re talking about Metformin, not for not for the treatment of diabetes and not for the treatment of cancer, but for the prevention of a variety of age related diseases. So yes, there are multiple studies going on right now, multiple institutes within NIH are really interested in this study. And the FDA is certainly interested in Metformin for individual diseases. But TAME is in no way designed to test Metformin effect on individual diseases. That’s simply not the purpose of the trial, though it will be tracked.

I get asked about the TAME trial all the time, of course, and I want to really know whether I’m telling the truth or how close to the truth what I’m saying is. I talk about the impact of the TAME trial on other trials, just even before it begins. Because what I like to try to argue is that now that the FDA has approved the TAME trial to be conducted, that any big pharma company who has a drug that they have on patent, and they actually feel that it has broad ranging age related effects, can now more or less just copy and paste the clinical endpoint that you guys negotiated with the FDA. And they’re going to basically get their trial approved to be conducted as well. Now, I’m sure that that’s an oversimplification, but I don’t know how bad and oversimplified it is, so if you could speak to that.

• It’s fine. One of the missions of TAME was to have a template so that every pharmaceutical company has kind of an idea of what is the design of a study to show age-related effects. So with the FDA, we never mentioned the word Metformin, believe me. There were two questions that we asked. The first was what do we call it? Because we said we’re going to target aging. They said no, aging is not a disease. I said, so what is it? They said, okay, we’re going to change a composite – we’re going to move a composite of age related diseases, that’s what we’re going to call it. And it’s fine for me, they can call it whatever they want, it’s still going to be aging. The second part was to ask them, look, this is the study that we want to do. We don’t want to get to the end of the study when you’ll suddenly say, no, you should have done something else. So we got their feedback on that. It’s interesting. They didn’t want diabetes to be an endpoint, which shocked me because I’m a diabetologist. Their claim is that diabetes is a chemical indication, and the complications happen in 40% of the people 10 years later, it’s not as convincing as having a heart disease or Alzheimer or stroke or cancer. It’s just interesting how the FDA thinks. So I think the template is really very important. And as far as I am concerned, the pharma companies should do it. In fact, what I’m busy doing, is that I’m trying to get my hands on the plasma and DNA from SGLT-2 inhibitor trials that have ended recently, and look at their biomarkers. One of the reasons for showing those other drugs that are potential geroprotectors earlier in this talk, is that if we can get to the people who did the clinical studies, they store a lot of stuff. If we can look at the biomarkers in those trials, we might get an aging biomarker ahead of TAME, and immediately.

Gait speed has a minimum as well as a maximum in the inclusion criteria. Do CVD, cancer, MCI also have a range of severity, i.e. those with too advanced disease are excluded?

• Not really. Gait speed criteria is the primary factor which determines event rates for TAME’s composite ‘incidence of new disease’ based on Health ABC and LIFE study. History of disease was included only for ease of recruitment by centers and had relatively little effect on event rate projections for a composite endpoint of incident new major chronic disease. And we did not include gradations of those diseases for entry, primarily because of the burden that it would put on the recruitment centers. When you’re doing not just history (yes, no), you have to do a lot of tests. And that costs money and time to do that, in order to sort of gate people in and out based on those really flexible criteria. Where gait speed is pretty simple, cost effective, easy to do.

Have you tried to quantify the effects of TAME or rather administration of Metformin to the population?

• We gave prof. Andrew J Scott all the TAME calculations. And he did a study that showed we’re going to save 30% of the world GDP if we extend healthspan by 2.6 years or something like that. Really quite incredible. Because by the way, it’s not about health care. For him, it’s about people who are going to be healthier for 2.6 years more. So they’re going to travel, they’re going to have fun, they’re going to contribute to the economy, it’s going to be really great. So he did one about Metformin. And we calculated that for every non placebo or Metformin user aware of the 1500mg dose, we save $80,000 in cost for the government. Over six years trials, that means that the TAME trial itself is going to save over $120 million. And it has cost only $50 million. So even just the TAME study is going to have a millionaires effect.

Can we use TAME, regardless of outcome, post hoc to establish a new surrogate endpoint biomarker stand-in for the TAME multimorbidity by having banked samples, and basically even if somebody comes up with a new test after the seven years are completely over, do we have enough data and biological samples to be able to go to the FDA and say, look, this biomarker predicts the same multimorbidity the TAME trial used, we don’t need to run a new seven year trial to establish that surrogate endpoint?

• Part of our challenge, Jamie’s challenge in particular, in writing the NIH biomarker protocol is we had to tell them that if TAME fails, there’s still a lot of data that can help us. So yeah, that’s essentially one of the remarkable things about working on this is that we’ve been writing and trying to develop it as a no fail trial – no matter what happens with the primary outcome, we built in multiple safeguards and ways that the data can be analyzed and used by the scientific community and those sorts of biomarker development. So we’re going to gain so much out of just making and building the infrastructure and the scaffolding for the framework of what this will be. It really is sort of a remarkable opportunity. And absolutely, that’s part of what we’re hoping to do is to build an enough sample collection of assays and try to get enough other people engaged in the trial, so that we can actually make sure that this is a fail proof endeavor. And we really are working on this. Jamie has actually built out tables of “if primary outcome fails, we’ll get this” and we’ve been keeping track of all of these, and it’s actually becoming really apparent that no matter what happens, it’s going to be a really useful experience, not just for those running the trial, but for the rest of this community.

What kind of budget are we looking at? And a related question to that is why are we focusing on the US? Why can’t it be done internationally? Why can’t it be a multicenter international trial so that we can try to drive down the cost?

• We’re looking at the target, and the target is the FDA. And that’s how we do everything. There are other people, there are other groups from all over the world that wanted to be a center in the TAME, there are actually maybe three centers in Australia that can be TAME. But they’re not going to be considered by the FDA. Because they are xenophobic in this way, you know. So we had to convince them that we have centers that are experienced in geriatric medicine, that can follow the protocols. One of the challenges imagined is that when collaborating with any Australian center or Singapore center, we could never meet at a certain time, because they’re exactly on the other side of the world. And changing data, getting DNA to do clocks – it’s not simple to transfer from place to place. So it was about how we can do this study and satisfy the FDA and not have it too complex, and the FDA is not going to believe anyone else, so it wasn’t an option.
• Regarding international trials and the opportunity for TAME to spread globally, the trial itself needs to be contained. But I would feel bad if I didn’t mention that we really are encouraging for other folks who are interested in running either parallel trials that would not be really included with TAME, but that could be coupled. Whether they’re run in different countries, we’ve had some inquiries around that, or in specialty sub populations, there’s been some interest of folks perhaps like with HIV and aging or other groups, that they’re not necessarily going to be included within the TAME trial or won’t be recruited enough. So we absolutely are encouraging that once TAME gets going, please reach out to us if you’re in either a different country, or working with specialty sub populations that you might be interested in running a parallel or a sister study in that could be linked together. People who are cancer survivors can have a TAME trial, HIV people can have a TAME trial, disabled people can have a TAME trial, maybe poor people who cannot afford good quality food or exercise or regime, maybe maybe Metformin for them, so I totally agree. There’s a need for many people for a Metformin trial.
• As far as the prices, our initial grant was for 80 million dollars, over six years. Which is really cheap compared to a new drug trial, it’s a billion dollars to do a trial with a new drug for aging. But in the version that we have now, that is going to be paid, probably by a foundation, we have a budget of about $50 million. Because what we did is that we took out the secondary endpoints that Jamie talked about last time. Because we tried to make it cheaper, and we tried to make it focus on the FDA. We’re still hoping to get the NIH to do the biomarkers. And we still hope to have the secondary endpoint. This study has a power such that it’s true that we want to see before and after what happens in individuals, but the groups are large enough. So at the end of the study, we can figure out lots of other things that are happening without doing longitudinal studies. So we have enough power no matter what and we’re trying to be cost effective so that people will bite into this idea.

What is the major stumbling block right now? Is it the money Or is it the approval?

• Well, first of all, the FDA doesn’t have to approve any study. They don’t approve TAME. When you consult with the FDA, you can do whatever study you want but at the end, they’re going to discuss the result of this study. So there’s no rate limiting here, we’re done with FDA, that rate limiting was the funding. And on top of that, it’s COVID. And even now, even if we had the money today, I’m not sure when will be the right time to start. We could not start it right now no matter what, so that was somewhat of the luck. Not to have the TAME study in the middle of COVID. It would’ve been interesting though, because there is another paper, 10th paper now from China, that shows that mortality for people on Metformin was 50% less when they have COVID compared to others. That’s one of the worst studies, others have shown a reduction of 66%. So maybe it would be interesting, but due to COVID we would have to stop a lot of the things and a lot of the services.

I frequently hear from exercise enthusiasts that Metformin will either interfere with the benefits of exercise in general, or muscle building from resistance exercise. And I wanted to get the knowledge from the experts. Is this true? And if it is, would it make a difference if I exercised in the morning and took Metformin later in the day?

• I recently published in Aging the definitive trial. So just to recap, in clinical trials, where elderly were exercised, with and without Metformin, muscle mass went up in all the studies but significantly less with Metformin. If you read the studies, they’re showing you MRI data in muscle, and all that. But the main thing is that in supplement 4 in the study, they actually show that the force didn’t change. The function of the muscle didn’t change. So if they have less muscle, and the function of the muscle didn’t change, it means that for a gram of muscle, the muscle was better. So I looked at it and took the muscle from those two trials because they had muscle biopsies, and we did a transcriptome. And we basically saw that all the work to get hypertrophy, you have to activate mTOR. And remember when you activate mTOR, it’s not good for aging. So the muscle growth was associated with mTOR, which Metformin blunted, because that’s part of what Metformin does. On the other hand, people on Metformin had a transcript that was a protective transcript for aging with genes for autophagy, against inflammation, and some other things. So there was a trade off. And for me, I’m exercising and I’m on Metformin, for me it’s not that important to bulge my muscles. For me, it’s more about aging. So if you want to show muscles, don’t take Metformin. But I think Metformin protects your muscle from the aging effects. And so if I were you, I would say do it together. And the question of timing, it depends. I’m on extended release Metformin. So it’s not that timing would have a huge effect. And I’m also exercising sometimes in the morning, sometimes in the evening.

You selected older individuals between 65 and 80 for the TAME trial. What was the average age of the participants for the previous trials (e.g. the large phase 4)? Do we know if it is equally effective across ages for healthspan? Was that considered when selecting the age range for this trial?

• That’s a terrific question. So the major reason we went for this age, based on the fact that the geroscience hypothesis is about still applying it in elderly, is that we need to find an age where there are enough events in the five or six years trial duration. If you start with 50 years old, or 40 years old, you can wait 20 years until you have all those events that you’re monitoring. So we need a lot of events, and we have a lot of events between 65 and 80, where elderly are starting to accumulate them. So that’s the main reason. Why are we saying it’s going to work there? Because, for example, in the DPP, 20% of the diabetes prevention trial was paid by the National Institute of Age in order to include 20% of the people over the age of 65. They failed as there were 20% over the age of 60, but still, they were there and they didn’t have different results than others. So we have from this study and other studies clear examples, that Metformin effect is not blunted with aging. We also did studies and we published them in the last few years, where we took elderly people and gave them Metformin and did biopsies to see what transcripts change with Metformin. By the way, the exercise was in 75 year olds, and we have data on 75 year olds and there’s a markant change with Metformin in the biology of aging. So we think it’s relevant.
• There were some discussions along the way about possibly having different age ranges for men versus women, whether that would affect event accumulation. And we eventually decided that it wasn’t worth the challenge of recruitment to do that. And so we ended up keeping it simple, but certainly, looking at different age ranges, when we’ve talked to other groups who are interested in those really special sub populations, like HIV and aging or others, that could potentially be worth consideration to revisit for special sub populations, but that doesn’t apply to the TAME trial. The TAME trial is for simplicity and to move forward really based on feasibility. Designed as something that would be fairly easy to define, and going for FDA indication on the back end as well.

What is your challenge for the longevity field?

• Phase 1 (now): We need to have clinical examples that we can target aging so we can move on with newer and better science, involvement of pharmaceuticals, support by politicians/government/economists and much noise by the media. We don’t need one, but several TAME-like trials with other drugs that can be repurposed soon (I will publish on those soon). Importantly, all such studies will help us narrow in on a ‘cocktail’ of biomarkers that will allow us to guess and test better upcoming gerotherapeutics.
• Phase 2 (science) is using our capacity as a species to live ~115 years at a time where the best life span is ~80. Realizing 35 years! Many centenarians are examples of subjects whose aging is slow and longevity genes have been identified. We need to capture ALL these genetics because it’s not single genes but pathways that need to be identified. So we need to recruit and sequence the genomes of >10,000 centenarians/supercentenarians. Start developing drugs based on human data.
• Phase 3 (in parallel) breaking age barrier (not to break age record) but to help in healthspan by thinking on stem cells and organ replacement (for older adults) or erasing aging monthly (maybe epigenetic beginning starting at age 20).
• (Warning, while doing it we cannot mis understanding major SEX difference in helathspan and longevity and follow those difference in pre- and clinical studies. I think that the differences between aging of men and women is incredible. Actually between male and female mice it’s also incredible. And I think we have to have a better handle of that, because certainly, it can apply to gerotherapeutics. I would say that we have no evidence that Metformin or SGLT-2 inhibitors have a specific role in males and females, but I would also say that sometimes you adjust for males, you adjust for females, and it doesn’t change much. But that’s not as much as if we did the initial assessment in males and females and see the differences. So I didn’t want to forget that. But I think it’s probably not relevant for Metformin.)

You have mentioned here that certain endpoints and data collection was stripped down on TAME to keep things simple for the FDA and keep the budget streamlined. And that this is mitigated by having enough statistical power to do analysis after the trial. That being said, certain kinds of physiological longitudinal data, like the six minute walk tests, are essentially kind of free and easy to collect using Apple’s healthkit. It doesn’t just collect pedometer data, it does the six minute walk test and everything. Can those sort of things be added without disrupting the budget or anything easily? Or is that still too difficult to add into the TAME protocol?

• I would love to add functional measures back in, I would love to see it included. As soon as we get launched, reach out to us. I mean, this is the way that we’ve structured our team, so that we can try to include as much as we possibly can, and try to work out plans for trying to expand. We have sort of a minimal TAM that’s going to get launched and started. But you know, we welcome your ideas and opportunities, and especially for function, I would love to see that going back in if there’s any way that we could afford it, or re-included again.

One point of context here is that when I’ve talked to people in the NIH, etc., I feel like there’s a disconnect there where I don’t think they understand how easy and cheap it really is to collect. I think they’re thinking that maybe these things are just pedometers and you’d still have the doctor walk them through the process. But it’s not that, the whole six minute walk test is prefabbed in the iPhone. So maybe there are conversations to be had there.

• We have centers all over the United States. And generally, the people that will be in the studies are less informed. I don’t think that many of those people will come because they heard something on Metformin, they’ll advertise that there is a drug that might have the health benefits because we also don’t want them to lose the placebo effect. And those people also don’t have access or knowledge or use the technology. So we need to do some of it ourselves no matter what, probably. But if we could put back the other $20 million, we’re talking about $2 million or $3 million more a year, it’ll be good to have the longitudinal functional ones included as well.