Q&A

Do dogs have their special growth hormone with a different sequence?

• Presumably they do, and it’s a key question, because I am also working with different people on dog aging intervention study, and since we don’t know how to get the dog growth hormone in any serious way, we are not thinking of running a TRIIM study on dogs right now. If anybody has ideas around that, I’d like to hear them. There have been studies when human growth hormone has been given to animals, but that will probably have side effects and is most likely not the way to go.

Do you think that Metformin and DHEA are so good that even if you don’t have an insulin problem it would be a win or is it mostly because of those anti-insulingenic features treatments?

• I know that DHEA has effects that are in addition to its anti-insulin effects, Metformin may have as well, but Metformin was particularly developed to be anti-diabetic drug, so that’s probably it’s major feature. There is one study that indicates that DHEA can lower insulin, but in most studies it does not – it lowers it only when insulin is raised by GH. That is not a coincidence, when we’re young, we have plenty of GH and we are not diabetics, I think the reason for that is that we also have a plenty of DHEA. So by combining the two DHEA naturally and physiologically opposes this diabetogenic effect of GH. Metformin is there just as a general purpose insulin sensitizer without any built in physiology behind it.

Is IGF-1 the same across mammals?

• This figure in this study maps the differences.

Does GH increase insulin without increasing blood sugar?

• It’s a matter of degree. First thing that happens is that insulin goes up. If you keep increasing the dose of GH, eventually the increase in insulin is not enough to overcome the insulin resistance that’s induced by the GH and at that point your glucose can go up as well. So both of them will go up in that case but it is a matter of dose.

With the cohort being biohackers, are you controlling for other treatments (e.g. NR, rapamycin, fasting) or letting participants continue these and tracking possible additive effects?

• Yes, that’s an ongoing issue with a lot of people – some people are taking mass quantities of NR, NMN, Resveratrol. Constant tension between what we’re trying to do and people doing caloric restriction (CR) even though they are really skinny. With our trial, CR doesn’t really make sense because we’re trying to grow you, build you up, increase your lean body mass, give you new cells in your thymus, and that’s all inhibited by CR, which is immunosuppressive in humans. On the other hand, we don’t want to deprive people of the benefits, so we are working with people on their regimen and trying to balance this.

Do you think cycling would make more sense in this case? Cycling of autophagy, cycling of GH and CR mimetics rather than simultaneously do all of that?

• Yes, definitely, you really don’t want to do CR and TRIIM-X simultaneously. It does not make sense. CR is good, but thymuses are good too. Cycling regimens makes more sense, you should want to use your time in TRIIM to maximize your TRIIM benefits. If you take your body out of CR for a year, you are not going to age by more than a year, but you are actually going in reverse with TRIIM. CR slows aging, TRIIM reverses it.

If 4x weekly dosing causes some degree of GH resistance, how might the protocol be adapted to once-a-week or twice-a-month GH dosing with regard to the combination protocol? In other words, do you think that metformin and DHEA might be best given on a different schedule than the intermittent GH? Speculations?

• The real question is whether to give Metformin and DHEA when you don’t take GH? Most likely yes, I don’t see any good reason not to. There are some hazards but they are the same whether you’re taking GH or not. So we ask people to take them simultaneously, mainly to make it as easy and cost efficient as possible. Some people are taking these things more frequently and some not, and based on that we’re beginning to reconstruct some information on which way most people should go, but we’re still in the process of figuring that out. But your point is well taken that we’re using Metformin and DHEA for specific reason in our protocol and that is to block diabetogenic effects of GH, but they have independent benefits as well so it makes sense to take them other times as well. We’re gonna have a lot more information about that later.

Will investors support clinical trials on drugs that are off patent? Why or why not? Your Stanford colleague Susan Athey (economist) has done work on this issue.

• Two major ways to address that issue. The first is to create new pharmaceuticals and the second to create workarounds that do not need the high-cost items. We work on both of those, we do a fair amount of work to find alternatives to GH which is the expensive part of our cocktail. So far we are not satisfied with the results and therefore are not ready to go down that path yet. But there is another way and that is to make the growth hormone ourselves. It might be off-patent but every time you make a new variation you have to go through the FDA approval process. And GH is not perfect, there are certain features and ways to improve GH without changing the molecule itself – just changing the stabilizing solution that GH is in for example – that would allow a new patent, which would reduce cost by ~5x and be superior to now available GH. If we can do that, we will own that version and we will have a massive advantage over potential competitors and to our treatment clients. So that could unlock the door to get the treatment to tens of millions of people, because it will be much much much more affordable. That’s a major thing of interest for us, it helps that I am a cryobiologist preserving proteins in my dayjob, and I have some ideas. But we don’t have that much money in the bank to do it fast, but we are working on it and are in talks with a few people. So that’s the future of our company.

Are you looking for investors right now?

• Yes, but it is sometimes problematic because of the IP. We’re growing our company by organic growth, even though this is a trial, we’re allowed to make a small margin for each person on the trial to have our administrative needs covered and we’re actually demonstrating that there is a market for this product despite the high cost. So we have a way forward with organic growth that would eventually lead to these new products I was discussing.

Does growth hormone stimulate growth of some features like nose or ears (that grow with age), and cartilages everywhere, and if yes isn’t it a concern as this therapy would likely need to be taken permanently or semi permanently? Is it something you measure in the trial?

• Time will tell on that, but we haven’t really noticed anything like that. Interesting thing is that even though all of the evidence shows that we are reversing aging, so far people are not looking facially much younger even when they get epigenetically younger. So we may get there, we have ideas, but so far we didn’t notice getting noses, ears, hair worse or anything like that.

Are you gathering daily facial pictures? It is interesting for aging, but even more for what was asked in the previous question.

• We have taken a lot of photographs of people and hair at baseline, yes. And we will continue to do so throughout the trial.

You mentioned eGFR going up, implicating improvement in renal function. Would this protocol be appropriate and compatible for someone with a kidney transplant – and immunosuppressed – to extend transplant life? If you could extend transplant life for a year, you could get a financial benefit out of Medicare, so potentially a financing opportunity?

• All kinds of ways how these things can intersect. Considering the cost of TRIIM-X for all the protocol and monitoring which is like 18k a year – pretty expensive for most people – but transplants are like 500k a year, plus dialysis a year which is more than 18k a year, so if we could marry these together, the cost aspect becomes negligible. So that’s one aspect of it. Another aspect is that GH seems to benefit kidney function, so if your transplant is not up to speed, we may even compensate for that deficiency. Then there are two competing approaches that have to be factored in. The first is that there might be some tension between regenerating thymus and immunosuppressants – it might accelerate transplant rejection, which would obviously be a problem. The other consideration would be the “thymic magic” aspect – the thymus has two jobs, manufactures cells to destroy enemies, and manufactures cells that do not destroy self (thymus). The second aspect is really interesting, because if you have a decent amount of thymus, you could re-engineer thymus to accept any graft and accept it. This has been shown in any animal model of transplant there is, and it always worked, including in large animals. And it seems like something that could be doable in humans, based on what we saw in TRIIM. We saw we are able to regenerate the thymus, that means there is some place to do this engineering work on, it involves a minor surgical procedure to introduce the right antigens into the thymus, but once you do that, you give it a few months and your transplant rejection should be eliminated for life. You can go off immunosuppression for the rest of your life and keep that kidney as if it was from your identical twin, which means it will last for 25 years instead of 5-10 years. And it gets better then that, because you could use the same process and technology to cure all autoimmune diseases by reprogramming the thymus and deleting the cells that are attacking yourself. This has also been tried and proved in all animal models, but haven’t been tried in humans. This is another multi billion opportunity. Somebody needs to do this and we’re gonna do it if nobody does. I run this company called 21st Century Medicine during the day where we have a lab with pigs where we can test this with little overhead and cost.

Do you have an investment number for those investor individuals among us?

• We’re looking for at least $1M, but of course $5 or $10 would be great.

We all want this to work, I just wanna make sure that we’re not biased in how we interpret the data. Do you feel good that these preliminary results are representative of overall performance as opposed to something that you (unconsciously) cherry-picked?

• At the end of the day you have to analyze the data. I am aware of the potential bias, but I am not aware of it right now. I’ve been very impressed with the leukocyte / monocyte ratio result in TRIIM. Partly because of the story it tells between what we’re doing and NAD. That if we increase the leukocyte / monocyte ratio by reducing CD38 positive monocytes, then we should increase tissue stores of NAD and we should rejuvenate the body and get the results that we are seeing. We have highly statistically significant results about this. There is this bizarre aspect of it though, that you don’t see this ratio with ordinary techniques and normal instrumentation, we see it only with these ultra sophisticated techniques that are used at Stanford – I am still trying to figure out how is it actually possible, we need to look into that. And by the way as far as the epigenetic aging reversal is concerned, tests and calculations are done by Steve Horvath, and he is the last person to be biased in this respect. As far as the preliminary results go, I showed you the favorable and didn’t show the not as favorable, but we’re so early in the trial that we’ll have to see with more data. What I’ve shown has basis in other results, so I think that it is right. But again, we’re less than 6 months in the trial, we’ve got probably another year and half to go before we have all the data in, a very limited amount of people, so take it as really very preliminary. I am not seeing any red lights, more of favorable things, globally.

Is there a structure that allows the trial to be self-funding? So anyone who wants to join the trial can join, pay for all the infrastructure costs and you deliver the therapy?

• Yes, TRIIM-X is that kind of study. Everybody in the trial is paying their own way – this leads to very committed volunteers. We are able to make a little bit of margin to keep us alive as a company. It’s all allowed and approved by the FDA and IRP. The beauty of this mechanism of funding is that we don’t have a limit of the people in the study as long as we can deliver it, up to some administrative point. At some point later we’ll have to turn it into something else than a study, however that is a long way ahead of us. But this mechanism functions so far. Actually that’s another thing for investors to participate in, people don’t want to pay for being controls, so that is something we could use the money for as well.

What can this group help you with?

• Tell your friends that TRIIM-X is open for enrollment, we keep the things going by enrolling more people. It’s our only source of income and knowledge. So anyone who is interested in the trial and is able to invest $18k into it – which is pretty steep I know, we’re working on it – will be appreciated.
• Tell your investment friends about TRIIM-X as well, just in case they might be interested in some of the things we’ve talked about, be it the GH alternative or the bioengineering and thymus reprogramming aspect.
• www.interveneimmune.com