James Peyer: Why primary indications matter

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“Aging” isn’t a disease as recognized by the FDA–not yet anyway. But then how will the companies trialing anti-aging drugs ever get regulatory approval? It’s simple: just choose a “primary indication” to test your drug with. Of course, that choice itself is rather difficult when you’re considering a geroprotector. Here’s how investors think about it (transcript below, and see the full interview here):

JAMES: So when you start a biotech company that’s focused on making therapeutics, you want to have a drug that’s approved for an indication. After you complete your preclinical development (which is when you test whether the drug works in mice, and that it’s not too toxic, and that it’s not broken down in the plasma the moment you take the pill), then you start your clinical trial, and that clinical trial usually has to be for a specific disease. In the aging space particularly, we are blessed and cursed with the fact that things in geroscience that extend the lifespan of animals, or target one of the hallmarks of aging, or are able to¬† rejuvenate the damage of aging can often be applied to a ton of different diseases. For example, when we eliminate senescent cells from the body of a mouse, we see muscle regrowth, bones get stronger, rates of cancer go down, lifespan goes up by up to 35%, hair regrows, kidney function improves, cardiovascular function, all sorts of things. So when you try and decide what primary indication you’re going to design your first clinical trials around, it can be quite challenging. Just to use a very concrete example and to continue with the senescent cell space, Unity Biotech, who are putting together small molecules to kill senescent cells, are going after osteoarthritis as one of their first indications. But I think that we all realize that the senescent cell space is intended to eventually be bigger. Ideally we would be eliminating our senescent cells for all of those things at once–restoring our muscles and bones and whatever else in old age–but we just can’t do that in the current regulatory system right now. Or perhaps even more accurately, we could, but the clinical trial risk of doing so doesn’t make sense, both from an investment perspective, and also from what exists in the insurance industry, and what’s going on in doctor’s offices right now. We need a little bit more time to validate the geroscience approach before we get there. So that’s what I mean by primary indication. For any given project, the biggest hurdle that is showing that your drug is safe and effective in human populations for the primary indication, and then all of a sudden it becomes very easy to say that that biology is also relevant to disease B, C, D, E and F, in addition to A. And so most investors will say that, instead of advancing A through F to the clinic at the same time and incurring the same cost for each of those indications, it’s worth spending a little bit of time to stagger those things, go with A first, and then plan B through F to follow up as soon as there is validation that A is really going to work. And that way you could actually throw a lot more things at the wall–you can try 10 projects instead of one, because you’re going to be doing 10 different As for 10 different projects, as opposed to one project with 10 different indications that you go for right away.

TEGAN: Interesting. You said something about “validating the geroscience approach”, how does one do that?

JAMES: Well, this is not my particular topic of expertise, but it is one I spend a lot of time thinking about. So let’s first define the geroscience approach. It’s the idea that by altering the fundamental biology of what makes us age we can prevent the diseases of aging, or at least delay the diseases of aging, making us healthier for longer. And sometimes that also means living longer. This includes topics like metabolic dysfunction that you can correct in the rapamycin/metformin type studies, but also altering our senescent cells, messing with our telomeres to make us live longer and healthier, etc–there are a bunch of different approaches that have been hypothesized or have already been shown in animal models. By validating the geroscience hypothesis I mean that we haven’t yet shown in humans that we can give a single therapeutic agent to a person and have that person be protected from multiple diseases of aging (or cured of multiple diseases of aging, but that’s even a further stretch, so let’s just say prevention). Once that happens, this regulatory structure that we’ve been talking about changes substantially, because once you can approve medicines for the prevention of multiple diseases at one time, then you don’t have to look for your one little thing to start with and then go branching out to other things. And this is why I’m such a big advocate of the TAME trial (and similar trials for NAD boosters and other types of geroprotectors in human studies), because I think that even a small success with regulatory approval showing that metformin–which is obviously not a great life-extending medicine but does have a serious effect, in mouse studies you’re talking about 5-10%–if that has an effect in humans that could justify insurance companies paying for metformin for high risk people, it completely changes the game for people doing senescent cell research, or telomere research, or stem cell research who want to rejuvenate the body. Because all of a sudden you have not just a precedent of FDA approval, but you’ll also get biomarkers and ways of making the clinical trials go faster, which you can use in future trials. So I think validation of the geroscience hypothesis will actually be a watershed moment in the history of medicine in the 21st century, whether it’s the TAME trial, or NAD, or any of a number of other compounds.

TEGAN: Circling back around to primary indications, are there any in particular that are better or worse?

JAMES: So one of the things that we specialize in at Apollo, and one of the things that I find really fascinating, is that we usually know which molecular targets geroprotectors are going after. Let’s just use a very basic example: rapamycin goes after the mTOR protein complex, and mTOR is certainly involved in aging, because when you inhibit mTOR and specifically mTORC1, lifepan of mice goes up, and it seems like that’s probably going to be true in dogs, and may even be true in people–we’ll see. Rapamycin is one decent tool for that, but a number of groups, including us, are working on other tools for interfering with mTOR as well. But we don’t wanna start with treating all diseases at once, so what we look for with primary indications are specific diseases that have a very high unmet need. And when that unmet need is really high, we can launch the drug targeting what is often a rare population of patients that have a real problem. When you look at the mTOR space, for example, there are a number of diseases in which mTOR is chronically overactivated, often very serious conditions that have high fatality rates and very few existing treatments, and then we would think about testing our compound in those conditions first. And then if it works in that little piece, if it’s effective and safe in patients, then we expand it out to a broader range of people in whatever way makes sense as quickly as we can do it. So the short answer is that we don’t look for a specific indication, and there isn’t one that I think is like “the” aging stepping stone indication. If we wanted to think of those we’d look at sarcopenia, osteoarthritis, some of these things that are very associated with aging decline. But I actually think the more promising route is to go after the genetic diseases, rarer conditions with a very high unmet need as a first stepping stone that will depend enormously on what the science underlying each individual therapeutic is.

TEGAN: How are progeric diseases as primary indications?

JAMES: So progerias are very interesting scientific cases, and we have actually talked with some groups that are working on treatments for progerias. The first thing to mention there is that different progerias are molecularly very different from each other. Secondly, one of the issues with many genetic diseases–including progerias–is that a lot of what occurs in progerias has already happened by the time you start the drug, so unless you can be highly rejuvenative, it’s often not enough. You might be able to help the situation and maybe ameliorate some of the existing decline, but usually with progerias the problems begin so early on that unless you can come up with a truly rejuvenative approach, it’s not going to have the sort of impact that I would want to have in treating a patient. So we have talked to a number of researchers working in this space, and I think that some of the work we’ve looked at that could truly make a difference in the lives of people with progeria. But because of the very severe nature of most of these progeria conditions, I think it’s a very tough one to develop really meaningful compounds for.

TEGAN: Are most of the therapies that you encounter preventative and not rejuvenative?

JAMES: No, most of the therapies that we encounter have the capacity to do both, but are specifically rejuvenative while broadly preventative. So for example with senescent cells, there are a number of conditions that we think the pathology is really driven by senescent cells, like sarcopenia, where getting rid of senescent cells acutely will restore the muscles of aging mice. But if you take a mouse that’s already very aged and then you get rid of its senescent cells–and to be fair, this hasn’t been shown in academic mouse data completely yet–but you can’t immediately just restore a nearly dead mouse to health. And this has been true no matter what treatment we see in the geroprotection space, that you can intervene late and reset things somewhat, but at some point once things go very bad there’s no coming back, even if you’re specifically rejuvenative in some areas. However, that same treatment can be broadly preventative in that, if you intervene early enough, it can prevent the mouse from entering a downward spiral that leads to the ultimate levels of pathology that are no longer sustained by senescent cells. So that’s usually what we see, and I think that the geroscience space, at least in the early days, is going to be defined by these dual-acting compounds which could be used first against specific pathologies and then pulled back to be used as broad preventatives. And then as the field develops, I think that it will go in two directions, one doubling down on specific mechanisms that will then have to be used in combination with each other in order to have a broad effect on the disease. And simultaneously there may also be specific things that are not rejuvenative in and of themselves, but once the geroscience hypothesis is proven in the clinical setting those compounds could be the next generation of things, following metformin or rapamycin analogues, that could be used to prevent diseases–but they’re specifically designed to prevent disease, not to go after existing indications.

Tegan McCaslin

Tegan is Geroscience's lead editor, and writes on a variety of topics--mainly science, medicine, and humans--here and elsewhere on the web.