Episode 33: IGF-1 Nasal Spray for Migraine Prevention
Voice-over: Welcome to Spotlight on Migraine, a podcast series hosted by the Association of Migraine Disorders. Through personal stories and interviews with experts, we expose the true scope of migraine by exploring symptoms, treatments, research topics, and more.
In this episode we hear a presentation given by Dr. Richard Kraig, the chief scientific officer and the inventor behind Seurat Therapeutics. Dr. Kraig explains the science and data behind Seurat’s Insulin-like Growth Factor 1 Nasal Spray, a novel migraine prevention treatment that is currently in development.
Dr. Richard Kraig: It’s a pleasure to have the opportunity to present work from my laboratory and, really, work that Seurat has put together now. We are trying to develop insulin-like growth factor as a novel nasal spray for migraine, and we all know that migraine is a disabling, costly, and disruptive disorder. But I wanted to spend a minute to set a sound groundwork for how we got started in this business. I was struck, after working at Cornell in a stroke center for decades, that we couldn’t come up with a stroke treatment. Instead, I started becoming attracted to the notion that if you repair the brain and strengthen the brain before it’s injured, you had a much better chance for preservation.
Well, this is called environmental enrichment. If you take animals and increase their exercise, socialization, and intellectual challenges — and in human beings, it’s simply taking a walk in nature with creative thought — you can have a 50% reduction in brain disease. This is best exemplified by Alzheimer’s disease. Simply walking three-quarters of a mile a day in nature results in a 50% less rate of Alzheimer’s. If it took 15 years to begin to lose your cognition, now it takes 30. There is no medication that can be that effective, and this works not only for stroke, Parkinson’s, but — down to the world I’m going to be talking about — the hyperexcitability of epilepsy and its concomitant disorder, migraine.
So we’re interested in using IGF-1. Well, IGF-1 is secreted from your liver when you exercise. And when you think, when you have sensory stimulation, the blood-brain barrier opens and that IGF-1 travels into the brain and becomes protective. Well, we thought, “What if we give that IGF-1 nasally to animals, then people who have migraine? Can it be equally effective as the environmental enrichment is in protecting before things are broken?”
And that’s the philosophy that let us start a company called Seurat Therapeutics. Seurat is a pointillism artist who had migraine with aura. His paintings are in Chicago. One of my students had the kindness to have the intellect to choose the name. We went with it, and our company is designed to stop migraines before they start with a nasal spray of IGF-1. And I’d like to show you our company. It consists of Yuan Zhang, who is really guiding us. We’re a small team, and it includes Martin Sanders, who’s a serial entrepreneurist who’s brought several companies fruitful to market, and me. That’s my conflict-of-interest, effectively, side. But the group of us three has already made it through SBIR-1. We’re on the way to SBIR-2. We anticipate clinical trials in about 2 years.
Let me begin with showing how I began with a basic science laboratory. We use slices of brain to set proof-of-principle studies before we move on to animals and then to humans. These slices of brain are like a piece of cheese laying out on a plate, but it replicates the brain entirely. So you can add drugs, study the physiology on multiple pieces of brain, and there’s where we set the principle that it mimics exactly that hyperexcitability that we know to be the cause of migraine aura that happens in humans.
Migraine patients are hyperexcitable than normal, and the trick is a burst of electrical storm triggers off something called spreading depression, a wave of electrical silence like a wave propagating on a pond. And that’s the migraine aura. Well, that migraine aura burns up so much energy, it spits out an exhaust that annoys the surface of the brain, and there’s where the pain comes from. I’m going to show you that in more detail with ours and the anti-CGRP medicines. But the important factor here is that it begins with a hyperexcitability burst, much like a seizure does.
So we worked by making a model from the human and putting it in a dish. These slices in the dish look exactly like the brain. Cells are perfectly normal — electrically stimulated — you measure a response. You prove that the electrical responses are normal, and then you give a rat-tat-tat-tat-tat burst of current, and then you increase the current, and then you increase the current, and then you increase the current. And finally, you fire off one of these giant spreading depressions. So it’s a way to measure the threshold of spreading depression or how much your drug raises that threshold that protects against a migraine.
Well, what that mechanistic work was able to show is very useful for us and, I think, the migraine field. Migraine begets migraine. The more migraines you have, the easier it is to have a migraine. The more spreading depressions you have, the easier it is to have a spreading depression. And part of the key of that is that there’s a neural inflammation soup — free radicals and proinflammatory cytokines are made — that makes neurons much more excitable.
What we’ve found in the dish was that IGF-1 shut this down, and it shut it down by quieting down a very important brain cell: microglia. They’re the immune cells of the nervous system that govern all immune reactions. Neuroinflammation to healing are governed by these guys. So our IGF-1, based on exercise, shuts that system down by being an anti-inflammatory substance to stop the excitability of migraine.
Well, we went from there — to switch gears here, now — to whole animal studies. And what I want to show you is a series of whole animal studies that then lead to the anti-CGRPs. Nose-to-brain delivery is becoming an increasingly popular and effective route to get drugs to the brain, but there’s a couple tricks, a couple neat points of this, that are important to see. This is not nasal delivery. This is nose-to-brain delivery. Nasal delivery goes to the lower half of your — lower third of your nose. You need to jet it past a valve here to get it up to the top of the brain, right between your eyes. That’s where the olfactory nerves are. But I’ll tell you that most pharmaceuticals and venture capitalists think that’s the principal route into the brain.
Well, if you give insulin-like growth factor radioactive, it’s in the brain in 3 minutes, but there’s an important difference that’s perfect for migraine. It travels up the trigeminal nerve, the pain nerve that’s associated with migraine. This is the superhighway up through the nose that gets to the back of the brain, where the pain of migraine is, in 3 minutes. It’s in the center of the brain in 30 minutes in a rat. So we know IGF-1 rockets in, and it’s rocketing in along this conduit that we want to study for a migraine relief.
Now, they always say that a rat isn’t a human, but a human has a gigantic trigeminal nerve facial innervation, the sinuses. And if it’s true that this is the principal conduit in, all that old-fashioned argument that nose-to-brain isn’t going to work in humans because it only has a small olfactory area in humans is irrelevant. It’s this that’s the key.
And that’s the way our imaging and science is being studied. And here’s results from us delivering nose-to-brain IGF-1. And sure enough, after a single dose of IGF-1, a day later, we fired off a spreading depression, and the threshold was higher. So it took more electrical energy, so we protected against migraine. Spreading depression is a well-accepted migraine model. But that was effective not only acutely — a day, 3 days, 7 days — and importantly in drug development — pardon me — there was no loss of function after you gave recurrent doses over 2 weeks. In fact, it got better. There’s no toxicity. We’ve measured out that far.
So the stuff works, and it bothers some people that say, “We are after the cause, not just the consequence.” Well, we’re really after the cause and consequence, but if environmental enrichment alters brain function, it’s altering the cause of a seizure disorder, a stroke, Alzheimer’s disease, and migraine. So I feel very scientifically valid in saying those first sets of studies begin to approach a cause of migraine. Whatever it might be, that brain is different.
Now I want to switch gears and show you that we’ve extended this work to what’s more commonly known, the trigeminal pain system activation, the migraine pain itself. Well, it comes from the trigeminal ophthalmic division that innervates the head. The important part here is the trigeminal ganglion, where these fibers come together, and then the trigeminal nucleus. These two guys are important metrics, are important waystations to monitor how effective will your migraine drug be in preclinical models. And I want to show you those results now to say how ours is working out.
We did a similar paradigm where we gave the animal the IGF-1, one shot. 24 hours later, you drop a little KCl on to trigger these spreading depressions and measure it over here. You do them every 10 minutes for 90 minutes to give it certainly a bunch of migraines to give you a robust signal. You then look at the trigeminal ganglion and you look at the trigeminal nucleus and say, “Are you activated or are you not activated by the treatment with IGF-1?”
Well, look at these data, and this is going to guide us into the anti-CGRPs. After that recurrent spreading depression and single treatment, we had an 80% drop. Here’s the staining of the experimental trigeminal ganglion, measuring an oxidative stress marker — semi-quantitative, blinded work; P 001 significance — and here’s the sham control. The sham control’s just the vehicle, the solvent that the IGF-1 was contained in.
And then you come over here, which is what I want to concentrate much for the rest of my talk. It’s that CGRP. You all know CGRP today. It’s the pain molecule that for 20, 30 years now has been shown to be in those trigeminal ganglion nerves and are released to help cause the pain. And the new anti-CGRPs mop up that pain molecules after they’ve been released. But our evidence shows that with the pain stimulus, we drop by 57% the content of the CGRP before it was released. In naïve animals I’m not showing you, we gave IGF-1, and we found a 75% reduction in the resting level of CGRP compared to sham. So if you’ve only got fewer molecules to release to cause pain, it sort of begins to make sense you’re going to cause less pain if you release them. And that’s an important caveat as we [inaudible] to hopefully publish this.
Well, we looked to see — that trigeminal nucleus is the first thing in the brain stem where — it’s called nociceptive center. It’s where signals that are sufficiently painful could move up to be perceived as pain. So it’s another nice place to say, “Hey, this could be painful.” So we commonly use it as a marker, count the neurons there; and there’s a 48% reduction in the number of lit-up neurons, activated neurons, after IGF-1 treatment than there is in the sham control.
So let me switch gears just a little bit as I begin to wind up. Here’s a recent, important paper that illustrates the power of the new anti-CGRPs. This was done by the Burstein laboratory in the Boston area. The trigeminal ganglion, under his work — he did electrophysiologic study. Well, the darker blue are the CGRP-containing fibers, and they too can cause headache pain. But what he found was he, too, fired spreading depression, like I did, that makes the blood vessels shrink, swell, shrink; and that mechanical change causes these trigeminal nerves to get activated. But it’s the CGRP one that releases CGRP, that activates the smaller Aδ-fibers. And what he did was put anti-CGRPs and then measured the electrical activity of these two nerves and found only this nerve stopped or reduced its electrical activity. The conclusion of this paper was that perhaps this is why the anti-CGRPs are effective only in a certain population of patients or in a certain degree of efficacy.
Well, let’s see what our work does to that. I mentioned cause, and again, we’ll kind of fight this out in the literature, but you could see the intellect or the rationale of where we’re coming from. Environmental enrichment changes the brain de novo. It makes it less susceptible to a seizure. It makes it less susceptible. I don’t know where exactly that migraine or seizure’s coming from, but there are less, so the box called the brain is reduced by treatment, so it’s causative.
But we’re also, for the first time, hitting the consequences of the pain. We significantly stopped — remember I said there was oxidative stress and inflammation in the nervous system? Well, every time you fire action potentials, you generate oxidative stress and a little bit of inflammation. But if you overdo it, it becomes a sick signal, and there’s where pain comes from. We significantly stopped the oxidative stress and the inflammation here in the trigeminal ganglion, and importantly, we stopped the CGRP levels by 75% before the material could be released and cause pain. Then when you go measure pain at the pain railroad station up to the brain, it’s significantly decreased.
So I’ll finish by summarizing to say where are we at. We are certainly delighted by the success of the anti-CGRPs. There’s no question that the physiology of the CGRP is involved in pain, and the anti-CGRPs take one tact to get at that — mopping it up from when it’s released. This is their conclusion that this may be why it’s partially effective, but we believe that we may be actually able to broaden that degree of efficacy either by IGF-1 alone or combining our IGF with the anti-CGRPs to more effectively hit the upstream signals, the cause of a migraine, and the consequence in the trigeminal system that will silence migraine by hitting both its cause and its consequence. I’ll stop there.
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