Addressing a Blind Spot in Treatments for the Cornea

The cornea is a transparent and multi-layered dome that sits at the front of the eye. It not only provides protection, but bends light to focus it on the retina. Many corneal diseases cause scarring that reduces the transparency of the cornea and results in the loss of vision. In fact, corneal diseases are a leading cause of blindness. Claris Bio is seeking to address the need for therapies to treat corneal disease by developing recombinant human deleted hepatocyte growth factor to improve and accelerate corneal healing. We spoke to Clarke Atwell, CEO of Claris Bio, about the cornea, the role hepatocyte growth factor plays in its healing, and the rare and chronic condition neurotrophic keratitis that it is focusing on as its lead indication.

Daniel Levine: Clark, thanks for joining us.

Clarke Atwell: Thank you, Danny. I appreciate it.

Daniel Levine: We’re going to talk about rare eye diseases, Claris, and its efforts to develop therapies that restore functional vision to people with these conditions. Let’s start with the cornea, which I imagine might be more complex than most people realize. For listeners not familiar with it, can you explain what the cornea is and its function with regard to vision?

Clarke Atwell: Yes, sure. So the cornea, they often say that the eyes are the window to the soul. The cornea is actually the real window. So it provides two main functions. The first is keeping things in and keeping things out. So what it’ll do is it acts as a barrier function, so it’ll prevent the eye from becoming infected by either viruses or actually by microbes. And so it provides very much that barrier function. The second most important or the second function, whether it’s more important or not, it depends on which one you’re about to lose, but the second function that it provides is actually optical power and that’s vision. So if you think of the eye as a machine for vision, the cornea provides two thirds of the optical power in the eye. And what that means is the ability to refract light, and so your cornea and your lens are basically the mechanism by which the back of the eye receives the image. So those are sort of the two main important functions of the cornea. When you think about the cornea, it is a transparent tissue, and that makes it sound very simple, but actually it’s an amazingly complex set of layers of tissues and cells that allow it to maintain that transparency, which makes it unique among the tissues in your body. So, for example, the cornea has a dense innervation where you have unmyelinated, so unsheathed, think of an exposed nerve or an exposed wire without the plastic sheathing around, it’s very much the same. You have a nerve without the myelin layer, and you have more nerves on the surface of your eye and the cornea than any other part of your body. So for example, it’s three to 400 times more than the surface of your skin. And if you think of the prototypical painful tissue, your genital pulp, it’s 20 to 40 times higher in density. That in and of itself makes it unique, and those nerves provide a lot of function and support to the cornea. The cornea also, because it’s clear, and this seems obvious, it’s very important that it has no vasculature. So, it’s avascular tissue. Oxygen is actually provided by the tear film, and then nutrients come partly from those nerves in the form of neurotrophins, but also the anterior chamber of the eye provide nutrients to the cornea. And then finally, it’s an immune-privileged organ in the sense that it doesn’t have a mature immune system that’s active within the tissues. So a lot of the immune system is present from the tear film or from the anterior part of the eye. So those three aspects make it unique among tissues and they provide that clarity and transparency that we require.

Daniel Levine: There are a number of rare diseases that can affect the cornea and lead to vision loss. Before we talk about any specific conditions in general, how broad a problem do these represent and how much commonality is there in what goes wrong with the cornea in any of these conditions?

Clarke Atwell: So, there are several diseases or areas where the eye can lose function. And if you, again, going back to the structure of the eye, you have these five layers of the cornea, and the first one is the epithelium, and those are cells that rapidly divide and provide that sort of initial barrier function. And the reason they rapidly replicate is because they’re dividing constantly to restore the cells that either die or are damaged. And as you can imagine, the surface of the eyes are under constant assault. So the epithelial cells, in any case where they become damaged, you actually will get ulcers, will get persistent epithelial defects. And so we see those in conditions like neurotrophic keratitis. We also see that in conditions like microbial keratitis where you actually get an infection and then you’ll see the epithelium itself break down. Underneath the epithelium you have a Bowman’s layer, which is an acellular matrix of collagen, and that provides protection from the stroma or into the stroma. And the stroma itself is a series of collagen matrices that is very orderly, put down in a very orderly way. And when that order is disturbed, i.e., again through physical or chemical injury, you get a scar forming. And the stroma is where you can actually get scar formation. And so that is a not so rare condition, but a rare condition in the sense where it may actually affect the center of the vision of the eye. So you can damage the cornea when it’s proximal to the pupil, you’ll lose vision there. And then finally underneath that you have the Descemat’s membrane, which is again an acellular membrane that protects that stroma. And then underneath that you have endothelial cells and they are responsible for transport of fluid across the stroma. And it’s that transport of fluid that allows you to see through that eye. And when you have damage to endothelial cells that will result in Fuchs dystrophy, which will result in a swelling because the water’s no longer being taken out of the cornea. You’ll get swelling and you lose vision that way. So if you sort of think of all of those tissues in various ways, they can be affected and result in diseases. So, you can get infections, microbial keratitis, you can get scars, you can have an effect on the endothelial cells, and get Fuchs dystrophy. And then of course in the disease, we’re interested in damage to the nerves. You’ll actually get neurotrophic keratitis. All of them will be blinding.

Daniel Levine: In general, do these represent unmet medical needs? Are there therapeutic options that are available to people with these conditions?

Clarke Atwell: So, in many of the conditions for the prevention of infection, there are antibiotics for these diseases in the sense of removing the infection. In the removal of scar, there are currently no therapies that are approved for the treatment of scars in the eye. When we think about Fuchs dystrophy, there are no medical treatments right now currently for that disease. When we think about neurotrophic keratitis, that is the one area where there actually has been for the first time, a biologic approved for the treatment of anterior disease in the eye.

Daniel Levine: Well, neurotrophic keratitis is your lead indication. What happens to someone with this condition? How does it manifest itself and progress?

Clarke Atwell: So, there is a codependent relationship between the nerves in the eye and the epithelial cells. As I mentioned, the nerves provide food, neurotrophins for the epithelial cells. They also provide factors that cause the epithelial cells to regenerate and also migrate and adhere to the stroma. So, when you have a breakdown between that code, between the nerve and the epithelial cells, you develop neurotrophic keratitis. You can come to this disease through various factors. It can happen approximately on the surface of the eye. And an example of that is herpetic keratitis, or it can happen systemically, and an example of that is diabetes. But regardless of the etiologies, what’s going to happen is that you’re going to get chronic degeneration of the nerves. The nerves are going to retreat. They’re no longer going to provide support to the epithelium. What you’re going to get then is a breakdown in the epithelium. Eventually you’re going to get a persistent epithelial defect, and then from there you are going to get an ulcer and scarring.

Daniel Levine: You indicated there were multiple causes for the condition. Is that right? Is it understood what generally leads to this?

Clarke Atwell: Yeah, so there are multiple etiologies, but common across all the etiologies is damage to the nerve and a loss of sensation. So, these patients, when you actually test their sensitivity, you can do that with a cotton swab or a Cochet Bonnet device, which is actually a thread that’s sort of dragged across the cornea. The patients either won’t react to it or will react to it in a way very different from you and I, because as you know, if you place any sort of pressure on your cornea, you’ll react in a very defensive fashion, very painful. I’m sure you’ve had pieces of sand or paper scratch against your eye and it’s extremely painful. But for these patients, it’s not so common among all these patients, is a loss of sensation.

Daniel Levine: How is it generally diagnosed? Is this a difficult condition to recognize?

Clarke Atwell: Up until I think probably two decades ago, physicians weren’t actually taught about the disease. And it’s only lately that it’s actually been taught in medical schools and in a rigorous fashion, the diagnosis itself. So first you have to suspect the disease. Second, the diagnosis itself is very simple. It is literally right now for most physicians, they use a cotton swab. They place it on the surface of the eye. If you react, then you don’t have the disease. If you don’t react, then it’s most likely that you have neurotrophic keratitis. It’s really the awareness that’s the issue about the actual diagnosis itself.

Daniel Levine: Your lead experimental therapy, CSB-001, is a recombinant variant of hepatocyte growth factor, which sounds like something you’d find in the liver. What is the role of hepatocyte growth factor and what does it do in the eye?

Clarke Atwell: That’s a really good question, and we’ve actually had that from some of the physicians when we first started exploring the drug. So it is called hepatocyte growth factor. It was discovered in about 1984, and the reason it’s called hepatocyte growth factor is it was first discovered in the liver. It has also been known as “Scatter Factor” and that was discovered in the kidney. But what everybody was discovering was indeed hepatocyte growth factor. So it actually is produced in the eye. It is produced in the lacrimal gland, and so you will find it in the tears of the eye. And we’ll also find it produced in the stroma by the keratocytes. So it’ll be produced in the stroma and the surface of the eye, and it provides a regenerative function, so it is able to regenerate nerve cells, epithelial cells, and endothelial cells. And so, it provides that function when the eye is damaged, at least in our hands and our co-founders hands, Dr. Reza Dana and Sunil Chauhan. They were able to demonstrate that it has an antifibrotic effect as well as an immunomodulatory effect. So it’s able to dial down inflammation as well.

Daniel Levine: And how is it delivered?

Clarke Atwell: So, we’re fortunate that we are able to deliver it topically right now in the diseases that we’re interested in. Many of the diseases I mentioned are amenable to topical therapy. So we’re actually delivering it in a drop sterile container that you can twist off the top and drop it right on the surface of the eye.

Daniel Levine: And what’s known about it from studies you’ve conducted to date?

Clarke Atwell: So, from the work that’s been done at Harvard with our co-founders, we know in several animal models, both in mechanical injury and in bacterial injury models, we know that we’re able to regenerate cells very rapidly, about 50 percent faster versus vehicle. We know that we can prevent fibrosis, so we can prevent scarring. We know that in tissues where scars have been formed, we’re able to regress those scars using HGF. And then we also know that when we place HGF into a situation where the immune system has been turned on and you have inflammation, we’re able to dial down that inflammation. So again, not suppress the immune system, but modulate the inflammatory process and that improves healing.

Daniel Levine: And what’s the development path forward?

Clarke Atwell: So currently we’re in our first phase 1/2 pivotal trial. I’ve never put those words all together, but based on the safety, the program, we were able to bypass a full phase 1 trial. And what we did is we screened our patients as they entered the trial. And at a certain point after we had 12 patients enrolled, we looked at their safety profile and were comfortable continuing enrolling patients into the trial, as we had discussed with the FDA. So we’ve enrolled 131 patients, and this trial will be the basis, it’ll be our first pivotal trial and will be the first of two trials to be the basis of our submission to the FDA.

Daniel Levine: Claris expects to apply this therapy in multiple ophthalmic indications. How broad a group of diseases might it be useful in treating?

Clarke Atwell: So, we’re excited about several diseases. The first obviously is neurotrophic keratitis, and that’s our lead indication. But we’re also very interested in another disease called limbal stem cell deficiency. So there’s a perimeter around the cornea called the limbus, and it is basically a holding area for stem cells. And those stem cells provide for the regeneration of corneal epithelium, but also prevent the migration of conjunctival cells onto the cornea. And in patients where there is death of those stem cells or destruction or deficiency in those cells, you actually have the conjunctiva moving across the surface of the cornea. And you can imagine that’s blinding. We’ve had some indications in the patients in our NK study that this might be effective. We obviously don’t know what the patients are on, but in mass data, we’re seeing some patients have regression of that disease. In that disease, there is no medical treatment, sorry, no pharmaceutical treatment. So, I think that would be a very interesting area for us. As I mentioned, the drug has an effect on scars. So we’re very interested in patients who have preformed scars where we can go in and try to reduce that scar, the impact of the scar. And we’ve started an open label study in that indication as well. Microbial keratitis, as I mentioned earlier on, is a disease where you have an infection in the eye, it can cause scars, and we feel that we would have an effect in preventing the formation of those scars. So that’s an area that we’re very interested in as well. So there’s several areas. We see this as a pipeline within a product, and so there’s several high end medical needs where there is no therapy or pharmaceutical therapy where we can go in and have an effect.

Daniel Levine: You mentioned you’re looking at this as a pipeline and a product. Is there a pipeline you’re planning on building behind it?

Clarke Atwell: Right now, our hands are full with all of the different activities that our drug has and that potentially it does have. And as we move these projects forward and add to the company, we’ll definitely be thinking about adding other drugs into our pipeline. But I can say that HGF now keeps us quite busy. We are a five person company, so our hands are full.

Daniel Levine: Claris launched in 2020. You emerged from stealth this year, you raised $57 million in a series A round. How far will existing cash take you?

Clarke Atwell: We’re completely funded to the readout of our data in the summer of this year and beyond that so we have plenty of cash to move from data to data readout. And that cash allows us to move at full speed into the next trial. So we’re assuming success in the summer, and we’ve already packaged our drug for the second trial that we’ll initiate before the end of the year. So, we’ve cash for that.

Daniel Levine: And what’s the plan for raising additional capital?

Clarke Atwell: So right now, as you mentioned, we’ve come out of stealth. We have been spending a lot of time with potential other investors in our series B, looking to investors who already augment the investors we have. So currently we have Novo, RA, Janus, and Mass General as our investors. The names, as you would know, Janus, Novo, and RA are large crossover investors and participate all the way through IPO. So, we’d like to add with people who have the same sort of phenotype as them. I’ve been very heartened by the fact that we’ve met a lot of receptivity with those type of investors. And the plan would be to move from there to an IPO in the middle of 2025.

Daniel Levine: Clark Atwell, CEO of Claris Bio. Clark, thanks so much for your time today.

Clarke Atwell: Thank you, Danny. I appreciate it.

This transcript has been edited for clarity and readability.

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