Learn about a gel that treats dry eye symptoms by engaging the central nervous system
In the latest episode of The Ophthalmic Project, Mark Dlugoss speaks with Tom Mitro, President and CEO of Signal 12, to discuss an innovative approach the company is pursuing for dry eye disease.
Mark Dlugoss:
Currently, there are over 10 major pharmaceutical companies, as well as many small companies, developing treatment options for dry eye disease. These options include drops, ointments, anti-inflammatory drugs, and nanotechnology. There are also treatment options on the horizon that could open the eyes of clinicians in their efforts to treating dry eye disease.
Hello, this is Mark Dlugoss, senior contributing editor of Ophthalmology 360, and welcome to The Ophthalmic Project, powered by Ophthalmology 360.
In today’s edition of The Ophthalmic Project, we will learn about a company that is developing a rather unique treatment that addresses the symptoms of dry eye disease and other related eye diseases by engaging the central nervous system to produce the body’s own tear film.
Joining The Ophthalmic Project to discuss this unique approach of dry eye disease is Tom Mitro, president and CEO of Signal 12. Tom, welcome to The Ophthalmic Project.
Tom Mitro:
Mark, thank you. I think it’s quite an honor to get interviewed by you and your organization that you represent. We look forward to being able to tell our story over and over again, so thank you very much, Mark.
Mark Dlugoss:
The crazy part about this, this is really a unique approach, and I think our viewers are going to be very interested in what you have to say.
Let’s begin our discussion with an overview of Signal 12. Can you provide a history of the company, how Signal 12 got formed, its mission, its focus, and what’s the company’s role as an ophthalmic company?
Tom Mitro:
Sure. Thanks, Mark. Signal 12 has actually spun out of a company earlier this year, that is 2024. The company it spun out of was GLIA. GLIA had done a lot of very important work on our product, Pro-ocular, to set us up for the success that we’re about to have.
As an example, GLIA developed a formulation and did all the CMC work to get the stability going for our product. They did the pre-clinical work, which established our MOAs that we like talking about, which are certainly unique.
They built a tested patent franchise of about 83 patents in 49 countries, which is amazing to see how well-protected our product is.
Importantly, they completed 3 phase 2 trials. Now, 2 of those trials were done in very unique, rare, and very tough-to-treat patients with dry eye. The first one is oGVHD or ocular graft-versus-host disease. The second is Sjögren’s syndrome. Both those trials were very successful reaching statistical significance in many signs and symptoms. We really look forward to telling that story more and continuing the progress of our company as we continue to pursue our product for the treatment of oGVHD and other dry eye conditions like Sjögren’s syndrome.
Mark Dlugoss:
Okay. Tom, you recently joined Signal 12. I think it was in August, wasn’t that sometime in the summer?
Tom Mitro:
That’s right.
Mark Dlugoss:
As CEO and President, for the viewers who don’t know about you, can you offer a little background about yourself and who you are, what you’ve done, what you accomplished, and what does your experience and background bring to the table for Signal 12?
Tom Mitro:
Sure, Mark, I grew up at Allergan. I spent the first 24 years of my life there. Early on in my career, I moved around the country in various sales and marketing positions, taking on different positions. After that, I came in and really started doing new initiatives at Allergan.
As an example, I started our managed care marketing department. Now, obviously a managed care marketing department is very commonplace, very important now in the industry, but people didn’t have a managed care marketing department at that time, so nobody really knew what to do. They put me in charge of that, sort of figured that out. After that, I started our generic drug subsidiary. We were actually the second company in this country to actually genericize its own products. Half the people thought we were foolish. The other people really didn’t know what to think, but we genericized our own products, and now that’s a very commonplace strategy to take as products end up losing their patent.
Then we started our skincare strategy and ran our program there around the world, including the aesthetic conditions for Botox. Then I ended up in e-business back when everybody was going crazy about the internet. In fact, that’s back when Walmart.com was worth more than Walmart. We started a company there and began a company with Essilor and J&J and Allergan to look at principles of and interesting things we could do with the internet.
I left Allergan, and then went on to a company called ISTA. I joined at an interesting time. We were out of money, and the 1 product we had failed its phase 3 program. We were out of products and out of money, but we turned that into a success. We got 4 products into our portfolio, 3 of which became market leaders in the market in which they competed. Ended up selling that company to Bausch + Lomb.
Then finally, I went to Aerie [Pharmaceuticals] where I was the president and COO of Aerie. I was employee number 7. We had a nice run there. We got 2 products approved in the United States and in Europe. They were new glaucoma medications, the first new glaucoma medications in more than 20 years to enter the market. We built a facility, a manufacturing facility in Ireland, and we ended up, when I left, that the employee ranks were over 400. We were quite successful with those companies as well.
One of the things I bring to a company like Signal 12 is the ability to start something and grow something and to turn it into success. Now, not that everything I touched turned into a success, that’s not it at all. Point of the matter is with enough persistence, diligence, luck, and creativity, I think you can really make things happen. That’s what I found in my career. That’s what I’m planning on certainly doing here.
Mark Dlugoss:
Great. Well, Signal 12’s leadership team has a strong ophthalmic experience. I was looking on your website about all the different individuals who had joined your company that can make a definite significant impact to Signal 12’s growth and development. Can you highlight the experience that the top executives, the board of directors, and the clinical advisors are providing Signal 12?
Tom Mitro:
Sure, I’ll be happy to. Our board has tremendous depth of ophthalmic experience. They’ve started, they’ve built, they’ve managed, and importantly, they’ve sold their ophthalmic assets or companies that they’ve run. I’m sure the listeners will recognize these names on our board, Vince Anido, Jim Mazzo, Bob Dempsey, all of which have just tremendous experience running ophthalmic companies. Now, in addition to those people, we also have Ken Sawyer, who is one of our co-founders, along with Dr. Wei Wei Chang, who’s another one of our co-founders. Ken was also the previous CEO of Par Pharmaceuticals.
Now, if you go into our management team, you’ll see that we have Neil Edwards. Neil is a very experienced CFO, experienced in raising money and in building numerous companies that he has worked with, and we also have Marv Garrett, who has more than 60 FDA approvals under his belt in ophthalmology and in other markets as well too. We also have Dr. Pamela Gallin, who’s a well-known, very well-respected ophthalmologist who provides a lot of clinical insights into the products that we are discussing and the things that we are discussing about developing.
If you go to our clinical advisors, we’re happy to say that we’ve got fantastic advisors. We start with Francis Mah down in San Diego, go up to Sam Garg, Jim Tsai, and Paul Karpecki. We also have Dr. Katie Luo and Stanley Chang as our clinical advisor.
Both from the advisory standpoint through the board, through our management team, we’ve just got a wonderful high-powered team of advisors. By the way, that don’t mind saying what their opinion is and can’t stop them from saying it. That’s an awful lot of fun and quite a challenge to manage all that.
Mark Dlugoss:
I’m sure it is, but provides a lot of good input for you too as well.
Tom Mitro:
Sure.
Mark Dlugoss:
I know some of those people you mentioned, so I could just imagine. Okay. Signal 12 obviously is developing a unique treatment approach to treating dry eye diseases like ocular graft-versus-host disease and dry eye disease. It’s a gel called Pro-ocular, that treats dry eye disease symptoms by engaging the central nervous system. Before we get into the details of Pro-ocular, can you explain how this approach came about? This is totally unusual, and how did the ophthalmic researcher to discover that they could treat dry eye by addressing the central nervous system? To me, it is totally fascinating.
Tom Mitro:
It is truly fascinating. It really is. This idea was born out of medical necessity, which is interesting as well too. The medical necessity was actually in one of our co-founders, Ken Sawyer. Ken had a very debilitating, very serious eye condition called zoster ophthalmicus, and he was losing the sight in his left eye and losing it very rapidly. There was really nothing they could do. He would go to ophthalmologist after ophthalmologist trying to find someone who had some idea of how to treat this condition and stop the progression of the disease and could really get no success anywhere. He couldn’t take eyedrops. They were not working at all. Today’s treatments just weren’t working at all. He began working with Dr. Wei Wei Chang, and they both had done some work with progesterone before and knew that it was a highly-selective and highly-potent molecule that had a lot of characteristics that they could work with.
They began working with progesterone, but they knew they couldn’t put progesterone in the eye, so they had to find another way to deliver it. They began working on different ways of delivering medications into the body so that they could actually get it to do its work and show its effectiveness. With that, through experimentation and trial and error, they found that applying progesterone to the forehead would create immediate tear flow in a person’s eye, even though Ken’s tear ducts were shut down. When you put that on their forehead, it immediately began producing tears again and reducing pain.
After they found that it worked, then they had to find out what the reasons why it worked, and that’s what they did through the MOAs. That was really based on medical necessity, as I said, and solving Ken’s problems, and he’s very happy that he did it. So are we. That’s how it all came about, Mark.
Mark Dlugoss:
That’s just amazing to me. When I heard that you guys were doing this, I go, “Wow, this is definitely unusual.” It’s not even the eye per se. It’s basically the forehead.
Tom Mitro:
That’s correct.
Mark Dlugoss:
It’s crazy. By treating oGVHD and dry eye disease via the nervous system, could Pro-ocular revolutionize how clinicians treat dry eye diseases as a whole?
Tom Mitro:
Yeah. I honestly believe the answer to that is a resounding yes. The fun thing … I could tell you why I said that, but the funnest thing I have is when I speak to one of my friends in ophthalmology and say, “Hey, I want to tell you the company I’m involved in,” and they’ll say, “Okay, give it to me quick because I’ve only got a couple of minutes.” When I start talking about this product and the forehead delivery and the neural signaling that’s involved in the product and all this kind of stuff, I find them sitting down and spending a half an hour with me. They are so fascinated by it. It’s quite interesting, but here’s why I think it could revolutionize things. First off, as you said, this is not an eye drop. It’s not an eye drop. It’s an aqueous gel that’s applied to the forehead. In fact, I’ll show you how I do that. This is the tube that we have here. You do a couple of dashes on your finger like this, you apply it to your forehead, and then you walk out the door.
Mark Dlugoss:
It’s basically the whole forehead, basically, huh?
Tom Mitro:
That’s right. That’s right. That’s from eye to eye. You rub it in there. Just imagine treating eye conditions without an eye drop. We all know that patients and practitioners have fought with eye drops for as long as eye drops have been in the market.
There have been many, many, as you well know, articles written in peer-reviewed journals that discuss the issues that patients have, be it they put in too many drops, they completely miss their eye, they contaminate the bottle, a slew of other issues that they have with eye drops. Those issues go away, and convenience is brought in to replace that.
In fact, interesting too, one of the things, I saw a survey done by one of the other ophthalmic companies, and the survey results was on their website. They said the last year survey was done on 100 consumers. Consumers rated eye drops the third most difficult way to self-administer a medication out of 11 choices that were given. The 2 that were more difficult than eye drops, 1 was eye ointments, makes sense, and the other is suppositories. Taking eye drops out of anybody’s equation will certainly revolutionize and improve their quality of life.
The other reason that I think this is revolutionary is this uses something that other products don’t. It’s called neural signaling. What’s neural signaling? It’s using neurons to communicate with the brain. This doesn’t enter the bloodstream like most products do. It doesn’t get into your systemic system at all. It stays on top, using neural signaling to communicate with the brain to cause the positive effects that the product brings.
Mark Dlugoss:
That’s incredible, Tom. That’s just an incredible story.
Tom Mitro:
It really is fascinating. It really is.
Mark Dlugoss:
Let’s get into the details of Pro-ocular as the gel is called. What’s its mechanism of action, and how does it target the underlying immunological processes that occur in dry eye disease, and basically, how does it work and how does it … Well, you showed us how it’s applied, but how does it work in the system?
Tom Mitro:
Sure. First off, Pro-ocular utilizes transappendageal delivery to stimulate the ophthalmic branch of the trigeminal nerve to cause the production of endogenous, natural, non-irritating tears and anti-nociception, which is relief of pain in the cornea. Now, let me back up a little bit. What’s transappendageal delivery? Transappendageal delivery is delivery via the hair follicles, which explains why we apply Pro-ocular to the forehead. The forehead has a very high density of hair follicles. In fact, the forehead has 10 times the amount of hair follicles than any other major body part that you’ll find. In addition, the forehead also has a high number or high density of nerve endings for the ophthalmic branch of the trigeminal nerve, which plays a very important role in our MOA. That’s why you apply it to the forehead. Now, going a little bit more in depth, Pro-ocular utilizes afferent neural signaling via the ophthalmic branch of the trigeminal nerve to communicate with 2 specific areas within the brainstem spinal trigeminal nucleus.
First off, what’s neural signaling? It’s using neurons to communicate with the brain, which is the exact purpose of neurons. Neurons are nerve cells that send signals to and receive signals from the brain. Now, in the case of Pro-ocular, it utilizes afferent neural signaling to alter c-Fos. C-Fos is a neuron. C-Fos expression in two specific areas of the brainstem spinal trigeminal nucleus. The first is the Rostral Vi/Vc area, and the second is the caudal Vc/C1 area.
Putting it all together, for an application of Pro-oculor stimulates neurons, specifically c-Fos neurons, to induce increased expression in the Rostral Vi/Vc area, which increases tear flow and homeostasis and tear production, and decreases c-Fos expression in a caudal Vc/C1 area that reduces and modulates corneal pain. By the way, that MOA there is documented in a published paper by Meng that can be found if all of our readers wanted to look into it with any bigger degree.
Mark Dlugoss:
I might check into that. I just amazes me how that all works. It’s amazing.
Tom Mitro:
It amazes me too. They were telling me this, and I’d say first off, “Are you kidding me? Secondly, when they said, ‘no,’ I’d say, ‘It’s amazing how we could be doing so much in ophthalmology in so many different ways, and all of a sudden you find a whole new pathway.'” It’s like you open up a door to your house that you never knew existed, and now you’ve got all these wonderful, wonderful benefits of it. We’re quite excited about our future.
Mark Dlugoss:
As you should be. It’s incredible, especially if it moves totally in that direction.
Tom Mitro:
Sure.
Mark Dlugoss:
What are some of the clinical features behind Pro-ocular?
Tom Mitro:
Certainly, Pro-ocular relieves dry eye very, very rapidly. You’ll find that within minutes of applying Pro-ocular to the forehead, you’ll immediately feel that your tears get produced. It relieves the symptoms of dry eye, absolutely no doubt about it. It also reduces blurry vision, which is very common with dry eye patients. By the way, it doesn’t cause blurry vision. As you know, many products today with their eye drops cause blurry vision when you put them in their eye. Obviously, this doesn’t cause blurry vision. It relieves blurry vision. It certainly decreases inflammation, which is painful for patients with their dry eye medication because Pro-ocular or progesterone has anti-inflammatory properties.
It’s obviously very, very convenient. I was at a baseball game back in baseball season with a person that was using Pro-ocular. She took it out of her purse, put it right on her forehead, rubbed it on her forehead, ready to go. Didn’t have to put an eye drop in, all that sort of thing. Anywhere, anytime.
It’s very well tolerated. You’ll see from the AE profile, and as I always say, its such got unparalleled ease of use. I think that this is just unparalleled ease of use. Those are some of the benefits that we see.
Mark Dlugoss:
Okay. Before we get into the clinical trials, my next question is up to this point in the trials, have any patients experienced any side effects with Pro-ocular?
Tom Mitro:
Sure, of course they have. There’s really 2 side effects that have occurred in our phase 2 trials above a 2% rate. Both of them are fairly interesting. The first is headache. There were actually 17 individuals that registered a headache in our trials. However, in 14 of the 17 cases, the headache occurred only once. It didn’t repeat, and it was very mild. The second AE was rhinorrhea or runny nose, but it had the same phenomenon. That is in 5 of 7 cases, it occurred only once. It didn’t repeat, and it was very mild. In fact, Mark, if you look at all of our trials, no patient has discontinued from our trials due to an AE that was positively related to the product itself.
Mark Dlugoss:
Interesting.
Tom Mitro:
Very clean profile.
Mark Dlugoss:
Pro-ocular has just completed its phase 2 clinical trials for treating all severities of dry eye disease and other autoimmune disorders including oGVHD and Sjögren’s syndrome. Can you give us a synopsis of the results of the phase 2 clinical trials, and what were the patient outcomes, and what endpoints were achieved?
Tom Mitro:
Sure, certainly, Mark. First off, Pro-ocular performed very, very well in the phase 2 clinical trial. It just makes us very excited as we get into phase 3. The first trial was oGVHD or ocular graft-versus-host disease, and for people that are listening that haven’t heard of that before, it is a very severe debilitating form of dry eye where it robs patients of not just their eyesight but also their quality of life. It’s a very serious form. It’s a rare disease that’s a complication of bone marrow transplants, and here’s how the trial worked. First off, we had 26 endpoints that we assessed at 3 study visits: week 2, week 6, and week 10. If you looked first at week 2, 9 of the 26 endpoints achieve statistical significance that the P is less than 0.05 level. One-third of the endpoints, 9, achieve stat sig at the 0.05 level at week two. Very, very quick acting.
If you look out at week 6 and week 10, you’ll see that 50% of the endpoints achieve stat sig at the 0.05 level. Those endpoints included not just signs, but also symptoms. Both signs and symptoms were relieved in week two, six and week 10, so very, very good. That study was extended past week 10 out to week 117, so two and a quarter years, which is really unheard of for a phase 2 trial, especially phase 2 trial for dry eye or something along that line.
If you go out to week 117, you see no tachyphylaxis, you see no efficacy drift, no loss of efficacy through that period of time. We’re quite excited about the efficacy was held throughout that entire time, so it just looks like we’ve got a product with not just good effectiveness, but also fantastic persistence through two and a quarter years at least.
Now, the other trial we did was in a subset. We looked at Sjögren’s patients. Sjögren’s was a subset of another trial that we did. Sjögren’s, we did 62 assessments, and people listening know that Sjögren’s is a very severe form of dry eye as well. We really put this product to the test, as you can see, looking at oGVHD, as well as Sjögren’s. With 62 assessments from week 2 through week 12, total assessments. In that period of time, 53% of the assessments achieved stat sig at the 0.05 level. Again, involving both signs and symptoms of dry eye. We were quite happy with that. That’s remarkable. As you know, many products have been tried as treatments for oGVHD and for Sjögren’s, and nothing has really turned out to be a success in the marketplace. Certainly, nothing has shown the success of hitting stat sig in so many signs and symptoms of dry eye. We’re quite excited about what this could bring to the severe dry eye marketplace like oGVHD and Sjögren’s symptoms, as well as regular dry eye as well.
Mark Dlugoss:
Great. Signal 12 is now preparing Pro-ocular for phase 3 trials. Can you provide an update of where the company stands right now, and when you expect to begin the phase 3 trials, and when do you plan to complete that trial then moving forward to a potential …?
Tom Mitro:
Sure. Here’s a couple of thoughts for you. We’re working with the FDA about our phase 3 program. In fact, we’ll have our pre-phase 3 meeting in the first half of 2025. At that point, we’ll start our phase 3 trials. Our phase 3 trials will probably be 2 phase 3 trials. One will last about a year. The other one will last about a year and a half, depending on the treatment period, the 2 different treatment periods for the 2 dry eye products, but we think that they’ll be quick to run, comparatively speaking, to other trials, and we think we can finish those within a year to a year and a half of when we start. Of course, the big thing we’re doing right now, Mark, is we’re raising money or attempting to raise money at this point, and as soon as we get that money in the bank, the sooner we’ll start our phase 3 program.
Mark Dlugoss:
Okay, good. With the initial success of Pro-ocular and the possible treatment also for oGVHD and dry eye diseases and Sjögren’s, does Pro-ocular have any other innovative applications in the ophthalmic arena? If so, how is the company exploring those options?
Tom Mitro:
Yeah, well, the first 2 that are really unique are obviously, like we’ve been talking about, is oGVHD, which there is no approved treatment for ocular graft-versus-host disease, nor Sjögren’s syndrome, so the FDA is highly interested in getting a approved product in the marketplace for that. I think we’ve got doors that are being opened for us. We just have to make sure that we do the right things and show the right things in our trial to get those products approved.
The other thing I’ll mention, to show you the application here, in our patent, as I said, we have 83 patents covering 49 countries. We have over 350 products that are mentioned in our patents. It just shows the application of this just isn’t a small segment of ophthalmology. It’s not just all of ophthalmology. It’s much more than that, including many systemic diseases that are very debilitating for patients.
Obviously, we don’t have arms big enough to tackle 350 indications by ourselves, but certainly that’s what our patent estate will cover today for us. We think that as years go on, you’ll see this type of application, and you’ll see neural signaling coming in and affecting many sort of diseases from eye diseases through many others throughout medicine.
Mark Dlugoss:
That’s an amazing story. Tom, our discussion today has covered a lot of information about Signal 12 and your evolutionary approach to treating dry eye disease. Are there any other points of discussion we may have overlooked, or is there anything you’d like to add regarding not only the company Signal 12, but Pro-ocular?
Tom Mitro:
No. This is what excites me about ophthalmology and optometry, eye care. It’s full of people, be they practitioners, be they industry folks, be they anywhere in between that have interesting ideas. I just think what this shows you is that we all have to be able to listen to these ideas. As I’ve said, when I speak to ophthalmologists, and I start talking to them about Pro-ocular and all this kind of stuff, commonly they say to me, “Is this one of your jokes?” I’d be, “No, this is not. This is real.” They sit down for half an hour and hear about the entire story of our product.
That’s the thing that excites me most about ophthalmology is they’re very inquisitive, very curious people, that if you’ve got an idea, people will sit down and listen. We just have to make sure that eye care continues to do that because eye care will continue to progress if people continue to do those sorts of things.
Mark Dlugoss:
I totally agree with you, Tom. I think it’s one of the greatest medical arenas to be in and be a part of because nothing is ever … Even when things fail, they don’t really fail. Someone comes up, looks at it and revisits the project and boom, we have a new product that’s going to work.
Tom Mitro:
That’s right. I agree with you, 100%.
Mark Dlugoss:
Well, that concludes today’s Ophthalmic Project podcast. I want to thank Tom Mitro for spending some time discussing Signal 12 and his plans for developing his concept for treating dry eye disease and oGVHD. I also want to thank you, the viewers for watching, and I hope you’ll join us again for the next edition of The Ophthalmic Project.
