Dr. Bala Ambati Discusses the Long Journey from Idea to Impact


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Balamurali “Bala” K. Ambati, MD, PhD, MBA, is in the Guinness Book of World Records as the world’s youngest doctor, having graduated from medical school at age 17.

In this episode, Dr. Ambati explains to host Paul Karpecki, OD, that this accelerated pace gave him a head start in meeting great people, exploring the field, doing deep dives in research, and building a strong network.

Dr. Ambati has had diversified roles over his career. “It’s been great to meld clinical work with research,” he said. “When you take the patch off somebody, that smile of them seeing again is something special.”

In addition to owning an ophthalmology practice in Oregon, Dr. Ambati is president and founder of iVeena Delivery Systems, a company Dr. Karpecki says is “really making incredible strides in advancing a treatment for keratoconus,” a degenerative disease of the cornea.

Dr. Ambati explains the company’s candidate to treat keratoconus, IVMED-80, has received orphan drug designation from the US Food and Drug Administration. He also talks about IVMED-85, which the company is developing for the treatment of myopia. Both drugs increase activity of lysyl oxidase (LOX), an enzyme responsible for natural collagen cross-linking in the cornea.

iVeena’s research started years ago with an experiment in corneal cells, comparing donor corneas to corneas of patients who had keratoconus. Said Dr. Ambati, “The journey from idea to impact is a long one that requires patience and perseverance. I think it’s key initially to secure the IP or the good patent attorney and put a team together around you to develop the business and the product.”

Dr. Ambati gives a few tips for successfully moving from concept to Phase III, including:
• Bring the right people together.
• Decide what you need to raise money for.
• Decide what to spend that money on.
• Raise enough money to get you through a Phase I/IIa study.
• Show that there are leaders in your field who are willing to back you.

Click “play” to hear Dr. Ambati discuss his fascinating journey!


Paul Karpecki: Hello, and welcome to the OIS Podcast. I’m Dr. Paul Karpecki. And I have the honor of getting to interview some of the top leaders and inventors and innovators. When it comes to the category of ophthalmology and eye care and entire space that’s involved in today, I’m extremely excited because I have a chance to interview someone who’s actually in the Guinness Book of World Records. You don’t get to say that too often in a podcast, but also someone who is really making incredible strides and advancing for a treatment for a condition keratoconus that has limited options. Although we are able to treat at this point, these patients are some of the ones who suffer the most. So of all I want to first of all, welcome you to the podcast. And thank you for making time in your busy schedule. As I say you’ve just come out of surgery. Thank you for joining us.

Bala Ambati: Thank you very much, Paul. I’m honored and happy. Very happy to be here.

Paul Karpecki: Thank you, Dr. Ambati. Tell me well, got to start with obviously Guinness Book of World Records, the youngest, you know, individual to graduated from medical school. Were you 17 I think at the time?

Bala Ambati: Yup. I’m 43. Now so I have gray hair. I’m not as young as I used to be. But yes, I graduated when I was 17.

Paul Karpecki: That is incredible. Right, tell me a little bit about why I even want to go back to the kind of the upbringing of was this just part of the family culture? Were you a prodigy early? Was it other members of your family able to achieve that? How was the process and allowing you to achieve so much so young?

Bala Ambati: So, yeah, everything I’ve done, has really been due to God’s grace and family support. And, you know, my parents and my brother were very instrumental in my academic upbringing, I learned a lot at home, I did a lot of independent study. Like all kids, I started first grade at six, or public school, my education, round up doing two years of school every year. And that’s how I was able to graduate from high school at 11. And then I went to NYU for college, and I completed my bachelor’s in two years. And so and it was off to medical school, and I went to Mount Sinai and graduated in ’95. Yeah, the time is a gift. You know, time is precious. And the Head Start so to speak, has given me time to meet a lot of great people, explore the field, really do deep dives in research, make mistakes, hopefully recover from mistakes, really build a good network of people around me who have helped carry, you know, these projects and other projects forward.

Paul Karpecki: That’s really impressive. And so it’s true, you do two years in one now that you know, you’re going to have that and it’s good to make mistakes, early failure is kind of one of those positives, if you know, can fail forward from them and learn and a little more difficult to make a you know, a to have something go wrong when it’s late in your career or in your retirement or something that’s truly a positive from that standpoint. And I love the family component that’s played a role. So you from Mount Sinai, then you went on to practice I think in Georgia, or you were on faculty there, and then now to where you’re at, and Eugene, tell us a little bit of that path as well.

Bala Ambati: Oh, sure. So after medical school, I actually did residency in internal medicine and residency in ophthalmology. So I was double boarded, in each and then I did my cornea fellowship with Alan Carson and Terry Kim and Duke. My first faculty position was MCG and Acosta, who was director of cornea there for five years. And then I moved to Moran Eye Center in Utah, where I was for almost nine years. My wife and I got married in 2015. And she had some family in the northwest and so we decided to move up here to Oregon in late 2016. So I joined Pacific ClearVision Institute. It’s a great private practice for MDs to optometrists and very busy surgically with cataract, refractive and cornea work, but the practice in July of 2019. So now in the business owner, it’s been a very interesting first year and a half of business ownership.

Paul Karpecki: That’s for sure, with a lot of things going on during that first year. I commend you, though, you’re obviously doing well through it. And I think that, you know, on the backside of what we’ve gone through, and COVID, things are looking up, and that’s a good time now to be a business owner of your practice. Tell me a little bit about the pathway and research and how you know, that developed was that early on in your career as well as part of what you did. Was that an interest that came later and how did it kind of lead even to the development of a drug like we’re talking about in terms of what the company IV No, but let’s take the research path first.

Bala Ambati: Sure. Um, I started doing cornea research in residency at Mass high near I learned from the best you know, I was one of the students of Tony Adamis, who went on to be a founder of Eyetech, and then it’s now with Genentech. And so I got to meet some of the giants in Cornea Research in Boston and continue to doing research. You know, throughout my academic career, where I had a laboratory at Georgia and in Utah was NIH funded with two, sometimes three our own grants. And fortunately, I’ve been able to keep my lab team and they’ve all moved to University of Oregon, which is in Eugene and with the Knight Campus for accelerating scientific impact, which is interdisciplinary, laboratory research, research building that Bureau has established just a year ago. And so my core group of four scientists is up here in Eugene, and we still maintain an NIH funded laboratory. So it’s been great to meld clinical work with research, when we take the patch off somebody, that smile of them seeing and there’s something special, you know, after surgery, that’s one of the best days of my week is to see, you know, an individual person. See, again, when you discover something in the lab, you’re having an impact on potentially, you know, dozens or hundreds of 1000s of people in the future. And so, that’s also very important and very special. And so I think too often, in medicine, we tend to say doctors should see patients and PhDs should do the science. But I think clinicians are uniquely positioned to appreciate what’s important and what’s feasible. And having clinician scientists be in the trenches with the laboratory scientists and lead and provide direction, I think is a key to making truly transformative advances. As far as the keratoconus research that my company iVeena at has been working on. This all started several years ago, with an experiment in cells and corneal cells so you can take fibroblasts are corneal stromal cells from normal donor corneas. Also keratoconic corneas, patients who underwent cornea transplants, and that tissue would normally be thrown away, but you can actually isolate themselves. And when you compare the two, what you find is something that’s very interesting that the cells from the keratoconic corneas don’t express as much of an enzyme or have as much activity of an enzyme called lysyl oxidase or lox. And so this lox enzyme is deficient in corneal cells from keratoconic patients, and it’s been published that lox activity is reduced in cells removed from the epithelium of keratoconic patients who undergo cross linking and that it’s reduced in cells from patients who underwent smile and that lenticule tissue if you isolate it, and compare normal smile patients to patients who have subsequently developed keratoconus, the locks activities reduced there. This is not my work. This has been previously published by Dr. Shetty and various other people finding these lox deficiencies. Separately, various other eye investigators have found lox mutations in keratoconic families. So there’s a large body of research that this native enzyme that’s responsible for collagen crosslinking in the natural cornea is deficient in patients. And that contributes directly to weakened corneal biomechanics and corneal thinning and ectasia and so on that we all see clinically. So our hypothesis from a lab perspective was how do we restore it lox activity, how do we risk you know, restore the normal balance in the cornea if you have insufficient lox activity, the collagenases that are present in tears and corneal tissue, specifically, something called MMP9 is unopposed. And so if you have insufficient lox, relative to baseline MMP9, that’s bad for corneal homeostasis. So when we look into the biology of lox, its requisite cofactor is covered. So my initial hypothesis was, can we add copper to the cells and restore lox activity? And so that was the very first experiment we did. We took normal corneal cells, we took keratoconic fibroblasts, we added copper to both. And remarkably, the both fibroblasts increased their lox activity, but the keratoconic fibroblasts came up to the normal level of normal fibroblasts levels. So we were able to restore lox activity with just copper incubation in the keratoconic cells. So naturally that led to the next set of experiments in rabbits where we demonstrated that copper eyedrops could increase crosslinking. So that was proven by biochemical testing for looking for biomarkers of crosslinking, specifically something called lnl or Lysinonorleucine. Then we assessed corneal topography, and you can take a handheld topographer to a rabbit cornea. And we found that we could flatten the rabbit cornea by about 1.7 diopters. With just about six weeks of these eyedrops. And of course safety, we observe no damage to the cornea, the lens, the retina. Now, there was no copper accumulation in rabbit, liver or kidney there was no elevated plasma copper levels. So we did all of those safety experiments in rabbits as well. There was no injection or inflammation on the ocular surface was a very well tolerated drop. So based on that cell culture work based on the work of my team and rabbits, and then also getting a series of keratoconic corneas from Frank Price, where we showed that native crosslinking was reduced. Well, I think we had a really solid foundation for moving forward with the strategy to restore lox activity, to try to increase native culture across looking.

Paul Karpecki: That’s impressive. I mean, even the 1.7 diopters is kind of what we’ve seen in research with current, you know, riboflavin, affected corneal crosslinking with UV light, so that’s impressive to see that in six weeks with a drop, but topical application.

Bala Ambati: So that was in rabbits, we were very pleased to see that amount of flattening and rabbits. The rabbit cornea is about 350 microns, the rabbit cornea is normally about 50 diopters. So even though the rabbit doesn’t have keratoconus, the rabbit cornea resembles mild keratoconus in terms of its thickness and topography. So it’s a good animal model for this.

Paul Karpecki: That’s impressive. Now, how do you go from let’s say, research idea be you know, listeners that are innovators that have come up with things have looked at the research may have come up with a possible theory of what’s gonna work to, you know, accompany lead, you have like iVeena now where you’re, of course, serving as the Chief Medical Officer, but having people surrounding, you know, creating board getting to where you’re at now, how does that process fall into place? I mean, who do you call, who do you how do you start that is to come to you with these ideas? How did you get from that bench concept, which is quite impressive, and research and animal models to a great potential to a company now iVeena starting, you know, Phase 3 trials.

Bala Ambati: Going from a project to a product is it’s a long bridge, you know, you have to build a lot of pillars along the way and as you say, get the right people together. So the company was a C-Corporation establishes C-Corpopration in 2015. And our initial investors included Park City Angel Network, from Utah, Salt Lake City Angels and a group of interested ophthalmologists mainly cornea surgeons around the country. And so with the funding from the investors as well as NIH grants, you know, we’re very thankful to NIH SPR grants for the company. We’ve been able to move this technology forward. And 2019 we commenced a phase 1/2 study in Mexico to study the question of whether these eyedrops can benefit human patients with keratoconus. So, we started this trial with Kodak Institute in Tijuana. Arturo Schad was the PI and could have Institute Dr. Schatz, very renowned cataract and cornea doctor and he’s done a lot of clinical studies for a lot of different companies. So as I recall, we enrolled over 30 patients I think about 32 or 33 patients in our study and 1/3 each, that’s two – three different arms of the study. So a third of our other patients who are enrolled in the study received placebo eyedrops third received IVMED-80, which is our proprietary formulation of these copper delivering eyedrops. So a third received agamid ad for six weeks and the third received IVMED-80 for 16 weeks. And then we followed everybody for six months. So the trial was structured to assess the impact of duration of therapy, as well as What happens after cessation of therapy probably took about six, seven months to complete enrollment. We had the final visit last December. And so we had the summary, executive summary in the clinical study report in January of this year. And what we found was remarkable. So first, there was not a single adverse event from IVMED-80. So that was very important in this phase one study phase one to a study in humans that there was not a single adverse event related to the drug, no change in cell count, no change and attracted or pressure, no injection or inflammation, it was very well tolerated. Second, efficacy wise, we observed that the group of patients that received six weeks of therapy, they may have experienced a slight reduction in K max maybe about playing for doctors of reduction in K max. But the group of patients that received the drug for 16 weeks, they have k max flattening of about a diopter relative to the placebo patients. And so we were very happy with that because we were seeing difference relative to placebo of a diopter at four months, whereas with surgical crosslinking it actually takes about six months after surgery to get to that one day after a flattening and in addition to the K max flattening, which is what the FDA requires as the benchmark for approval, we observed reduction and corneal astigmatism on typography, and some suggestions of improvement on corneal biomechanics. So and outside the US the Oculus Corvis, has biomechanic assessment capability and Kodak actually got the Oculus Corvis. And we were able to observe improved stress strain index on the patients who received IV met at for 16 weeks relative to placebo. And that correlated nicely with what we saw in rabbits that we had better corneal biomechanics and rabbits. So this kind of builds this complete picture of a drug that induces locks cells and animals increases the biomarkers of cross linking. And in both animals, and humans, flattens the cornea and improves the corneal biomechanics, without any significant safety issues to date. So based on all of that, you know, we have to go to the next step, we spoke with the FDA pre-ind meeting, and they laid out the path that was required, we don’t have to repeat a Phase 1 to a study in the US, we can proceed directly to Phase 3 studies talk through how many patients are needed, and the length of the trial needs to be in all of these things. But we have a very clear path from the FDA as to what needs to be done to get approval along the way, the FDA also granted us orphan drug designation for this product, which is key. from a business standpoint.

Paul Karpecki: That’s wonderful. I always have, you know, felt for keratoconic patients simply because, you know, when you finally could get them to a stable level of contact lenses maybe early on, or what’s necessary, things would change again, and they’d be all let down one more time. And then, you know, even the technologies we had in the past in tax and things like that, they’ve kind of worked for a bit and then they wouldn’t and then crosslinking, as you said, came along and kind of you know, halted things but if you were a fairly advanced it halted it. So it didn’t really necessarily reverse a lot. So this is a group even when they eventually have to go to a transplant the transplants had a higher rejection rates. And so it was always that patient category that whenever I made the diagnosis, you know, 10-20 years, I always thought odd. So it’s gonna be a tough path. But we’re going to do everything we can together. It’s exciting to see and I love that there’s an orphan designation, or there’s something that could really help a very needy population that would greatly benefit and a topical application to that. And then for, you know, for the future of iVeena, I think you’re working even on the potential progressive myopia. Now we’re starting to talk about, you know, billions of people around the world, what’s the theory and our thought process and how that might work and slowing down that actual length progression by working on the cornea through this pathway, Bala?

Bala Ambati: Yeah, let me see if I can just finish up on the keratoconus piece for just a minute, then proceed to the myopia. Keratoconus is a condition that affects a lot of people. It’s causes a lot of burden on patients. I think somebody did a econometric model and found that the lifetime burden of keratoconus due to reduce productivity and wages and so on educational opportunities, it’s over 25,000 that’s significant burden for patients who are in high school or college or who have just had a college. And it’s something as you note that is poorly served by a current stable of therapies, you know, as you say in tax doesn’t do everything you want it to do. transplant has some significant risks. And, you know, contact lenses only go so far and unsuitable. crosslinking. As you know, I think most optometrists and ophthalmologists are aware. It’s a bit of a mass, you know, it’s very pricey. It causes a lot of pain for several weeks and has a significant healing time with visual fluctuation for months and a significant risk of haze and epithelial defect. Sure, crosslinking is way better than a transplant. But if you can treat these patients medically rather than with a surgery, I think everyone will be happier. I’m a surgeon, I love doing surgery, but I’d much rather do a cataract or LASIK to a crosslinking surgery and I’m sure optometrists would much rather treat patients medically whenever possible. You’re asked about myopia, so I’ll just pivot over to that. So we have demonstrated that we can flatten the cornea. I flatten the cornea every week to treat myopia with LASIK, right. So, you know, if we can flatten the cornea with a pharmacologic eyedrop, then that can have a significant impact for progressive pediatric myopia, which, as you noted, is an epidemic and that’s not treatable by LASIK right, you’re not going to operate on eight year olds with LASIK. And so what we have found in our preclinical work with a related product that also delivers copper to the eye, it’s called IVMED-85 is that it can deliver drug both to the cornea and the sclera. So we’ve formulated it such that it increases not just corneal lysyl oxidase, but it increases scleral lysyl oxidase. So we’ve observed increased scleral crosslinking in guinea pigs, which are a model of spontaneous myopia, spontaneous animal model, myopia model, we’ve observed reduction of axial elongation in the guinea pig die, reduction of the vitreous chamber depths and the guinea pig eyes. And a hyperopic. Shift on cycloplegic refraction done by a masked pediatric ophthalmologist of the guinea pig eye. So in animals, this IVMED-85, which is the product name for the myopia product, as looked very promising, there’s been no, you know, safety events where, you know, seeing about one and a half or two diopters of hyperopic, shift on cyclo, and, you know, a substantive reduction of axial elongation rate and metric just chamber. So, we have some more experiments to do with animals, we’re not just guinea pigs, but also rabbits. But we are gearing up to do a phase one to a study of pediatric myopia. And that hopefully, they’ll be a longer observation period the year so we will have final data on that till late 2022 or early 2023. But I think it would be a huge market for Caribbean.

Paul Karpecki: Very exciting, what would be your advice? It’s kind of a final question here, Bala for some, you know, a clinician who, you know, or a surgeon or optometrist or ophthalmologist who finds themselves, you know, interested in research may even come across a concept that could make a potential impact on patients lives and eyes, what would be your advice for them moving forward and what steps they might take in that direction.

Bala Ambati: So, the journey from idea to impact is, was a long one that requires patience and perseverance. I think it’s key initially, to secure the IP with a good patent attorney and put a team together around you develop the business and the product. So you know, figure out what you need to raise money for and what to spend that money on in terms of cell culture work or animal work or technology development. And then, you know, raise enough money to get you through some reasonable number of patients in our phase one to a study. So talk with your friends who tend to be other ophthalmologists probably are optometrists, and you can show that there’s leaders in your field willing to back you that makes it easier for the professional investors, such as Angel Networks and so on to view you and your company as an investable concern, to build the enterprise, you need both the confidence of subject matter experts as well as the confidence of professional investors. And so I think that’s what’s made iVeena successful today is the backing of both angels and ophthalmologists as well as our grants.

Paul Karpecki: That is fantastic. Oh really wonderful insights thank you for your openness and sharing kind of a your history and so you’re so humble. And you know, in terms of that, you know, I’ve been in the Guinness Book of World Records, but also they call it pets and what you’ve done and where you’ve taken it, and congratulations on your path and now your wife and your family in Oregon and but also even the insights for someone you know, who may have a passion for this and come up with an idea that’s innovative, but doesn’t know the next steps and sharing what you’ve done and your continued success. And I expect it will only continue just in the brief time of getting to speak with you could see there’s so much potential here and so much good leadership you and the team are providing. So I want to thank you for taking time out of your busy schedule to share those insights with so many listeners in the eye care field. And certainly, you know, my hope is that the continued continued success iVeena you know, will do well, it’s going to serve an incredible need. And it’s great to have someone of your caliber and ability kind of carrying that forward.

Bala Ambati: Thank you so much Paul. Appreciate the opportunity and more wishes to the whole OIS community. Thank you very much.

Paul Karpecki: Thank you.