Towards True Epi-On

The last few years have seen some game changing innovations in the keratoconus space – thanks mainly to the development and refinement of corneal cross-linking. However, there are concerns about the impact of removing the corneal epithelium. Patients report that treatment is often painful – and endothelial damage and keratitis have been reported complications. Preserving as much of the epithelium as possible is universally desired – but is true epi-on cross-linking possible on a wide scale? To find out, we sat down with two individuals who are working on just such an approach.

How prevalent is keratoconus – and what does the diagnostic landscape look like?
 

Webb: We’ve estimated the incidence in the US for keratoconus is about 52,000 patients a year with a prevalence over three million.

Belin: Some great research – the Raine study in Australia – was recently published on this topic (1). They used current modern tomographic parameters for diagnosis and came up with 1.2 percent of the population as positive – and that would translate to a little over three million in the US.

Keratoconus is clearly under-diagnosed – mainly because the equipment used to diagnose early disease (which is really when you want to diagnose any disease, not just keratoconus) isn’t found at the screening level of the school and the optometrist.
Our approach to keratoconus should be the same as the approach the rest of medicine takes to disease – you try to diagnose disease at the earliest possible stage and then intervene before you have sequela. If you were a primary care physician and your patient suffered a stroke because of undiagnosed blood pressure, you have failed as a physician. Unfortunately, the current treatment we have for keratoconus is for late-stage disease – and you have to document progression; in other words, we have to let the disease get worse before many insurance companies will allow treatment. That is not how we should be practicing medicine.

Tell us about EpiSmart^®; how does the mechanism of action differ from current CXL treatments?
 

Belin: Well, cross-linking is cross-linking; biomechanically, you are stiffening the cornea. But to get the riboflavin into the stroma with current treatment methods, you have to remove the epithelium. As you know, that is not a completely benign process; it’s uncomfortable, there is an incidence of scarring and, although not common, there is some incidence of persistent epithelial defects. With EpiSmart, all innovations aim to maximize stromal loading of riboflavin without removing the epithelium; in particular, we’ve added sodium iodide to the drug component, which removes peroxides, protects the cornea, and catalyzes efficient cross-linking… In short, it’s pretty smart (or “genius,” as Michael describes it in “Meet the Michaels.”).

The main advantage of our approach is the rapid rehabilitation. Most patients return to their activities within 24 to 48 hours – and we can, if the patient qualifies and desires, treat both eyes. This is a major shift. Comparing EpiSmart with current approaches is a little like comparing PRK with LASIK. PRK was always kind of a single eye treatment – patients had a long rehabilitation, and it was very uncomfortable for a few days (some patients even opted not to have even the second eye done because of the poor experience they had with surface ablation). Then LASIK came along and changed the entire treatment paradigm.

Perhaps even more importantly, if you want to intervene at the earliest possible stage, you have to have a process with an extremely high risk–benefit ratio. And that’s why I like to use the analogy of statins for cholesterol. If statins had a long list of side effects, many patients would not opt to take them. Why? Because they’re asymptomatic – even though they have high cholesterol.

With EpiSmart, we have something that has such a high safety profile that we can offer it at the earliest possible stage. Again, the goal in medicine is not treating disease, but preventing disease.

The FDA will probably never let us describe this as non-invasive, but that’s really what it is. Consider MIGs – going into the anterior chamber, putting a device into the trabecular meshwork… If MIGs are minimally invasive, our procedure is non-invasive!

Tell us about your results so far – and give us a glimpse into your development timeline…
 

Webb: Back in June 2019 we finished our 2,000 patient phase II trial, which ran across nine states. And I’ll say that 2,000 keratoconic patients in 18–24 months is a lot of people, really fast! And that’s why we believe there’s a very large reservoir of patients that are waiting for a minimally invasive or practically non-invasive procedure. We did a major capital funding in September 2022 (over $30 million), and that’s propelling us rapidly into starting the phase III trial program. We anticipate that phase III will start over the summer of 2023. We hope to be in front of the FDA for approval a couple of years after that.

Belin: In terms of the results from the phase II trials, we presented some data at the major ophthalmology meetings – but it’s actually available online now, ahead of print (2).  As Mike said, we recruited over 2000 patients – the bulk of whom were keratoconic patients – but it was a prospective, randomized, controlled, open-label, multicenter trial. And that’s very different from what we’re doing in phase III, of course. Certainly, we documented the effectiveness of the treatment, but more dramatically, we showed the lack of adverse events. Our regulatory person says the safety profile is very similar to dry eye medication.

How would you like to see keratoconus treatment evolve over the next 10 years?
 

Belin: We’re actually in an unusual situation. More commonly, we may have a newfound ability to diagnose a disease earlier but no therapy to prevent progression. Here, we have a potential treatment, but the limiting factor is actually the ability to diagnose disease early. So I’d say the field needs to focus on highly cost effective tomographic screening to pick up the disease at the earliest possible stage. Admittedly, my statin analogy – despite being catchy – falls away slightly in this regard because statins are used by patients who may not even have disease. In the case of keratoconus, we are treating true disease, but we’re reliant on much earlier diagnosis.

Webb: I agree with Michael. In 10 years, I would also like to see schools screening for keratoconus, and for that to be made possible with an economically viable tomographic imaging system. We know we can diagnose keratoconus prior to vision loss based on the Belin framework (3). And so my dream is to see all these kids treated before they have any significant vision loss whatsoever. Additionally, I’d like to see this technology and the treatments made accessible across the globe. Keratoconus prevalence in Africa and the Middle East is five times higher than in Western Europe and the US. In those areas, people don’t have ready access to corneal transplants, so they can go untreated for years, which impacts their socioeconomic standing and ability to support their family. Moreover, epi-off cross-linking isn’t viable in those areas because of a lack of resources and follow up which makes it too invasive and risky.

Our technology should be translatable to those environments quite readily because it doesn’t require surgical or chemical disruption of the epithelium, meaning that people can go back to work or school quickly.

Belin: I’d like to see the same shift we saw in glaucoma – something I am unfortunately old enough to have been around to witness. When I first started residency, the only drug available was pilocarpine, which patients hated because it caused browaches, headaches, miosis, and night vision problems.

Back then, clinicians didn’t intervene early; they would wait until a patient had field loss. And even then, patients were very resistant to taking medication. The first breakthrough came with the Timoptic^® beta blocker, which was relatively well tolerated. Now, we have more and better offerings; we even have once-a-day drugs. In short, if someone who is at risk of glaucoma presents with an IOP that is slightly high, we will commence treatment because the treatment is far more benign than the potential risk. That’s exactly where we want to get to with keratoconus.

Webb: I’d also like to see more recognition of and research into the genetic component of keratoconus, which could really help feed into the screening needs. Before I started this project, I’ll admit that I had never heard of keratoconus, but I was really fascinated by it. About a year into the project, I found out that I had two first cousins on my mother’s side with keratoconus. Notably, they’ve been holding off on treatment – waiting for something that is minimally invasive and does not require long recuperation or risk their basic vision. I hope that they won’t have to wait much longer.