Dry Eye remains one of the more dynamic sectors of ophthalmology with Shire’s recent news about its lead Lifitegrast product moving toward FDA approval. Ora knows Dry Eye better than most, and Vice President George Ousler helps fill in the blanks about Dry Eye’s future. Ora also published a paper in the October issue of Review of Ophthalmology, Delving into the Dry-Eye Pipeline. To access the paper, go here.
George has 20 years of pioneering pharmaceutical development in the area of dry eye. He has authored over 200 publications on dry eye and has been invited to present his research at numerous national and international symposia.
Tom Salemi: Hi, George, welcome to the Podcast.
George Ousler: Hi, Tom, thanks so much for having us.
TS: It’s great to finally connect. Dry eye has been on fire lately. There’s a lot to talk about. And just this week Shire released its clinical data on Lifitegrast after the week before announcing a bit of a speed bump. What was your take of Shire’s position with Lifitegrast? It seems like all systems are once again seem to be go.
GO: Yeah, Tom. So this is definitely very exciting news for Shire, and really for investors and patients around the world. It looks as though with Opus 3 demonstrating a positive primary endpoint for symptoms, that they’re one step closer to a potential approval here. As you can see in the press releases, it looks like Shire is ready to submit or resubmit their NDA the first quarter 2016. We’ll certainly see if this is enough clinical data to bring it to market. But it is exciting to see confirmation of symptoms in the Opus 3 trials, which we all know dry eye is a symptomatic driven disease, so to have additional relief there would be great. Also it’s exciting to see that there’s a product here that potentially will treat both signs and symptoms, which we know is different, and currently not available in today’s market.
TS: How long has Aura been focused on the dry eye area? As I said earlier, there’s a number of potential treatments that are popping up, both in the drug and device side, but this is a space where you’ve been paying a lot of attention to for quite a long time, correct?
GO: That is correct, yeah. Aura has been in business for over 35 years to date, and really has targeted all different indications within ophthalmology. Specifically, in dry eye we’ve been involved for a little over 25 years now. And this has given us a great opportunity to evaluate many of the therapies that have been looked at over the years, everything ranging from some of the early barrier function type therapies to the more recent new chemical entities to treat dry eye. So we’re in a unique position, and an honorable position where we’ve been able to see how the different therapeutic approaches – sorry. We need to reset on this one, sorry.
TS: Sure. Want me to re-ask the question?
GO: Yeah, that would be great.
TS: OK, great. The question wasn’t worded that well, either. All right, we’ll start in 3 seconds. As I stated at the start, there’s a lot of news popping up in the dry eye area. It seems like a lot of things are coming to light around this time. But Aura has a long history in dry eye. What services do you provide, and how long have you been helping companies to come up with new therapeutics for dry eye?
GO: Sure. Yeah. So Aura has been in existence for over 35 years in the area of ophthalmology. Specifically, we do a lot of clinical research across all indications. Specifically for dry eye, we’ve been involved for a little over 20 years now. This has put us in a unique situation where we’ve had the opportunity to evaluate various therapeutic approaches to the treatment of dry eye, probably over 90% of drugs that have been evaluated over the years. This ranges from everything, barrier function type therapies to NCE’s and – yeah. So we basically provide clinical services. We’ve been very involved in the development of the clinical regulatory pathway over the years. We’ve developed a number of clinical models and methods which help to reduce the variability associated with a disease like dry eye and enhances the likelihood of success for evaluation of a therapy, hopefully towards approval. Beyond the clinical services, we also have preclinical formulation services and all the additional seroactivities such as monitoring and you know, the other services. But yeah, we’ve been involved for quite some time, and it’s really exciting to see now that things are happening, and we’re seeing many programs go from phase 2 into phase 3 and are approaching approval.
TS: What is it about this time that is causing us to see so much movement in dry eye? There’s been a lot of work and a lot of attention paid to it. But are there other developments, changes at the FDA, changes in the market, changes in physician attitude that have sort of helped this sector mature?
GO: Yeah. So there’s certainly been an evolution in the regulatory requirements. The FDA has always been very consistent and helpful in guiding sponsors along their dry eye pathway. But we do see that some of the regulatory requirements in so far as evaluating signs and symptoms in separate trials rather than within the same trial has evolved. I think we’re seeing this with the Shire compound, Lifitegrast. This is the approach that they’ve taken. And ultimately it may be something that’s really going to help bring more products to market. Beyond regulatory evolution, we have seen that there’s many more potent agents and evolution from things like barrier treatments. There are new technical entities being investigated in ophthalmology for the first time. And not only that, but different delivery mechanisms. So we’re seeing that there’s formulations that help with making certain active compounds more soluble. There’s different unique delivery mechanisms to help with the agents to stay on the ocular surface for longer periods of time. And at the end of the day, this all helps with enhancing potency and activity of the compounds. Another category is that we’ve really learned, we’ve evolved our understanding of dry eye, the disease itself, and how to study it. And what we’re really doing is we’re doing a better job of finding what we call the right patient, and matching that right patient to the mechanism of action of the compound that we’re evaluating. And this is a lot of the work that we’ve done at Aura over the years. What we’ve tried to design clinical methods and models which ultimately help to enrich patient populations within clinical study programs, and we reduce that variability. One model in particular is the controlled adverse environmental model that we’ve developed. And this is a ocular stress test which has a way of exacerbating signs and symptoms of dry eye, and based on a patient’s response, we can enrich the patient population to have a more homogeneous group and a group that may be more predictive in a clinical trial. Beyond that, there’s been an evolution of scales and ways of evaluating different endpoints such as corneal staining or symptomatology. So we’ve really gained better understanding around what’s a more precise method and something that’s more clinically relevant or meaningful to what we’re trying to measure. And beyond that, other endpoints, there’s been significant advancements to take something like an older evaluation of tear production or tear volume and try to have a more evolved way of measuring this tear production. So things like fluorophotometry. Also looking at tear film stability, there’s something called the ocular protection index, which looks at not only the time at which the tear film becomes – breaks apart, becomes less continuous, but it’s really looking at the quality of the tear film itself. So there’s a variety of different endpoints that have evolved. But at the end of the day, with our improved understanding of disease, the dry eye disease, as well as how to evaluate and enrich patient selection, we are seeing that compounds are having a better chance of demonstrating efficacy. In fact, when we look at dry eye studies today versus 10 or 15 years ago, the screening and enrollment rates have dropped significantly, meaning if we screened 100 patients a while back, we’d enroll 80 patients into a dry eye study. Nowadays, we screen 100 patients and we enroll only 40. But what that tells us is that we’re finding the right patient and we’re doing proper enrichment, and ultimately we’re seeing better study results as a result of it.
TS: What happens to the other 40 that aren’t enrolled now? Is it just they didn’t technically fit the dry eye criteria?
GO: It’s not that they didn’t meet the criteria of dry eye. But what it tells us is that we know there’s multiple etiologies for dry eye. We know that a patient can have a deficiency in any one of 3 tear film layers, so that could be aqueous, lipid or mucin layers. And there’s even other categories: neuro loop dry eye and more. So what’s critical now in our understanding of dry eye is how do we find the right patient that is going to benefit from a certain mechanism of action of a compound that’s in evaluation. So the 40% or 60% that may not be included in a particular dry eye study may just not be those who were right for that mechanism of action for that particular product. And again, it’s all about finding the right patient and enhancing our likelihood of success. And it makes good clinical sense, too, because we only want to test a drug on patients who ultimately will respond to that drug.
TS: We’re seeing some innovation on the medtech side as well. Obviously this year Allergan made some news with its acquisition of Oculeve, which is got a neurostimulation device that is supposed to encourage the production of tears to alleviate dry eye. What do you think of approaches like that? Do you see more coming from the medtech side?
GO: Absolutely. There’s a very healthy pipeline on the pharmaceutical side, but as far as medical devices in the treatment of dry eye, we’re seeing that is a growing and an active area as well. The Oculeve tear production neurostimulation device is a very interesting approach. What we see is that this is an acute treatment for dry eye that we’re going to have a mechanistic improvement in tear production immediately upon using the device, and some of the earlier data really suggests that this will be a powerful product, and one which that will address symptomatology and other signs of dry eye over time. So that’s very interesting. And I think an approach like this also is one that will be considered quit broad-acting, that it’s going to really help a variety of dry eye patients. Really, any dry eye patient that, whether it’s a mucin deficient, aqueous deficient or lipid deficient, they’re going to ultimately benefit from increased tear production. So yeah, we have high hopes for this product and device for dry eye.
TS: What impact do you see Lifitegrast having on the market? Is this the kind of product that will steal large market share, piece of the market, or does it – I don’t know, does it sort of lift all the boats and just draw more attention to dry eye and really help other therapeutics in dry eye grow business as well?
GO: Yeah. So Lifitegrast is an anti-inflammatory. What’s interesting about this agent is that if they have the label that is intended here, it’ll be the first therapy that addresses both the sign and symptom of dry eye. And that will be unique to the market place on the Rx side. The symptomatology is a key piece because ultimately it’s a symptom driven disease, and patients should benefit from the use of Lifitegrast to make their eyes feel better. Beyond that, they also have efficacy on corneal staining. And that’s a very traditional hallmark sign of dry eye. So it would be a very good addition to the options for the treatment of dry eye. Again, it will be the first product that has efficacy in both the sign and the symptom. So I think it’s going to be nice to have additional choices. As you indicated, it’s going to be good for the whole market. There’ll be a lot more attention to dry eye and I think overall efficacy. So it really should help move the market forward. The other thing that’s wonderful about it is it will demonstrate that there is a chance or a way to have additional dry eye therapies approved. And this is great for patients, but also the whole industry, where there’s significant R&D efforts underway for developing treatment for dry eye, but beyond that, there’s very large investment community that’s interested in seeing more dry eye therapies come to market. I do think that since there are so many different therapeutic approaches to treating dry eye, we are going to see in the future what we call a polypharmacy for the treatment of dry eye. There will be multiple options and choices. So there’ll be anti-inflammatories. There may be hormonal therapies for dry eye, secretagogues specifically of mucin, additional agents that will be really interesting in the underlying issues of dry eye, so the neuro loop of dry eye. But it will be a polypharmacy, and there may be patients who are on more than one therapy and some adjunct therapies. So we look at this as what we call a spandex market, that it will continue to grow and grow, and there won’t be necessarily just a small market share that multiple companies are fighting over. Rather, it will be a growing and multi-factorial approach to treating dry eye.
TS: Spandex market. I don’t know if I’ve heard that before, but I like the imagery. Are you having an easier time finding investigators to participate in dry eye trials? Has that ever been a problem?
GO: Um, it’s not necessarily been a problem, but we are recognizing that more and more ophthalmologists and optometrists are interested in being involved in dry eye clinical research. I think what’s causing this is the recognition of dry eye being a real disease, rather than just a nuisance, and the increased number of patients who are being diagnosed with dry eye or coming in with coming in with complaints of dry eye has really risen pretty dramatically. So investigators are interested in really helping out with that research and development and providing solutions for their patients or options to be in clinical research trials. So it’s really been an improved awareness of dry eye, and a lot more patients asking for this assistance. So we have seen that more and more investigators are interested in participating.
TS: Terrific. And just finally, you’ve – Aura has issued a paper recently on dry eye. Any insights in there you’d like to share? Or is that something that’s available to anyone who’s listening to this podcast?
GO: Sure, absolutely. So the article is really looking at the dry eye pipeline and what’s in development. And it’s very exciting to see the options that may be ahead of us. As you pointed out, Lifitegrast is advancing quite quickly here, and especially with their Opus 3 results, we’ll see what – if that will be enough for the FDA to give it approval. But beyond Lifitegrast, there’s some other very interesting technologies. Specifically, there’s the company called Mimetogen and they’re developing a compound called MIM-D3. This is a TrkA agonist for the treatment of dry eye. What’s so interesting about this particular product is that it looks as though it’s targeting the underlying cause of dry eye. So we do know that over time, the cornea will decrease in sensitivity within dry eye patients. And ultimately that has a damaging effect on tear production, not only quantity but quality. So this TrkA agonist is intended to help with – so revitalizing the corneal sensitivity and ultimately allowing the eye to make more mucin and have better tear production, but tear quality as well. So this is an agent that’s been in a couple clinical trials currently. They have a very fast onset of action within one month. They’re demonstrating efficacy in both signs and symptoms, and it appears to be a very comfortable product as well. So that’s in phase 3 and it’ll be interesting to see how that one evolves. There are other compounds that are what we call modified HA’s or hyaluronic acids. HA has always been a very comfortable and efficacious product. The issue with HA generally is that sometimes it doesn’t stay in the eye for long enough periods of time. So there are a couple of companies, one called Seikagaku or SKK, based out of Japan, and Jade Therapeutics, which both have modified HA’s. And the intention is to take these HA’s and have them adhere to the ocular surface for longer periods of time. And this increased dwell time hopefully will translate into increased efficacy. So these programs are under investigation as well. This would be a very nice first line therapy for dry eye, but also as an adjunct to therapy. So if you have a patient that’s on an anti-inflammatory, but you put them on HA as well as a barrier function to help protect the ocular surface, that would be beneficial. A couple of others of note. There’s a company called Mitotech. This is a company based out of Russia, and they have a very interesting anti-inflammatory, anti-apoptotic wound healing agent. It’s called SkQ1. It’s an antioxidant that specifically targets the mitochondria. So it’s a unique mechanism of action. They’ve conducted a phase 2 where they demonstrated both efficacy on the sign and symptom in the controlled adverse environment model. So that’s an interesting one that is moving forward as well into phase 3. There’s a company called ReGen Tree. It’s actually a joint venture with a company based in South Korea known as G-tree and another company based in Washington, DC known as RegeneRx. This new joint venture is evaluating a compound called Thymosin beta 4, which is an agent that’s demonstrated wound healing capabilities, also anti-apoptotic and anti-inflammatory. This was investigated, again, in the CAE model in a phase 2 program and demonstrated efficacy. And now this new company, new joint venture is pushing forward and they’re currently in a phase 3 program for dry eye as well as for the treatment of neurotrophic keratitis. This also has shown a very fast onset of action, so it’ll be interesting to see how ReGen Tree’s compound plays out. And there’s another company called Novaliq based in Germany, and they have a cyclosporine based product with a unique delivery mechanism which really helps with the cyclosporine be more soluble. And the intention is to help with efficacy, enhanced efficacy, but also maybe minimize the stinging associated with cyclosporine. So that company is moving forward as well in the area of dry eye. So there’s a lot of activity as you pointed out at the beginning of the discussion, and a lot of hope that we’ll have additional therapies to market relatively soon, and a lot of different options and different ways of addressing the multifactorial aspect of dry eye, and hitting all the underlying etiologies.
TS: The pipeline is fuller than I thought. That’s a very comprehensive report. Is this available to the public? And how might they obtain it if they’re interested in reading more?
GO: Absolutely, yes, it is available to the public. In fact, it was just published in Review of Ophthalmology, the October 2015 issue. It was the cover focus on dry eye, and again, walks through the pipeline of dry eye, and also actually addresses a lot of the questions you had about what’s changed in dry eye and why are we seeing more successes today, and what are the advances of advanced study designs such as the controlled adverse environment, different endpoints and patient criteria. So it’s a pretty comprehensive article that I hope to be a good resource.
TS: Excellent. Well, we’ll try to make the link available to the article or the magazine in this Podcast. So George, it’s been a great overview. I understand you’re going to be part of the breakfast breakout discussion at OIS@AAO coming up. Thank you for doing that. I’m sure that’s going to be a very popular part of the conference to hear an overview from you. And I think a representative from Allergan will be there, and a few other notable folks as well. And I should have that in front of me. I’m going to do that one over again.
TS: George, I understand you’ll be taking part in our breakfast breakout session at OIS@AAO. I’m sure it’ll be a well-attended event. There’s a few notables on the panel in addition to yourself, so anyone interested in getting more information – oh, I can’t do that either because it’s not on the website. I’ll just cap it.
TS: George, thanks for joining us. I look forward to seeing your presentation. I know you’ll be part of the breakfast breakout session on dry eye at the upcoming OIS@AAO.
GO: You’re very welcome, Tom. It was a pleasure to share our thoughts today and we’re looking forward to the breakout session. I know that it’ll be very healthy discussion with some very noted individuals on the panel, so looking forward to that.
TS: Excellent. And feel free to come back any time when you’ve got more reports to talk about.
GO: Sure thing. That’s a promise.