Episode Transcript
Speaker 0 00:00:00 Welcome to the dry eye coach podcast series. Click on dry eye. Your insider passed to the most exclusive dry topic. The series will raise awareness about the current and future state of ocular surface disease. The podcast will focus on a variety of topic.
Speaker 1 00:00:15 In today's episode, we have the pleasure of speaking with one of my partners and mentor in John Shepherd, who is a president of Virginia eye consultants. John is a cornea on uveitis specialist, who I worked with for the past 14 years between him Steve scope or Liz you and Albert Chung. I mean, you all helped me with my 14 years of cornea fellowship that you like to tease me about as well. Uh, thanks John, for joining us on click on dry eye.
Speaker 2 00:00:39 It's a real pleasure. Well, good to see you and good to talk about this important ocular surface condition.
Speaker 1 00:00:46 So John, I know your practice, but not all the listeners may know of it. So can you tell us a little bit about Virginia eye consultants and eyecare partners?
Speaker 2 00:00:54 Absolutely. Uh, we've enjoyed fulfilling the role of an academic referral center in our region. Since the medical school has a, a small and all volunteer department, thus, we provide all sub-specialty care and we have what I believe to be thanks to your initiative. Uh, the leading, uh, optometric referral practice in the country. And we have a, a wonderfully interdigitated, uh, cooperation with our, uh, highly trained and, uh, proficient and many times residency trained referral optometry. These, uh, practices are medical in nature. We share surgical patients with them and we share the long term follow up of a wide variety of clinical conditions when retina oculoplastic, uh, glaucoma surgical problems, corneal surgical problems arise, refractive surgery, both cataract and corneal. We collaborate together in a co-management situation. We've grown, uh, since your arrival waled about 20% a year. And with that growth, we've added, uh, practices in town.
Speaker 2 00:01:56 We've, uh, now opened a, a total of seven satellite offices and we've opened a new six room operating room across the street, an entire new new building that doubles our floor space with this, uh, continued growth. We've also enjoyed a lot of clinical research, particularly in ocular surface diseases and refractive surgery. We get a chance therefore, to use a lot of these newer medicines when they're not yet FDA approved or, uh, unfortunately carry them through a clinical trial that leads to no approval. And unfortunately, that's the, the case in the vast majority of, of new drug entities introduced into clinical research, even in phase three. So we have, uh, enjoyed being the first to use Restasis first to use SEQA first to use is U Sovi in many forms. And, uh, we were participants in neurostimulation as well as the tier via, uh, analysis at the very beginning of those, uh, concepts of trigeminal stimulation.
Speaker 2 00:03:00 We look at so many exciting new medications on the market. It's almost impossible to keep track of that, but that's what we really enjoy. That's what gets us out of bed. We have a cracker Jack clinical research department, uh, for full-time folks. Uh, most of whom are CRCs and we with our specialists and our optometry staff look at a lot of patients every week who are enrolled in clinical trials. And that's how we came to know the approved drugs, as well as the drugs that we believe to be the next approved entities in our marketplace and in our P for providing the best possible therapy for that patient sitting in your chair at that moment in time at that moment in their life.
Speaker 1 00:03:44 Hey, John, you know, you just mentioned some of the different medications that are available and, you know, the involvement within clinical research. So what are some of the biggest changes or recent innovations that, that you've seen, or what are some of the trends? And we're gonna talk about some specific, uh, entities coming up, but, uh, what are some of the biggest trends or innovations you've seen?
Speaker 2 00:04:05 I think the trends are to get away from anti-inflammatories initially we've seen the, the parasympathetic stimulation that got tier via to approval. Niclin the active ingredient and tear via has been around for decades as Chantix and anti-smoking medication. And, uh, the safety profile is there for unparalleled. And considering the fact that you get a, a small fraction of the systemic dose from the pills into the body, with the nasal spray, we're clearly reassured that this is a very safe approach for chronic use. Uh, the tier via stimulates the same pathway as the neuro stimulator, the true tier from OCUL X and then Allergan, that was a very successful intervention, but it turns out that folks didn't wanna buy the expensive stimulator and didn't wanna stick an electrode in their nose market research just doesn't tell you everything before approval, but with the, the, the spray into the nose, we have a, a new delivery route, and we have a new mechanism of action, a very brave, uh, foray into the dry eye marketplace by oyster point pharmaceuticals.
Speaker 2 00:05:13 And this is great for our patients because, you know, they, they don't have to put drops in their eyes. They don't have to have medicament in the case of a, a corneal or a uveitic or a glaucoma patient, and those who have tremors or a inability with their appropriate except to put a drop in their eye properly, or who might have digital arthritis that just can't squeeze a bottle or cervical arthritis, and can't flip their head back. Uh, they're very excited to have something to treat their dry eye, to, to produce, uh, an up upgrade in the production of the entire lacrimal functional unit that is, uh, the aqueous and the mucin and the lipid tier components. And this is synergistic with anti-inflammatories because multiple mechanisms are relevant to just about every dry eye patient. So that's, that's been a really exciting development, I think, and caring forward that new approach, uh, with a, a more patient friendly, uh, delivery system.
Speaker 2 00:06:10 We've also looked at, uh, so many of the interventions to directly manipulate the meibomian gland and starting with warm compresses, which are universally detested and incorrectly applied and, and probably inadequately utilized by most patients despite their motivation. We saw a revolution with thermal pulsation that is the, the lip and flow from tier science and now Johnson Johnson, and the Don Corb approach produces a, a warming on both sides of the lid milks. Those glands out of there gets rid of the inspisated infected, dead clogged up glands in the, the surviving my Boian organ systems in each Taral plate, and can rejuvenate the, the lipid component of the tear film, uh, magnificently because of the success of thermal pulsation. So many other companies have come up with, uh, variations of that approach, all of which seem to be retail and not insurance reimbursed. And with that new, uh, realization that manipulation of the Mabo glands and therefore the lids themselves can improve ocular surface disease.
Speaker 2 00:07:21 We've seen a, a real burgeoning of, of the, the dry eye center of excellence concept that, that you, so, uh, personably accelerated in our practice and that collaboration between patients and referring docs and MDs and ODS in the practice and educated, skilled technicians. And we use the breed bone of, of the lid margin. I was taught to do that with cotton tip applicators. Now we have a device that, that polishes the lid margin with the BlephEx, which is now, uh, an Alcon product, and so many other devices, uh, like site sciences, like the LuxS and, uh, many others, uh, in development. And then with that to further, you've quite a bit of
Speaker 3 00:08:04 Experience.
Speaker 2 00:08:05 Yeah. You've
Speaker 3 00:08:06 Had quite a bit of experience with all of these different, um, innovations, I guess, over the years, what would you say is your go to Forland expression?
Speaker 2 00:08:18 I think the, the original treatment that gets both sides of lid and, and applies that pressure with the, the Lipa flow, the, the thermal pulsation in its original form is, is what you want the patient to use if they can afford it. And if they accept that it's, it's not a required procedure, it's not a vision saving procedure, but it's essential to management of, of so many of these patients that have MGD and then the anti-inflammatory of choice, which is, uh, you know, initiation with a steroid that is the induction therapy with maintenance using perhaps another agent such as cyclosporin or other agents that are really useful, like Lires in their very well tolerated, uh, topical preservative free formulation. So it is kind of a, a one, two punch, you know, you get the drops in there and you get the Mabo glance tuned up. You gotta come up with, uh, a maintenance therapy for the Mabo gland too. And that entails retail education in your practice and creating a routine for the patient. So they can take care of themselves on a regular basis that matches their schedule and their abilities. So that's the go to and shorter phrase as I can pro
Speaker 1 00:09:33 Yeah. Hey John, you know, oh, go ahead. Go ahead, Tracy.
Speaker 3 00:09:36 That's okay. I'm just with, with your vast knowledge and experience, I'm just really excited, um, to pick your brain about where you see, um, things going next, actually. So what's your opinion on, um, RAs or R E S P? Where do you think that's, um, that's gonna take us,
Speaker 2 00:09:56 It's just not, T-cell, it's just not steroid mediated pathways that are creating inflammation in the eye. And in fact, throughout the body and throughout school, we all memorize the steroid pathways and the Adon acid and the psycho oxygenase and the lipo oxygenase and the vascular permeability, and even the stabilization of the membranes, including the mass cells. So steroids do work for everything, and they have their panoply of, of side effects. Now we've learned that there are parallel inflammatory pathways that have been around for millennia, obviously that have here to, for been undiscovered and done underutilized. And this includes not only reactive aldehyde species or the rasps inviting rasp inhibition as a, as a clinical intervention, uh, but also, uh, a C T H mediated pathways through the melanocortin stimulating hormone receptor complex, which is again ubiquitous, particularly in ocular, ocular and neuronal tissues. So we we've learned that we can manipulate other inflammatory cascades without the traditional steroid intervention, the T-cell intervention or a non-steroidal aspirin like intervention.
Speaker 2 00:11:13 And that's where things get really exciting. And we're also looking at, at, at new vehicles too, and these have become quite innovative. We look at the nanoparticles with SEQA and the mucus penetrating protein with, uh, Kali's drug is UVIS. We also look at the semi fluorinated Alkins that are being used, uh, at the Nova leak protocols with both soluation of cyclosporine, a traditional, uh, API or active pharmaceutical ingredient, or just the, the, the Porro HETA by itself. And it turns out this Nole drug Novo three is a very outstanding intervention for dry eye patients who have concomitant mem gland disease, because these, these semi fluorinated ADEs actually penetrate and change the chemistry of the meibomian glands. So we're looking in the future at new pathways in new delivery systems and delivery systems can be very convenient. You can give a steroid dexamethasone with the ocular therapeutics Punal plug and the patient's on autopilot for a month.
Speaker 2 00:12:22 What a great way to solve so many compliance and surface toxicity problems. But looking now, as you said, Tracy, at the, the newer inflammatory pathways, I'm very excited about reactive aldehyde species because a company called Al DRA formerly Al DXA, uh, based outta new England has really been at the forefront almost by themselves and, and looking at at rasp inhibitors. And they have a premier drug reap that can be given topically it's well tolerated, and it's been investigated for a wide variety of ocular surface and intraocular inflammatory conditions. In fact, the first trial that we did was for anterior non-infectious acute uveitis, and we got to phase three, the phase two data was amazing. We had a couple of phase three trials and, and found that in its current vehicular form, the intraocular penetration was not quite adequate to produce, uh, a meaningful, uh, statistically significant response in, in the inflammatory endpoints. It produced a reduction in inflammation, but it was not superior to the comparator, but we believe that how do
Speaker 3 00:13:40 You, how do you see this helping with ocular surface dryness?
Speaker 2 00:13:43 We know that it'll help because it was so well tolerated in uveitis and, and produced a therapeutic effect. I think delivery is more of a challenge for intraocular, uh, penetration of, of these rasp inhibitors, like, but it's well absorbed and, and highly potent on the ocular surface. And again, we found that there are elevated levels of Malon aldehyde, which is a metabolite of, uh, rasp acceleration in an inflamed organ system, including the eye. So you can actually measure Malon aldehyde in the tears. And it turns out that folks with dry eye have elevated Malden aldehyde. And it turns out that if you give reap to folks who have dry eye with significant signs and symptoms who have elevated tear Malden ALD high levels, that the level goes down, can common and parallel to improvement in signs and symptoms. What an incredible model here, we have a direct biomarker for efficacy of a drug here to before never established in any organ system.
Speaker 2 00:14:52 And, you know, we look at steroids for years. One of the best models for steroids is internalization of the glucocorticoid receptor. That's a very complicated assay, or you look at the, the fated swelling on mouse feet. Those are not sophisticated assays that give you a biomarker, but this is a very powerful biomarker found in the tears of dry eye patients. And it turns out that this drug works very well for allergic redness and allergic itching and tearing as well. So we, we have what may be a, a drug that's not a steroid with steroid like effect and steroid like comfort that treats a wide variety of ocular conditions, especially ocular surface conditions where we can now deliver the drug in meaningful concentrations.
Speaker 1 00:15:40 So are you saying that we're gonna have new biomarkers? That is gonna be that we're gonna look at me right now. Traditionally, it's been MMP nines. We've been looking at osmolarity. We we're hearing about, uh, I L 17 a and, and others, I mean, is, is, is that what you're thinking? This is gonna be another one that we're gonna start looking at in the future.
Speaker 2 00:15:59 I think you're very right in that. And we're gonna look at it in two ways. First for clinical trials. Uh, the FDA has stated that, uh, indeed, a, a marker so directly related to the drug itself could in fact be, uh, a primary endpoint in a clinical trial, uh, that that's fantastic. And, uh, unprecedented, we will also find therefore that this may be another target like MMP nine, like osmolarity for the direct assays of patients, tear film, for instance, or even a direct application to the ocular surface. A number of companies of course, are working on this Quadel and tear lab are leaders, but Lac science has developed a, uh, a gold plated monitor that can detect up to five different antigens on the surface or osmolarity and several antigens and, and give a profile very much like a lipid profile for patient with hypertension and hypercholesterolemia. So we're not as good as the, the cardiac doctors, but by golly, we may be able to assemble a, a small panel of inflammatory markers or surface disease markers, maybe IgE, or eosinophillic basic protein for allergy itself, and maybe lipo polysaccharide for gram negative infections in a contact lens patient, or her antigens for a patient suspected of having her ocular surface or stromal disease. So yes, biomarkers are, are in and rising strongly.
Speaker 1 00:17:31 Hey, whatever happened to the, the discovery unit from tear lab. Cause you know, we heard about it several years ago, but we haven't really anything about that.
Speaker 2 00:17:39 Well, tier lab's been working on that, it's been a funding issue, tier lab was acquired and, uh, there's a, now a private equity firm. It'll give you osmolarity and M and P nine. It's a, a proven, uh, collection method. Our staff knows how to use it. The device is readily available in many offices and we still do osmolarity tests, but we're anxiously waiting for the launch of discovery that will allow us to take that same specimen and then run two simultaneous tests, looking at a, a concentration for the tear film, as well as an inflammatory marker in the tear film. Of course there's gonna be carpet competition in that marketplace.
Speaker 1 00:18:16 Mm-hmm <affirmative> mm-hmm <affirmative>. So what are some of the other indications for RAF inhibition? I mean, you mentioned allergy. I mean, do you see us using it more for intraocular uses? I know there's studies for proliferative, uh, retinopathy, if I'm correct.
Speaker 2 00:18:32 Right. The same company Al there is, is working on, uh, several intraocular agents, including a cousin of rep lab, another ADX compound, but they're also looking at intravitreal methotrexate. And until now folks have been giving methotrexate for a wide variety of inflammatory conditions or proliferative conditions in compounded form and clearly, uh, an FDA approved and analyzed and, uh, validated, uh, preparation of methotrexate, uh, would be, uh, safer and better and, uh, more accepted by both patients and clinicians. So there's also oral forms of rasp inhibitors and they're being investigated for a wide variety of diseases, including allergy, including severe allergy, like atopic disease and for psoriasis, and also for COVID 19, which as you know, in its fatal form is basically, uh, an overreaction of inflammatory cascades in the lungs and the heart. And that it turns out that rasp is, is quite a bit of a, a factor in, uh, COVID inflammation in, in the, the cardiovascular and pulmonary system and another condition
Speaker 3 00:19:46 I, I do, I do hate to cut this short cuz we have to keep, um, we have to keep it focused on the ocular surface and we only have 20 minutes with you. There's so much in your brain. <laugh> um, we just, we just have one last question, one more anti-inflammatory that we want to get your opinion on because we know you have some, we know we have an opinion on it. Um, can you tell us about Acthar?
Speaker 2 00:20:09 Sure. Acthar is a gel. It's an a C T H gel mm-hmm <affirmative> it's injected by the patient or family member and it can be used twice or three times a week. It's a very effective anti-inflammatory with steroid potency and without steroid effect. In fact, only about eight or 9% of its effect is actually steroidogenic the rest is this melanocortin stimulating hormone receptor, uh agonism and these are inflammatory and inflammation, counter controls in the body that are very important in a wide variety of inflammatory processes. And clearly, uh, they're involved in severe ocular surface disease. Those folks who just can't use the Restasis or adverse steroids or use them and don't get all the way better. And also in patients with uveitis, uh, in addition to uveitis and severe ocular surface disease, I've also used AAR to prevent rejection of corneal transplants in patients who seem to be prone to doing so.
Speaker 2 00:21:08 So it's a very powerful way to treat a patient. You don't have to take pills. It doesn't create GI at the side effect profile is very benign and to get a, the same effect as 60 milligrams of, of oral steroid, uh, you only have about a, a six milligram oral steroid profile of side effect in that patient. It can be weed, it can be tapered and it can be used for, you know, really bad Sjogren's patients and patients with devastating ocular surface disease, like atopic disease, OCP, Stevens, Johnson, and chemical burns. So I'm excited about that. In fact, one company's working on a topical, a C T H medication that looks promising in phase two for dry eye. So suddenly this particular mechanism is becoming popular and we just saw a competitor come out against a C T H, which is, uh, claiming to be just as good, but we know how generics work. So I'm, I'm excited about using a C T H gel. It lasts a long time because it's in the gel, it's a, polypeptide, it's a porcine de derivative it's kosher, and it shouldn't be used in people who are allergic to pigs. Otherwise it's extremely, uh, safe. It's a very effective agent. Uh, it's pretty easy to get it approved and I'm really looking forward to additional trials.
Speaker 3 00:22:30 Okay, well, I could talk to you for hours and hours and pick your brain because you literally have tried everything. I don't think there's another dry eye specialist out there who hasn't has tried as many things and as completely as you have. So thank you so much for your time tonight. Thanks for joining Walt. Thanks for trading Walt. And, uh, we look forward to maybe having you back again to talk some more because you were just a F of knowledge.
Speaker 2 00:22:53 Well, you'll be back,
Speaker 3 00:22:54 John. Thank you so much.
Speaker 2 00:22:56 Oh, it's my pleasure. It's a great working with so, uh, bright and experienced and intelligent, uh, team here. Thank you for inviting me and have a great night.
