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“Bullish on Glaucoma, A 30-Year Perspective on Patient Care, Clinical Research, and Industry.”
Richard A. Lewis, MD, Co-Founder of Sacramento Eye Consultants and Former Director of Glaucoma, University of California, Davis; President of the American Society of Cataract and Refractive Surgery, and Past President of the American Glaucoma Society, delivered the Glaucoma 360 - New Horizons Forum keynote lecture in San Francisco on January 29, 2016.
The Drs. Henry and Frederick Sutro Memorial Lecture, the keynote talk at New Horizons, features key opinion leaders and innovators in the field of glaucoma.
Andrew Iwach, MD: Now, it's my pleasure to introduce our keynote speaker this morning. This will be our third Henry and Frederick Sutro memorial lecture. Who is Dr. Sutro? He bequested $3.2 million and his passing a few years ago was to focus on supporting research and education.
He was a faculty member at the School of Dentistry here to the University of Pacific. Locally, he practiced in Oakland and after his pass - I didn't know, he's a very kind humble man but only after he passed that I learned that his great-grandfather had been Adolph Sutro, former mayor of San Francisco and he had actually been one of the largest landlords in San - landowners in San Francisco in 1898.
Rick Lewis is our keynote speaker this morning and he's a KOL, Key Opinion Leader. What is a Key Opinion Leader?
Well, Rick is one of those. His education spans from UC Berkeley as an undergraduate, Ophthalmology Residency at UC Davis. He ran the glaucoma service there for a while and started a surgical center, now he's in private practice in Sacramento.
He's involved in many different areas: In publications for the Ocular Surgery News, the Academy's EyeNet, Glaucoma Today, he's one of the - he's Editor Emeritus. Video journals, very creative, innovative, looking for ways to get the word out and educate.
He's very involved with our societies, with the American Academy of Ophthalmology and I suspect very few of you know Subspecialty Day, those first couple of three days, retina, refractive surgery, glaucoma, that was his idea.
He was the one who had that idea and led them - founded that program which has been an extremely successful program at the Academy meeting. He's a past president of the American Glaucoma Society. He's been involved with the asterisk and as well as the cutting-edge meeting.
And he also has great experience with industry. Not only with pharmaceutical but with devices and even with government agencies such as our state agencies here in California. So I think it's fair to say that Rick Lewis meets all and exceeds the criteria to be a KOL, and it's my pleasure to introduce Rick Lewis here to give his talk bullish on glaucoma 30-year perspective on patient care, clinical research and industry.
And Rick, before you speak, I'd like to present you with a small token of our appreciation of this plaque.
Rick Lewis, MD: Thank you Andrew. Andrew it's always a humbling to hear that. I appreciate it. It's a pleasure to be here. I've come to this meeting many years and always impressed by the ability of Adrian and Andrew to give - to collect such a incredible crowd and industrial support. It's great for Glaucoma and I'm really proud to be here.
These are my financial disclosures but actually more importantly are the acknowledgments. I'm a part of everyone I've ever met and I certainly want to acknowledge my family and physician partners for giving me the time to do this. But many of you are listed in here as friends and colleagues who either gave me ideas or trusted me to go ahead and do some of the consulting I did.
So I thank you and also one, of course, thank the Glaucoma Research Foundation for allowing me to present this material. If we could advance this - there we go. I was born and raised here in San Francisco. I went to high school at Lowell, went to college at Cal and the Sutro name was a big name when I was a little boy. Growing up, the Sutro Baths were down by the Cliff House. And, they're no longer there.
They're in ruins now but if you go down by the Cliff House, you'll see where the pools were and it was a - when I was a little boy, it was it was a fabulous place to explore. They had a museum there and when I was asked to give the Sutro lecture, they gave me a chance to review this. The fact that Adolph Sutro who really was born in Germany, educated in mining, came to San Francisco during the gold rush and saw an opportunity in the Comstock Lode which was silver mining where he came up with the first of many tunnels that allow the silver miners to extract their silver.
Like all wealthy men, he then became mayor of San Francisco, and as Andrew mentioned, acquired over 10% of the property. So Donald trump is not the first to be thinking along these lines. It's really his great-grandson Henry who - the dentist - who donated the money.
And as I read about him, the key, what he wanted was to have talks in Glaucoma regarding innovation and I feel that's something that has been a passion of mine from the very beginning. So as a consultant, I've played various roles and I thought it was important to start off with definitions. We could define a consultant as a person who provides expert advice professionally but we also know a consultant as someone who borrows your watch to tell you the time, and then keeps the watch, and charges you for it.
And I, there's some element of truth to that, hopefully I'm not quite mad category. My own career consulting started at the end of my fellowship when I published my first peer-reviewed paper on trabeculectomy and has continued up until this year where we have a paper coming out on medication implants. And it's been a fabulous career and I thank all of you for so much help.
Over the years, the title of consultant has varied. I started off as a clinician or a glaucoma specialist in 83. Became an investigator, and then consultant and advisor, advisory board member, medical monitor, medical director and more recently, chief medical officer and it's given me a chance to see the good the bad and the ugly of what's happened in consulting.
And there's been unfortunately a lot of ugly that gets kind of buried along the way, and I think all of us could benefit from knowing some of the bad things as well as some of the good things that we've all seen as consultants. It's interesting that in 2015 was a particularly interesting or good year from a consultant perspective for me.
There were three companies that I was involved in that were acquired: Foresight Biotherapeutics, Oculeve and Aquesys. And interestingly, two of three of those were not even glaucoma companies, but once again, great learning experience and a lot of fun to be part of a successful company.
So my goals today are to describe what makes a technology successful, what makes a company successful and how do you get clinicians to support new technology, and this perspective is strictly from the clinician side. Your definition of successful may be very different than mine but I think it's important for those in industry to appreciate what the clinician wants because we are your customers. So...
We're going to start off looking at three companies; three glaucoma surgical companies that I was very, very involved with from the beginning to the very end. And we're look each of those three, we're going to describe what actually happened and kind of summarize some of the, again, the good, the bad and the ugly.
iScience was founded in 1999. The company was based nearby in Menlo Park. Did their first U.S. procedure in 2002. And the company was - did their first U.S. procedure in 2002 and then went about trying to get clinicians to appreciate the glaucoma space, the canal space.
They raised $37 million. They finally got approval about nine years after they were launched and unfortunately, ran into financial troubles and became - they dissolved in 2013 and they were acquired by LX.
One thing I do want you to appreciate is the, in these videos, if we get them to work, is the complexity of the procedures. And as we kept moving forward, the glaucoma surgical procedure actually got easier.
Okay, so again, just to summarize, the Canaloplasty Procedure was where we place a stent through the canal space and in which we try to induce greater outflow through the canal system. They ceased operations in 2012 and then were acquired by LX in December of 2013. The procedure is still being used. Unfortunately, the company no longer exists.
Company number two is Glaukos. Glaukos, we think of Glaukos as a new upstart company. In reality, the company was founded in 1998, 18 years ago. It did their first U.S implant in 2003. They raised over 150 million dollars of venture capital funds to keep going, took a long time to get FDA approval and that's a story all by itself which would be fun if we had more time to talk about.
They receive medical panel approval in 2009 but didn't get FDA approval until 2012, and finally went with an IPO in June of last year under the trade name of GKOS. And at one point was remarkable for a glaucoma surgical company to have a valuation of a billion dollars, and no one from my entire career, no one ever thought that glaucoma surgery would ever have evaluation at that level.
Company number three is Aquesys. Again, Glaukos, I actually did the very first U.S. implant. I also did the very first canaloplasty in the U.S and so I had experience from the very beginning with these companies, and the same thing with Aquesys. I was very involved right from the start even before Ron Bache became CEO.
This company was incorporated in 2006, 10 years ago. Did their first u.s. implant six years later and they raised $90 million. FDA approval is still pending. Hopefully, we'll get it this year and then in October of 2015, they were acquired by Allergen.
So as we look at the three companies that again, very closely involved with, all glaucoma surgical companies and in a space in which we really, really needed help. We really needed advancing the glaucoma surgical procedure. We've been doing trabeculectomy for close to 100 years, and with a few exceptions have had very little innovation.
What I want you to notice here is how long it took from founding the company to FDA approval and the variance and the amount of money that was raised to actually get there. And as you look at the specifics of each of these companies, in the iScience case, they had challenges they spent a lot of time and effort developing an ultrasound to validate the canal space which didn't really help them in the long run clinically and they had very tough time getting acceptance by the clock glaucoma community. One of their successes was launching the era of canal based surgery and that was really important as we open up another opportunity for treating glaucoma.
Glaukos, big challenges with or with the FDA and the trial. I think you have to be sympathetic to Glaukos in this case because the initial surgeons in that trial had never done this type of surgery before. They took a group of novice surgeons, and expected them to get great results. And it's challenging. It's a challenging procedure. There's a learning curve and then as a result of this challenges they had, the glaucoma community was very skeptical.
However, what they were remarkably successful was in the commercial launch. And as I'm going to talk about in a few minutes, their commercial launch was probably the best I'd ever seen Pharma or surgical and by any company, and particularly in getting adaptation or adoption by the cataract surgeons.
And then finally, Aquesys challenges with FDA trials that would not let them go off label with mitomycin and so they had to use a procedure that wasn't the way the device was intended. So the U.S. trials had very hard a very hard time getting success. However, they were able to do the procedure as expected in Europe and their commercialization in Europe is what led to their acquisition later by Allergen.
So we could spend a lot of time talking about these companies and I think it's fascinating in so many different avenues, but again, I'm trying to point out the clinical aspect of this. And some of the factors that led to commercial success clearly reside with the CEO and the board.
In my years, I've come to really appreciate the value of a board. They can be good and they can be bad but when they're good, they are really helpful in getting these procedures through the FDA process. But there's so many other aspects to commercial success, and I've listed here.
Due to the limitations of time, I can only talk about a few of these. And some of the disasters that I've seen over the years just points out the value of having good, clinical consultants. And then, of course, we can't ignore timing and good fortune in getting this done.
So as you look at the successes for these companies, without exception, FDA is absolutely key. And typically, we think of FDA approval as validating efficacy and safety. But it isn't always the case and there's a number of instances in my career in which it wasn't true. Combigan for example by Allergan actually missed its FDA efficacy endpoints but got approved on enhanced safety.
ReSure which is a sealant used in cataract surgery, and I was an investigator for that trial, actually hit the FDA endpoint by efficacy for a 510(k) but in the process of their study, the FDA changed leadership and made Ocular Therapeutix go through a PMA trial all over again at great expense.
LenSx through Alcon got a 510(k) approval with essentially no clinical data and very, very few peer reviewed publications. And then lastly, we have collagen cross-linking, the Avedro, which we were investigator for in my office; amazing amount of efficacy worldwide, great safety, reams and reams of data and yet very, very poorly collected by the company and insufficient, forget FDA approval.
So the process for regulatory approval is an interesting chess game. I look forward to hearing from Wiley and Malvina later but we're all in this together. We all want to see these approvals, we've got to play the game the right way. There's no question about it.
Now if you look at over the years in my career of consulting, the approval process has gradually for all NDAs increased. There's been a gradual increase in the number of approvals but if you look at the ophthalmology space which is in yellow on the bottom, it's essentially unchanged over the past thirty years. There's been very very little increase or decrease in the number of approvals.
So that led to some other interesting aspects as I was preparing for this talk and that had to do with substantiated and unsubstantiated claims. One of the striking things over the past 20 years has been fines against pharmaceutical companies for unsubstantiated claims.
And it's been interesting, I'm going to give some examples of some of those, but I thought if we'd start off this by talking about a substantiative claim. And one of the ones that was critically important for glaucoma clinicians was validating that lowering IOP makes a difference.
Many of you may remember David Eddy who is a professor at Duke suggested that the federal government in Medicare specifically stopped funding therapy for glaucoma because there had at that point in 1983 been no study validating that lowering pressure made a difference. That led to the OHTS trial which completely revolutionized many of the things but it especially focused on giving us a reimbursement that we knew we deserved but we didn't have the studies to validate it.
Now, as you look at, over the years, some of the unsubstantiated claims and there's a lot of them. Travatan, when it first came out, suggested that it is more effective in blacks which they couldn't validate. Rescula suggested they could enhance optic nerve blood flow. Again, not proven. Brimonidine came out with great fanfare about providing neural protection. We would've loved that, not proven.
Brimatoprost, you know it was trying to differentiate itself from the other prostaglandins and claimed it was a prostamide but not a prostaglandins, and that turned out not to be true. So it's very interesting over the years, the regulatory side of this and the impact it has.
Now as you - this part two of the consulting aspect is getting reimbursement. You can get FDA approval but that's only part of the game because you've got to get reimbursement and I've been involved in companies in various ways, representing them and trying to get reimbursement.
The easiest way, of course, is to get FDA approval, get the CMS or Medicare to authorize it and then get insurance coverage. We have that with trabeculectomy and drainage devices. But sometimes you get FDA approval and you get Medicare authorization but you don't get insurance - private and commercial insurance coverage and that's the example at least in California with the ExPress, Canaloplasty and the iStent.
These are covered by Medicare on the Street Medicare Patient but they're not covered by a Blue Cross and Blue Shield. And then the third option that was very interesting for ophthalmology and I think ophthalmology is unique in this is to get FDA approval to not get CMS authorization not covered by insurance.
It's actually a cash pay and this is the example we have with Femto laser and the premium IOL channel with toric and multifocals, and it's actually, some cases, this is good. So Medicare and/or insurance coverage may not always be the reimbursement goal and the key is to really focus in on the strategy with a specific device.
So we're gonna turn our attention now to some of the successful and unsuccessful product launches I've seen over the years. In the past, we always thought that the key to a successful launch was getting peer-reviewed publications and then getting insurance authorization. And there's other components of the launch that make it significantly successful. Some things that we just take for granted like production and I'm going to show you example where the production component wasn't inline with the launch of the product.
Other things like marketing and/or training, teaching a new technology, very critical. I'll show you examples again of some that that weren't so good but one that was really good was Glaukos, I've already mentioned. They did a very limited release of their product to well-trained, anterior segment surgeons and they also sent a number of the thought leaders to Armenia to get further training before they actually had the product here in the U.S. So they came in and they were they were doing a great job.
And then the interesting role of ophthalmic celebrities in KOLs. And in the beginning of my career, Tom Sherman was one of the great thought leaders. He was a funny guy and everyone loved to listen to him. Later, Dick Lindstrom became sort of his replacement, and more recently, we've got Ike Ahmed and Ike is irreplaceable. And he is the thought mind of the glaucoma surgical market.
So let's talk about a couple of product launch failures and many in the audience who worked back in the late 90s and early 200s - well, 2000s, will remember this one. The ExPress, the glaucoma filtration device was originally developed by Optinal, an Israeli company and they licensed it to CIBA to launch it in the US.
CIBA who had very little contact with ophthalmologist really had a big contact lens market but not much in the way of surgical work hired a group of individuals. And to my recollection, most of them we're very good-looking women and I'm not trying to be sexist, but they put them in white coats and had them come to the American Academy of Ophthalmology meeting.
And all you had to do was get - to get your certification for the ExPress, was to inject the ExPress into an Eye-Bank eye and in a matter of five minutes, they issued you your certification and you're off and running.
Well, within months, there was a number of reports of coronal hemorrhages, exposed implants, infections and it led to this device being recalled off the market. It was an absolute disaster and amazing that the ExPress actually resurfaced again. It took a couple years, it was re-launched with more training putting it under a flap and a number of other advances that were so critical to the device but a big - a good example of how not to launch a product.
Another example is a Merck. Merck was very big in the US market as we all know with Timolol and Cosopt, and they decided to re-enter the market in 2010 with the concept of preservative free drops. They launched Zioptan and Cosoft preservative free but for some reason they didn't put a lot of effort into the marketing and ended up divesting from the market only a few years later.
I don't know how many millions of dollars that cost but the strategy was not well thought out from the very beginning. Now, probably the single biggest disaster I'd seen in my career and this goes back aways to 1991 and hopefully some of you remember this. Maybe Alan Crane will remember the Orcolon story.
Orcolon was a viscoelastic like Healon that was polyacrylamide gel produced by a company called ORC or Optical Radiation Corporation. They launched this product in 1991 to aid cataract surgery.
As many of you know, we use viscoelastic in every one of our cataract procedures and in many of our glaucoma procedures, it's a key piece of the of the procedure and keeps the anterior chamber formed. Well, they did they did their production work and had great results, great safety and efficacy, got FDA approval and then launched it.
Unfortunately, when they launched it, they changed because they had to ramp it up. They changed the production model and they didn't realize there was contaminant in the gel. It turned out that when they launched this, it was launched in certain states more than others.
And Colorado was one of the big states that this product was launched in, and almost immediately, they had a number of patients who had acute rise in pressure that was in was impossible to control without glaucoma surgery. And in fact, 10 of the patients went blind.
This is after routine elective cataract surgery. Not a good thing. It turned out, again, that the production model was different. It had particles that were left in the in the syringe that got caught up in the mesh work and it could not be washed out or burped from the wound. The company ended up filing for bankruptcy under a flood of lawsuits and you seldom ever hear about this.
In fact, this was the first company in my career that actually got front-page Wall Street Journal news and it was a big, big deal at the time. But again, a good example of what not to do.
Now a couple of interesting issues that I saw in my career with packaging. I thought Latanoprost for example was a godsend when it came out in 1996. It was the first in its category. It had a new mechanism. It was additive, it was better, it was safer, it was once a day, it was everything that we wanted.
The only problem that wasn't so good was that my patients kept telling me that they forgot to fill the bottle. The patients would spend $100 for the bottle and then they'd come to me and say, "Wait a minute, they only gave me half the bottle," and I'm sure many of you remember this too.
Well, the mistake there was they put it in a clear bottle. If the bottle had been opaque, no one would have said anything, and that led to a lot of issues.
So a couple of other patent extension issues with with drug products prostaglandins, I think it was interesting and I was involved with Travertine and Alcon on their Travatan Z launch. Alcon used the same concentration but an effort to enhance ocular surface conditions replaced the BAK preservative to protect the ocular service.
Now, at almost the same time, Allergan took the complete opposite approach. They lowered the concentration of bimatoprost and added more BAK as if the ocular surface doesn't really matter.
And then what was probably the most surprising in terms of patent extensions was that Latanoprost did not pursue a patent extension or was unable to. It's unclear to me how they could let a billion-dollar product just go to a generic market because no one else has done that to my knowledge in ophthalmology.
So in the interest of time, I'm going to actually skip this one slide but I'd like to talk about another thing that I'm very involved in which is the development of clinical trial protocols. And there have been some very good products that failed in clinical trials. I'd like to talk about a few of them briefly. Again, this could be a lecture all by itself of what as what I thought or others thought went wrong.
Anecortave from Alcon was a very interesting drug for treating glaucoma for pressure. In many ways sort of an anti-steroid drug. The problem with it was that it had to be injected subconjunctivally as you could see here in this picture. And the deposits would end up collecting at the limbus and the patients would come out of the office with this chemolic swollen conjunctiva; looked terrible.
And even though it had some success clinically, it really wasn't ever gonna fly. The patients would never tolerate having this kind of injection every six to eight weeks. Other major failures of clinical trials, good idea that failed, memantine. We were in the memantine trial for low tension glaucoma and this was a product for neural protection. It's already approved on the market for Alzheimer's disease. We would have loved a neural protection product. Big study complicated by visual field outcomes.
The only way they could validate that it worked was to show that they had stabilization of the visual field and in anybody who does visual fields or any company that depends on visual fields, there is so much noise in the visual field outcome that you can't really rely on it. And we heard some of that last night with the catalyst for cure of people as well.
So it's too bad because it would have been wonderful to have a truly neuroprotective drug out there. But one of the biggest surprises in my career was the inability to develop a combined prostaglandin beta blocker product. In every other country in the world, that product is the leading drug, and all of our patients, about 50% of the patients on a prostaglandin are taking a beta blocker.
So from a standpoint of compliance and ease of use and perhaps better pressure control, it would be wonderful to have a combination product. The reality is that the FDA to their judgment and I actually agree with this that you have to prove that the individual components are better than the combination. And none of the three big prostaglandin manufacturers could prove it, and none of the three could ever get this approved.
So it's unfortunate from our patient standpoint because there are so many who are taking it but the reality is the reality. And the question that I think often comes up is should the FDA consider more than safety and efficacy in some of these glaucoma farmer trials.
And we're going to hear from the FDA folks in a few minutes and I think it's an important topic as we really try to deal with compliance adherence issues.
So I'm going to kind of summarize a few things now. Again, I could - we could go on and on with examples of good and bad, but you know commercial success in the future is going to depend on modifying clinical behavior. And the issue is, can industry change clinical behavior? And absolutely true.
I think it can. I think it takes an effort. It takes again a good strategy. Glaukos did it with the iStent and other companies have done it but it does take sort of a different approach to launch.
I think as we look at launching these products, the ability to get on formularies whether it's drug or insurance formularies. Will they pay for it? And if it's cash, pay a feasible option for some of the devices?
You know, the pricing issue is really a big deal right now. It's of course going to Congress because our generic drugs are so expensive. You know we have issues about pass throughs and bundling, there's all these terms.
And so, the success in the future is going to be different and it's hard to predict how we're going to be able to change it because managed care has - is certainly at least in California where I am, is the big player. They're going to to dominate how excepted these newer products are.
And then dealing with the newer doctors and their practice style and their approach to new technology is very important.
As we look at the business side of glaucoma, in 1986 when I was completed my fellowship, no one thought that anybody would ever touch the four in a million mark that timolol got for Merck in those days. That was the gold standard and then of course that changed when Latanoprost came out in 2001. It became the first billion dollar-a-year glaucoma medical product.
And the surgical side, no one thought that anybody would ever have a successful surgical company in glaucoma. Glaukos changed that. I mean, again, their initial valuation approached a billion dollars. Right now, with the market doing what it's doing, it's not quite there but the point is that there is a big, big market in the glaucoma surgical side that should not be ignored as it was in the past.
But yet, as we compare what we do to what the retina docs do, the VEGF drugs are currently at about $9.3 billion. So, we're dwarfed by what's going on the retina side.
So just to end this lecture, we're going to talk about what is the next big thing in glaucoma. And first of all, pointing out that the money that's being invested in ophthalmology continues to go up, and that's, if you follow that red line on the top.
Overall, the average amount of money is going up. There seems to be fewer device deals but as we look around, particularly, as we hear the rest of the lectures today, there's a lot of interest in glaucoma and there's a lot of new things happening.
What is the next big thing? Well, there's two new drug mechanisms coming. Rhopressa/Roclatan from Aerie, and there's Adenosine coming from Meditec. These are two new completely different mechanisms, look very exciting and they're there in clinical Phase 3 trials right now.
As we're going to hear about later today, we've got new drug delivery systems and there's a number of them. It's very, very exciting. It's going to eliminate the whole compliance problem that we have with our patients.
New MIGs devices, new applications of existing MIGs devices, neuroprotection is being talked about. We heard about it last night during dinner. Stem cell work and new diagnostic testing, both imaging and IOP monitoring.
Lots of new things happening in glaucoma; a lot of investment going on. And in summary, I'd like to say that I remain very bullish on glaucoma. I think it's been a - it's been a fabulous career and an amazing period of time to be doing what I'm doing. I feel very fortunate and appreciate all of you who have trusted me over the years.
I think the role of the clinician consultant will remain critically important going forward and there's been a lot of barriers that have been put in front of the clinicians. The Pharma Guidelines, the FDA, Medicare, they put a lot of barriers into us being able to work with industry and I don't think that industry can do it without us.
So somehow, we have to overcome those barriers and continue that relationship. I think it's critically important. Lastly, I think great medical advances require sound clinical strategy. I encourage you to keep talking to us. All of us. There's many great clinicians in the audience and I think we can help provide that kind of strategy.
And last thing I've sort of learn the hard way is experience is something you don't get until just after you need it, and unfortunately that's true but I think we have a lot to gain. Thank you all very much.
Last reviewed on May 17, 2019