TAPE STARTS – [00:00]


Warren Joseph: I am really, really excited to be here today to speak to you about onychomycosis. How often do you hear those words together? But you know what the fact is there is actually some really interesting science behind onychomycosis. I don't know how many of you are familiar with MyNCBI, which is part of pubmed.gov where you can actually sign up for emails notifications weekly, monthly, daily, whatever you want of every abstract that has been published for anything you want. I get three -- every Monday, I get there emails. Ones on onychomycosis, ones on osteomyelitis, and ones on diabetic foot infections. And pretty much week in and week out, there are more papers published in area of onychomycosis than diabetic foot infection or osteomyelitis. So there is actually quite a science to it above and beyond 11721 and the so-called debridement and making the diagnosis. So we will talk a little bit about some of that today. I do have to give you a disclosure. Unlike, the previous lecture, which was a corporate lecture, it was a funded talk, non-CME talk, this is a regular CME talk. So I do have to disclose that I am consultant on the speakers bureau of Ortho Dermatologic, which used to be Valeant and also a consultant to a Japanese Company now in the field of onychomycosis, Meiji. So these are just the objectives you can read a few one. Relatively rare -- onychomycosis, we think of is being around forever. Actually, it was relatively rare as recently as about 120 years ago. In fact, I was looking through a copy of Shapiro's [phonetic] topical dermatology. This was a bunch of years ago when I was still at the University. And you are all familiar with Shapiro, he is the guy with agar. Shapiro's topical dermatology, there is one paragraph in this entire book on dermatology about fungal infections and it's a dermatomycosis is a rare condition.

[02:03]

Dermatomycosis, so skin infections by fungus is a rare condition as recently as about 120 years. It has become more common because of the environmental factors, social factors. I love whenever you read a paper on this, it always talks about communal bathing facilities. How many of you communally bathe? Not that there is anything wrong with that. I mean I know that there is some cultural these things, some cultures believe in communal bathing. But most people don't think communally bathing but occlusive footwear, certain occupation, soldiers, miners, people who are in boots for long periods of time who traumatize their foot, whose feet sweat tend to have more onychomycosis and tinea pedis. Now, notice, I said onychomycosis and tinea pedis, because the two are inextricably linked. You can't have one without the other. I mean it's the natural history of the disease. Onychomycosis starts as tinea pedis on the skin that then works its way up under the hyponychium. So some of it causes break in hyponychium and allows to fungus to invade the nail bed stratum corneum. So onychomycosis is really nothing more than tinea pedis of the nail bed stratum corneum. It's not really an infection of the toenail itself. These are old numbers now. They talk between 35 and 36 million have it, 6.3 million have been diagnosed, about 2.5 million receive treatment each year, which leaves a lot of untreated patients. Now, I have been showing these rough numbers for a lot of years now because I remember when I was speaking about Lamisil a lot, oral terbinafine and I would have podiatrist come up and this was 20+ years ago when it was unheard of to actually treat onychomycosis. All we had was Griseofulvin and podiatrist would come up to me and say, Warren, why would I want to use this drug? I want to cure away my practice. Cure away your practice, are you serious?

[04:01]

A 36, 37, 40 million people with it no one is getting treated. Maybe if you actually cured a couple of these patients, they would refer other patients to you for an actual cure and it's amazing how many people don't just want you to debride the toenail. They actually want to be cured of the fungus. So maybe there is some opportunity there with some of the different therapies. And I have also always talked about the aspect of onychomycosis as an infection. We don't think twice about treating a bacterial infection with an antibiotic. Why do we hesitate to treat a fungal infection with antifungal and some of you have heard me use the example I have used for many, many years of my son. My younger son is now 28 years old. Well, back when he was in elementary school, he came home from school one day with a note from the school nurse saying your son has ringworm at the arm. He will not be allowed back in school until we have a letter from your family doctor saying that the ring worm is being treated and it's no longer contagious. What is ringworm of the arm? It's tinea corporis. It's the exact same infection caused by the exact same organism. You have onychomycosis in tinea pedis. What's the difference? Hidden under shoes and socks versus in the arm of the kid wearing a short sleeve shirt. So if it's important enough to treat in that case, why isn't it important enough for us to treat it more aggressively? The mycology of this primarily caused by dermatophytes. Now, there are labs out there promoting all this new molecular testing. I have an entire lecture just on -- I have only done it twice now on molecular techniques for diagnosis of infection, primarily, in the diabetic foot, but it also applies to the mycology. And what you end up doing is you end up finding all of these different organisms when you send out for one of these molecular tests. Well, it's just like if you take a swab cultures of a diabetic foot wound, you are going to grow everything known to man.

[06:01]

It doesn't mean it necessarily any of it is causing infection. These tend to be colonizers. So we know that the dermatophytes by definition that's trichophyton, epidermophyton and microsporum are capable of actually digesting human keratin to survive. We don't have that with these organisms like these molds you hear about, Scopulariopsis, Aspergillus or Fusarium. For Fusarium, there was one paper published about three or four years ago that said it was suggested it can digest human keratin. But the point is that we tend to believe at this point until proven otherwise that most of these infections are caused by dermatophytes, particularly tricophyton rubrum, T. interdigitale which causes the white superficial. Now, does that mean I don't believe that molecular testing is useful? No, I think it is useful. It's a lot more rapid in trying to grow a fungus, which can take four to six weeks and get result in a matter of two or three days and if you need to get a positive result in order to get a drug covered, it might be the best way to go because it's so sensitive. Because molecular techniques can discriminate between dead and live organisms because you don't depend on it to grow, you just depend on the presence of some of the genetic material. So if you got the genetic material, you get a positive test. You may be able to get a drug covered. But overall, I am not quite sure how we are supposed to interpret this and I take offence to some of the companies out there that are using results of these molecular techniques to sell their non-FDA approved never-tested over-the-counter medications for the treatment of onycho or tinea pedis for that matter. In fact, there is just -- I mean it's amazing how many over-the-counters there are. Now, back in the early 70s, Nardo Zaias, he’s a dermatologist down in Miami, identified - he is kind of like the godfather of onychomycosis.

[08:02]

He is the first person who came up with a classification for onychomycosis that's still used to this day. And it's very straight forward. People made all sorts of modifications of it but basically there are two types we have to worry about. Distal subungual onychomycosis now called distal lateral subungual onychomycosis and white superficial onychomycosis. There are certainly other types proximal subungual, which is found in HIV AIDS, candidal onychomycosis associated with mucocutaneous candidiasis. There is a relatively new one called endonyx onychomycosis. Many of you haven't even heard of endonyx onychomycosis. I don't know if anyone has even seen it before, but it's out there. And this is the classification system that is still used in every scientific paper that's written about onychomycosis. But it's amazing how few people on our profession know it. I always lectured both at residency summit east and residency summit midwest who are present and I will ask the residents and I said, raise your hand, how many people here know the Lauge-Hansen classification of ankle fractures. And the residents all raised their hand unless they are afraid I am going to call on them. I don't have to assure them I won't. And I said, okay, how many of you know the Zaias classification of onychomycosis? No one raises their hand. I say, okay, hold on. So you all can recite a classification system for a condition that maybe half of you in this room may see twice a year but none of you can recite the classification system used in every scientific paper of an infection that you are going to see multiples times a day. And I think that's a problem with our education system. I mean we don't have to debate that now but certainly I think there is such a focus on the surgical aspect of our profession, which comes at a cost of not spending more time and effort teaching the medical aspects of our profession, which I think something I have been involved in my titer are just as important if not may be even more so because you are going to see more of it.

[10:02]

So this is just a little schematic. This is from Jim Garaso [phonetic] who is actually here in Las Vegas. He is a well-known dermatologist in the area of onychomycosis, just showing the different types of onychomycosis, distal lateral subungual starting under the hyponychium, white superficial actually attacking it. But I mean this is proximal subungual. This is white superficial where it looks like just the chalk has been rubbed on the toenail and this is just a subungual onychomycosis. You all see this many times a day. I just love this. I mean this just reminds you that the fungus is not an infection of the toenail. Onychomycosis again is an infection of the toenail bed. It's not the toenail itself. So what the best thing to ever happen to the treatment of onychomycosis. Lamisil, in particular, not just Lamisil. This little guy who used to sell Lamisil, Digger, The Dermatophyte. Digger The Dermatophyte was one of the most successful direct-to-consumer advertising campaign ever and it started a whole series of campaigns where almost every drug was using like an animated monster to sell their drug because when Digger popped up that toenail on national TV, everybody who watched cringed. And then he crawled underneath and any of you of certain age remember patients coming waving the Digger, The Dermatophyte ads from the press you know the news media that were daily that was before social medial. Digger was extremely effective. But got everybody thinking that this is in fact something that maybe can be treated. And when you look at treatment approaches, Bob already mentioned this. A lot of people get debrided toenails. I am sorry, debridement is not treatment. Go one step further debridement is not treatment and you won't get payment. And how many of you read Barry Block's PM News. It's like I have seen any recently, but for a while it's like every couple of weeks there was another podiatrist having to give back a couple of hundred thousand dollars to Medicare for "surgery" on fungus toenails.

[12:08]

So I mean you are going to end up -- overuse of debridement is not doing anything other than getting you into trouble. It's not doing anything to cure the infection. Lot of patients are just untreated. Over half the patients are untreated. Why? Well, you haven't given them options for treatment or they haven't come to see you if you have options for treatment. They read the internet and they say there is no way to treat it or just use Vicks VapoRub or something. It's just really difficult. Some patients just don't care. Some patients, it just doesn't matter at all that much. Topical treatment, 10% get topical treatment and that includes the over-the-counter remedies, which you guys all like to sell or some of you like to sell from your offices to make a couple of bucks. I will tell you there is one topical that's being promoted a lot in the profession right now. I am not going to mention any names. My very good friend texted me some pictures of his wife's toenails just like two days ago and said, I have been using lesser like 3, 4 and 5, one in two look pretty good. I have been using this topical that the podiatrist sold me for the last couple of months. What do you think? I said, well, it's for crap and you toenails look terrible. He said the only thing that it's done it soften the nail enough that I was able to pull the toenail off. I said, okay, now that you pulled the toenail off, go buy some Lamisil over-the-counter cream and just rub that on the nail bed. That's going to be just as effective as this other stuff. So there is amazing numbers over-the-counter things that are being promoted to you out there and I will tell you none of them, not a single one of them has a single lick of human evidence to support the treatment of onychomycosis. None of them are FDA-approved.

[14:00]

There are only there drugs currently FDA approved topically for onychomycosis, that's ciclopirox or Penlac. It is efinaconazole or Jublia and this tavaborole or Kerydin. That's it. All of those other products if they are trying to tell you to sell, they have never been tested for onychomycosis and aren't FDA-approved for onychomycosis. And that doesn't mean it won't work. In some patients, it would work. Alright. But in some patients, you are going to have the same experience that my good friend had with his wife's toenail. They were lesser toenails. I can imagine if it was a hallux. In fact, there is one product that he is using. I have to admit I have tried it on my right hallux because I have got about 40% involvement on my right hallux, whatever. Just be aware of it. So where are the approaches. You got debridement. I am not saying debridement doesn't do anything. It just doesn't cure the infection. Debridement can certainly thin the nail, make it more comfortable, make it look better, may decrease fungal load and it may potentiate the use of topical antifungals because you might get better penetration through the nail with debrided nail. Then there is a pharmacologic approaches topical, oral or combination. Oral agents, this is nothing new. There has been nothing new in this since 2014. There has been no new data. There has been no new product out since 2014 with any topical or oral. The oral has not been a new data out or new product out since terbinafine came out over 20 years ago. So pretty much terbinafine is still the gold standard and it's cheap. I mean you can get a month of terbinafine at many of the pharmacies for something like $4 for a month of terbinafine. It's real tough for a company to justify development of new antifungals when they know that they will come up with expensive fancy new antifungal that they spent hundreds of millions of dollars developing and then the insurance company is going to say, well, they have got to fail generic terbinafine first, which is one of the reasons they are just hasn't been a lot of oral development.

[16:12]

This is an incredibly cool antifungal. It's a designer antifungal, it's called tetrazole. It's not a triazole or biazole, it's tetrazole. It's by a company that used to be called ViaMet. They are now out of business. VT-1161 is the compound. Now, this was their phase 2 clinical trials just at 24 weeks and yes, this is a 24 weeks. That's incredibly impressive. I mean lesser toenails are totally cured. The hallux nail is mostly cured again at 24 weeks. In fact, what they found is their 24-week midpoint. Their cure rates were as good as terbinafine at 52 weeks. So this is exciting. I mean almost no drug interactions, everything looked really safe with it. There were no liver toxicity associated with it. So wonderful. Where is it? I mean this was back three years ago, two and half years ago that they did this. I was one of the consultants on their trial. Well, what happened is the company decided they want to go onto phase 3 research, to a phase 3 clinical trial. They couldn't get funding for it. It would have been over 100 million dollars because these trials are 52 weeks to 60 weeks long and the venture capital people were not willing to give the money for it because like I said you are going to run into trouble competing with $4 terbinafine. So this drug is just -- I mean they might be developing it recurrent vulva vaginal candidiasis, which looks wonderful. I mean the results of that study were incredible. But the point is that we aren't going to see this drug for onychomycosis at least not in the foreseeable future.

[18:01]

Topical therapies, we know ciclopirox or Penlac, efinaconazole in June 14, tavaborole on July, luliconazole completed phase 2. I haven't heard anything in about three years from it. Meiji 1111 did complete phase 2. They are re-doing their phase 2 studies and I am one of their consultants on that particular study. Ciclopirox or Penlac, this has been around forever, we always hear the same thing. That crap doesn't work. Actually, Penlac did work if you used it for the right patient. And this is what I mean by the right patient. This is one of my patient who I used Penlac on and this was the perfect patient because if you look at the nails, she has got about 25% involvement, there is not a lot of thickening and she was motivated. She was a karate instructor. She literally had her foot in people faces. In fact, she was my karate instructor. You wouldn't know it but at point this body was a lethal weapon. We studied karate and my wife and I studied karate over seven years, but the point is that she wanted this taken care of. Well, you know what she was adherent to the therapy and she got a very good result with it. So the drug does work. I mean it's a pain because it's sticky and it takes a long time to dry because it's a lacquer as opposed to the newer drug that are alcohol based solutions. They dry extremely quickly. When we talk about the drug working, we have to just review efficacy terms a little bit. What does it mean, that drug works? All these over-the-counter things, you ask them how often -- how well does your drug work? We work 80% of the time. What does that mean? Is that mean that one out of 10 toenails gets 80% better or 8 out of 10 toenails get 100% better? Or does that mean that you make an 80% profit margin selling it? I mean nobody seems to really understand except the pharma companies who have to do these studies.

[20:00]

So the primary endpoint that everyone looks at that the FDA requires is it got a complete cure. And a complete cure says that at the end of 52 weeks, the toenail is 100% perfect looking. Compare that to what we just talked about with new antibiotics. At 48 to 72 hours, the cellulitis has gotten 20% better. That's how -- in two days if it's 20% better, you can FDA approved. For onychomycosis study, it has to be 100% perfect at 52 weeks. You know how hard to keep the patient motivated and keep the patient in a clinical trial for that long? There are all sorts of intermediate endpoints that companies use and I will show you some examples of those. So this is efinaconazole or Jublia 10% solution and like I said the trial design was 48 weeks of treatment with four weeks of followup with the patient off treatment and the patient had 20% to 50% nail involvement without matrix involvement, which means that matrix is never involved. Matrix can't be involved. That's a big misconception out there and it had to be 100% perfect looking toenail at 52 weeks for it to be a cure. That's why these numbers are what they are. The two clinical trials as I said before FDA always requires to 70.8%, 15.2% complete cure. That is versus vehicle. These are called superiority trials. The superiority trials unlike the studies we are talking about with antibiotics are non-inferior, remember I said the drug is non inferior. It's a different power. It's a different study design. When you compare to drugs you look for non-inferiority, when you look at the drug compared to its vehicle, that's called a superiority design. So in these cases, these numbers were statistically superior to the vehicle. And then I had like mycologic cure, negative carriers, negative culture over half the patients, treatment success complete or almost complete cure about a quarter of the patients.

[22:05]

That was defined as the end of the study less than 25% nail involvement. So let me show you how this is done. Here is a patient in some clinical trials. There are three patients going left to right. Now if we look here, the investigator said that this was 40% involved. How did the investigator decide that this was 40% involved? Yeah, that's 40% involved. That's it. It's all subjective. Some studies use computer planimetry but in this case they did not. So at the end of 24 weeks, they said this is 20% involved. Alright, maybe. And that this is 3% involved. How is this 3% and this 20%. I have no idea. But that's what the investigator called it. So 3% involved. Now, let's start it here and end it up here. That's pretty good. I think you would be happy with that result. Well, because it wasn't a complete cure because it wasn't 100% perfect, the FDA would call that a failure. So here we have 50% involvement, okay, maybe. 20% involvement, okay, maybe. What about here? What do you think that is? Investigator said 5%. So this is 3%, that's 5%, that's 20%. How did they do this? But the point is it started here which looks terrible, when here, which pretty good and another four weeks it probably would have been 100% cured but the study ended at 52 instead of going out to for 60+ weeks. And that is a failure according to FDA. Now, this is my favorite of all time. How much involvement would you say is in this toenail? 80%, 90%? Remember, to be enrolled this trial, the patient could only have 20% to 50% involvement. So if it had any more than 50%, it couldn't be enrolled. The investigator wouldn’t get paid. So what do you think the investigator called this? 50%, right?

[24:00]

No, they called it 45%. Are you serious? Let me tell you, I have been involved with three clinical trials on onychomycosis where I have had final say whether or not the patients enrolled on the trial. They sent me photographs and I looked on an iPad, I can blow them up and look at the measurements in different lighting situations. I would have laughed if that cross my desk. I would have laughed at that. This investigator needs to be dropped from the trial. He is trying to game the system. But look at the cure. Started here, went to there. That's incredible. How is that not a perfect cure? How is that 5% when this is also 5%? So you see this subjective nature of these trials and why it makes it really difficult to determine what the actual cure rates are and how these should be looked at. This was the original clinical trials done like 2012 or so. There have been multiple other post-talk analyses. They've looked at preventing of spread of the infection to other toenails. They have looked at it for a diabetic in fact Tracey Vlahovic and I published this post-talk analysis. We published it in Journal of Drugs in Dermatology because after all we know that all podiatrists read that. They looked at once daily statistic, great improvement in quality of life. Boni Elewski and Antonella Tosti looked at that. This is again Boni and Richard Pollock looking at the vehicle of efinaconazole when applied spreads under the toenail. Lots of different post-talk analyses have been done on this drug to show that it does in fact have some decent efficacy. Safety, as you would expect with any topical, there is not a lot of safety issues. Number one issue with almost all topical antifungal besides local irritation is ingrown toenails. In fact, that's for all. That's oral also. Ingrown toenails. I have my own theories on why that happens, but application site dermatitis and vesicles probably the most common.

[26:04]

Now, that is efinaconazole or Jublia. This is Kerydin or tavaborole. It's a unique drug and that it's not an azole like econazole. Even the VT-1161 is an azole and it's not an allylamine like terbinafine. This is a new class of antifungal that is called an oxaborole. So it's a boron based drug that is fungicidal and works differently because it works as a protein synthesis inhibitor as opposed to working to inhibit squalene epoxidase or the -- I am blanking on the name of the chain. Anyway, it dries quickly just like efinaconazole. These are solutions not lacquers. You don't need to remove it. Studies slightly different than the Kerydin study. Patients could have 20% to 60% involvement. Patients 18 to no upper limit whereas it was 18 to 70 on efinaconazole. So people ask me all the time. How does Kerydin compared to Jublia. I can't tell you. The studies were designed differently and there has never been a head-to-head trial. With no head-to-head trial, you can't make any claim that a drug is better or same or not inferior to another. So here the endpoints 6.5. Again, statistically superior to the vehicle 0.5, 9.1 versus 1.5. Secondary endpoints, about quarter of the patients were completely or almost completely cured. Mycologic cure, you can see the numbers there. I want to show you the same sort of three patients just to be fair balance that I showed you with the efinaconazole. This is a failure because the patient they felt that there was still little fungus up here. So it wasn't 100% cured. But I think if you started with that, you would be pretty happy with that result. Same here, you start with that, get to that. I think you are pretty happy. Is that a 100% perfect? No, of course not. There is some involvement up here, but you know what it is still a big improvement. It's not a failure.

[28:03]

Your patient would be thrilled with this result. And same thing here, I mean maybe there is a little fungus still here a little fungus in the corner here, but it started with this and ended up like this. And not only that, this wouldn't have even been included in lot of trails because it has what most people in the area would call dermatophytoma. That's the term that no one in podiatry uses. The dermatologists love to throw that around. Dermatophytoma is either a tumor or fungus within the nail. And that pretty much looks like a dermatophytoma right there. So that's exclusion criteria for most studies but it wasn't in this case and the patient did well. They are not well enough to be a complete cure. Same thing here. That's not a complete cure. That's a failure. So the bottom line, you just have to be very careful when evaluating the numbers on these antifungal studies. Safety data, just like with efinaconazole not a lot of issues when you have safety. I love doing antifungal talks, even promotional antifungal talks because unlike all that stuff I have to read you in the antibiotic studies, it's like one slide in the antifungal studies. Lasers, you know what I have a minute left and really my bottom line on lasers is it was really hot for a period of time and everyone was buying lasers and they were like five companies selling lasers. When is the last time you have seen a laser company at any podiatry meeting? It kind of tells me where it's gone. It's kind of gone the way of the dodo, I think. Those of you who have lasers works for you, you get paid for it. God bless you, that's great. There is very little evidence to support it. I mean every study is done differently. I get people coming up to me all the time, hey Warren, I used a laser and I get like an 80% success rate. I called the 80% solution because everyone claims 80% success on everything. I get 80% success rate. Of course, every patient I give laser to, I also give them oral terbinafine and Jublia. It's like come on, but that's kind of the studies that are not particularly well done. This was just - Aditya Gupta [phonetic] [30:00] in Canada is one of the gurus on onychomycosis.

[30:03]

And this was just the conclusion that Aditya came up with. Laser studies, however, do not provide efficacy rates for medical endpoints that equate or exceed those found with traditional therapies, oral or topical treatments. There is just no real way to compel. There is the drilling stuff that's being done now. Have any of you ever seen that drilling? I don't know if any of you are doing it. I actually watched a demonstration of it once and it took like an hour for the guided drill the holes to apply the topical. The big study they get on this and they claim they have better studies. I have never found them. If I am wrong, I'd love to see the study. I will include a slide. Basically, the authors present three cases. Robert Baron is one of the gods and he is from France. He is one of the gods in onychomycosis world and Ivan Bristow is in the UK. Again, they have done a lot of good onychomycosis research and I am just kind of surprised that they would come up with this three case studies. So I am not even going to go there. So in summary, onychomycosis is an infection. It needs to be treated. Most of the work is being done as topicals because there's very little to compete against the $4 arch generic. VT-1161 looks great. I don’t think we are going to see it in our lifetime. The device is being studied to offer a new way to treat onycho. There is little data to support them. But if they are working for you, you make some money off of it, you can manage you lease payments or all the cash you spent on it, good for you. Any questions on any of this? Okay, thank you very much.


TAPE ENDS - [31:42]