Warren S Joseph, DPM, FIDSA discusses the current treatment options available for onychomycosis and reviews mechanical, topical and oral therapies. Dr Joseph also discusses physician perception of these treatments as well as the difficulty of FDA approval and actual treatment success rates.
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Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Warren Joseph Warren S Joseph, DPM, FIDSA has disclosed that he receives Honorarium/Expenses, is a Consultant to and serves on the Speaker's Bureau for Pfizer and Merck.
Dr. Harold Schoenhaus: -- speaker. He has a list of accolades and appointments that it’s just too long. He wouldn’t have time to talk. I just call this gentleman, Dr. Bugs. Nobody knows more about bugs than Warren Joseph when it comes to the foot and ankle area. Please welcome, Dr. Warren Joseph, who will enlighten us.
Dr. Warren Joseph: Thanks, Harold. Yes, I second, Dr. Schoenhaus’s comment. Thank those of you who are here, still hanging out and being here. What I’m going to talk about for the next half hour is new treatments for onychomycosis. I’ve got to tell you, I’m really excited to be here to talk to you about onychomycosis. When is the last time you heard those words together? Not all that often. But in fact, it is an interesting time for this disease state with two new drugs being approved within a month of each other back in June and July of this past year, 2014. For the first time in over 15 years, we have new FDA approved treatments for onychomycosis. Think what that means to us. You are going to be inundated with reps and dinner meetings. I mean, think of all the weight you’re going to gain. Fifteen years ago, it was easier for me to lose weight after I went to these dinner meetings. Not so much anymore. We’re going to talk about onychomycosis treatment. Now, this is actually part two of the lecture. I did the first part of the lecture just in front of a totally empty audience this morning. This is going to be posted up 1% where I actually talked about the science behind the disease state of onychomycosis. Because quite frankly, there’s a lot of science behind it, which we in podiatrist even though we’re the number one treaters of this condition, we don’t know and we don’t spend enough time studying. Once that’s posted, catch that online and that will get you up to speed to talk about the treatment of onycho which is what I’m going to do right now. Now, I do have some disclosures. I’m both a speaker and a consultant both at CME and promotional for Valiant and for PharmaDerm, both manufacturers of the two new antifungals that have recently been released. Now, what is the single best thing that ever happened to the treatment of onychomycosis? Well, if you had to vote for one thing, here’s where my vote would go. Digger the Dermatophyte, love Digger. Digger did more for the treatment of onychomycosis in just about anybody or anything could ever do. Everyone in this room of a certain age had patients come in waving the latest Digger ad, saying, “I’ve got this condition. How are we going to treat it?” Or you talk to a patient about onychomycosis in your office and they say, “Oh, like the little yellow guy who crawls under your toenail.” Because when Digger lifts up that toenail and crawls underneath, he's got millions of people watching TV that time. Just amazing how effective he was. Digger is the precursor to just about every direct to consumer little monster there is, be at the Nasonex bee or the mucus, whatever. Now, we’ve got the little punching bag toenail or the football playing toenail for efinaconazole JUBLIA. Digger really started at all and got people thinking about onychomycosis. When I talk about onychomycosis, I talk about the treatment disconnect. What I mean by that is there’s a disconnect between how many people have the disease and how many people are treated with it. There’s a disconnect between patient’s perception of the disease and the need to treat it. First is how many actually get treated for it? There’s a disconnect between what we perceive as podiatrist to be effective therapy and what we really use, and there’s a disconnect between this overriding fear of oral antifungals. The fact that, frankly, oral antifungals, terbinafine in particular, these are relatively safe drug without all the drug, drug interactions everybody thinks it has, especially those people in primary care and internal medicine. This is the disconnect. Let me give you one of the examples of that disconnect. This is podiatric physician’s perceived efficacy versus what we do in practice. If you look at the top graph, we perceive that the most common thing we recommend is debridement. The least common thing we recommend is oral antifungal therapy. But if you compare that to the bottom graph, you’ll see that overwhelmingly, we believe that oral antifungals are the most effective therapy but it’s the least common thing we do. We believe that debridement really doesn’t do anything, but it’s the most common thing we do. That’s what I mean by disconnect.
This is another disconnect. There are over 20 to 30 million untreated people with onychomycosis. Now, why is that? Well, they don’t care. It’s just not that important to them. They don’t know about it. They don’t know that there are good treatment options available. They just don’t bother, for whatever reason, and they go untreated. Of the 35 to 36 million people thought to have onychomycosis, only one to two million people actually received oral antifungals. That’s it. Less than 10% of people with onychomycosis actually receive effective prescription therapy for the onychomycosis. That’s a disconnect. A lot of people get debridement and we’re going to talk about debridement a little detail on a second, but frankly, debridement is not doing anything for the infection. Then the topical treatments, there the OTC treatments, which have never had a single leak of evidence, it’s amazing to me. I don’t know if I get a chance to talk about it timewise at the end of the lecture while I have it. How many people love to dispense topical onychomycosis products from their office because they make money doing it? I’m all for making money, that’s why I do the lecturing I do, the consulting I do, but you’re giving your patient a drug that’s not been ever tested for onychomycosis. You’re giving your patient a drug that has no FDA indication for onychomycosis just because you’re making money doing it. That’s, to me, a little bit of an ethical disconnect. You can take minutes to ask for that, be my guest. But the point is, I have an issue with that. There are other prescription antifungals, certainly, ciclopirox lacquer was out there. First, we’ll talk about that and then the two new drugs. What are our current approaches to onychomycosis? We’ve got three. You got either mechanical or surgical debridement, you’ve got topical therapy and you’ve got oral therapy. Well, you see how these three rings are totally separated. I would suggest bringing them together like the Olympic rings, making one giant Venn diagram of onychomycosis. Maybe, we should be using mechanical debridement and topicals. Make sense. You thin the nail, you shorten the nail, may allow topicals to penetrate a little bit better, may get rid of some of the fungal load, combine topicals and orals. The topical works from the inside out or excuse me, the outside in. The oral works from the inside out. Let the fungus get caught in the middle or maybe use all three. Unfortunately, these have not been studied. The FDA doesn’t allow it to be studied this way. We have to do an effective mistrial like Dr. Kirshner was talking about a little bit later to see what role this play. The only one that’s been done, actually, is a combination of orals and debridement. It was called the ironclad study over 500 patients. Orals and debridement. They found that debridement really had almost no effect whatsoever on oral therapy effectiveness. Maybe they expand the data a little bit to make it look like debridement. It might have a little effect but if you really look at the role data, there wasn’t much. Mechanical debridement is what I call the main stay of the podiatric approach. It has its value. It reduces the thickness of the nail. May potentiate oral and topical therapy, decreases fungal load, makes the nail feel better, relieves pressure so our patients with diabetic neuropathy don’t get ulcerations, but it doesn’t address the fungus. It does nothing to address the fungus. Back when Lamisil first came out, went around the country and there was a group of about four of us. Went around the country, doing a whole program, was about a three-hour program, CME that we inserted into various programs and meetings all over the country, all of the big meetings. We caught that onychomycosis, a new practice paradigm and it was myself, and a dermatologist and Harry Goldsmith talking about billing and coding. It was a whole onychomycosis package. Basically, out of that paradigm discussion, came three points that are still as valid today as they were over 20 years ago. Now, these points might get you upset with me, in fact, because in one of these points, I’m no longer allowed to lecture in the state of Iowa. Even if you hear from Iowa, good, that’s no great loss. But, anyway, no, I’m just kidding. Iowa is a lovely state. But let me just show you what I mean by the paradigm, alright. Repeat after me. Debridement is not treatment. Alright. Debridement is not treatment. If you read PM News, Barry Block’s newsletter, you know all the podiatrists who are in jail and giving back hundreds of thousands of dollars to Medicare for a debridement of mycotic toenails. Debridement is not treatment and you can’t get payment. It just causes a problem. This next one is why I’m no longer allowed back in Iowa. Be a physician, not a technician. There is nothing we do debriding toenails that can’t be done by somebody with a six-grade education and a few weeks of vocational training. I challenge any of you to question that.
Think of how you were taught to debride toenails. You didn’t have any great training. You are given a pair of nippers, given a chart in the school and they told you to go cut up the toenails. Do you think the clinician watched you, told you what to do? Hell no. I was a clinician at Pennsylvania for 15 years. We were too busy drinking coffee and reading the newspaper. Just kidding, I wasn’t doing that. Probably while I’m not there anymore. But the point is, there is nothing magical, nothing sacred about cutting toenails. It’s a technician level service just like cleaning teeth, dentist learn how to clean teeth. It’s not worth their while. Who do they get to clean the teeth? The hygienist. Same idea. I could explore this if I had more time but I don’t. Let’s go along to point 3 of the paradigm. Think with your head, not with your hands. Ninety percent of all medicine is cognitive. It’s in the mind. It’s thinking. Why do we have to be proceduralist? Why do we always have to pick up an instrument? Try seeing a patient while sitting on your hands. Brings up the story I had back when I was at the Coatesville VA, we had a residency there. I saw a patient with a posterior tibial tendon dysfunction. We did a whole HNP. We did a gait analysis. I ordered an MRI. We put the patient in a brace. I went in to see another patient, I come back and what do you think the resident is doing? Cutting 10 totally normal toenails. I went nuts. I said, “What are you doing?” This is a direct quote, I’ll never forget it. He said, “Doc., I felt we had to do something for the patient before they left.” Something for the patient? You can’t always chorally doing something with the patient with picking up an instrument. Think with your head, not with your hands. That’s the onychomycosis treatment paradigm. Surgical approach, certainly you have an isolated thick dystrophic nail, surgery might be a good way to go. The days of doing 10 PNAs across the board probably not so much anymore, especially with oral antifungals. The oral agents, again, we know that these are the gold standard. There are three FDA approved oral agents, itraconazole, terbinafine and griseofulvin. Diflucan and fluconazole never did get its approval even though there were studies that showed that it did work. I think it’s pretty clear. Most of us agree that terbinafine is the gold standard. Then analysis has showed about 70% overall success rate and its dirt cheap now. You can get three months of terbinafine for about 12 bucks at Walmart or any of those pharmacies. It’s an inexpensive drug and it works very well. The problem is, patients are afraid of it. They’ve read on the internet about how terrible it is, how it can ruin your liver. Or they go to their family doctor and the family doctor says, “You can’t take that. You’re on a statin.” There’s never been a drug, drug interaction between statins and terbinafine, yet, the family docs don’t know that. The internists don’t know that. They tell the patient, “No, no, you can’t take that.” The fact is, good drugs, gold standards. I will tell you almost no research whatsoever into new oral agent stuff. Why? Well, how much better, how much more effective do you have to be? How much safer do you have to be than terbinafine to have any return on investment of your billion plus dollars it’s going to take to develop a new antifungal orally? Forget it. You’re just not going to see a lot of new oral antifungals being studied at this point. But where we are seeing a lot of work is topical therapies. Certainly, the first FDA approved drug over 15 years ago, ciclopirox 8% lacquer, efinaconazole, one of the two new that’s received its FDA approval in June of 2014. Less than a month later, tavaborole received its FDA approval in July of 2014 and that’s not the end of it. There’s a drug called luliconazole. Some of you are familiar with it because of luzu, the topical that Valiant is currently selling for tinea pedis. There was a phase 2 trial on this in a solution for onychomycosis. I’m not sure that they’re going to phase 3, I’ve not heard. There’s a company out of Japan called Meiji Psychopharmaceuticals that’s working on a drug called Meiji 1111, and in fact, that is just completed phase 2 trials. That’s just scratching the surface. There’s a lot of work going on. Next week, I’ll be attending the nail council meeting of the American Academy of Dermatology in San Francisco and I’ll probably even hear about some new drugs that I’m not even aware of. Lots of work in the topical realm. Llet’s look at the drugs we have. Ciclopirox lacquer, the first one out. Now, I will tell you right now, ciclopirox lacquer worked.
We said, “Oh, that stuff doesn’t work.” No, it did work. It was a pain in the butt to use because it was a lacquer, it took forever to dry. Every seven days, you were supposed to remove it. The package insert said use alcohol, that never worked. You have to use toenail polish remover. You have to debride the nails every 30 days or whatever. The patients just weren’t particularly adherent with it because it was a pain to use. But for the right patient, it did work. Here’s the right patient. This was one of my patients early on with Penlac. She was the perfect candidate for topical antifungal. She had about 25% nail involvement, she didn’t have a lot of thickening and she was a karate instructor. In fact, she was my karate instructor. You wouldn’t know it by looking at me but after seven years, I was pretty much a deadly weapon. Alright. But back then, she literally had her foot in people’s faces. She was adherent. She followed instructions and, in fact, within about two months, the nail cleared. The drug did work for the proper patients. It’s just was not the most elegant solution. When we say drug works, certainly, Dr. Kirchner talked about effectiveness versus efficacy and I talked to him after his lecture. I said, “Here’s the problem with those effectiveness studies you’re talking about. It’s all well and good. They’re great. But the FDA doesn’t accept them.” The FDA will not accept them to improve it to get a new drug approved. Instead, you have ridiculous endpoints that the FDA makes you achieve. Let’s look at some of those. For a drug to be FDA approved for onychomycosis, you have to have a couple of endpoints. Mycologic cure, this is usually a secondary endpoint, is to find that at the end of the study, the nail is KOH and culture negative. Now, that’s pretty easy barrier to read. That’s the highest number. This is the number you’ll frequently hear companies touting because they can say we work 70% of the time. In fact, the Lamisil refuse to do that all the time against Penlac. They will say, “Doc., why would you use Penlac? That works 5 to 8% of the time, we work 70% of the time.” What they were doing was a little bit disingenuous because they were comparing FDA complete cure rates, 5 to 8% to Penlac versus the FDA mycologic cure rate, 70% with Lamisil. Reps being dishonest. Back in those days, it happened a lot. Now with the Department of Justice and the FDA all over them, not so much anymore. But there was a lot of that nonsense, so you need to understand the data. The primary endpoint for every toenail study is complete cure. Complete cure is define as, at the end of the study, the nail is 100% normal looking and there’s a mycologic cure. How often does that happen? Not very often. Five to 8% with Penlac, 12%, 15% with JUBLIA. We’re going to talk about all those numbers. Fourteen percent with Sporanox, it was only 38% with Lamisil. This is a crazy strict endpoint but this is what the FDA requires. Every study, every drug looks an intermediate endpoints. They call them things like clinical success, almost clear, overall success. You can call them whatever you want. What is the FDA call them? A failure. But they’re not. They’re not failures and I’m going to show you that. Let’s look at the two new antifungals. Tavaborole or Kerydin, this is PharmaDerm’s drug. There’s another class of antifungal. It’s a boron-based molecule. It’s an Oxybral antifungal. They actually have done some work on Oxybral antibiotics too, especially for multidrug-resistant gram-negatives. It has a totally unique mechanism of action. It’s fungicidal. It works by protein synthesis inhibition. Now, is that good? Yes. It is bad? No. It’s just different. Is it better than any other drug? No, because there’s never been a head-to-head trial comparing drugs. You can’t say one is better than the other and reps can’t tell you one is better than the other. If you ever hear that from a rep, I want you to call me with the rep’s name because I personally can get them fired, right, because they’re putting the company out on the limb. Both of these drugs are solutions, both the efinaconazole and the tavaborole. Unlike the lacquer, they dry quickly. They’re alcohol based. There’s no product removal necessary, you don’t need to use alcohol or toenail polish remover every seven days. The study of tavaborole enrolled patients from 18 to 88 years of age and patients had between 20 and 60% involvement of at least one hallux nail and no debridement was performed.
Didn’t need debridement. It wouldn’t have been useful. It just wasn’t performed in the trial. The drug penetrates the nail using C14 isotope labeled penetration studies. When was the last time any of your OTC drug used C14 labeled penetration studies? What you’ll find is the blue bar, is the amount of penetration of the tavaborole through the nail. The bar that you can’t even see, the yellow number next to that is how much ciclopirox lacquer or Penlac penetrated into the nail. The drug does penetrate through the nail. The design of the study, this was a true efficacy study, was a multicenter randomized double blind vehicle controlled trial. There were two studies as the FDA requires. The first study was in the US and Mexico. The second was in US and Canada. Again, 18 to 88 years of age, 20 to 60% nail involvement. They’re complete cure rate. The primary endpoint of the FDA requires for one study was 6.5%, for another study was 9.1%. The mycologic cure rate, 31% and 35%. The negative culture, you can stop a positive KOH with a negative culture, 87% and 85%. Then there are the intermediate levels like the almost completely cleared, 24 and 25% in the two studies. Now, I will tell you that none of this data has yet been published. This is all publicly available but it’s yet to be published in any of the peer review literature. Let’s show pictures. Here’s a patient on your left, it comes in with a mycologic toenail. On the right, you happy with that result? Patient happy with that result? Yeah. But the investigator called that almost clear nail. There was like less than 5% involvement or less than 10% involvement. Alright. But there was still involvement. What’s the FDA called that? That’s a failure. Here’s another case. The nail on the left, the nail on the right. You’ll get the nail on the right and I’m like, “Yeah, okay, it’s not totally cured, but it looks better than the nail on the left.” But because it wasn’t totally cured, FDA considers that a failure. But I think you and your patient would be satisfied with that result. Here’s one that kind of puzzling to me because this is a fairly good infection on the left picture but on the right, I don’t see much remaining fungus. Maybe you can make the argument that in the corner is for the medial corner a little bit, maybe there are a couple little streaks but the investigator said that’s not completely clear. You happy with that? Yes, your patient happy with that. Yes, I’d be happy with that. FDA is not happy with that. That is not in a complete cure numbers. That’s considered a failure. Same thing here. You have to be very careful when you look at these numbers that people are throwing around. What do they really mean? Complete cure is a wholly unrealistic number that to this day, the FDA still requires. What was one of the big questions we used to get to Penlac all the time? What happens if the patient wants to use nail polish? This is actually a poster that was presented at the Winter Clinical Derm Symposium this past year in Kona. The derms have it right. They do two winter meetings a year in Hawaii. When APMA does Hawaii? When do we do it? July. Alright. But what they did is they took five fingernails, four deceased female donors, they put one code on or no polish and then there was a non-dose control. If you look at the blue line, that shows the penetration through the lacquer. This light greenish line was the control. For some reason that no one can explain, they’re actually seem to be more penetration through the lacquer, through the nail polish than there was without the nail polish. Again, no one can explain that. They’ve repeated this study and the results were almost exactly the same. Safety, as you would expect from any topical relatively low adverse events, number of discontinuations, 2.5% for tavaborole, 1.5% for the vehicle and the second study, 0.8% for tavaborole, 0.5% for the vehicle. This is, as you would expect, with topical antifungals to be a safe product. This is the other drug. This is Valeant’s drug, JUBLIA efinaconazole. This is an azole antifungal and you’re all familiar with the azoles. They work on ergosterol synthesis. Egosterol is necessary for healthy cell walls. What this does is it blocks 14-alpha demethylase, which is one of the enzymes in the steps.
Now, this is the trial, three to one randomization, efinaconazole versus vehicle. Notice how long out this study goes. One thing that I didn’t tell you before when I’m talking about how ridiculous that endpoint of compete cure is, which is by the way, the same endpoint they have to use here. One thing I didn’t tell you is for onychomycosis studies, they have to be 48 weeks of treatment with four weeks of followup. In other words, these studies have to be 52 weeks long. You know what the current recommendations are for new antibiotic studies? The new antibiotic, the primary endpoint for any new antibiotic study is at 48 to 72 hours. The cellulitis is resolved by 20%. If you can reduce cellulitis, 20% in 48 to 72 hours, you can get an antibiotic approved. For onychomycosis, you have to treat for a year and the nail has to be perfect. Think about that. Think how crazy that is. But also think about all those topicals you’re dispensing. All those over the counter products. How many of them have undergone studies like this? Here is their numbers, 17.8% in one study, 15.2% in the other for complete cure. Mycologic cure, 55 and 53 over half the patients had mycologic cure. Complete or almost complete cure over a quarter of the patients at the end of the study had less than a quarter or less than 5% of the nail involved. But again, the FDA doesn’t include that in the complete cure numbers. But this study was somewhat different than the tavaborole study. This had an upper age limit of 70 and patients were only allowed to have 20 to 50% nail involvement. Now, did that make any difference at all in the outcomes? We don’t know. Again, there’s never been a head to head trial. The only way you can determine which antifungal is better than the other is to study, do an effectiveness trial like Dr. Kirchner talked about as opposed to doing one of these FDA efficacy trials. Here’s just another graft showing their complete cure versus vehicle, 18 and 15% for the two studies versus the vehicle that was statistically significantly different, 0.01 and therefore, the drug got approved. These are the clinical pictures of their failures. They’re almost complete cures. Look on the upper left. The investigator called that 40% involved. Look at the bottom, the investigator look and say, “That’s 3% involved.” I don’t know how all that is 3% as outline, but this gets to the subjectiveness of these trials. But whatever the result, it looks pretty good. I think we’d all be happy with that result. FDA, that’s a failure. Look at the middle, 50% to start out. There’s some good thickening of that nail. Look at the endpoint. Now, at the bottom center, I agree that’s not clear, that’s not completely cured, but look at what they started with. You happy with that result? Yes. Patient happy, yes. What did the investigator call that? Remember, it’s 3% on the one next to it. What do you think the investigator call that one? Five percent. That’s how subjective it is. Here’s my favorite. Look at this upper right. What percentage of involvement you think there is there? Eighty, 90%? Yeah. Let me tell you this little point. The investigator could not enroll the patient in the study and therefore cannot get paid for enrolling the patient in the study unless they had less than 50% or less. Now, how much you think the investigator call that? Fifty percent, right? Actually, 45%. It’s all subjective. I would have never allowed this patient in the study. I’ve been involved with a couple of trials where I’ve had final say, yes or no, whether the patient gets in the study or not, I would have not allow this in the study. But, you know what, look at the bottom picture. That’s an incredible result. Now, how that’s not 0%, how that’s the same 5% is the one in the middle? I don’t know. But that’s how subjective these studies are. That’s a good result. All of this look good, all of this would be considered a failure. Now, they also did a nail polish study. What they found using different nail polishes, Dior, SC, Revlon, I didn’t know there were so many. They basically show their control lines at the middle there somewhere. There was no difference in penetration with the nail polish or without the nail polish. I will tell you, as of last week, both of these drugs had new labeling applied by the FDA. On the new label applied by the FDA for both of these drugs say that the efficacy in the face of toe nail polish in unknown.
Alright. It has not been tested. We can look at these penetration numbers but the point is, what the FDA says in the package insert is the use of these drugs and toenail polish is, they’re not saying you can’t do it, they’re saying the results are unknown or the effectiveness is unknown. In their safety studies, much like you would expect with the tavaborole, again, another topical, low treatment discontinuations, 3.2% for efinaconazole versus 0.5 and in study two, 1.9% versus 0%. The most common reasons for discontinuation, application site dermatitis and application site vesicles. With that, I’ll tell you what, I’m just going to it because my time is up and I’ll primarily wanted to get through these new drugs, I just wanted to let you know that it’s a neat time to be involved with onychomycosis. Please see the first lecture I did. I want you to learn the science of this disease, stop just cutting the toenails, this is an infection and that’s what I stressed in the first lecture. We don’t think twice about treating a bacterial infection with antibiotic. We should be treating a fungal infection with an antifungal. We have two new effective topical antifungals for the treatment of onychomycosis. Thank you very much.