Warren S Joseph, DPM, FIDSA discusses how to look past the common practice of treating onychomycosis with debridement and recognize that it is an infection and should be treated accordingly. Dr Joseph reviews currently available treatment options and discusses both patient and physician views on onychomycosis and its treatments.
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Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Moderator: Next speaker is Dr. Warren Joseph. He is very unique to our profession. He is the Editor of the American Podiatric Medical Association Journal. He is world renowned as a specialist in infectious disease. He has been talking about onychomycosis and its importance to us, patients and our profession for years. He is an enjoyable speaker, dynamic, and he will educate you. So please welcome Dr. Warren Joseph.
Dr. Warren Joseph: Thank you Dr. Shawn House [phonetic]. Glad to see everybody this morning. What we’re going to do is we’re going to talk about onychomycosis. Now I know you had a talk by my old classmate and friend Matt Garoufalis on onychomycosis the other day, but I do onychomycosis differently. I approach it differently than most people who spoke of onychomycosis. I'm going to give you my viewpoint on it, why I think it's something you need to take seriously.
And we’re going to recognize that onychomycosis is an infection and it should be treated with antifungal, so I expand on that. You have to appreciate the pathophysiology and the classification systems of onychomycosis, and you have to understand the evidence behind the new topical therapies and where they should be used. Now, as a disclosure I am considered a key opinion leader in the area of onychomycosis and as such I am a consultant and a speaker for both PharmaDerm and Valeant and in the past have run advisory boards for Merck and Novartis and lots of the companies in the area. I also am a consultant to Viamed, who has a new oral drug that’s in the works.
So here is where I differ from other people who speak on onychomycosis. If you read most of the literature on onychomycosis, what specialty writes that literature? It’s usually dermatology. Well, I need to tell you there are about 10 dermatologists in the world who give a damn about onychomycosis. Well, maybe 10 in the country, 15 in the world. The point is, they just don't care all that much onychomycosis. I know them, I work with them, I’ve sat on advisory boards with all of them. I know the derms who really care about onochomycosis, but it seems in every paper that’s written on onychomycosis is written and published in the dermatology literature.
Well, the dermatologists look at this as a nail condition or a skin condition. I don't; as Dr. Shawn has mentioned, my background is Infectious Diseases. So I look at this as an infection. This is an infectious disease that we should treat with an anti-infective. When we have a bacterial infection we don't think twice about using an antibiotic, why do we hesitate to use an antifungal when we have a fungal infection?
I use the example and I have for years of my younger son who is 24 years old. When he was in elementary school, he came home one day from school with a note from the school nurse saying your son has ringworm on the arm, he will not be allowed back in school until we have a note from the family doctor saying that the ringworm is being treated and he is no longer contagious.
Well, what's ringworm on the arm, it's tinea corporis. It’s the exact same condition caused by the exact same organism we have in onychomycosis. The difference is visible in the arm of a kid wearing a short sleeved shirt versus hidden under shoes and socks so people can’t see it, people can’t appreciate it. So it's a fungal infection we need to treat it as an infection. As an infection there is a genetic predisposition to it, I’ll go into that in some detail.
It’s a progressive disease. It starts in one nail, spreads to the rest of that mail, spreads to other nails, spread to other parts of the body, and can spread to other people. They can cause an immunologic response, it can affect quality of life, it and can relapse and reinvent. Let’s go back to the history a little bit.
Onychomycosis is any fungal infection of the foot, was in fact rare only a hundred years ago. You think that fungus of the foot has been around so long look at a statue of Michelangelo's David, he probably has onychomycosis. But the point is that I took a look once at the book by Sabouraud called Topical Dermatology, you all heard of Sabouraud argument. He wrote a book at AD 1890, and in that book, there is one paragraph, one fungal infections of the foot, and says dermatomycosis of the foot is a rare condition.
So as recently as 110-15 years ago, dermatomycosis of the foot was a rare condition. Well, it has become more common over the years, and that could be urbanization; we are living more closely together. I love this, I mean I would never say this just came from a reference; communal bathing facilities, how many of you here communally bathe? Not that there is anything wrong with that, but I just don’t think it’s very common. But certainly swimming pools we know there are incidences where they cultured swimming pools, and they found fungus around the swimming pool docks.
Occlusive footwear, I mean, we’re not as good about changing shoes as we should be, and increasing incidence of diabetes and HIV. We know with diabetes, increasing amounts of fungus and we’ll talk about that. And then there are some occupations where there's an increased risk –minors, soldiers, runners, anybody who has a lot of trauma to the foot, wears a lot of those occlusive shoes, maybe isn't paying very good attention to their hygiene, you're going to end up with increased risk.
Well, these are soft numbers, I mean, there’s not a lot of hard data on this, but it is estimated that between 35 and 36 million people in the United States have onychomycosis. Now they say that about 6.3% of those or 6.3 million have been diagnosed by a physician, maybe 2 million have actually received treatment. The point is the bottom line there. There are somewhere in the neighborhood of 30 to 33 million untreated onychomycosis patients in the United States.
I remember when I used to lecture on lamisil when lamisil first came out, people will come up to me and say, Warren, why would I ever use this drug, I'm going to cure away my practice. Cure away your practice, I mean, maybe if you actually treated a patient and cured a patient with onychomycosis, instead of debriding their nails every 61 days, you actually have patients coming in to see you, as opposed to going away to other places.
So the point is, there are lot of untreated patients where patients do want to get rid of this disease, this infection and there are ways to do it. What is the best that we ever have on onychomycosis? In my humble opinion, it was Digger the Dermatophyte, because I will tell you, when lifted up that toenail and crawled underneath, everybody watching TV in the United States got totally skied down. That was gross. I can imagine sitting there after dinner watching the evening news and you see this little monster ripping your toenail off.
But every one of a certain age came in or every one of us have a certain age, docs have a certain age, had patients come in waving Digger ass or you would talk to them about onychomycosis and they say, oh, like that little yellow guy on TV; everybody knew Digger. We had Digger Bobbleheads, we had digger paperclip dispensers. It was incredible. Back then in that day companies to give away stuff like that, the Digger Bobblehead was still my favorite, but the point is that Digger raised awareness of onychomycosis and what onychomycosis is.
In fact he was so popular, still talked today in business schools as a model for direct to consumer pharmaceutical advertising. It's no coincidence that just about every drug now that does direct to consumer advertising uses a little animated creature or monster, and I think a lot of that is because of Digger.
Well, when you talk about any infection you have to talk about epidemiology. Now I know I see, even though I can’t see the fingers, I got four bright lights in my face, I can see your eyes glazing over when you see the word epidemiology. But don't worry, it’s only one slide. And the point is at epidemiology you've got three issues with which you have to be concerned. Number one is environment, number two is host, and number three is the pathogen. Environment, host, pathogen; these are the three things you have to be aware of in onychomycosis.
So what do we have? Well, environment we talked about some of these – your hygiene, shoe gear, hyperhidrosis, communal habitats, contagious. How many of you are walking around in this hotel wearing shoes and socks when you're walking around in your room wearing slippers when you're walking around in your room. Boni Elewski, when the world of dermatology is considered Dr. Fungus. Boni did a study where she cultured hotel carpets, and she found that or she jokes around that there's like the AAA diamond rating, she was going to come up with Elewski spore rating. Now this is a 2 spore hotel, a 3 spore hotel.
So think about that. Next time you're walking around with bare feet in a hotel. Now Hilton just took over this place and have big plans to renovate, but these carpets haven’t been changed in a couple of years that I've been coming here, and I'm not sure that that document is taking care of it. So just think about that with the environment. The host certainly age, we know that as you get older there's more onychomycosis. Patients over 70, about 50% of them have onychomycosis, genetics we’re going to talk about, Isaiah showed that.
Peripheral arterial disease, diabetes, all things we’re going to talk about, all patients who have higher incidence and prevalence of onychomycosis. Well, back in 1972 Nardo Zaias came up with a classification that is still used today of onychomycosis. Now I've done this at a couple of residency summits are there are not enough of – I'm not going to do today, I did it last year at this meeting and I did it last year at the TENAC meeting where we had four house of residents, and I said to you, I asked you how many of you can recite for me the Lauge-Hansen classification of ankle fractures. And every single resident in the room raised their hand. I said okay, how many of you can recite for me the Zaias Classification of Onychomycosis, not a single one of you raised your hand.
So what I said back I'm going to say to you today, because I know you're thinking whether or not you knew these or not, is that I find it interesting that everyone in the room could name a classification system for a condition that one third of you will see twice a year, none of you can name the classification system used in a condition that every one of you will see 20 to 30 times a day. I think that's disgraceful. I think that's an indictment on our educational system. You're so busy learning about ankle fractures that you're not going to see in most of your practices, so you're going to see rarely, that you're not taking seriously a condition that affects 30 million people, this is an infection, and I think that's just wrong.
And this is the classification system that’s used in every scientific paper that's written on onychomycosis. You might scoff, scientific papers written on onychomycosis, yeah, right. Well I assume as residents you're familiar with Pubmed.gov pub that’s how you do your med line searches. Well, go to pubmed.gov and there’s a little button that says My NCBI, and you can sign up for emails every week, every day, every month. You set the duration, you set the timing, and you can get a subject matter, and every week let's say, you get an email from My NCBI with all the papers that have been published in the world in that subject matter for that week.
Well, I get three emails every Monday morning, one on osteomyelitis, one on onychomycosis, and one on diabetic foot infections. And I will tell you that every week onychomycosis beats the other two combined. In fact just this past week, there were eight papers on onychomycosis; one each on diabetic foot infection and osteomyelitis. So there's an incredible body of science out there on onychomycosis that our profession ignores, and I'm being hard on you as residents only because you can change it.
When I lectured the people of my generation, forget about it, can’t change them, but I can change you hopefully, I can get you thinking a little bit differently that this in fact is something, and why don’t we learn the science behind it. Clipping toenails is not glamorous, but you don’t have to do it. Debridement is not treatment, think with your head not with your hands. And my favorite that I came up with many years ago when we were doing the Lamisil talks, be a physician, not a technician. There is nothing you do cutting toenails that can’t be done by somebody with a sixth grade education and a couple of weeks of vocational training.
Think about how you learned to cut toenails. Somebody gave you a nipper. One of your clinicians gave you a nipper and a chart and said, go do it. Did they even watch you; probably not, they were busy reading the newspaper or drinking coffee. I know I was a clinician for 15 years. So the point is that there's something to be said for considering this a medical disease that needs to be treated.
So the Zaias classification is very easy. There are only three that you really have to aware of: Distal subungual and I’ll call distal lateral subungual, white superficial, and proximal subungual. Proximal subungual you're going to see very rarely. It used to be associated with HIV infection, now it tends to be associated with people going to get like manicures, mani-pedis, things like that.
Candida onychomycosis you do occasionally see more common in the fingernail though, and it is not something that I concern myself with overly. Then there have been other types added end-stage onychomycosis also known as Total dystrophic onychomycosis, there is one called endonyx onychomycosis, mixed pattern onychomycosis secondary onychomycosis, don't worry about it. Just worry about knowing those three, and you will be able to read any of the literature on onychomycosis – white superficial, distal subungual, distal lateral subungual, now it’s called proximal subungual.
Mycology, almost every onychomysis just like every tinea pedis is caused by dermatophyte, in particular T rubrum. Distal subungual, certainly T rubrum, and then you’ve got T mentagrophytes is now called T. interdigitale for your white superficial.
I was telling you that if you listen to the dermatologist speak on onychomycosis, they will say, oh well, 10 to 15% of onychomycosis is not caused by dermatophytes, it’s caused by the nondermatophytic molds, scopulariopsis, fusarium, scytalidium, acremonium, aspergillus; you name it.
Well, I don’t know that I buy that. See, to me it’s very similar to doing the old diabetic foot swab. If you take a swab of a diabetic foot, what are you going to grow? Everything known to man – staph, strep, E. coli, proteus, pseudomonas. Doesn’t mean that any of them are actually pathogenic. They are colonizers, same thing with these other mold organisms.
By definition, a dermatophyte survives by digesting human keratin. The molds do not do that. So what is the pathophysiology of a mold infection? I’ve asked the top derms in the world on this and no one can give me an answer of that pathophysiology. I think it's secondary. I think the vast majority are caused by the dermatophytes. What about diagnosis?
There are lots of diagnostic techniques we have, certainly PAS staining has become the most sensitive. The literature is very clear on this. Very sensitive test is just not particularly specific, it won’t tell you what the lab is. If you want specificity you have to go more towards the culture. The problem with the culture is that it's got false negatives about 48% of the time. So about half of them you send are not going to grow even if it's onychomycosis. But it does have the ability to tell you the organism.
It’s like, okay, this is a T rubrum, which a PAS stain or KOH cannot do. I think the future of onychomycosis diagnosis, just like the future of bacteriological diagnosis, is going to be molecular techniques. Things such as PCR or 16S ribosomal sequencing, where you actually get very rapid, very specific, and sensitive results. A single strand of DNA will show what? The problem is there are very sensitive, but they're not overly specific. So you'll get 15 different organisms, you don't know what's actually causing the infection. I think that still needs to be worked out. But the point is, lots of diagnostic information you can gather.
Well, what about clinical diagnosis. I will tell you that if you listen to the dermatologists who lecture on this, they will tell you you can never make a clinical diagnosis, because after all 50% of all dystrophy toenails are not caused by fungus, they are caused by Lichen planus, psoriasis, 20 nail dystrophy congenital abnormalities, on and on and on. I don’t buy it, I think they released in podiatric practice about 80% of what we’re seeing is in fact caused by fungus. And I think that diagnosis can be made clinically.
In fact this is a paper by Fletcher that was published in the British Journal of Dermatology that showed the physicians labor to accurately diagnose fungal nail disease based on clinical observation only with a positive predictive value .91, that's twice as good as a culture. In fact both Fletcher Garcia Duval in another paper published in the British Journal of Dermatology came out and said that we feel that clinical diagnosis is accurate enough, that it’s accurate enough to begin therapy.
Well, there are two issues where I would not begin therapy based on clinical diagnosis alone. Number one is if you are going to use an oral antifungal, because if you actually look at the package insert for Lamisil, this is what you see. Prior to initiating treatment, appropriate nail specimens for laboratory testing and they even spell them out, should be obtained to confirm the diagnosis of onychomycosis.
I have reviewed cases of death by Lamisil, and I will tell you that this is where they nail the doc, not on failure to do blood work or anything like that, they nailed the doc on failing to confirm the diagnosis before starting therapy. That’s instance number one where you need to use confirmatory information.
Instance number two, who is going to require it? The insurance companies. So if the insurance companies require you do confirmatory diagnosis, you’re going off to do confirmatory diagnosis. Onychomycosis and Quality of Life, Lynn Drake as President of the American Academy of Dermatology published this in 1998, where she did a quality of life survey and found that 48% of patients with onychomycosis have pain; 48%. Yet when we try to get this covered the insurance companies say we’re not covering that, it's a cosmetic issue, but you got 48% of people have pain.
74% are embarrassed. Now there's embarrassment but then there is embarrassments. And I told the story of a patient I had many years ago who had 10 toenails and 10 fingernails involved. He didn't care about his toenails, he cared about his finger nails, why, he was a priest. And he was concerned his parishioners were staring at his fingers when he was giving communion. Well, I had to assure him that the oral antifungal I was going to give him would not work against his fingernails because in the Commonwealth of Pennsylvania I'm only licensed to treat the toes.
But you know what, he must have known somebody, hallelujah, it was a miracle. Both his toenails and his finger nails cleared up. That's embarrassment when you can't do a job. Genetics of Onychomycosis, I mentioned Nardo Zaias before who came up with a classification system, he is a derm down in Miami. Nardo also followed 500 families into genetic mapping of them.
And what he found is that there's a cell-mediated immune deficit that’s passed through autosomal dominant trait that causes people to be susceptible to fungal infections. Now let me give you my N of 1, not high-level of evidence, but this is my N of 1, I have onychomycosis and tinea pedis; anybody else? 35 million people and no one here, I don’t believe any of you. But the point is that I’ve been with my wife 30 years; she doesn't have onychomycosis or tinea pedis, yet both of my sons do. So I really do think there's something to it and you have to be aware of and ask questions.
In fact Zaias went on to say that because it's a genetic predisposition, the patients with onychomycosis were predisposed to have onychomycosis and fungal infections in other parts of the body including tinea pedis, tinea corporis and tinea cruris. So think about that. Now it’s a little tough as a podiatrist to ask to investigate for tinea cruris. At least ask them about it. What about tinea and onycho, these two are connected, it’s the natural history of the disease; these two are linked.
What happens is onycho starts tinea pedis, there's some damage to the hyponychial seal which allows the fungus to invade underneath, and then you basically get the fungus invading the nail bed stratum corneum, because that's where the infection is, it’s in the mail bed stratum corneum. So essentially all patients with onychomycosis have had or do currently have tinea pedis, now that might not be obvious, but sometimes it looks like little dry skin, little flakiness on the bottom of the foot, that’s not dry skin, that’s tinea pedis, and you can’t treat one without treating the other.
With orals this is a nonissue, you give orals you treat both, but if you’re using a topical for onychomycosis, and you don't treat the tinea pedis, you’ll clear the onychomycosis, the skin or the infected nail just as how it all started. Likewise you have a patient with – you treat topically for tinea, and you don't treat the onycho, the onycho reinfects the skin, so you really need to treat both. And this just shows you your that's the typical serpiginous lesion of tinea pedis, and you can see how there has been some opening up of the distal mail and the invasion is allowed through the distal now.
Just little cartoon I had drawn up, starts from the skin, gets up under the toenails. Now you cleared the skin but you haven’t cleared the toenail. The toenail then acts to reinfect the skin. And this is just one of my patients, you can see the obvious moccasin distribution of the tinea pedis, and you can see the onychomycosis, the total dystrophic disease of all toenails. This is not just dry skin or xerosis, because look at the dorsal skin. The dorsal skin is absolutely fine, it's in the moccasin distribution, is moccasin T rubrum tinea pedis.
Diabetics, we know have more onychomycosis. This was shown by a doctor back in 1998. Patients with diabetes had 2.8 times more onychomycosis than patients without diabetes. Well what does this lead to? Things like this. That's an onychogryphotic nail in a neuropathic patient, and you end up with an ulceration. Or you get what I call clink, clink, squish syndrome. You start debriding these nails, you pull out your nipper and you go clink, clink, clink, you get to that hallux nail, you go squish. go squish. And that bead of pus cost comes out from under the toenail and as you debride it away, you see now that there's a subungual ulceration.
Remember back to your days of lower extremity anatomy, how much tissue is there between the skin, the nail and the bone? Not a lot. Now you’ve got onychomycosis leading to osteomyelitis leading to possible amputation. Just another example of cling cling squish, you can see the lesser nails we clinked and the hallux nail we squished and where the pus came out from underneath and just another subungual ulceration.
Alright, we are going to spend the last 15-20 minutes talking about treatment considerations for onychomycosis. Well I should talk about the onychomycosis disconnect. There is a disconnect between what we know about onychomycosis treatment and what we do with onychomycosis treatment.
For instance, this particular graph shows that there are 20 million people untreated with onychomycosis. They don't like the options they are unmotivated to treat. They are just uninformed that there are options.
We’ve got oral medications only 1 to 2 million people have been put on oral medications though we know that terbinafine in particular is considered the gold standard when it comes to the treatment of onychomycosis. That’s a disconnect.
Debridement: 8 to 10 million people just getting routine debridement by podiatrist but we know that debridement doesn’t do anything to treat the infection that’s a disconnect. And then topical treatments this was before the advent of Efinaconazole and tavaborole.
And you can see that very few patients were getting topicals and in fact most of the topicals they were getting were over-the-counter. Now I love the fact that people like to sell things out of their office to make a living, I'm all for making a living that's why I do the lecturing I do, but I will tell you that I personally have a problem with you selling a patient something that is never been tested in onychomycosis and not only hasn’t it been tested, it's not FDA approved for onychomycosis.
There's never been a single study to prove that any of these products you sell for a profit out of your office work against onychomycosis. I think that’s a disconnect. This shows the disconnect between patient or podiatrist perception of what is effective versus what we do as podiatrist.
This is old data but you can see off to the right oral antifungals we perceive is the most effective but it's the least common thing we do, it’s the least common thing we do. We don’t perceive debridement is being particularly effective but it's the most common thing we do.
So when you are looking at the current approaches there is mechanical approaches, topical approaches and oral approaches. Well I will look at this not as three separate rings I will look at this as the Olympic rings, picture this as a giant venn diagram of onychomycosis and consider combining mechanical debridement with topical therapy, may be by thinning the nail you allow better penetration.
Topicals and orals, the topicals work from outside in, the orals works from the out, maybe that would be more effective. We don't know there's not a lot of good studies that have looked at this but you just don't care about the studies in that case you want the patient to be better use combination therapies.
Debridement as I talked about is the mainstay of the podiatric approach may make the nail look better and feel better it does nothing to treat the infection, it may potentiate treatment of the infection but we don't know that for a fact.
Surgical approach, sure you can remove a mycotic toe, nail, remove the toenail not the toe unless you’ve got one of those osteo cases. But the point is that the days of doing 10 PNA's across-the-board are long gone. I think this is for isolated really severe cases may be where there has been trauma to the nail and the nails just not going to get any better.
We’ll just going to now talk about the topical therapies. Now the first topical therapy that was out there Ciclopirox Lacquer or Penlac. Now people always say, you know this stuff doesn't work, we’ll talk about the Ciclopirox in a second. Well why I get excited on onychomycosis now, and I know there is words you don't hear often to get excited on onychomycosis is that there were two new topicals just to prove this past summer.
We had Efinaconazole approved in June, we had tavaborole approved in July, so two new FDA approved topicals for the treatment of onychomycosis that to me is exciting. That to me is interesting it shows there are people who think that onychomycosis is worth treating and there is science being applied to onychomycosis.
Then there are a lot of other topical therapies that are being studied luliconazole probably not going to be continued not the tinea pedis version of luliconazole but an onycho version that another company has. And then there is a Japanese product, ME-1111, which has just completed phase two studies.
So let’s look at the Ciclopirox, I’ve heard for years, oh, I am not going to use that stuff, it doesn't work. Penlac doesn't work. Penlac did work. It worked for the right patient who is going to be adherent with the right amount of infection. Here is my problem with Penlac. That was a lacquer. It was miserable to use, it was sticky and took forever to dry, patients would get what we call black hairy toenail syndrome, you know they put their sock on before the Penlac is fully dry when they took their sock off all the fibers would be attached to the nail, it should be debrided every month.
Patients had to remove it every seven days, the bottle wouldn't open but it did work in select patients. This is one of my patients I had on Penlac and this is a patient who was perfect for Penlac or for any topical therapy. She had about 25% 30% nail involvement, there wasn't a lot of thickening of the nail and she was adherent. She wanted this to go away why, she was a karate instructor. In fact she was my karate instructor. You wouldn’t know by looking but this body used to be a deadly weapon. But the point is that this woman literally had her feet in people’s faces.
Also she was extremely adherent with treatment and sure enough it got better so I am tired of hearing this Penlac doesn't work. It did work for the right patient. All of the topicals would work for the right patient with the right disease.
If you use a topical on a patient that has total dystrophic onychomycosis who stops using it after a week or two it's not going to work and it's not to be the drug's fault it's going to be the patient adherence fault and your fault for using it on the wrong patient. Don't blame the drug; blame the patient selection and the patient adherence.
So we have to talk about efficacy. Now I am going to be recording a whole lecture for presenting after you guys leave, they will be up online, which looks at clinical study design for onychomycosis studies. And it’s crazy what the FDA requires is absolutely inane in my humble opinion but it's what we are stuck with. And there is certain terms we can't get around.
The FDA likes to look at mycologic cure. Now mycologic care is usually a secondary end point but what it means is at the end of the study the patient is KOH negative and culture negative. Well the fungus can be dead but the patient could still be KOH positive. KOH doesn't differentiate live from dead fungus, so it can take a long time for that nail to grow well and for the fungus to in fact be gone totally from the nail. It’s a lowest barrier though it’s easiest number to hit so it tends to be the highest number.
Now this is where we run into an issue because the FDA requires, this is the primary endpoint, in other words for a drug to be approved by the FDA this is the endpoint it must meet, is complete cure which is defined as at the end of the study the nail is not only mycologically cured it is 100% normal in appearance, looks like your thumbnail. How often does that happen? I mean, come on, think about that. Let’s look at new antibiotic development.
To get a new antibiotic approved in 2015 through the FDA, you know what the primary end-point is? Forty eight to 72 hours after you start the antibiotic the nail has to -- excuse me -- the cellulitis has to have reduced by 20%. Forty eight to 72 hours, cellulitis reduced by 20%. This is at 52 weeks, 48 weeks of treatment, four weeks off treatment, 52-weeks one full year the nail has to be perfect looking KOH in culture negative.
I think that is a highly, highly inappropriate endpoint that is just way too rigorous to try to get any sort of drug approved. Because of that every company comes up with some intermediate endpoints almost clear, clinical success, overall success, everyone has a different end point. What does the FDA it? Failure. If it’s not a complete cure, it’s a failure.
So let's finish up by looking at the two new drugs: tavaborole. Tavaborole is a solution in fact both of these two new antifungals are solutions that are alcohol-based, they dry very rapidly, they are not lacquers they don't require product removal every seven days like we have with the Cyclopirox, right.
This is a novel antifungal and that it is an oxaborole it’s a Boron based drug. Boron is a natural molecule that occurs in lagoons, vegetables, fruits, has an LD50 similar to table salt and it has a unique mechanism of action. It's a fungal protein synthesis inhibitor. Now is that good, is it bad. It's different, it's a different way of looking at antifungals that’s all I am saying.
The studies that were done in this study -- the studies that were done in this drug looked at patients [Indecipherable] [0:35:15] normal. So the youngest was 18, oldest was 88, and they had between 20 and 60% nail involvement. There was no debridement performed, alright. Here you can see the data there was about 1200 patients in the two studies with 20 to 60% nail involvement.
They had to have 3 mm or more clear nail from the proximal nail fold, less than or equal to 3 mm of distal toenail, plate thickness. So there had to be only up to 3 mm of thickness, and of course they had to have probably a positive KOH and positive culture. Patients were randomized two to one to receive tavaborole or vehicle. Again daily application for 48 weeks followed by four weeks of follow-up and here are their numbers.
If you look at the primary endpoint which is complete cure, study number one was 6.5%, the second study was 9.1% versus placebo you can see the very low vehicle not placebo, excuse me, very low vehicle rates that was statistically significantly different. The drug was considered superior to vehicle and therefore was able to get its approval.
Completely clear nail defined as less than or equal of 10% of nail involvement. Over a quarter of the patients at the end of the study had less than 10% nail involvement. And mycologic care you look at 31% versus about 36% or excuse me 31% and 36% in the two studies. And here are some pictures from the trial.
Now take a look at the nail on the left you see there's about 30% involvement, take a look at the nail on the right, anybody unhappy with that result. Is your patient unhappy with that result? Well the investigator felt that there was a little distal involvement still so this was not a complete cute. This was only a almost clear.
Again what does the FDA call that? A failure. I don’t think anyone can call that a failure. Another case I would agree that I mean maybe that nail on the right is not a 100% cure but look how it started on the left, anybody unhappy with that result. Yet the FDA considers that a failure, that's not listed in the efficacy numbers.
I think you have to be very careful when you look at these numbers that you understand the definitions you can't just look at numbers in a vacuum. And here is another case that's a pretty nasty looking nail on the left, probably about 40% involvement. On the right I think that looks pretty good maybe in the medial aspect there is a little involvement still. Investigator traced that out and said there was an involvement less than 10% though that was considered almost clear. That’s a failure.
So be aware when you see numbers of what these definitions mean and just another case the same thing. That was asked -- that to me, I don’t know how that’s not a complete cure. Safety data as you would expect with any topical antifungal it’s going to be safe.
Study discontinuations in the one study 2.5% for tavaborole, 1.5 for vehicle, 0.8 for tavaborole, 0.5 for vehicle in the other study. And none of the serious adverse events were considered treatment related. Efinaconazole: Efinaconazole was approved in June. This is the other new topical antifungal. It is also a solution as I mentioned alcohol-based, dries rapidly, no product removal required, right.
Efinaconazole is an azole antifungal. As an azole antifungal it works on ergosterol synthesis. Ergosterol is necessary for healthy cell wall so if you inhibit ergosterol synthesis you have no more Ergosterol, the cell becomes disruptive that’s how all the azole antifungals work.
So this was the study design of Efinaconazole 10% solution. This was a three to one randomization of about 1600 patients and what you saw here is just like the other studies because this is what the FDA requires, 48 weeks of daily therapy with a four week follow up to evaluate the primary endpoint. Well, let’s look at the numbers.
The primary endpoint of complete cure in the first study which was done in the US and Japan 17.8%, the second US and Canada 15.2%. Always tend to be higher efficacy in Japan I don't know if it's a cultural thing and adherence thing but studies done in Japan tend to have higher efficacy than studies done in other, just North America and you can see that here between these two studies.
The mycologic care, over half the patients 55% in one study, 53% in the other study were mycologically cured and complete or almost complete 26.4% and 23.4%. So again you can see the numbers here these were both statistically all statistically significantly better than vehicle thus the drug got approved.
So this is the other drug that’s been FDA approved, just again showing the cure rates versus vehicle. But let's look at their pictures. Now for this slide we are going to play clinical investigator because how do you determine the extent of nail involvement or back in the days Penlac they used to use a computer it called computer planometry but one of these new studies used planometry basically the investigator just eyeballs the nail.
So let’s look upper left corner and it’s a shame I can’t really point to it here. Upper left corner where it says 40%, okay maybe down to 20% and at the end on the bottom there week 52 that's 3% I don’t know how that's 3% that looks little more like 10% to me but okay 3% doesn’t matter, still failure. Just like the pictures I showed you in the Tavaborole study that all looked really good. They were almost clear. These are almost complete care.
Similar definition, failure according to the FDA. You start with that up top in the left and get to the bottom I don’t care if it’s 3% or 10% I think you're happy, I think your patient is happy. Look at the middle one, 50% enrolled. Alright 20% by week 24, yeah let’s play investigator. Look at that bottom picture in the middle if the one on the left is 3% what would you call this one. Anybody? Five, really I would look at that and say 12, I mean if that’s 3% I don’t know. Well what the investigator call.
You are right 5%, maybe that one was too easy for, I don't see how that's 5% if the other is 3% but okay let’s look at that upper left-hand corner, what does the investigator call that. What would you call that? Forget what the investigator called what would you call that? How much involvement is there? Eighty percent yeah, 90% I think they are all valid numbers.
Well remember that the study for Efinaconazole only looked at patients with 20 to 50% nail involvement. So if it was more than 50% the patient is not enrolled in the study and the investigator doesn't get paid. So now how much would you call it? Fifty percent, right, well the investigator call that 45%.
But look at the bottom, now how is not a complete cure? I don't see any fungus there. That to me is a complete cure but the point is investigator said, no, no, no that's not a complete cure there still a little there, there is 5% left that's an almost cure but the point is, look what it started at, look what it went to. That's a good result even though the FDA looks at that as a failure.
So I think we really do have to be very careful. When we are by the way safety data just like with the tavaborole you would expect safety to be very similar, I mean there are topical drugs discontinuations 3.2% versus 0.5 for the vehicle on one study and the other study 1.9 versus 0% for the vehicle and the most common adverse events were local skin reactions, in fact for both of these drugs in the package insert the most common is now listed as ingrown toenail which I think just next the procedure they do.
But the point is that you really can't compare study to study. There may be you know this push they want to do that, none of these drugs have ever been studied against each other. None of these drugs have been studied against each other. Look at each of these drugs we’ve got two new drugs different mechanisms of action, different study designs but I think it's just an interesting time to be involved in onychomycosis. Get excited about onychomycosis, it's an infection.
You love to treat diabetic foot infections. At least if you're not, you're sick, but I mean everyone loves to treat diabetic foot infections. You’ll love to treat bacterial infections. You can get as excited about treating fungal infections. Onychomycosis is an infection and should be treated aggressively with anti-infectives. Clinical diagnosis maybe even better than laboratory diagnosis but we need laboratory diagnosis to confirm the diagnosis for oral therapy or in just case you need from an insurance company standpoint. Onycho and tinea it’s rare to have one without the other you need to treat both.
Patients with diabetes have more onychomycosis and serious secondary infections can result and treatment can involve mechanical, surgical or medical modalities or consider that big Venn diagram a combination of all. Thank you very much.