Expert Insights on Onychomycosis

This content is supported by Ortho Dermatologics.

Video #1:

Hello! My name is Dr. Warren Joseph. I'm a podiatrist, specializing in infectious diseases, and I split my time between the Philadelphia area and Sedona, Arizona. I am currently an adjunct clinical professor at the Arizona College of Podiatric Medicine at Midwestern University, in Glendale, Arizona, where I teach lectures and infectious diseases, and I am course director for a course on evidence-based medicine and research.

I think the biggest challenge facing clinicians in onychomycosis is making a proper diagnosis. You know, if you read the literature from the dermatologists, they will tell you that 50% of all dystrophic nails are not fungal, 50% are things like psoriasis or lichen planus, or just post-traumatic nail syndromes, yellow nail syndrome. There's a whole list they come up with. So when you read this literature, they really stress the point that you should confirm the diagnosis. Now, most of the time I've been of the belief that as podiatrist, we see so much onycomycosis then, really, I think we're better diagnosing it than just about any other specialty by far, and there've been a couple of studies that have implied that.

But the problem is nowadays it's getting a little bit trickier, because you really need to confirm the diagnosis for a couple of reasons. Number one is insurance. Let's let's get very pragmatic about it. Most insurance companies are going to require at least some sort of confirmatory testing before they pay for an antifungal therapy. So that's one reason. Another very pragmatic reason might be medical-legal. For example, in the in the package insert for oral terbinafine, it comes right out and says, confirm the diagnosis before beginning treatment. So if you were to start a patient on, let's say oral terbinafine, and let's say the patient develops a complication. It's rare, but it does happen, then you wouldn't have a leg to stand on because you haven't confirmed the diagnosis. And finally, the third reason I think it's important to confirm a diagnosis is because it's not going to improve on antifungal therapy if it's not a fungus. So if you have a dystrophic nail, that secondary trauma, lichen planus, or any of that other huge list that the dermatologists and all the literature might say. And you try to treat them with an antifungal. Things just aren't going to get any better. And what's going to happen? You're going to get frustrated, the patients going to get frustrated. So it's really important to confirm the diagnosis. But I'm going to add a special bonus reason why you need to confirm the diagnosis.

It's coming to our scientific consciousness, in the last year or so that there is, in fact, increasing rates of anti fungal resistance. Now, this has never been a problem. It's not like antibiotics and bacteria where we've known about multi-drug resistant organisms. For a very, very long time. This whole knowledge of increasing rates of resistance to antifungals in the dermatophytes particularly is really becoming a clinical issue. So if you're treating a patient, let's say, with terbinafine, and the patient's not getting any better. It may be because they have a terbinafine resistant organism. So there are ways now to test for that your genetic test that can be done. There are some sensitivity tests that can be done. That's really not widely available yet. But that's just another reason. We need to start considering confirming the diagnosis because you may be dealing with an organism that is resistant, an issue we've never had to worry about in the past.

Jublia is efinaconazole, a 10% topical solution that is indicated for the treatment of onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes. Now, the original package insert always talked about adult patients. But as we'll talk about a little bit later in this video is that, in fact, they now have an indication for pediatric population from 6 years of age, and up, all right up through adults. 

There are a couple of properties that you have to be aware of when you're selecting an antifungal. We have to take into account the physiology of the toenail. Well, the toenail really consists of about 25 tightly bound layers of dead, flattened cells, and those cells are filled with keratin. So if you apply a topical compound that likes keratin, then what's going to happen is that compound is going to get all bound up in those 25 layers of cells and never make its way down to the nail bed stratum corneum because, remember, where is the locus of infection and onychomycosis? It's in the nail bed stratum.

So number one, you want an anti-fungal that has low affinity for keratin. It is not keratinophilic. Number 2. You want a hydrophilic molecule. You want a molecule that likes water because the nail can act like a concentrated hydrogel and therefore you give a hydrophilic compound. It also will penetrate through. And number 3, you want a small molecule, because the larger the molecule, the more difficulty. It's going to have penetrating around the nail and around the nail cells. So they're the 3 primary properties you're looking for. You're looking for a drug with low carbon binding. You're looking for a drug that is hydrophilic and is a small molecule. And in fact, they are 3 of the key components or the key properties of the efinaconazole. All it is a drug that is hydrophilic with low carbon binding, and is a very small molecule, so can penetrate through the nail bed,  but it also has a very low surface tension. Because it has a low surface tension, it spreads. If you apply it to the top of the nail. It not only goes through the nail, but it just spreads all around the nail and gets under the end the distal tip of the toenail and can spread through what they've named the air gap. So you have air gap penetration. So with Jublia, you have a product that fulfills all the criteria for an ideal antifungal that can get to the site of infection.

Video #2:

The major clinical trial that looked at efficacy was published in 2013 in the Journal of the American Academy of Dermatology. That is what we call the pivotal trial, or the trial on which the FDA decided to approve the drug. All drugs pretty much, be it antifungal, antibiotics, just about anything, need to have 2 randomized, controlled clinical trials that look at its efficacy in this case against the vehicle. So this is powered and is what's called a superiority trial. They're looking for how it works versus the vehicle. Now, this is not new data. This data, again, has been out there since 2013. There've been lots of lectures about it. So most of you were probably familiar with it. There was 1,655 patients with mild to moderate onychomycosis in women aged 18 to 70. Before I was looking at 75 to 80. So let me correct that, and say 18 to 70 and anacomycosis in involving at least one great nail.

Now, when you look at the FDA requirements for an onychomycosis clinical trial, they are very, very strict. The patient has to be on the drug for 48 weeks ,with a 4 week, let's call it a wash out period or a treatment-free period. So the primary endpoint occurs at 52 weeks. Can you imagine keeping a patient in a clinical trial for 52 weeks? How difficult that is! Because we all know their troubles with patient adherence, and patients following up with things. So in this case they had to apply the drug daily for 48 weeks, and then, after 4 weeks of treatment-free time, they were evaluated. To be considered a treatment success, which the primary endpoint is complete cure, the toenail had to be 100% normal looking. So imagine pretty much like looking at your thumbnail and have a negative mycology, or a mycologic cure which is defined as negative KOH and negative culture. So think about this at one full year, in order to be considered a complete cure.

The patient had to have a perfectly normal looking toenail and a mycologic cure meaning negative KOH and negative culture. How often does that happen? I mean, that is a very, very strict end point. Let's compare that to the current endpoint the the FDA requires for a new antibiotic to be approved under what's called the acute bacterial skin and skin structure infection guidelines. Under those guidelines, if the cellulitis reduces by 20% in 48 to 72, not days or weeks, hours, that drug can be approved. So we compare reduction of 20% of infection in 2 to 3 days versus a 100% perfect nail after a year. That is an incredibly strict endpoint, and that's why our numbers are a complete cure. Numbers tend to be relatively low with any antifungal study, and if we look at those 2 pivotal trials that had to be done, the complete cure rate in trial. One was 18 and trial 2 is 15%.That's compared to the vehicle, which was 3% and 6. So you had 18% in study, one with the drug, 3% with the vehicle. That is a statistically superior difference that allows this drug to get approved. Likewise, with study 2, 15% and 6% for the vehicle. That is a statistically significant difference. 

The drug was superior to the vehicle, and that is the basis on which this drug got FDA approved. Now, because that endpoint is so strict, there are other endpoints, such as complete or almost complete cure. Or let's look at mycologic cure. Mycologic here again defined is negative culture, and that's a good endpoint, because that gives us the idea of the fungus is gone. Maybe the nail doesn't look any better or maybe the nail still takes some time to grow out, but at least the fungus is dead and gone, and in those cases, in both of the studies, over 50% of the time, there was a mycologic cure at 52 weeks, 55% for study, one and 53 for study 2. So that's the data that's been out there for quite a while.

The newer data is on the pediatric population, and that to me is really interesting. Before I mentioned that the drug is approved for ages 6 and older. Well, before that it was 18 and older. Well, there was a clinical trial that was performed. It was a phase 4 multi-centered open label study. Looking at primarily the pharmacokinetics and safety of the drug, but also the efficacy, and they took 60 patients, aged 6 to 16, with mild to severe onychomycosis. The adult trial, remember, was mild to moderate. This included up to severe onychomycosis and looked at safety and looked at pharmacokinetics, so how much of it was absorbed into the system, and then looked at efficacy.

And what they found was number one. The drug was safe. There was only 2 patients or 3.3% of patients that had one treatment-related adverse event. So only 2 out of the 60 patients there was very little absorption. I mean, the peak absorption was something in the neighborhood of 0.55 nanograms per milliliter through into the system. So there was very little drug absorbed. That's the pharmacokinetic data. But if we look at the clinical data, the complete cure rate again, same definition as before, 52 weeks. Perfectly normal nail was 40%, not 15 or 18% like with the adults.

It was 40% in the pediatric population and as high as 70% in the mycologic cure rates. So kids do seem to do better treating with onychomycosis. And there are a number of reasons I have theorized about this, but that's probably to me, the other data like I said, it's been around since 2013. This is much newer data. It's data on which they got their pediatric indication. And you can see that the drug works not only in adults, but also pediatric population down to the age of 6.

Nail polish is a really interesting issue. I think every one of us who have tried to prescribe one of these antifungals have heard, especially from our women patients. And let's face it. Even in the clinical trials about 75% of the patients in all these clinical trials were male. The marketing and sales data show the best number of patients, the best majority patients who get prescriptions for these drugs tend to be women. And one of the questions we've always gotten, especially in the summer, like where we are in Arizona, could be year-round, is, "Can I wear nail polish?" And there was never a really good answer for this. But then in the Journal of Clinical and Aesthetic Dermatology, back in 2014, actually looked at 3 different types of nail polish, and applied the Jublia to the toenail that contained these different toenail polishes. Then they used a control group with no toenail polish, and found that, in fact, there was no statistically significant difference in penetration, and they used carbon 14 labeled efinaconazole So this was really the sine qua non for how you determine penetration. They see carbon 14 labeled efinaconazole and found no difference in the nail that had no nail polish versus the nails that did have nail polish. So we know that the drug can penetrate through the nail, even if nail polish is present. Now, on top of that there were some studies that looked at the aesthetics of it. You know you're brushing this on and by brushing it on, is it dissolving the nail polish or making the nail polish smeared? And actually they found that no, that did not happen, that the application of this drug does not affect the appearance of the nail polish on the nail. So that should also make your patients happy.

There were a number of post-hoc analyses done on that 1,655 patient clinical trial data that was collected in the pivotal trials. I published with Tracey Vlahovic, DPM, a post-hoc analysis of patients who had diabetes, well-controlled diabetes, because they are the only patients who were allowed in the trial, and we actually found that there was no difference in outcomes in patients who had well-controlled diabetes versus patients who had no diabetes.

Another post-hoc analysis that was done, looked at the duration of the disease. Now this is going to make totally practical sense to you. The longer a patient has onychomycosis the more difficult it's going to be to cure it. So if the patient had onychomycosis for less than one year they got complete cure 42 percent, whereas if the patients had onychomyosis for greater than 5 years, their complete cure was down at about 16 percent. The I guess the take-home message there is the earlier you can get started on this with patients the better they're going to be the better off. They're going to do so. If a patient comes to you complaining about onychomycosis, try to document how long they've had it, and know that the patients who have had it for a longer period of time are not going to do as well as the patients who had had it for less period of time.

And thirdly, there was a study that looked at age and basically found that there was no difference in outcomes based on the patient's age. So there have been a number of post-hoc analyses of the pivotal clinical data that shows that the drug works in a vast spectrum, let's say, of different patient types.