8/1/2017
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`Onychomycosis remains a major clinical challenge | Lower Extremity Review Magazine
`
`Millet;
`
`
`
`mums &
`
`Ii-I-lmm-Du'PJIImL'
`
`I”
`
`// November 2011
`
`Onychomycosis remains a major clinical
`challenge
`
`-~ 14 W 21
`
`FMATT. SI IRSCRTP'T'TON
`
`Despite the ongoing development of new treatments,
`
`onychomycosis is still an extremely recalcitrant disease with high
`
`rates of relapse and reinfection, and the associated physical and
`
`cosmetic implications can negatively affect patients’ quality of life
`
`and self esteem.
`
`By Greg Gargiulo
`
`Onychomycosis is a general term used to describe fungal infections of
`
`the nail unit, which includes the nail plate, nail bed, and periungual
`
`tissuefiy2 Usually caused by dermatophyte fungi, onychomycosis is the
`
`most common condition affecting the nails, accounting for 50% of all nail
`
`disorders and 33.3% of all mycotic infections of the skinfl-5
`
`The prevalence of onychomycosis varies drastically throughout the world
`
`occurrence rates have been reported as high as 23% in Europe and up
`
`to 14% in the US.1 It can occur in either fingernails or toenails—or
`
`sometimes both, often from spreading—but occurs more frequently in
`
`http://|ermagazine.com/article/onychomycosis-remains-a-major—clinical-challenge
`
`1/15
`
`Page 1 of 15
`
`Kaken Exhibit 2079
`
`Acrux V. Kaken
`
`IPR2017-00190
`
`
`
`Onychomycosis remains a major clinical challenge | Lower Extremity Review Magazine
`
`Millet;
`
`
`
`mums &
`
`Ii-I-lmm-Du'PJIImL'
`
`I”
`
`// November 2011
`
`Onychomycosis remains a major clinical
`challenge
`
`-~ 14 W 21
`
`FMATT. SI IRSCRTP'T'TON
`
`Despite the ongoing development of new treatments,
`
`onychomycosis is still an extremely recalcitrant disease with high
`
`rates of relapse and reinfection, and the associated physical and
`
`cosmetic implications can negatively affect patients’ quality of life
`
`and self esteem.
`
`By Greg Gargiulo
`
`Onychomycosis is a general term used to describe fungal infections of
`
`the nail unit, which includes the nail plate, nail bed, and periungual
`
`tissuefiy2 Usually caused by dermatophyte fungi, onychomycosis is the
`
`most common condition affecting the nails, accounting for 50% of all nail
`
`disorders and 33.3% of all mycotic infections of the skinfl-5
`
`The prevalence of onychomycosis varies drastically throughout the world
`
`occurrence rates have been reported as high as 23% in Europe and up
`
`to 14% in the US.1 It can occur in either fingernails or toenails—or
`
`sometimes both, often from spreading—but occurs more frequently in
`
`http://|ermagazine.com/article/onychomycosis-remains-a-major—clinical-challenge
`
`1/15
`
`Page 1 of 15
`
`Kaken Exhibit 2079
`
`Acrux V. Kaken
`
`IPR2017-00190
`
`
`
`8/1 /2017
`
`Onychomycosis remains a major clinical challenge | Lower Extremity Review Magazine
`
`
`
`Figure 1. This patient had onychomycosis for about 20 years, involving all the nails and the entirety of each nail,
`and extending to the back of each nail. (All images cour— tesy of Shari Lipner, MD, PhD.)
`
`toenails due to their slower growth rates,7
`
`Despite its prevalence, onychomycosis remains a major clinical
`
`challenge for dermatologists, podiatrists, and other healthcare
`
`professionals? This is primarily due to the overall ineffectiveness of
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`available treatments—which include topical and oral medications and
`
`laser therapy8-10—and the fact that onychomycosis is an extremely
`
`recalcitrant disease with high rates of relapse and reinfection.”12
`
`In addition, though onychomycosis is a relatively minor, nonthreatening
`
`condition, many patients experience negative social or emotional effects
`
`and a reduced quality of life (QoL) due to the aesthetic appearance of
`
`affected toenails”,14
`
`“It’s not a major public health issue, and I don’t think much attention is
`
`focused on it, but it’s still an important condition that’s very difficult to fix
`
`and therefore should not be taken lightly,” said Ella Toombs, MD, a
`
`dermatologist at Aesthetic Dermatology of Dupont Circle in Washington,
`
`DC.
`
`Background
`
`Up to 90% of onychomycosis cases in the US are caused by the
`
`dermatophytes Trichophyton rubrum or Trichophyton mentagrophytes,
`
`though yeasts and nondermatophyte molds can also be responsible.‘
`
`Often, patients with onychomycosis also have concurrent tinea pedis
`
`(athlete’s foot) since both are caused by T. rubrum.15116
`
`Advanced age is the greatest predisposing risk factor for the
`
`development of onychomycosis, as approximately 50% of the population
`
`older than 70 years has it.”18 Reports have also shown that men are up
`
`to three times more likely to have onychomycosis than women, though
`
`it’s unclear why this discrepancy exists.17
`
`According to Shari Lipner, MD, PhD, a dermatologist and assistant
`
`professor at Weill Cornell Medical Center in New York City, the gender
`
`difference may be related in part to the ability to cover it up.
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`“It’s probably fairly equal between men and women, but it’s a more
`
`common complaint in men because women have the advantage that the)
`
`can camouflage the onychomychosis with manicures or nail polish, and
`
`it’s less obvious,” she said.
`
`A number of other factors can increase the likelihood of incurring
`
`onychomycosis. Immunocompromised populations are at an especially
`
`elevated risk, as roughly 30% of patients with diabetes and 20% of HIV-
`
`positive patients have onychomycosis; other immunodeficiencies, poor
`
`peripheral circulation, nail trauma, obesity, and family history and
`
`genetics are all risk factors as well.3v19v20 Wearing occlusive footwear,
`
`perspiring heavily, and walking barefoot in public spaces are known
`
`environmental factors that can also increase the risk of infection.15
`
`Onychomycosis usually affects one or two toenails and manifests with
`
`relatively minor symptoms like nail discoloration—often yellow-white, but
`
`it may also be orange or black—brittleness and thickening of the nail, ant
`
`mild pain and discomfort.13 If the infection is left untreated, as it
`
`progresses, this pain and discomfort will increase and can lead to
`
`difficulty walking or performing daily activities. The risk of secondary
`
`infection also increases in neglected cases, especially in patients with
`
`impaired immunity, and it can spread to elsewhere in the body or to
`
`others“)!13
`
`The physical and cosmetic implications of onychomycosis, however,
`
`don’t end there, as many patients also experience image and self-esteen
`
`issues, which can hinder QoL and lead to negative perceptions of those
`
`with the conditional”!21
`
`“Onychomycosis is a disease that significantly impacts those with it, and
`
`a large percentage of patients have pain that affects their mobility—
`
`particularly elderly patients—which affects their quality of life,” said
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`Mahmoud Ghannoum, PhD, director of the Center for Medical Mycology
`
`at University Hospitals in Cleveland, OH.
`
`Patients with mild asymptomatic cases of onychomycosis generally don’t
`
`seek treatment until it has advanced to a more severe, sometimes
`
`debilitating, stage.22 When patients do present, an accurate diagnosis is
`
`critical, since other nail conditions like psoriasis and yellow nail syndrome
`
`can mimic onychomycosis.23
`
`A fungal culture is regarded as the gold standard for diagnosing
`
`onychomycosis, but a positive microscopy test is also helpful to confirm
`
`the diagnosisfia24 Clinicians should test for other fungal infections like
`
`tinea pedis, corporis, and cruris as well.23
`
`Treatment options
`
`
`
`Figure 2. This image shows a case of subungual hyperkeratosis, with debris under the nail. This nail is thicker
`than the one in Figure 1, so it may need to be debrided as well, as it’s difficult to deliver topical medication when
`the nail is this thick. Scales are also visible along the foot, meaning the patient also has tinea pedis around the
`toes. The two conditions will need to be treated together.
`
`Once onychomycosis has been diagnosed, most clinicians then offer
`
`patients treatment options focused on the overall goal of eliminating the
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`fungus if possible and restoring the nail to its normal state when it grows
`
`out.15 The two main courses of action are usually topical or oral antifunga
`
`agents but, in some cases, laser therapy and other alternatives may be
`
`offered as wellm:25
`
`“Given a diagnosis, I generally explain to patients that they have three
`
`options to treat the fungus: topicals, orals, and lasers, and I do a risk-
`
`benefit analysis of the pros and cons of each treatment,” said Carolyn
`
`McAloon, DPM, a podiatrist at Bay Area Foot Care in Dublin, CA. “I want
`
`to make sure they’re informed in their decision, and then following that
`
`conversation we’ll decide which way we want to go.”
`
`It’s particularly important for patients to be aware that treatments are
`
`often long term, and that it may be 12 to 18 months before the nails
`
`appear normal again.9
`
`Oral treatment is currently regarded as the gold standard and the first line
`
`of therapy for onychomycosis. If, after discussion with a clinician, a
`
`patient decides to try topical therapy first but doesn’t respond well after
`
`six months, the patient may be switched to oral medication.8 Oral
`
`medications, however, have the potential to interact with other drugs or
`
`cause side effects such as hepatotoxicity, particularly in the elderly
`
`population and those with comorbid conditions.10,1~°»25
`
`Currently, terbinafine is the most frequently prescribed and efficacious
`
`oral antifungal used for onychomycosis in patients without
`
`contraindications.823y26 Terbinafine is usually taken as a 250-mg daily
`
`dose for 12 to 16 weeks and is generally well tolerated; however, those
`
`with hepatic dysfunction should avoid its use since it may cause further
`
`liver problems.8v23
`
`One meta-analysis of oral monotherapies found the mean rate of
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`
`
`Figure 3. In this less extreme case, the nail is somewhat thickened, and the infection doesn’t extend all the way
`back to the nail matrix.
`
`mycological cure (clearance of the nail based on negative mycological
`
`test findings) among 18 studies was 76% at nine to 18 months with
`
`terbinafine.27 Another study reported a complete cure rate (when the nail
`
`is free from fungus and appears normal) of 38%.28
`
`The only other oral medication approved by the US Food and Drug
`
`Administration (FDA) for onychomycosis is itraconazole, which is usually
`
`offered as a ZOO-mg pill and may be dosed daily or as a pulse
`
`regimenf’v23 ltraconazole has broader coverage than terbinafine for
`
`Candida and nondermatophytes, but its effectiveness is lower, at 54%
`
`and 14% for mycological and complete cure rates, respectively. It also
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`has been associated with multiple drug-drug interactions and is
`
`contraindicated for patients with ventricular dysfunction.23
`
`“I only use terbinafine these days,” McAloon said. “I haven’t used
`
`itraconazole in years. Given their profiles of efficacy and safety, my
`
`experience is that terbinafine should definitely be the standard.”
`
`Topical medications—which come in ointments, creams, and lacquers—
`
`present other challenges, since to be effective, they need to penetrate
`
`the nail plate and reach the nail bed in sufficient quantities",29 For this
`
`reason, they are generally less effective than oral treatment, but may be
`
`preferred in mild cases of onychomycosis or for patients at risk of side
`
`effects from oral medications.23
`
`
`
`Figure 4. In this case, the nail is not extremely thick and the extent of the infection is not severe. However, it
`does extend to the matrix, includes nail dystrophy, and the nail is split down the middle, which will complicate
`topical treatment.
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`
`Until the summer of 2014, the only FDA-approved topical agent for
`
`onychomycosis was ciclopirox 8%.30 The nail lacquer, which is applied
`
`once daily for 48 weeks, has been associated with a mycological cure
`
`rate of 36% and complete cure rate of 8.5% with monthly nail
`
`debridement to increase penetration.31
`
`The FDA approved efinaconazole 10% liquid solution for the treatment 01
`
`onychomycosis in June.30 In recent clinical trials, efinaconazole showed a
`
`mycological cure rate of up to 53.4% and a complete cure rate as high as
`
`17.8%.23 Efinaconazole also has a minimal side-effect profile and does
`
`not require debridement.22
`
`One month later, the FDA approved tavaborole 5% liquid solution for
`
`treatment of onychomycosis based on clinical trials results that have not
`
`yet been published.32 In two trials of 1194 patients, complete cure rates
`
`were 6.5% in the first trial and 9.1% in the second; mycological cure rate:
`
`were 31.1% and 35.9%, respectively. According to Del Rosso, only with
`
`further trials and the introduction of these two new drugs to the market
`
`will their overall effectiveness become more clearly understood.30
`
`“Recent articles have shown efinaconazole to have a clinical success
`
`rate that’s much higher than the previous topicals,” McAloon said. “So l’n
`
`cautiously optimistic that those who choose this drug will have greater
`
`success and that the medications will be more effective than what we
`
`had previously.”
`
`Luliconazole is another topical antifungal agent under development. It
`
`has a low binding affinity for keratin, allowing it to be released more
`
`readily from the nail plate matrix than other topicals before crossing into
`
`the nail bed. It has demonstrated potent and broad-spectrum activity
`
`against dermatophytes and has been reported to be safe and well
`
`tolerated, but is still being tested in clinical trials.33
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`
`
`Figure 5. Both of these cases are much less severe than those in Figures 1-4. Each patient had onychomycosis
`for about one year. Both will likely respond to oral medications and possibly topicals.
`
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`
`Regardless of a whether a patient decides to go with an oral or topical
`
`approach, compliance is an important determinant of outcomes,3
`
`particularly due to the long course of treatment with topicals and the high
`
`rate of recurrence for onychomycosis, which can be up to 25%.34 Over
`
`time, the repeated application of a medication and the discouraging effec
`
`of a relapse can negatively affect compliance.
`
`The promise of lasers
`
`Given the potential for side effects of oral therapy and the overall lack of
`
`effectiveness coupled with the compliance challenges of topicals, the
`
`search for a safe, noninvasive, and effective alternative has led to recent
`
`interest in lasers and other light-based treatments.10
`
`Podiatrists have been using lasers in clinical practice since the 19808,
`
`but they were first introduced for the treatment of onychomycosis in
`
`2009. Unfortunately, since then, evidence has not yet met expectations.35
`
`Five lasers are currently FDA-approved for treating onychomycosis, four
`
`of which use a 1064-nm neodymium-doped yttrium aluminum garnet
`
`wavelength and deliver energy in a short pulse duration.”36 The exact
`
`mechanism of action for lasers is still not understood completely, but it
`
`has been proposed that they penetrate the nail plate and reach a
`
`temperature that kills the fungus.36
`
`Some studies have reported preliminary success with lasers, but their
`
`overall effectiveness is still far from confirmed.23~36 A recent systematic
`
`review on laser treatment evaluated 12 studies, two of which were
`
`randomized controlled trials (RCTs), and concluded that most available
`
`research is reported at a low level of evidence with small numbers of
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`
`patients, and that results are predominantly conflicting with no clear
`
`evidence of efficacy.35
`
`Other types of lasers and similar systems—such as photodynamic
`
`therapy, carbon dioxide, near-infrared diode, and femtosecond infrared
`
`lasers—are also being studied, but are not yet FDA-approved, and their
`
`effectiveness is not well establishedfiv22
`
`The cost of laser therapy is also a major consideration for patients, since
`
`according to McAIoon, “Treatments run approximately one thousand
`
`dollars, and there’s no insurance coverage for lasers, so that’s
`
`completely out of pocket.”
`
`Ivan Bristow, PhD, the program lead in podiatry at the University of
`
`Southampton in the UK, and author of the aforementioned systematic
`
`review?5 called for more randomized controlled trials of laser systems.
`
`“These need to demonstrate efficacy against current treatments like
`
`topical and oral therapies, as well as longer follow-ups, to truly assess
`
`the effectiveness of the systems,” Bristow said. “Fungal nails grow more
`
`slowly than normal nails, so a follow-up period of 52 weeks is probably
`
`needed to give lasers a fair trial.”
`
`Several other therapeutic avenues have the potential to expand and
`
`improve treatment options for onychomycosis.
`
`Combination therapy has been associated with more rapid recovery,
`
`higher cure rates, and reduced duration of oral drug exposure compared
`
`with individual modalities.37 One RCT found improved mycological cure
`
`rates (88.2%) when adding ciclopirox to a terbinafine monotherapy
`
`regimen (64.7%).38 Two other studies, by Sanmano et al and Nakano et
`
`al, combined oral terbinafine with topical terbinafine and also found
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`impressive outcomes, with complete cure rates of 65.2% and 77.3%,
`
`respectively.”40
`
`Defining a cure
`
`Some have proposed an alternative approach to the very definition of
`
`“cure” for onychomycosis, as this is not always straightfonNard and may
`
`be open to interpretation“)!25 As defined earlier, a mycological cure is
`
`clearance of the nail based on negative mycological test findings (eg,
`
`microscopy, culture, Periodic Acid-Schiff stain), but this can be
`
`complicated when the results of different tests for a single patient are
`
`conflicting. In addition, a negative culture does not always equate to an
`
`improvement in the nail appearance (a clinical cure)?5
`
`Based on this, Ghannoum has suggested that the definition of
`
`onychomycosis cure be reassessed, along with other changes such as
`
`longer treatment periods and follow-ups to better evaluate the
`
`effectiveness of available management protocols.25y35y41
`
`“We plan to keep refining and discussing these concepts with our
`
`colleagues,” Ghannoum said. “lmportantly, once this is done we need to
`
`enter into discussions with the FDA to make inroads in
`
`incorporating these ideas into clinical trials for approval of novel
`
`antifungals.”
`
`But, according to Richard Scher, MD, a professor of dermatology at Weill
`
`Cornell Medical College in New York City who specializes in nail
`
`disorders, this process is still ongoing.
`
`“Primary endpoints really have not changed, and the FDA has remained
`
`firm on that,” he said. “However, many companies are trying to add more
`
`lenient secondary endpoints, which would not affect the FDA approval,
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`necessarily, and, if the FDA goes along with that, then they can use that
`
`as a marketing tool. We’re going to have to wait to see what happens.”
`
`Greg Gargiulo is a freelance medical writer based in the San Francisco
`
`Bay Area.
`
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`© 2009-2017 Copyright Lower Extremity Review Magazine. All rights reserved.
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