New topical antifungals provide better penetration

Efinaconozole and tavaborole use non-lacquer vehicles to help them penetrate the nail surface more effectively versus previous topical antifungal agents for onychomycosis, according to David M. Pariser, M.D., professor, Eastern Virginia Medical School department of dermatology and past president, American Academy of Dermatology (AAD). 

"Toenail fungus, although not the scourge of the earth, is a very common problem which can produce discomfort and physical and cosmetic disability," Dr. Pariser says. To date, he adds, the primary treatments for onychomycosis have been systemic agents.

Conversely, "The topical agents we've had up to now have not been that effective. And many people either don't want to take systemic drugs for toenail fungus, or they're afraid of side effects."

Many patients fear such side effects more than actual adverse event rates warrant, Dr. Pariser emphasizes. Still, "Most doctors don't want to prescribe a drug to somebody who doesn't want to take it for fear of side effects."

Additionally, he says, "The primary challenge in topical treatment is getting the active antifungal ingredient to penetrate through the nail and get under the nail where the infection actually is." The infection does not penetrate from the nail bed into the nail itself until late in the infection's course, he explains. "So if you're just treating the top surface of the nail, you're not getting where the action is."

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More effective formulations

To avoid this problem, Dr. Pariser says, the new topical antifungals have been formulated to penetrate the nail much more effectively than nail lacquers, which essentially remain on the nail surface. In contrast, he says that the water-soluble vehicles for efinaconozole and tavaborole are "clear, runny liquids containing surfactants that allow them to penetrate either through or around the nail to the nail bed. And that's what gives them the higher efficacy" than previous topical agents provide.

In phase 3 studies, subjects used either efinaconozole or tavaborole daily for 48 weeks, with an efficacy assessment at 52 weeks. Efficacy calculations also depend partly on how much of the nail was affected at baseline, Dr. Pariser adds. In this regard, the efinaconozole and tavaborole studies' enrollment criteria stipulated that patients could have up to 50 percent nail involvement and 60 percent nail involvement, respectively.

Comparing cure rates in onychomycosis studies requires caution, Dr. Pariser says. In such studies, the Food and Drug Administration (FDA) mandates that the definition of "complete cure" include complete clinical and mycological cure – a completely normal nail appearance and a total absence of fungus observed in culture and KOH stain.

"With even the best oral agents available now, complete clearance rates are slightly under 50 percent. That's because of the extremely stringent criteria" set by the FDA. "Even if you had a treatment that completely and permanently eradicated the fungus, the nail may never look completely normal because the infection may have damaged the nail matrix. Or the nail itself might have experienced some sort of trauma originally, and that's why the patient got the fungal infection in the first place."

Conversely, the new topical agents offer complete cure rates of six percent to 18 percent, depending on the study. Specifically, efinaconozole's complete cure rate was 18.5 percent, versus 4.7  percent for vehicle (P<0.001; Gupta AK, Elewski BE, Sugarman JL et al. J Drugs Dermatol. 2014 Jul;13(7):815-20.). Additionally, in two separate studies, tavaborole achieved complete cure rates of 6.5 percent and 9.1 percent, versus 0.5 percent and 1.5 percent, respectively, for vehicle.¹

For both products, however, Dr. Pariser says, "The rate of negative cultures – actual obliteration of the fungus, even if the nail isn't completely normal – was above 50 percent." Furthermore, he adds, approximately 30 percent of patients achieved 90 percent clinical clearance, although it was defined differently in the two studies.

"If you look at the mycological cure rate, the number for efinaconozole – around 55 percent – is almost the same as for oral itraconazole, but still a bit less than for oral terbinafine (just under 70 percent). The two new topicals do not have as high an efficacy rate as the oral drugs do, but they're better than any of the topical drugs we've had" in terms of efficacy.

NEXT: Side effect profiles

Side effect profiles

As with previous topical agents, Dr. Pariser says, "The side effect profiles of the new topicals are pretty minimal, including, in some cases, a very small amount of irritation." But the new treatments provide no systemic absorption and therefore cause no systemic side effects, he says. As such, "There's no real or perceived problem with side effects. So patients may be more likely to use them" than existing oral agents.

The most commonly used oral antifungal, terbinafine, requires liver function testing because it has been associated with liver problems in some patients. "Also, a small number of patients on the drug experience alterations in their sense of taste," he says. Additional patient concerns include the fact that oral antifungals can interact negatively with other drugs such as blood pressure and cholesterol medications.

Because some patients indeed experience adverse events with oral antifungals, Dr. Pariser says, "It's good that we've got some new topical alternatives that have better efficacy" than previous topical treatments for this condition.

From a practical standpoint, he adds, study protocols prohibited the use of nail polish. "In the real world, there are patients who will not go a year without using nail polish." To see what would happen when one applies these drugs over nail polish, Dr. Pariser tried it on a highly anecdotal sample – his own nails.

"I found that efinaconozole, which has the higher efficacy rate, dissolves nail polish." Accordingly, he says that it's more practical to use tavaborole in these circumstances because it doesn't dissolve nail polish. "That may be a factor in why patients would choose one versus the other – the ability to wear nail polish while under treatment."

Disclosure: Dr. Pariser has been an investigator and consultant for Valeant, maker of efinaconozole, and an investigator for Anacor, maker of tavaborole.

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Reference:

1 http://investor.anacor.com/releasedetail.cfm?ReleaseID=858211