Onychomycosis is primarily caused by dermatophytes, which are fungi that infect the skin, hair or nails. The infection involves the nail plate, the nail bed and, in some cases, the skin surrounding the nail plate. Onychomycosis causes nails to deform, discolor, thicken, become brittle and split and separate from the nail bed. Toenails affected by onychomycosis can become so thick that routine trimming of the nails becomes difficult. The condition can also cause pain while individuals wear shoes, leading to difficulties walking. Onychomycosis can also lead to social embarrassment due to the unsightly appearance of the infected nails and because it may be perceived to be an active infection and contagious.
According to Podiatry Today , 35 to 36 million people in the United States have onychomycosis. Over 95% of onychomycosis infections are infections of the toenail, according to a report in U.S. Dermatology Review . According to the manufacturer of Lamisil, 47% of those affected by onychomycosis are not receiving treatment. For those who do seek treatment, options include debridement, oral or topical drugs or a combination of debridement and drug therapies. Debridement consists of scraping, cutting away or removal of the affected nail. Onychomycosis may persist or worsen if not treated. Onychomycosis often recurs in susceptible individuals because the fungi that cause onychomycosis are present in many common locations such as floors, the soil, socks and shoes. Consequently, the nail can be reinfected, and additional courses of treatment are frequently required even after successful treatment.
Limitations of Current Onychomycosis Therapies
Current therapies for onychomycosis include debridement and drug therapies. Debridement is time consuming and only marginally effective in eliminating the fungal infection. Approved drug therapies are available in two types, either oral therapies such as Lamisil (terbinafine) or topical therapies such as Penlac Nail Lacquer (ciclopirox). According to the Lamisil product label, 38% of patients treated in clinical trials with a 12-week course of therapy achieved 100% clear nail and mycological cure. However, Lamisil has been associated with rare cases of liver failure, some leading to death or liver transplant. We believe this risk of liver failure limits acceptance of this therapy by both physicians and patients. Patients are recommended to undergo liver function tests prior to initiating Lamisil treatment and those patients with pre-existing liver disease cannot be treated with it. Penlac is the only topical therapy approved in the U.S. for onychomycosis and is used in conjunction with frequent debridement. In the two clinical trials cited on Penlac's product label, even with frequent debridement, only 5.5% and 8.5% of patients treated with Penlac achieved 100% clear nail and mycological cure. We believe that a significant barrier to effective treatment by current topical therapies is the difficulty of formulating the drug product to penetrate through the nail plate and reach the site of infection.
In spite of the limitations of these two approved products. Lamisil had worldwide peak sales of $1.2 billion in 2004, before generic entry, and, ccording to IMS Health, for the 12-month period ending December 31, 2010, 1.4 million new prescriptions were filled in the United States for both branded and generic versions of terbinafine. Penlac had U.S. sales of $125 million in 2002, before generic entry. According to IMS Health, for the 12-month period ending December 31, 2010, over 350,000 new prescriptions were filled in the United States for branded or generic ciclopirox.
Our Solution: tavaborole
By addressing the limitations of current therapies, we believe tavaborole has a potential safety and efficacy profile that can make it a best-in-class therapy for the treatment of onychomycosis. We designed tavaborole as a topical antifungal with three distinguishing characteristics:
Enhanced nail penetration properties. We utilized our expertise in medicinal chemistry to design tavaborole with enhanced nail penetration properties, allowing for improved delivery of the compound through the nail plate to the nail bed, the site of onychomycosis infection. Preclinical studies indicate that tavaborole is able to penetrate the nail plate 250 times more effectively than Penlac.
Novel mechanism of action with potent antifungal activity. We have utilized our expertise in boron based chemistry to design tavaborole with potent antifungal activity. Tavaborole inhibits an essential fungal enzyme, leucyl transfer RNA synthetase, or LeuRS required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection. We have shown that this inhibitory activity requires the presence of boron within the compound, as the replacement of the boron atom with a carbon atom in tavaborole inactivated the molecule. The unique boron based mechanism of action underlying tavaborole was detailed in the June 22, 2007 issue of the journal Science.
No detected systemic side effects after topical dosing. We have conducted clinical trials to assess systemic absorption of tavaborole. The results of these trials found that topical treatment with tavaborole resulted in little or no detectable levels of drug in the blood or urine. No treatment related systemic side effects have been observed in any of our clinical trials, and we believe it is unlikely that treatment of onychomycosis with tavaborole will result in significant systemic side effects.
In January 2013, we announced positive results from two Phase 3 studies of tavaborole in onychomycosis. Tavaborole achieved a high degree of statistical significance on all primary and secondary endpoints. Each study enrolled approximately 600 patients with distal subungual onychomycosis, randomized two-to-one to receive either tavaborole or vehicle. Eligible patients were at least 18 years of age (with no upper age limit) with a clinical diagnosis of distal subungual onychomycosis involving 20% - 60% of the total area of the target great toenail, at least 3mm of clear nail from the proximal nail fold to the most proximal visible mycotic border and positive mycology. Patients were instructed to apply tavaborole solution or vehicle to the target great toenail once daily for 48 weeks.
The primary efficacy endpoint is a composite endpoint measuring complete cure of the great toenail at week 52, which is consistent with the FDA requirement for Lamisil. Complete cure requires both a mycologic cure and a completely clear nail. Mycologic cure is achieved when the fungus present in the nail plate is killed by treatment. Achieving a clear nail requires a complete elimination of the diseased portion of the nail by replacement with a new healthy growing nail and nail bed.
Anacor’s New Drug Application (NDA) was accepted by the FDA for review in October 2013. The PDUFA date is July 29, 2014.