Terbinafine hydrochloride is a drug which has been available as an oral and topical agent since the early 1990s. When it was first introduced and entered the market it showed superiority over many of the existing agents at the time both orally and topically (1-3). The topical skin treatment has been available in the UK and across the globe for many years as a cream, gel and film-forming solution indicated for athletes’ foot. With the drug demonstrating efficacy (4) and safety (5) it has been adopted as the first-line antifungal against dermatophytes, but there has always been something missing from the terbinafine family – a topical nail solution. But is that likely to change soon?
The development of a topical nail solution of terbinafine is well underway. Moberg Pharma, who many in the UK will know as the manufacturer of Emtrix® nail solution, have been developing this new nail treatment. Currently, according to them, two phase III clinical trials are ongoing. One in Europe and another in North America. A phase three trial is where patients with the condition (onychomycosis in this case) are treated with the drug under study compared with placebo to test its effectiveness and safety. Following successful phase three studies, the next stage normally is for the drug to be approved by the regulatory authorities in each country before coming to market.
The first of these phase III studies, from North America, has published its findings in the respected Journal of the American Academy of Dermatology (6). This work was conducted on patients from 12 - 75 years of age with mycological confirmed onychomycosis affecting at least one hallux (20-60% of its surface area). The 10% terbinafine nail solution (TTNS) was compared against a placebo (vehicle) for 48 weeks in a cohort (double-blind) randomised to either treatment group. The safety of the solution was also assessed.
At the conclusion, 287 patients (which was 78.6% of the group) completed the 52-week follow-up. The results showed that at week 52, the TTNS patients had a mycological cure rate of 69.9% versus just 27.7% in the placebo (vehicle) group. Complete cure (meaning mycological negative results plus complete improvement in the nails appearance) was achieved in just 4.5% of the TTNS and none of the placebo group. Adverse reaction rates were 2.8% in the TTNS group and 4.2% in the vehicle group although none were related to the study medication itself.
So, what does this all mean? Firstly, the results of TTNS on mycological cure are very encouraging - 69% cure rate is a high figure for any topical antifungal agent. In fact, it is approaching the cure rate of an oral antifungal agent. The authors suggest this may be in part due to the high concentrations of terbinafine achieved in the nail following topical application – this was found to be 1000 times higher in the nail plate and 40 times higher in the nail bed compared with oral terbinafine. This is borne out also, by the fact that 80% - 90% of the mycological cures were attained within 3 months of starting treatment and was maintained throughout the trial suggesting this is as quick to work as oral terbinafine. As it is applied topically, virtually none of the drug is absorbed limiting potential systemic side-effects according to the results of the phase II trial.
This study ran for one year so gives a fair time span on which to assess its effectiveness. The high cure rate appears to be at odds with the low “complete” cure rate. Clinically translated, this means the nails were free of fungus but still didn’t look perfect. The low complete cure rate may, in part, be caused by the effect of the topical medication (containing urea, lactic acid and other agents). These substances can cloud and stain the nail altering its opaqueness, affecting the visual nail improvement scoring system, as the authors suggest. Alternatively, perhaps the nails were damaged before the fungus infected the nail, so the treatment just rolled back time? If the vehicle was responsible for the nail changes, given the high mycological cure rate, a shorter dosing regime would probably still achieve a good cure rate but improve the nail appearance and so complete cure at one year follow up.
In a press release from the manufacturer, Moberg Pharma, following advice from key opinion leaders in the light of these study results, have suggested that once-daily treatment period of three months, followed by maintenance dosing once weekly until week 48 should maintain high concentrations of terbinafine within the nail unit, to improve the visual appearance of the nail at week 52. This would need to be tested but sounds like a rationale proposal.
As with many of these onychomycosis trials, it’s important to know what patients were excluded from taking part and in this case, it was anyone with a nail thickness in excess of 3 mm, patients with nail involvement extending to within 3 mm of the eponychium – so at least the proximal three millimetres of the nail had to be clear to be included, patients with a spike of onychomycosis extending to the eponychium (these are often tricky to treat) and patient with severe moccasin tinea pedis (perhaps from this there was a high risk of reinfection)?
Overall, the work is very encouraging, and the market is always open for a new antifungal drug which is safe and improves on currently available agents. Let’s hope we see the product enter the market soon.
References
1. Krob AH, Fleischer AB, Jr., D’Agostino R, Jr., Feldman SR. Terbinafine Is More Effective Than Itraconazole In Treating Toenail Onychomycosis: Results from a Meta-analysis of Randomized Controlled Trials. Journal of Cutaneous Medicine and Surgery: Incorporating Medical and Surgical Dermatology. 2003;7(4):306-11.
2. Hart R, Bell-Syer SEM, Crawford F, Torgerson DJ, Young P, Russell I. Systematic review of topical treatments for fungal infections of the skin and nails of the feet. Brit Med J. 1999;319(7202):79-82.
3. De Doncker P. Itraconazole and tèrbinafine in perspective: from petri dish to patient. J Eur Acad Dermatol Venereol. 1999;12:S10-S6.
4. Haugh M, Helou S, Boissel JP, Cribier BJ. Terbinafine in fungal infections of the nails: a meta-analysis of randomized clinical trials. Br J Dermatol. 2002;147:118-21.
5. O'Sullivan DP, Needham CA, Bangs A, Atkin K, Kendall FD. Postmarketing surveillance of oral terbinafine in the UK: report of a large cohort study. Br J Clin Pharmacol. 1996;42(5):559-65.
6. Gupta AK, Surprenant MS, Kempers SE, Pariser DM, Rensfeldt K, Tavakkol A. Efficacy and safety of topical terbinafine 10% solution (MOB-015) in the treatment of mild-to-moderate distal subungual onychomycosis: A randomized, multi-center, double-blind, vehicle-controlled phase 3 study. J Am Acad Dermatol. 2020.