Radhakrishnan Pillai

Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies

BACKGROUND Onychomycosis is a common nail infection, often resulting in nail plate damage and deformity. Topical lacquer treatments have negligible efficacy. Oral treatments, although more efficacious, are limited by drug interactions and potential hepatotoxicity. OBJECTIVE We investigated the safety and efficacy of efinaconazole 10% solution (efinaconazole), the first triazole antifungal developed for distal lateral subungual onychomycosis. METHODS Two identical, multicenter, randomized, double-blind, vehicle-controlled studies were conducted in patients with toenail distal lateral subungual onychomycosis (20%-50% clinical involvement [study 1: N = 870, study 2: N = 785]). Patients were randomized (3:1) to efinaconazole or vehicle, once daily for 48 weeks, with 4-week posttreatment follow-up. Debridement was not performed. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. RESULTS Mycologic cure rates were significantly greater with efinaconazole (study 1: 55.2%, study 2: 53.4%) compared with vehicle (P < .001). The primary end point, complete cure, was also significantly greater for efinaconazole (study 1: 17.8% vs 3.3%, study 2: 15.2% vs 5.5%, P < .001). Treatment success (percent affected target toenail [0%-≤10%]) for efinaconazole ranged from 21.3% to 44.8% in study 1 and from 17.9% to 40.2% in study 2, compared with 5.6% to 16.8% and 7.0% to 15.4%, respectively, with vehicle. Adverse events associated with efinaconazole were local site reactions (2%) and clinically similar to vehicle. LIMITATIONS A period of 52 weeks may be too brief to evaluate a clinical cure in onychomycosis. CONCLUSIONS Once daily topical efinaconazole appears to be a viable alternative to oral treatment options for onychomycosis.

Comparison of In Vitro Antifungal Activities of Efinaconazole and Currently Available Antifungal Agents against a Variety of Pathogenic Fungi Associated with Onychomycosis

ABSTRACT Onychomycosis is a common fungal nail infection in adults that is difficult to treat. The in vitro antifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates of Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1,493 isolates, efinaconazole MICs against T. rubrum and T. mentagrophytes ranged from ≤0.002 to 0.06 μg/ml, with 90% of isolates inhibited (MIC90) at 0.008 and 0.015 μg/ml, respectively. Efinaconazole MICs against 105 C. albicans isolates ranged from ≤0.0005 to >0.25 μg/ml, with 50% of isolates inhibited (MIC50) by 0.001 and 0.004 μg/ml at 24 and 48 h, respectively. Efinaconazole potency against these organisms was similar to or greater than those of antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole, and terbinafine. In 13 T. rubrum toenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in another 8 dermatophyte, 15 nondermatophyte, and 10 yeast species (a total of 109 isolates from research repositories). Efinaconazole was active against Trichophyton, Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces, Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon, and Candida and compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with a broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

Mechanism of Action of Efinaconazole, a Novel Triazole Antifungal Agent

ABSTRACT The mechanism of action of efinaconazole, a new triazole antifungal, was investigated with Trichophyton mentagrophytes and Candida albicans. Efinaconazole dose-dependently decreased ergosterol production and accumulated 4,4-dimethylsterols and 4α-methylsterols at concentrations below its MICs. Efinaconazole induced morphological and ultrastructural changes in T. mentagrophytes hyphae that became more prominent with increasing drug concentrations. In conclusion, the primary mechanism of action of efinaconazole is blockage of ergosterol biosynthesis, presumably through sterol 14α-demethylase inhibition, leading to secondary degenerative changes.

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

ABSTRACT Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.

Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials

Background: Individuals with psoriasis are at increased risk for psychiatric comorbidities, including suicidal ideation and behavior (SIB). Objective: To distinguish between the underlying risk and potential for treatment‐induced psychiatric adverse events in patients with psoriasis being treated with brodalumab, a fully human anti–interleukin 17 receptor A monoclonal antibody. Methods: Data were evaluated from a placebo‐controlled, phase 2 clinical trial; the open‐label, long‐term extension of the phase 2 clinical trial; and three phase 3, randomized, double‐blind, controlled clinical trials (AMAGINE‐1, AMAGINE‐2, and AMAGINE‐3) and their open‐label, long‐term extensions of patients with moderate‐to‐severe psoriasis. Results: The analysis included 4464 patients with 9161.8 patient‐years of brodalumab exposure. The follow‐up time–adjusted incidence rates of SIB events were comparable between the brodalumab and ustekinumab groups throughout the 52‐week controlled phases (0.20 vs 0.60 per 100 patient‐years). In the brodalumab group, 4 completed suicides were reported, 1 of which was later adjudicated as indeterminate; all patients had underlying psychiatric disorders or stressors. Limitations: There was no comparator arm past week 52. Controlled study periods were not powered to detect differences in rare events such as suicide. Conclusions: Comparison with controls and the timing of events do not indicate a causal relationship between SIB and brodalumab treatment.

Nonclinical safety assessment of Efinaconazole Solution (10%) for onychomycosis treatment

Efinaconazole is a triazole developed as a 10% solution for topical treatment of onychomycosis, a common fungal nail infection. Efinaconazole solution and topical formulation vehicle administered dermally to mice (13weeks), rats (6months) and minipigs (9months) produced transient erythema, minimal to modest hyperkeratosis, and mild microscopic skin inflammation. The liver was the target organ of systemic toxicity; reversible, minimal to moderate vacuolated changes were noted in the rat dermal study at 15 and 50mg/kg/day. No systemic toxicity was observed in mice and minipigs, at approximate high dermal doses of 930 and 170mg/kg/day, respectively. Daily subcutaneous injection of propylene glycol vehicle or efinaconazole to rats for 6months produced severe local inflammation and systemic spread, evidenced by peritoneal adhesions, spinal cord necrosis and urinary tract disease. Mortalities occurred in all groups but were increased at the high dose (30 or 40mg/kg/day), suggesting that vehicle effects were exacerbated by efinaconazole. Efinaconazole was not carcinogenic in a 2-year mouse dermal study and was not genotoxic. Exposure-based safety margins at the NOAEL were 70-698 relative to onychomycosis patients. In conclusion, efinaconazole demonstrated low/moderate toxicity, consistent with other azole antifungals, and high safety margins for topical onychomycosis therapy.

In Vitro and In Vivo Assessment of Dermatophyte Acquired Resistance to Efinaconazole, a Novel Triazole Antifungal

ABSTRACT Efinaconazole is a novel triazole antifungal drug for the topical treatment of onychomycosis, a nail infection caused mainly by dermatophytes. We assessed the potential of efinaconazole to induce resistance in dermatophytes by continuous exposure of Trichophyton rubrum strains to efinaconazole in vitro (12 passages) and in a guinea pig onychomycosis model (8 weeks). There was no evidence of efinaconazole resistance development in the tested strains under the experimental conditions used.

Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3)

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Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-to-severe plaque psoriasis: Results of 2 phase 3 randomized controlled trials

Background Topical corticosteroids are the mainstay of psoriasis treatment, with long‐term safety considerations limiting their use. Combining them with tazarotene may optimize their efficacy and minimize safety and tolerability concerns. Objective To investigate the safety and efficacy of halobetasol propionate 0.01% plus tazarotene 0.045% (HP/TAZ) lotion in moderate‐to‐severe plaque psoriasis. Methods Two multicenter, randomized, double‐blind, vehicle‐controlled phase 3 studies (N = 418) were conducted. Subjects were randomized (2:1) to HP/TAZ lotion or vehicle once daily for 8 weeks with a 4‐week follow‐up. The primary efficacy assessment end point was treatment success (at least a 2‐grade improvement from baseline in Investigators Global Assessment score and a score of clear or almost clear). Safety and treatment‐emergent adverse events were evaluated throughout. Results HP/TAZ lotion demonstrated statistically significant superiority over vehicle within as few as 2 weeks. By week 8, 35.8% (study 1) and 45.3% (study 2) of subjects were treatment successes compared with 7.0% and 12.5% of those treated with vehicle (P < .001). HP/TAZ lotion was also superior in reducing signs and symptoms of psoriasis and body surface area affected by psoriasis. The most frequently reported treatment‐related adverse events were contact dermatitis (6.3%), application site pain (2.6%), and pruritus (2.2%). Limitations Studies did not include subjects with more than 12% of their body surface area affected by psoriasis. Conclusions HP/TAZ lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, with no safety concerns.

Efinaconazole Topical Solution, 10%: Factors Contributing to Onychomycosis Success

To provide an adequate therapeutic effect against onychomycosis, it has been suggested that topical drugs should have two properties: drug permeability through the nail plate and into the nail bed, and retention of their antifungal activity in the disease-affected areas. Only recently has the importance of other delivery routes (such as subungual) been discussed. Efinaconazole has been shown to have a more potent antifungal activity in vitro than the most commonly used onychomycosis treatments. The low keratin affinity of efinaconazole contributes to its effective delivery through the nail plate and retention of its antifungal activity. Its unique low surface tension formulation provides good wetting properties affording drug delivery both through and under the nail. High antifungal drug concentrations have been demonstrated in the nail of onychomycosis patients, and effectiveness of efinaconazole topical solution, 10% confirmed in two large well-controlled multicenter Phase 3 clinical studies in patients with mild-to-moderate disease.