A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Efficacy and Safety of VT-1161 Oral Tablets in the Treatment of Patients With Distal and Lateral Subungual Onychomycosis of the Toenail

B. Elewski; S. Brand; T. Degenhardt; S. Curelop; R. Pollak; R. Schotzinger; A. Tavakkol

Disclosures

The British Journal of Dermatology. 2021;184(2):270-280. 

In This Article

Results

Participant Flow

In total 688 patients were screened for this study. There were 429 screen failures, primarily due to not meeting the eligibility criteria regarding establishment of onychomycosis of the TGT. The remaining 259 patients were randomized to one of the four VT-1161 treatment groups or matching placebo. Patient recruitment lasted 6·5 months and the follow-up period was an additional 22 months. The trial was completed as planned without interruption or early termination. The patient disposition is summarized in Figure 2.

Figure 2.

Patient disposition. aNot due to lab abnormalities.

Demographics and Baseline Characteristics

The mean age of the ITT population was 50·0 years, and it was similar among treatment groups. The majority of patients were white (83%), not Hispanic or Latino (87%), and male (80%). In general the demographics were similar among treatment groups, as depicted in Table 1.

Outcomes

Complete Cure. The proportions of patients in the ITT population with complete cure at week 48 ranged from 32% to 42% in the VT-1161 treatment groups, with the lowest rate in the 300-mg 12-week treatment group and the highest rate in the 600-mg 12-week treatment group. No patients receiving placebo experienced complete cure at week 48. The proportion of ITT patients with complete cure was statistically significantly higher for all VT-1161 treatment groups compared with placebo at week 48 (P < 0·001) (Table 2).

In the per protocol population, the proportions of patients in the VT-1161 treatment groups who experienced complete cure at week 48 (36–55%) were higher than in the ITT population (32–42%) and were statistically significantly higher (P < 0·001) for all VT-1161 treatment groups compared with placebo at week 48.

At 48 weeks, the median improvements from baseline in percentage nail involvement were 92%, 86%, 88% and 83% in the four VT-1161 groups (300 mg for 12 or 24 weeks; 600 mg for 12 or 24 weeks, respectively) vs. 13% in the placebo group, indicating that a substantially greater number of patients experienced significant improvements compared with those on placebo. Another measure of treatment success is the percentage of patients who reached almost cure, as many will be expected to achieve complete cure during longer follow-up due to additional clear nail growth. In total 74%, 66%, 57% and 55% of patients treated with one of the VT-1161 regimens achieved cure or almost cure (defined as ≤ 10% nail involvement) after 48 weeks, compared with only 8% on placebo. Longer follow-up resulted in higher complete cure rates at week 60 (Figure 3).

Figure 3.

Complete cure over time (intent-to-treat population)

Dystrophic nails are often difficult to treat and have poor prognosis. Figure 4 highlights the progression towards complete cure of the toenails of a 58-year-old man with extensive onychomycosis of the left hallux following treatment with VT-1161. The patient was clinically and mycologically cured at week 48 and remained cured at week 60.

Figure 4.

Representative photographs of a patient showing complete cure over time.

Mycological Cure. Consistently with the literature, the most commonly occurring dermatophyte noted in this study was Trichophyton rubrum, isolated in 96% of study participants. Trichophyton mentagrophytes was identified as the causative pathogen in the remaining study participants.[18–20] The mycology data revealed rapid eradication of dermatophytes, with negative cultures recorded in up to 81% of patients after 48 weeks, and with mycological cure (negative KOH and negative culture) achieved in 61–72% of patients across the VT-1161 groups at week 48. All mycological cure rates numerically increased from week 48 to week 60 (Figure 5).

Figure 5.

Mycological cure over time: intent-to-treat population.

The proportions of patients with complete cure at week 60 ranged from 41% to 45% in the VT-1161 treatment groups (ITT population). No patients receiving placebo experienced complete cure at week 60. The proportion of ITT patients with complete cure was statistically significantly higher for all VT-1161 treatment groups compared with placebo at week 60 (P < 0·001).

Compared with patients randomized to receive placebo, patients receiving VT-1161 achieved statistically significantly (P < 0·001) improved outcomes for complete cure at weeks 48 and 60, therapeutic success at weeks 48 and 60, mycological cure at weeks 48 and 60, and clinical cure at weeks 48 and 60. Similarly, patients treated with VT-1161 achieved statistically significantly (P < 0·001) improved outcomes for negative KOH at weeks 48 and 60, negative dermatophyte culture at weeks 48 and 60, complete cure and negative dermatophyte culture at weeks 48 and 60, and percentage change in mycotic nail involvement from baseline to week 48 compared with patients receiving placebo.

Although patients with dystrophic nails, dermatophytomas and nail spikes were excluded from the study, as historically they respond poorly to current treatment options, those who did enter generally responded well to VT-1161. Figure 6 highlights a 39-year-old male patient enrolled in the study with clear markings of dermatophytoma and spikes, in whom a significant clinical improvement was observed at week 60.

Figure 6.

Dermatophytoma response to VT-1161.

Safety. VT-1161 was well tolerated throughout the study. The rates of any treatment-emergent AEs (TEAEs), related TEAEs and serious AEs were similar across the VT-1161 treatment groups and placebo, with a slight numerical increase in patients randomized to the 600-mg, 24-week VT-1161 cohort.

Common TEAEs included ingrown toenail, dermatitis, headache and cough. These AEs were generally mild to moderate in severity and occurred with similar frequencies across all groups including placebo. Notable TEAEs deemed 'possibly to definitely' related to the study drug by the blinded investigator included nausea (2%), constipation (2%) and dysgeusia (2%), averaged across the VT-1161 treatment groups. There were no drug-related serious AEs reported and no patient discontinued the study due to a laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or QT intervals. A summary of AEs reported through week 60 is provided in Table 3. A summary of TEAEs occurring in at least five patients in total by preferred term is presented in Table 4.

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