Imiquimod Cream 2.5% and 3.75% Applied Once Daily to Treat External Genital Warts in Men
We assess the safety and efficacy of imiquimod cream 3.75% and 2.5% in men with external genital warts (EGWs). Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 447 (225 from study 1 and 222 from study 2) male patients (aged ≥12 years) with 2 to 30 EGWs and a total wart area of 150 mm2 or greater. Participants were randomized (2:2:1) to imiquimod cream 3.75% or 2.5% or placebo applied once daily until complete clearance or a maximum of 8 weeks (end of treatment [EOT]). There was an 8-week follow-up period (end of study [EOS]) for participants who did not achieve complete clearance by EOT. Participants who achieved complete clearance were observed for an additional 12 weeks. The primary efficacy end point was complete clearance rate. Safety assessments included visual assessment of local skin reactions, number and duration of required rest periods, adverse events (AEs), and clinical laboratory tests. Study results indicated that new imiquimod formulations are beneficial in treating EGWs in men.
Practice Points
- Imiquimod cream, both 2.5% and 3.75% concentrations, is more effective than placebo in treating external genital warts (EGWs) in men.
- Imiquimod cream, in both concentrations tested, is somewhat less effective in men than in women in the same protocol.
- Imiquimod cream treatment of EGWs is better tolerated in men than in women in the same protocol.
The median time to complete clearance was shorter in the 2 active treatment groups compared with placebo. For those participants who attained complete clearance, the median time to complete clearance ranged from 57 to 59 days in the imiquimod cream 3.75% groups (studies 1 and 2, respectively), 60 to 74 days in the imiquimod 2.5% cream groups (studies 1 and 2, respectively), and 76 to 81 days with placebo (studies 2 and 1, respectively).
Safety
Less than one-third of male participants in each treatment group experienced AEs during the studies. The incidence of serious adverse events (SAEs) and AEs leading to study discontinuation was low. In total, 4 participants (0.9% [3 in the imiquimod cream 2.5% group and 1 in the imiquimod cream 3.75% group]) had AEs that led to study discontinuation. Application-site reactions were reported in a total of 46 participants (10.3%). The incidence and severity of local skin reactions was mostly mild or moderate, similar in both active treatment groups, and higher than in the placebo group. Local skin reactions were coincident with the treatment period and rapidly decreased when treatment was concluded. There were no clinically meaningful trends in vital sign measurements or laboratory measurements.
Comment
Imiquimod cream 5% has been shown to be a safe and effective treatment of EGWs. Our study was designed to evaluate lower concentrations of imiquimod cream (2.5% and 3.75%), which may permit daily dosing and a shortened treatment course in men with EGWs.
Efficacy of imiquimod cream 2.5% and 3.75% was established through both primary and secondary end points, though only the higher concentration was significantly more effective than placebo in both studies. In addition, a number of participants who were not completely cleared following 8 weeks of treatment went on to be completely cleared at EOS, demonstrating continued activity of imiquimod despite cessation of active treatment.
Imiquimod cream 3.75% was particularly effective when compared to placebo, with 18.6% of participants completely cleared at EOS, though the PP (observed case) results (22.7%) may be more encouraging and can be used to motivate patients.
Although there are limitations in making direct comparisons between studies, complete clearance rates in our studies were lower than those reported previously with imiquimod cream 5%.17 Lower efficacy rates might be expected given the differences in methodology. In the 2 studies reported here, participants had to have no EGWs (baseline or new, treated or untreated) in any of the anogenital areas specified to be reported as having achieved complete clearance. In earlier studies with imiquimod cream 5%, not all anogenital regions were required to be treated, and any new EGWs arising during treatment were not included in the analysis.17 Also, our analysis focused purely on a male patient population in which efficacy results tend to be lower regardless of treatment modality employed.
Recurrence is another important issue in the treatment of EGWs. Although not studied specifically in a male population, recurrence rates of 16.7% to 17.7% were seen in the 3 months following successful treatment with imiquimod cream 2.5% and 3.75% in the 2 pivotal studies. These results were consistent with the recurrence rates reported following successful treatment with imiquimod cream 5%.17
In general, complete clearance rates increased in a dose-dependent manner. Complete clearance rates were lower in the male subpopulation across all treatment groups compared to those previously reported in females,24 which was consistent with prior results reported for imiquimod cream 5% as well as other topical treatments.17 It has been suggested that this difference may be due in part to the distribution of female EGWs in areas of less keratinization. Complete clearance rates in the current analysis tended to be higher in male participants with baseline EGWs in anatomic sites with less keratinized skin such as the perianal, perineal, or glans penis areas.
Daily application of imiquimod cream 2.5% and 3.75% generally was well tolerated. Most reported AEs were mild or moderate, and few participants discontinued because of AEs. Few SAEs were reported and none were considered to be treatment related. There was no difference in the incidence rates of AEs between the 2 active treatments. The incidence of SAEs and study discontinuations was much lower than previously reported in the female cohort of these 2 studies.24
Conclusion
In conclusion, 2 well-controlled studies of males with EGWs who were treated for up to 8 weeks with imiquimod cream 2.5% and 3.75% applied daily demonstrated good tolerability and superior efficacy to placebo in complete clearance of all baseline and newly arising warts in addition to reducing EGW counts.
