Benefits of Zyclara® for the treatment of actinic keratoses

Department of Dermatology and Venereology, Otto-von-Guericke University,

Magdeburg, Germany

Email: [email protected]

Actinic keratoses (AKs) are pre-cancerous skin lesions with high incidence regarded as squamous cell carcinoma in situ.(1) AKs are often recurrently found on sun-exposed areas such as face, balding scalp, neck, chest and upper back, forearms or on the back of the hands. Apart from ultraviolet light exposure, including from artificial sources such as tanning beds, further risk factors include age, male gender, blond or red hair colour, light-coloured eyes, fair skin, immunosuppression or some rare genetic diseases (for example, Xeroderma pigmentosum). Appearing single, or more often within a large area of chronically damaged skin, it can further convert into a squamous cell carcinoma clinically unremarkable and visibly undetectable (field cancerisation; Figure 1). Therefore treatment of AKs or field cancerisation is recommended to prevent further conversion into squamous cell carcinoma, the most frequent cancer worldwide.(1)

Treatment options include lesion- or field-directed procedures. Physical removal or destruction of AK lesions by liquid nitrogen cryosurgery, curettage, shave excision, electrocautery and laser ablation are lesion-directed whereas pharmacotherapeutic options, such as topical imiquimod, diclofenac, 5-fluorouracil, retinoids or photodynamic therapy, are field-directed including treatment of field cancerisation.(2,3)

Imiquimod, one of the pharmacotherapeutic field-directed treatment options, is a toll-like receptor 7 agonist that enhances the immune response within the skin, when topically applied, resulting in recruitment of immune cells (mainly natural killer cells, macrophages and dendritic cells) and increased production of cytokines.(4) In addition to its use against AKs, it has been successfully used also in transplant recipients for treatment of squamous cell carcinoma in situ (for example, Bowen’s disease and keratoacanthoma), molluscum contagiosum, complicated warts, vaginal epithelial neoplasia, melanoma in situ and dermal melanoma metastasis.(3,5,6)

There are currently three different concentrations approved for treatment of AKs: 3.75% and 2.5% cream (Zyclara®) and 5% cream (Aldara®, Beselna®).(7,8)

This article will critically review clinical efficacy including long-term results of imiquimod 3.75% and 2.5% cream (Zyclara®) compared with imiquimod 5% (Aldara®).

Zyclara® 3.75% and 2.5% cream is a prescription medication approved for the topical treatment of clinical visible or palpable AK of the full face or balding scalp in adults (not in individuals younger than 18 years of age) in immunocompetent patients without limitation to treated areas in the US. In Europe, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending marketing authorisation for Zyclara 3.75%® cream. In addition, Zyclara® 3.75% cream is also approved for the topical treatment of external genital and perianal warts or condyloma acuminate in patients older than 11 years, for which efficacy has been shown, but not for children below 12 years of age, in the US. Approved use includes topical but not intra-anal, intra-vaginal, ophthalmic or oral application. Topical treatment of AKs has been approved for two two-week treatment cycles that are separated by a two-week no-treatment cycle (2/2/2 regimen).(7)

The reason for the development of lower imiquimod concentrations is the possibility of shorter treatment cycles that might be more convenient for elderly patients with similar effectivity but lower side effect profile than with imiquimod 5% used for 16 weeks or 12 weeks with a two four-week cycle regimen. Furthermore, a more frequent use of imiquimod 5% than 3x/week, for example daily, was not well tolerated in patients.9 In the US, imiquimod 5% is restricted to an area of 25 cm2, which excludes sufficient treatment of field cancerisation especially of the face and balding scalp.

Three clinical treatment studies leading to the approval of Zyclara® investigated the efficacy and safety of imiquimod 3.75% and 2.5% cream for the treatment of AKs of the face or balding head (but not both) for an area >25 cm2.(7,8,10) This had been evaluated in adults with 5–20 lesions who were randomised to either placebo, imiquimod 2.5% or 3.75% cream, and applied up to two packets (250mg each) once daily for two two-week with a two-week or three-week no-treatment interval.(7,8) All studies included a screening phase and a follow-up period, and patients were assessed regularly after a baseline visit, at weeks 1, 2 (end of cycle 1), 4, 5, 6 (end of cycle 2), 10 and 14 (end of study) in the first study (2/2/2 regimen) and at weeks 1, 2, 3 (end of cycle 1), 6 (beginning of cycle 2), 7, 8, 9 (end of cycle 2), 13 and 17 (end of study) in the second study (3/3/3 regimen). Median baseline AK lesion counts for the treatment groups were nine-to-ten in the two trials.(7,8)

The first clinical study, where the 2/2/2 regimen was used and resulted in approval of Zyclara® 3.75% and 2.5% cream for AKs, included 479 patients from 25 study centres in the US. Results showed complete clearance in 35.6% for Zyclara® 3.75%, 30.6% for Zyclara® 2.5% and 6.3% for placebo at the end of the study. Partial clearance, defined as >75% lesion reduction compared with baseline, was seen in 59.4% for Zyclara® 3.75%, 48.1% for Zyclara® 2.5% and 22.6% for placebo, which was statistically significant for both imiquimod concentrations versus placebo (p<0.001) and for 3.75% against 2.5% (p=0.047). Reductions from baseline for lesion counts were 81.8% for Zyclara® 3.75% 71.8% for Zyclara® 2.5% and 25.0% for placebo (p<0.001 for both concentrations versus placebo and p=0.048 for 3.75% versus 2.5%).(7)

In the second clinical study, where the 3/3/3 regimen was tested, 490 subjects from 26 study centres were included. Complete clearance rates were 34.0% for Zyclara® 3.75%, 25.0% for Zyclara® 2.5% and 5.5% for placebo, whereas partial clearance rates were 53.7% for Zyclara® 3.75%, 42.7% for Zyclara® 2.5% and 12.8% for placebo, which was statistically significant (p<0.001, imiquimod concentration versus placebo and p=0.034 for 3.75% versus 2.5%). Median reductions from baseline in lesion count were 80.0% for Zyclara® 3.75%, 66.7% for Zyclara® 2.5% and 23.6% for placebo.(8)

After completion of these two trials, a follow-up study was initiated in patients who had complete clearance at the end of the study, which was eight weeks after the end of the second cycle. To test long-term clearance and to compare it with other treatment options, especially imiquimod 5% where long-term clearance is one of the most important criteria, those patients were seen at six and 12 months after completion of the previous trials.(11) Interestingly, patients who had applied a 2/2/2 regimen showed lower complete clearance rates after six months and 12 months than after completion of the 3/3/3 regimen after six months and 12 months.

Furthermore, Zyclara® 3.75% was further tested for efficacy when combined with cryosurgery, a cost-effective and lesion-directed treatment option used worldwide.(12) Adults who had a minimum of ten AKs (≤1cm2 in area and <1mm in height) on the face had cryosurgery of 5–14 lesions, and a minimum of five lesions were randomised to Zyclara® 3.75% or placebo without having cryosurgery. AKs treated by cryosurgery were also randomised to imiquimod 3.75% or placebo subsequently using the 2/2/2 regimen. A total of 247 patients from 20 centres in the US and Canada with an average of 16 AKs were enrolled and evaluated at weeks two, four and six during treatment and at 10, 14, 20 and 26 weeks post-treatment.

Results of complete clearance rates and median reduction from baseline, respectively, were 59.5% and 83.9% for cryotherapy, 34.1% and 68% for Zyclara® 3.75%, 29.8% and 73.1% for cryotherapy followed by placebo, and 5% and 21% for placebo.(12)

Overall, comparing the results from these trials, the 2/2/2 regimen showed a higher complete and partial clearance rate compared with placebo, 3.75% being superior to 2.5%, and similar to the median reduction from baseline in lesion counts.(7,8) All were superior to the 3/3/3 treatment regimen but, in contrast, the long-term complete clearance rate was higher with the 3/3/3 regimen. Furthermore, combination with cryosurgery is feasible and more effective than the topical treatment with Zyclara® 3.75% cream alone when analysing the 2/2/2 regimen.(7,8,12)

Only two serious adverse events (diarrhoea and pancytopenia), possibly related to the study drug, during all clinical trials were reported for Zyclara® 3.75%. In general, the incidence was higher in patients using 3.75% compared with 2.5% or placebo. Fatigue, headache, pyrexia and lymphadenopathy or influenza-like symptoms were the most common non-application-related adverse events.(7,8) During the 3/3/3 regimen, adverse events with Zyclara® 3.75% cream also included ectropion, eye swelling, chemical eye injury and rhinorrhoea.(10) In addition, the prescribing information for Zyclara® also mentions nausea, fever, myalgias, arthralgias and chills as potential side effects. Erythema increased during all treatment cycles and decreased below baseline during the follow-up period for Zyclara® 3.75% and 2.5%. Local inflammatory reactions, such as irritation, pain, pruritus, erythema and oedema, were more frequent with 3.75% than with 2.5% and more frequent than with placebo. Furthermore, side effects were more frequent in the 3/3/3 regimen group than in the 2/2/2 regimen group (for 3.75%: 59.9% versus 48.1%; and for 2.5%: 50% versus 43.8%).(7,10–12)

The drug should be discontinued in cases of intense inflammatory reaction and the appearance of influenza-like systemic signs and symptoms. Concomitant use of imiquimod (for example, Aldara® cream 5%) at the same area should be avoided to limit the severity of local skin reactions. Exposure to sunlight, including sun lamps, should be avoided. Finally, there is a risk of potential exacerbation of other inflammatory skin diseases, and use is not recommended when those are present.(3,4)

A direct comparison of Zyclara® 3.75% and 2.5% cream with imiquimod 5% (for example, Aldara cream) in clinical trials is not available. However, there are numerous data available for imiquimod 5% from clinical trials. In two phase III randomised, double-blind, vehicle-controlled studies, the efficacy of imiquimod 5% cream compared with placebo was evaluated in the treatment of AK lesions on the face and balding scalp. It was applied once daily, two days per week for 16 weeks in 436 patients. The complete clearance rate was 45.1% for imiquimod 5% and 3.2% for placebo, a partial clearance rate of 59.1% and 11.8%, respectively, which was similar to Zyclara® 3.75% in a 2/2/2 regimen. However, severe erythema was reported in 17.7% of participants in the imiquimod 5% group.(13) A second phase III, randomised, double-blind, parallel group, vehicle-controlled trial with 286 patients in Europe evaluating imiquimod 5% cream for AKs on the face and balding scalp against placebo using a regimen once daily, three days per week for 16 weeks showed higher complete clearance and partial clearance rates (57.1% and 72.1% for imiquimod 5% versus 2.2% and 4.3% for placebo; p<0.001) that were superior to Zyclara® 3.75%, as well as long-term complete clearance results for 18 months (84%) and 24 months (80%).(14)

However, side effects, including erythema (30.6%), scabbing/crusting (29.9%) and erosions/ulceration (10.2%), were more frequent compared with the 2/2/2 regimen of Zyclara® 3.75%, but less frequent compared with the 3/3/3 regimen.15 Another regimen using imiquimod 5% three-times a week for four weeks in one or two courses on the face or balding scalp was evaluated in a multicentre, vehicle-controlled, double-blind study in Europe in 259 patients. At eight-weeks post-treatment, complete clearance rate was 55.0% for imiquimod 5% versus 2.3% for placebo16 and an open-label, phase IIIb trial in Germany including 829 patients showed complete and partial clearance rates of 68.9% and 80.2%, respectively for imiquimod 5%.(17,18)

Daily treatment of AKs of the face and balding scalp with Zyclara® 3.75% and 2.5% cream is safe and well tolerated with regard to local site reactions typical for imiquimod, and better tolerated in a 2/2/2 regimen than a 3/3/3 regimen. Overall 2.5% is slightly better tolerated than 3.75%, but both are much better tolerated with lower side effects than imiquimod 5%.7–9 Data from current trials suggest similar efficacy to imiquimod 5%. An additive effect was observed when cryosurgery was combined with imiquimod 3.75%, allowing further treatment options. Zyclara® 3.75% and 2.5% creams are interesting treatment options for AK of the face and balding scalp when compliance is critical because they are indicated for daily use, a short treatment period (for example, 2/2/2 regimen), provide a lower side effect profile than imiquimod 5% and are also approved for the use on areas >25 cm2.

• Imiquimod 3.75% or 2.5% (Zyclara®) is a well-tolerated and safe treatment option for actinic keratoses of the face or balding scalp and can be used topically on larger areas than 25cm2 to which imiquimod 5% (Aldara®) is limited in the US.
• It is indicated for daily use and short time periods such as two two-week cycles with a two-week off-period (2/2/2 regimen) or two three-week cycles with a three-week off-period (3/3/3 regimen).
• Whereas the 2/2/2 regimen showed higher complete and partial clearance rates in clinical trials than the 3/3/3 regimen, the latter demonstrated a higher complete clearance rate 12 months after the end of treatment.
• Results from clinical trials suggest that imiquimod 3.75% in a 2/2/2 regimen has similar efficacy compared with imiquimod 5% used twice weekly for 16 weeks, but seems to have lower efficacy when used three-times/week for 16 weeks or two x four weeks with a four-week break.
• Imiquimod 3.75% can be combined with other therapeutic options such as cryosurgery, for which an additive effect was shown.

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