Kora Wierzby

Pharmacotherapeutic group: Antineoplastic agents; Antimetabolites; Pyrimidine analogues, ATC code: L01BC52 Mechanism of action of fluorouracil The active substance fluorouracil (FU) is a cytostatic agent that has an antimetabolite effect.‍‍‍‍‍‍​​​‍​​​​​​ Due to its structural similarity with the thymine (5-methyluracil) occurring in nucleic acids, FU prevents its formation and utilisation and in this way inhibits both DNA and RNA synthesis which results in growth inhibition. Mechanism of action of salicylic acid Topical salicylic acid (SA) has a keratolytic effect and reduces the hyperkeratosis associated with actinic keratosis. Its mechanism of action as a keratolytic and corneolytic agent is thought to be related to its interference with corneocyte adhesion, its solubilising effect on intercellular cement, and its loosening and detachment of corneocytes. Clinical efficacy and safety In a pivotal randomized, placebo-controlled, double-blind, three-armed, parallel group, multi-center Phase III trial 470 patients with actinic keratosis (AK) grade I to II (see below) were treated with Actikerall or placebo or a diclofenac gel (30 mg/g) (DG). 187 patients were exposed to the fixed combination Actikerall for up to 12 weeks. The primary endpoint was the histological clearance of a lesion 8 weeks post end of treatment. Topical treatment with Actikerall showed superiority to placebo treatment and to DG treatment. Secondary efficacy endpoints, such as total lesion count, total AK lesion size, lesion response, physician's global assessment and subject's overall assessment of efficacy, confirmed the results of the primary endpoint. In 72.0 % of the subjects in the Actikerall group actinic keratosis could no longer be detected in the biopsy taken, whereas clearance rates in the DG and placebo groups were 59.1 % and 44.8 % respectively (per protocol analysis). The number of subjects with complete response (all lesions clinically cleared) was also highest in the Actikerall group 55.4 % compared to 32.0 % in the DG group and 15.1 % in the placebo group. The most frequent adverse reactions to Actikerall were application and site irritation (including burning) (86.1 %) and application site inflammation (73.3 %). Also, application site pruritus (44.9 %) and application site pain (25.1 %) occurred at a high frequency. Other adverse reactions were application site erythema and erosion. Discontinuation due to skin and application site reactions was low (0.5 %). In a randomized, placebo-controlled, double-blind, two-armed, parallel group, multi-centre Phase III trial, 166 patients with actinic keratosis (AK) grade I to II were treated with Actikerall or vehicle (2:1 ratio). Patients were exposed to treatment for up to 12 weeks by applying Actikerall or its vehicle on an affected area of 25 cm 2 with 4 to 10 actinic keratosis clinical lesions and, in a subgroup of 30 patients, with at least 3 subclinical lesions identified by reflectance confocal microscopy (RCM). The primary endpoint was complete clinical clearance (CCC) of AK lesions in the treatment field 8 weeks after the end of treatment. In 49.5% (intention-to-treat analysis) or 55.1% (per protocol analysis) of the Actikerall group, CCC was observed compared to 18.2% or 19.6% of the vehicle group, respectively. Topical treatment with Actikerall showed superiority to vehicle treatment. Secondary efficacy endpoints, such as partial clearance, total lesion count, severity of lesion grade, physician's global assessment and subject's overall assessment of efficacy, confirmed the results of the primary endpoint. From the RCM subgroup analysis on complete clearance of a single clinical AK lesion and lesion count of selected subclinical lesions, Actikerall was shown to be significantly more effective than vehicle (87.5% vs. 44.4%, p=0.0352 and 89.6% vs. 47.1%, p=0.0051 respectively). The majority of adverse reactions to Actikerall were application-site reactions, most were of mild intensity. There were 30 application site bleeding events reported in 27 patients (24.1%) treated with Actikerall: 26 of mild, 3 of moderate, and 1 of severe intensity. Four application site ulcer events were reported in 3 patients (2.8%) treated with Actikerall: 3 of mild and 1 of moderate intensity. Discontinuation due to drug-related skin and application-site reactions in the treatment group was low (n=1, 0.9%). Clinical efficacy is further supported by a Phase II, randomised, parallel-group, multi-centre study with cryotherapy as comparator. Actikerall showed a higher histological clearance rate at 8 weeks after a 6-week treatment (n = 33) than cryotherapy at 14 weeks after the first treatment on Day 1 and on Day 21, if necessary (n = 33) (62.1% vs 41.9%). In addition, a lower AK recurrence rate was found in the Actikerall group at 6-month follow-up (27.3% vs 67.7%). Efficacy of Actikerall in terms of treatment duration (from ≤ 4 to > 12 weeks) was demonstrated in a multi-centre non-interventional study in AK grade I to III patients (n = 1,051). At approximately 8 weeks after treatment, the average reduction in lesion number and size was 69.7% and 82.1%, respectively, which was achieved in about 50% of the patients within less than 6 weeks on treatment. All treatment durations (≤4 weeks; >4 to ≤6 weeks; >6 to ≤9 weeks; >9 to ≤12 weeks; and >12 weeks) showed an average reduction in lesion number of 65-70%. In both the Phase II and the non-interventional studies, the safety profile of Actikerall was found to be consistent with the adverse reactions of the drug product (see section 4.8). When deciding on treatment of other parts of the body than the face, forehead and bald scalp the epidermal thickness in different areas may be taken into consideration. The mean epidermal thickness of different body parts has been published as: face 49.4 µm, forehead 50.3 µm, upper trunk front (décolleté) 42.2 µm, and arms/legs 60.1 µm (Koehler 2010, Skin Res Technol 2010, 16:259-264; Sandby-Moller 2003, Acta Derm Venereol 2003; 83(6):410-3; Whitton et Everall 1973 Br J Dermatol 1973; 89(5):467-76). Actinic keratosis lesion intensity was graded according to the 4-point scale based on Olsen et al.,1991 (J Am Acad Dermatol 1991; 24: 738-743): Grade Clinical description of intensity grading 0 none no AK lesion present, neither visible nor palpable I mild flat, pink maculae without signs of hyperkeratosis and erythema, slight palpability, with AK felt better than seen II moderate pink to reddish papules and erythematous plaques with hyperkeratotic surface, moderately thick AK that are easily seen and felt III severe very thick and / or obvious AK The European Medicines Agency has waived the obligation to submit the results of studies with Actikerall in all subsets of the paediatric population based on a class waiver for the treatment of actinic keratosis (see section 4.2 for information on paediatric use).