Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, other chemotherapeutics, ATC code: D06BX02.

Mechanism of action
The mechanism of action of ingenol mebutate for use in actinic keratosis remains to be fully characterised. In vivo and in vitro models have shown a dual mechanism of action for the effects of ingenol mebutate: 1) induction of local lesion cell death and 2) promoting an inflammatory response characterised by local production of proinflammatory cytokines and chemokines and infiltration of immunocompetent cells.

Pharmacodynamic effects
Results from two clinical trials on biological effects of ingenol mebutate have shown that topical administration induced epidermal necrosis and a profound inflammatory response in both epidermis and the upper dermis of the treated skin, dominated by infiltrating T cells, neutrophils and macrophages. Necrosis in the dermis was rarely observed.
Gene expression profiles of skin biopsies from the treated areas is suggestive of inflammatory responses and response to wounding, which is consistent with the histology assessments.
Non-invasive examination of the treated skin by reflectance confocal microscopy have shown that the skin changes induced by ingenol mebutate were reversible, with almost complete normalisation of all measured parameters on day 57 after treatment, which is supported also by clinical findings and studies in animals.

Clinical efficacy and safety
The efficacy and safety of Picato 150 mcg/g, administered on the face or scalp for 3 consecutive days was studied in two double-blind, vehicle-controlled, clinical studies including 547 adult patients. Likewise the efficacy and safety of Picato 500 mcg/g, administered on the trunk and extremities for 2 consecutive days was studied in two double-blind, vehicle-controlled, clinical studies including 458 adult patients. Patients continued in the studies for an 8 week follow-up period during which they returned for clinical observations and safety monitoring. Efficacy, measured as complete and partial clearance rate, as well as median percent reduction, was assessed at day 57 (see table 2).

Patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic, actinic keratosis lesions within a contiguous 25 cm2 treatment area on the face or scalp or on the trunk or extremities. On each scheduled dosing day, the study gel was applied to the entire treatment area.
The compliance rate was high, with 98% of the patients completing these studies.
Study patients ranged from 34 to 89 years of age (mean 64 and 66 years, respectively, for the two strengths) and 94% had Fitzpatrick skin type I, II, or III.
At day 57, patients treated with Picato had higher complete and partial clearance rates than patients treated with vehicle gel (p<0.001). The median percent reduction in actinic keratosis lesions was higher in the group treated with ingenol mebutate compared to the vehicle group (see table 2).
Table 2 Rates of subjects with complete and partial clearance and median percent (%) lesion reduction in actinic keratosis
Face and scalp          Trunk and extremities
Picato        Vehicle       Picato       Vehicle
150 mcg/g      (n=270 )     500 mcg/g     (n=232 )
(n=277 )                    (n=226 ) a               d
Complete Clearance Rate            42.2%          3.7%         34.1%d        4.7% 
Partial Clearance Rateb (≥         63.9% d          7.4%          49.1% d           6.9% 75%)
Median % Reductionc                 83%                 0%          75%             0% a
Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible actinic keratosis lesions in the treatment area.
b
Partial clearance rate was defined as the percentage of patients in whom 75% or more of the number of baseline actinic keratosis lesions were cleared.
c
Median percent (%) reduction in actinic keratosis lesions compared to baseline.
d p<0.001; compared to vehicle by logistic regression with treatment, study and anatomical location.

The level of efficacy varied between the individual anatomical locations. Within each location the complete and partial clearance rates were higher in the group treated with ingenol mebutate compared to the vehicle group (see table 3 and 4).

Table 3 Number and percent (95% CI) of subjects achieving complete and partial clearance at day 57 by anatomical location face and scalp
Complete Clearance                        Partial Clearance( ≥ 75%) Picato 150 mcg/g              Vehicle          Picato 150 mcg/g            Vehicle (n=277 )                 (n=270 )              (n=277)                 (n=270) 104/220                     9/220               157/220                 18/220 Face
47% (41-54%)                4% (2-8%)           71% (65-77%)            8% (5-13%)
13/57                    1/50                   20/57                   2/50 Scalp
23% (13-36%)             2% (0-11%)             35% (23-49%)            4% (1-14%)



Table 4 Number and percent (95% CI) of subjects achieving complete and partial clearance at day 57 by anatomical location trunk and extremities
Complete clearance                    Partial clearance ( ≥ 75%)
Picato 500 mcg/g             Vehicle            Picato 500 mcg/g           Vehicle (n=226)                  (n=232)                (n=226)                (n=232) 49/142                    7/149                 75/142                  11/149 Arm
35% (27-43%)               5% (2-9%)            53% (44-61%)             7% (4-13%) 10/54                    0/56                  16/54                    1/56 Back of Hand
19% (9-31%)               0% (0-6%)            30% (18-44%)             2% (0-10%) 11/14                    2/11                      12/14                  2/11 Chest
79% (49-95%)             18% (2-52%)               86% (57-98%)           18% (2-52%) 7/16                   2/16                       8/16                  2/16 Othera
44% (20-70%)             13% (2-38%)               50% (25-75%)           13% (2-38%) a
Other includes shoulder, back, leg.

Safety of Picato 150 mcg/g treatment for 3 days or Picato 500 mcg/g treatment for 2 days was assessed up to day 57, the majority of the reported adverse reactions and local skin responses were mild to moderate in intensity and all resolved without sequelae.

Statistically significant differences in patient reported outcomes were observed in favour of patients receiving Picato compared to those receiving vehicle gel. Higher mean patient global satisfaction scores, indicating a higher level of overall satisfaction, were seen in the ingenol mebutate groups compared to the vehicle groups (p<0.001) as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM).

Long term efficacy
Three prospective, observational long term 1 year follow-up studies were conducted to evaluate sustained efficacy by recurrence of actinic keratosis lesions in the treatment field, and safety in patients who had received treatment with Picato. One study included patients treated with Picato 150 mcg/g on the face or scalp for 3 days and two studies included patients treated with Picato 500 mcg/g on the trunk or extremities for 2 days. Only those patients who achieved complete clearance in the treated area at the end of the phase 3 studies (day 57) were eligible for long term follow-up. Patients were followed every 3 months for 12 months (see table 5).

Table 5 Rate of recurrence of actinic keratosis lesions
Picato                   Picato
150 mcg/g gel            500 mcg/g gel
Face and scalp       Trunk and extremities
(n=108 )                 (n=76c )
Recurrence Rate 12 months                       53.9% (44.6-63.7)        56.0% (45.1-67.6) KM estimate (95% CI)a
Lesion Based Recurrence Rateb 12                   12.8% (19.1)             13.2% (23.0) months
Mean (SD) a
The recurrence rate is the Kaplan-Meier (KM) estimate at the target study date of the visit expressed as a percentage (95% CI). Recurrence was defined as any identified actinic keratosis lesion in the previously treated area for patients who achieved complete clearance at day 57 in the previous phase 3 studies.
b
The lesion-based recurrence rate for each patient defined as the ratio of the number of actinic keratosis lesions at 12 months to the number of lesions at baseline in the previous phase 3 studies.
c
Of these, 38 subjects were previously treated in a vehicle controlled phase 3 study and 38 subjects were previously treated in an uncontrolled phase 3 study.

Risk of progression to squamous cell carcinoma
At end of study (day 57), the rate of squamous cell carcinoma (SCC) reported in the treatment area was comparable in patients treated with ingenol mebutate gel (0.3%, 3 of 1,165 patients) and in vehicle treated patients (0.3%, 2 of 632 patients) in the actinic keratosis clinical studies conducted with ingenol mebutate gel.
SCC in the treatment area was reported in no patients (0 of 184 patients previously treated with ingenol mebutate gel) in the three prospective, observational long term 1 year follow-up studies.

Experience with more than one treatment course
In a double blind, vehicle-controlled study, up to two treatment courses of Picato 150 mcg/g were administered to 450 patients with 4-8 AKs in a 25 cm2 treatment area on the face or scalp. Patients, in whom a first treatment course did not lead to complete clearance of all AKs in the treatment area after 8 weeks, were randomised to another treatment course with Picato or vehicle. Patients in whom the first treatment course led to complete clearance were seen at 26 and 44 weeks and randomised to a second treatment course if they had a recurrence in the field. In all patients, assessment of efficacy was 8 weeks after the randomisation. The first treatment course, given open label, resulted in a complete clearance rate of 62% (277/450).
The results of the randomised and blinded second treatment course are presented in table 6.

Table 6 Complete clearancea of the field 8 weeks after randomisation and Month 12 Field recalcitrantc    Field recurrentd
Picato    Vehicle     Picato       Vehicle
150 mcg/g (n=49) 150 mcg/g (n=20) gel (n= 92)            gel (n= 42)
8 weeks after randomisation                     47% (43) 18% (9) 60% (25) 25% (5) (p=0.001b)            (p=0.013b)
Month 12                                        18% (17)   4% (2)     31% (13) 15% (3) (p=0.016b)             (p=0.10b) a
Complete clearance rate is defined as the proportion of patients with no (zero) clinically visible actinic keratosis lesions in the treatment area.
b
Cochran-Mantel-Haenszel test of Picato gel 150 mcg/g compared to vehicle adjusted for anatomical location (face/scalp) and country.
c
Patients, in whom the first treatment course did not lead to complete clearance of all AKs in the treatment area.
d
Patients in whom the first treatment course did lead to complete clearance and who had a recurrence in the treatment area at either week 26 or 44.

Actinic Keratosis of the Face and Scalp, sequential use after cryotherapy In a two-arm study, 329 adult patients with AK on the face or scalp were randomised to treatment with Picato gel, 150 mcg/g or vehicle 3 weeks after cryotherapy of all visible lesions in the treatment area. The study enrolled patients with 4 to 8 clinically typical, visible, discrete non-hypertrophic and non-hyperkeratotic AK lesions within a 25 cm2 contiguous treatment area. Eleven weeks after baseline which is 8 weeks after Picato gel or vehicle, the complete clearance rate was 61% among patients randomised to Picato gel, and 49% among patients randomised to vehicle. At 12 months, the complete clearance rates in these groups were 31% and 19% respectively. The percent reduction of the AK count in the Picato group was 83% at 11 weeks and 57% at 12 months, where in the vehicle group it was 78% at 11 weeks and 42% at 12 months. The mean number of AKs in the Picato group was 5.7 at baseline, 0.8 at week 11, and 0.9 at month 12 as opposed to 5.8, 1.0 and 1.2 in the vehicle group at these time points.
Safety results from the study were comparable to the safety profile of Picato gel, 150 mcg/g as monotherapy.

Experience with treatment of a larger area
In a double-blind, vehicle-controlled study to evaluate systemic exposure, Picato 500 mcg/g, from 4 tubes, was applied to a 100 cm2 contiguous treatment area daily for 2 consecutive days. Results demonstrated no systemic absorption.
Picato 500 mcg/g was well tolerated when applied to a contiguous treatment area of 100 cm2 on the trunk and extremities.

In a double-blind, vehicle-controlled study in patients with AK on trunk and extremities, an investigational product with ingenol mebutate gel 600 mcg/g was applied once daily for 2, 3, or 4 days to a skin area of 250 cm2. The trial included a large group of severely sun-damaged patients. 12/163 subjects treated with an investigational product of ingenol mebutate reported 16 skin tumour events inside the treatment area (1 SCC, 1 Bowen's disease and 14 keratoacanthoma following centralised pathology review) compared to 0/61 in the vehicle group.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Picato in all subsets of the paediatric population in actinic keratosis (see section 4.2 for information on paediatric use).

Elderly population
Of the 1,165 patients treated with Picato in the actinic keratosis clinical studies conducted with ingenol mebutate gel, 656 patients (56%) were 65 years and older, while 241 patients (21%) were 75 years and older. No overall differences in safety or efficacy were observed between younger and older patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The systemic pharmacokinetic profile of ingenol mebutate and its metabolites has not been characterised in humans due to the absence of quantifiable whole blood levels following cutaneous administration.

Absorption
No systemic absorption was detected at or above the lower limit of detection (0.1 ng/mL) when Picato 500 mcg/g from 4 tubes was applied to an area of 100 cm2 on the dorsal forearm in actinic keratosis patients once daily for 2 consecutive days.

In vitro study results demonstrate that ingenol mebutate does not inhibit or induce human cytochrome P450 isoforms.