PICATO Gel Ref.[9589] Active ingredients: Ingenol mebutate

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 studies 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:

^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:

Table 4. Number and percent (95% CI) of subjects achieving complete and partial clearance at day 57 by anatomical location trunk and extremities:

^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:

^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 clearance^a of the field 8 weeks after randomisation and Month 12:

^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 nonhyperkeratotic 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.