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Picato gel - Scientific Information

Manufacture: LEO Pharma
Country: Canada
Condition: Actinic Keratosis, Keratosis
Class: Topical antineoplastics
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: ingenol mebutate, isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified water

Pharmaceutical information

Drug Substance

Proper name (I.N.N.): ingenol mebutate
Chemical name:



Alternative chemical
2-Butenoic acid, 2-methyl-, (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-1a,2,5,5a,6,9,10,10a-octahydro-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1H-2,8a-methanocyclopenta [a]cyclopropa[e]cyclodecen-6-yl ester, (2Z) -
(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H 2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl (2Z) 2 methylbut-2-enoate.
Laboratory code name: PEP005
Molecular formula: C25H34O6
Molecular mass: 430.53 g/mol
Chirality: Eight chiral centres with specific optical rotation range 44o - 49o

Structural formula:


Physicochemical properties:
Physical form
Solubility


Melting point
pH
White to pale yellow crystalline powder

Freely soluble in benzyl alcohol and isopropyl alcohol,soluble in methanol, ethanol, acetonitrile and acetone, very slightly soluble in ethanol-water (1:3) and practically insoluble in n-heptane and water
154.1 oC – 156.8 oC
Weakly acidic, pKa 12.7

Clinical trials

The efficacy and safety of PICATO (ingenol mebutate) 0.015% gel administered on the face or scalp for 3 consecutive days, and 0.05% gel administered on the trunk or extremities for 2 consecutive days was studied in four multi-centre, double-blind, randomized, parallel group, vehicle-controlled studies. For both treatment locations, eligible patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic, actinic keratosis (AK) lesions within a contiguous 25 cm2 treatment area. On each scheduled dosing day, the study gel was applied to the entire treatment area (25 cm2). Patients continued in the studies for an 8 week follow-up period during which they returned for clinical observations and safety monitoring.

The efficacy of PICATO in AK is based on clinical clearance; histological assessment of clearance was not performed. The primary efficacy endpoint was complete clearance rate, defined as the proportion of patients at Day 57 with no clinically visible AK lesions in the selected treatment area. The secondary endpoint was partial clearance rate, defined as the proportion of patients at Day 57 with a 75% or greater reduction in the number of clinically visible AK lesions identified at baseline in the selected treatment area. The median percent reduction from baseline in the total number of AK lesions at Day 57 was also determined.

Face and Scalp

Study patients (n=547) ranged from 34 to 89 years of age (mean 64 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 85% of subjects were male, and all subjects were Caucasian. A total of 536 subjects (98%) completed these studies (see Table 1).

Table 1. Clinical Efficacy Studies of Actinic Keratosis on the Face and Scalp
Study # Trial design Dosage, route of
administration
and duration
Study patients
by dose group
Mean age
(Range)
years
Gender by
dose group
M/F
PEP005-016 Multi-centre,double-blind,randomized,parallel group,vehicle-controlled PICATO 0.015% or vehicle, once a day topical, for 3 consecutive days 135
134
63.5 (37-88)
63.0 (40-85)
116/19
120/14
PEP005-025 Multi-centre,double-blind,randomized parallel group,vehicle-controlled PICATO 0.015% or vehicle, once a day topical, for 3 consecutive days 142
136
64.8 (34-88)
65.0 (46-89)
117/25
112/24

At Day 57, patients treated with PICATO gel had statistically significantly 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). Efficacy varied between anatomical locations (Table 3). Within each group, the complete and partial clearance rates were higher in patients treated with PICATO gel than patients treated with vehicle.

Table 2. Rates of Patients with Complete and Partial Clearance and Percent (%) Reduction on the Face and Scalp
Study PEP005-016 Study PEP005-025
PICATO 0.015%
gel
(n=135 )
Vehicle
(n=134 )
PICATO 0.015%
gel
(n=142)
Vehicle
(n=136)
Complete Clearance Ratea 50 (37%)d 3 (2%) 67 (47%)d 7 (5%)
Partial Clearance Rate
(≥ 75%)b
81 (60%)d 9 (7%) 96 (68%)d 11 (8%)
Median % Reductionc 83% 0% 87% 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 Cochran-Mantel-Haenszel test stratified by study site.


Table 3. Number and Rate of Patients with Complete and Partial Clearance at Day 57 by Anatomical Location (Face and Scalp Studies PEP005-016 and PEP005-025 Combined)
Complete Clearance Partial Clearance ( ≥ 75%)
PICATO 0.015 % gel
(n=277 )
Vehicle
(n=270 )
PICATO 0.015 % gel
(n=277 )
Vehicle
(n=270)
Face 104/220
47%
9/220
4%
157/220
71%
18/220
8%
Scalp 13/57
23%
1/50
2%
20/57
35%
2/50
4%

The safety of PICATO 0.015% gel treatment was assessed up to day 57 and ingenol mebutate gel was found to be well tolerated. All adverse drug reactions and local skin responses resolved without sequelae.

Trunk and Extremities

Study patients (n=458) ranged from 34 to 89 years of age (mean 66 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 62% of subjects were male, and all subjects were Caucasian. A total of 447 subjects (98%) completed these studies (see Table 4).

Table 4. Clinical Efficacy Studies of Actinic Keratosis on the Trunk and Extremities
Study # Trial design Dosage, route of
administration
and duration
Study patients
by dose group
Mean age
(Range)
years
Gender by
dose group
M/F
PEP005-014 Multi-centre,
double-blind,
randomized,
parallel group,
vehicle-controlled
PICATO 0.05%
or vehicle,once
a day topical, for
2 consecutive
days
126
129
67.2
(43-88)
66.9
(36-87)
86/40
73/56
PEP005-028 Multi-centre,
double-blind,
randomized,
parallel group,
vehicle-controlled
PICATO 0.05%
or vehicle,once
a day topical, for
2 consecutive
days
100
103
65.3
(43-87)
64.9
(34-89)
59/41
68/35

At Day 57, patients treated with PICATO gel had statistically significantly 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 5). Efficacy varied between anatomical locations (Table 6). Within each group, the complete and partial clearance rates were higher in patients treated with PICATO gel than patients treated with vehicle.

Table 5. Rates of Patients with Complete and Partial Clearance and Percent (%) Reduction on the Trunk and Extremities
Study PEP005-014 Study PEP005-028
PICATO
0.05% gel
(n=126 )
Vehicle
(n=129 )
PICATO
0.05% gel
(n=100)
Vehicle
(n=103)
Complete Clearance Ratea 35 (28%)d 6 (5%) 42 (42%)d 5 (5%)
Partial Clearance Rate
(≥ 75%)b
56 (44%)d 9 (7%) 55 (55%)d 7 (7%)
Median % Reductionc 69 % 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 Cochran-Mantel-Haenszel test stratified by study site.


Table 6. Number and Rate of Patients with Complete and Partial Clearance at Day 57 by Anatomical Location (Trunk and Extremities Studies PEP005-014 and PEP005-028 Combined)
Complete Clearance Partial Clearance ( ≥ 75%)
PICATO 0.05 % gel
(n=226)
Vehicle
(n=232)
PICATO 0.05 % gel
(n=226)
Vehicle
(n=232)
Arm 49/142
35%
7/149
5%
75/142
53%
11/149
7%
Back of Hand 10/54
19%
0/56
0%
16/54
30%
1/56
2%
Chest 11/14
79%
2/11
18%
12/14
86%
2/11
18%
Othera 7/16
44%
2/16
13%
8/16
50%
2/16
13%

a Other includes shoulder, back, leg.

The safety of PICATO 0.05% gel treatment for 2 days was assessed up to day 57 and ingenol mebutate gel was found to be well-tolerated. All adverse drug reactions and local skin responses resolved without sequelae.

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 0.015% on the face or scalp for 3 days and two studies included patients treated with PICATO 0.05% 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 Tables 7).

Table 7. Rate of Recurrence of Actinic Keratosis Lesions
PICATO
0.015% gel
Face and Scalp
(n=108 )
PICATO
0.05% gel
Trunk and Extremities
(n=76c)
Recurrence Rate 12 months
KM estimate (95% CI)a
53.9% (44.6-63.7%) 56.0% (45.1-67.6%)
Lesion Based Recurrence Rateb 12 months Mean (SD) 12.8% (19.1%) 13.2% (23.0%)

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.

bThe 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.

Local Tolerability

Results of 3 topical safety studies in healthy volunteers showed that PICATO gel did not produce a sensitization response and results indicated no potential for dermal phototoxicity, or dermal photosensitization.

Detailed pharmacology

There is no adequate disease model for AK. Therefore, in vivo and in vitro models using tumour cell lines, including squamous cell carcinoma, were used to investigate the mechanism of action of ingenol mebutate (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

In safety pharmacology studies, ingenol mebutate did not inhibit IKr ion channel activity in vitro or adversely affect QT intervals or electrocardiogram waveform morphology in vivo in dogs at the highest doses evaluated (5 μg/mL and 15 μg/kg, respectively). Mild haemodynamic effects (≥5 μg/kg) and increased respiration and minute volume ventilation (≥7.5 μg/kg) were observed in dogs following a single IV administration. No significant effects on central nervous system parameters were noted in rats following IV administration of ≤10 μg/kg ingenol mebutate.

Toxicology

In all topical administration studies, dose limiting toxicity was associated with the severity of the irritant response to ingenol mebutate gel administration. Dose- and frequency-dependent skin responses in rats and minipigs, characterised by erythema and oedema, and microscopic observations of acanthosis, dermal inflammation/fibrosis, epidermal hyperplasia, erosion/ulceration, and scab formation, were similar between species and were consistent across studies.

Gross and histological observations of dermal irritation were reversible at all tested dose levels in both rats and minipigs.

In topical administration studies, single or three daily repeat doses of 0.1% ingenol mebutate up to 500 μg on 150-600 mm2 in rats or minipigs did not produce mortality or systemic toxicity.

Chronic topical application of 0.02% ingenol mebutate gel up to 30 μg on 600 mm2 for 3 consecutive days repeated monthly for 6 months in rats and 0.03% ingenol mebutate gel up to 180 μg on 2400 mm2 for 3 consecutive days repeated monthly for 41 weeks in minipigs also demonstrated no systemic toxicity.

Clinical pathology findings were limited to occasional increases in circulating neutrophils and/or monocytes in rats which were associated with acute/chronic dermal inflammation..

Reproduction

In rats, ingenol mebutate was not associated with fetal developmental effects at IV doses up to 5 μg/kg/day (30 μg/m2/day). In rabbits, dams receiving 4 μg/kg/day showed an increased incidence of early embryonic deaths compared with the controls (13% vs 7%). Minor foetal abnormalities were also observed at an increased incidence in the foetuses of ingenol mebutate treated dams (at doses of 1-4μg/kg/day), including variation in the origin of arteries arising directly from the aortic arch, unilateral/bilateral rib costal cartilage not attached to sternum, incompletely ossified cervical vertebral arches and jugal connected/fused to the zygomatic process of the maxilla.

No fertility studies have been performed with ingenol mebutate.

Carcinogenesis and Mutagenesis

Carcinogenicity studies with ingenol mebutate have not been conducted.

Ingenol mebutate was not mutagenic in an in vitro Ames test, mouse lymphoma assay, and in vivo rat micronucleus test. An in vitro Syrian hamster embryonic (SHE) cell transformation assay was positive. The SHE transformation assay gave a positive result after the 24 h and 7 day exposure periods. There was an increase in toxicity (decrease in relative plating efficiency) and increase in morphologically transformed colonies (MTC). Toxicity noted at ≥ 0.05 μg/mL at 24 h and after 7 days. A statistical increase in MTC was seen from 0.1 μg/mL at 24 h and 0.025 μg/mL at 7 days.

A 6-month repeat dose IV rat study in 154 rats found that one male and one female dosed twice weekly with 15 μg/kg had a kidney tubular adenoma and tubular hyperplasia of the kidney. A pituitary adenoma was also present in the female with the renal adenoma. At the 1-month recovery kill, one male had a thyroid follicular cell carcinoma. There was no evidence of neoplasia at lower IV doses or in the 6 month dermal rat and 41 week dermal minipig repeat dose studies.