Enstilar

Enstilar Mechanism of Action

betamethasone + calcipotriol

Manufacturer:

LEO Pharma

Distributor:

DKSH
Full Prescribing Info
Action
Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations. ATC Code: D05AX52.
Pharmacology: Pharmacodynamics: Mechanism of action: Enstilar foam combines the pharmacological effects of calcipotriol hydrate as a synthetic vitamin D3 analogue and betamethasone dipropionate as a synthetic corticosteroid.
In psoriasis, vitamin D and its analogues act mainly to inhibit keratinocyte proliferation and induce keratinocyte differentiation. The underlying antiproliferative mechanism of vitamin D in keratinocytes involves the induction of the growth inhibitory factor transforming growth factor-β and of cyclin-dependent kinase inhibitors, with subsequent growth arrest in the G1 phase of the cell cycle plus down-regulation of the two proliferation factors early growth response-1 and polo-like kinase-2.
In addition, vitamin D has an immunomodulatory effect, suppressing activation and differentiation of Th17/Th1 cells while inducing a Th2/Treg response.
In psoriasis, corticosteroids suppress the immune system, particularly pro-inflammatory cytokines and chemokines, thereby inhibiting T-cell activation. At the molecular level, corticosteroids act via the intracellular glucocorticoid receptor and the anti-inflammatory function is due to transrepression of pro-inflammatory transcription factors such as nuclear factor κB, activator protein-1, and interferon regulatory factor-3.
In combination, calcipotriol monohydrate and betamethasone dipropionate promote greater anti-inflammatory and anti-proliferative effects than either component alone.
Pharmacodynamic effects: Short term data: Under maximum use conditions, in subjects with extensive psoriasis on the body and scalp treated for up to 4 weeks, adrenal response to ACTH was determined by measuring serum cortisol levels. None of 35 subjects had suppressed serum cortisol levels at 30 or 60 minutes post ACTH stimulation. Thus it appears that for Enstilar, the risk of adrenal suppression is low when applied to extensive psoriasis vulgaris for 4 weeks. Similarly, there was no indication of abnormal calcium metabolism following application of Enstilar to extensive psoriasis vulgaris for 4 weeks.
Long-term data: The adrenal response to ACTH challenge was evaluated in adult subjects with moderate to severe psoriasis vulgaris involving at least 10% of the body surface area. The subjects were randomised to receive Enstilar or foam vehicle twice weekly for up to 52 weeks (long-term maintenance treatment). Subjects experiencing a relapse were treated with Enstilar once daily for 4 weeks, then continued randomised treatment.
The trial results were in line with a low risk of adrenal suppression in subjects with extensive psoriasis (BSA 10-30%) who use Enstilar twice weekly and as outlined for up to 52 weeks. There was no clinically relevant effect on the calcium metabolism in this trial.
Clinical efficacy: Short-term data: The efficacy of once daily use of Enstilar has been investigated in three randomised, double-blind or investigator-blind, 4-week clinical trials including more than 1,100 subjects with psoriasis on the body (also scalp in Trial Two) of at least mild severity according to the Physician's Global Assessment of disease severity (PGA), affecting at least 2% body surface area (BSA), and with a modified Psoriasis Area Severity Index (m-PASI) of at least 2. The physician's global assessment is made using a 5 point scale (clear, almost clear, mild, moderate, and severe) based on the average psoriatic lesion.
The primary endpoint was subjects with 'treatment success' ('clear' or 'almost clear' for subjects with at least moderate disease at baseline, 'clear' for subjects with mild disease at baseline) according to the PGA at Week 4. (See Tables 1 and 2.)

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Results for the primary endpoint 'treatment success' (PGA) of body at Week 4 showed Enstilar to be statistically significantly more effective than all the comparators included and responses were observed in all categories of baseline disease severity.
In Trial Two, the effect of Enstilar on scalp psoriasis was investigated as the percentage of subjects with 'treatment success' according to the PGA of the scalp at Week 4. (See Table 3.)

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Enstilar was statistically significantly more effective compared to calcipotriol and also associated with a higher rate of treatment success than BDP but this comparison did not reach statistical significance.
The effect of Enstilar on itch and itch-related sleep loss was investigated in Trial One using a visual analogue scale (VAS) ranging from 0 mm (no itch/no sleep loss at all) to 100 mm (worst itch you can imagine/worst possible sleep loss). A statistically significantly higher number of subjects in the Enstilar group compared to vehicle achieved a 70% reduction in itch and itch-related sleep loss from Day 3 and throughout the treatment period.
The effect of Enstilar on quality of life was investigated in Trial One using the generic EQ-5D-5L questionnaire and the dermatologically specific DLQI questionnaire. Statistically significantly greater improvement in quality of life in favour of Enstilar was demonstrated for DLQI from Week 1 and throughout the treatment period and for EQ-5D-5L at Week 4.
Long-term data: The efficacy and safety of treatment with Enstilar was investigated in a randomised, double-blind vehicle-controlled trial (Trial Four). Subjects were treated once daily with open-label Enstilar for 4 weeks and responders were then randomised to receive Enstilar (long-term maintenance treatment) or foam vehicle twice weekly for up to 52 weeks. Subjects in both treatment arms experiencing a relapse were treated once daily with Enstilar for 4 weeks, and those responding then continued randomized treatment. (See Table 4.)

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Subjects on long-term maintenance treatment with Enstilar had longer time to first relapse, greater proportion of days in remission during the trial, and fewer relapses than subjects using foam vehicle. The table as follows presents an overview of the effect on relapse in this trial. (See Table 5.)

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Paediatric population: The effects on calcium metabolism were investigated in an uncontrolled, open-label, 4-week trial in 106 adolescents aged 12 to 17 years with scalp and body psoriasis. The subjects used up to 105 g Enstilar per week. No cases of hypercalcaemia and no clinically relevant changes in urinary calcium were reported.
The adrenal response to ACTH challenge was measured in a subset of 33 subjects with extensive plaque psoriasis involving at least 20% of the scalp and 10% of the body surface area. After 4 weeks of treatment with Enstilar, 2 subjects had a cortisol level ≤18 mcg/dL at 30 minutes after ACTH challenge, but had normal response at 60 minutes. A third subject had minimal cortisol response to the ACTH challenge test at baseline resulting in inconclusive results after the treatment. None of these cases had any clinical manifestations.
Pharmacokinetics: Following systemic exposure, both active ingredients - calcipotriol and betamethasone dipropionate - are rapidly and extensively metabolised.
The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate showed that the kidney and liver had the highest level of radioactivity.
The extent of percutaneous absorption of the two active ingredients following topical application of Enstilar was determined in the HPA axis trial in subjects with extensive psoriasis vulgaris (see Pharmacodynamics as previously mentioned). Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in most samples from 35 patients treated once daily for 4 weeks for extensive psoriasis involving the body and scalp. Calcipotriol was quantifiable at some time point in 1 subject, betamethasone dipropionate in 5 subjects and metabolites of calcipotriol and betamethasone dipropionate were detectable in 3 and 27 subjects, respectively.
Toxicology: Preclinical safety data: Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.
Calcipotriol has shown maternal and foetal toxicity in rats and rabbits when given by the oral route at doses of 54 μg/kg/day and 12 μg/kg/day, respectively. The foetal abnormalities observed with concomitant maternal toxicity included signs indicative of skeletal immaturity (incomplete ossification of the pubic bones and forelimb phalanges, and enlarged fontanelles) and an increased incidence of supernumerary ribs.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Dermal carcinogenicity studies with calcipotriol and betamethasone dipropionate in mice and an oral carcinogenicity study in rats revealed no special risk of to humans.
In a local tolerability study in minipigs, Enstilar caused mild to moderate skin irritation.
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