SORILUX (Page 2 of 4)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Calcipotriene is a synthetic vitamin D3 analog that has a similar receptor binding affinity as natural vitamin D3. However, the exact mechanism of action contributing to the clinical efficacy in the treatment of psoriasis is unknown.

12.2 Pharmacodynamics

Effects on Calcium Metabolism

In 19 subjects with psoriasis aged 12 to less than 17 years treated with SORILUX Foam two times a day for 15 days, there was no significant effect on indices of calcium metabolism including serum albumin adjusted calcium, urine calcium/creatinine ratio, iPTH, alkaline phosphatase, magnesium and phosphorus.

The effects of SORILUX Foam, 0.005%, on calcium metabolism were evaluated in 18 pediatric subjects 5 to 11 years of age receiving SORILUX Foam administered twice daily for a minimum of 14 days (mean: 56 days, range: 14 to 69 days). These subjects had plaque psoriasis involving an average of 10% of the body surface area (BSA) (range: 0.5%-36.5%). There was no relationship between urinary calcium/creatinine ratio (comparing Week 2 to Baseline) and % BSA treated.

12.3 Pharmacokinetics

The systemic absorption of calcipotriene in subjects with psoriasis of the body was evaluated at steady state following application of either SORILUX Foam or calcipotriene ointment to a body surface area of 5% to 10%. In the SORILUX Foam treatment group, 15 out of 16 subjects had calcipotriene plasma concentrations below the limit of quantitation (10 pg/mL), while in the calcipotriene ointment treated group, 5 out of 16 subjects had measurable calcipotriene plasma concentrations at various time points. All measurable plasma calcipotriene concentrations were below 25 pg/mL.

The pharmacokinetics of SORILUX Foam, 0.005% was investigated when applied topically for 15 days to 17 subjects aged 12 to less than 17 years with moderate plaque psoriasis involving a mean BSA of 24%, excluding face and scalp, and a mean scalp involvement of 43%. Systemic concentration of calcipotriene were not quantifiable in any of the subjects (limit of quantification = 10 pg/mL).

In 11 pediatric subjects 7 to 11 years of age with plaque psoriasis involving a mean BSA of 10%, plasma concentration of calcipotriene was measured following 2 weeks of twice daily administration of SORILUX Foam. No subject had quantifiable calcipotriene plasma concentration (limit of quantification = 10 pg/mL).

The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin D. Absorbed calcipotriene is known to be converted to inactive metabolites within 24 hours of application and the metabolism occurs via a similar pathway to the natural hormone.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Calcipotriene topically administered to mice for up to 24 months at dose levels of 3, 10, or 30 mcg/kg/day (corresponding to 9, 30, or 90 mcg /m2 /day) showed no significant changes in tumor incidence when compared with controls.

The genotoxic potential of calcipotriene was evaluated in an Ames assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, and a mouse micronucleus assay. All assay results were negative.

Studies in rats at oral doses up to 54 mcg /kg/day (318 mcg /m2 /day) of calcipotriene indicated no impairment of fertility or general reproductive performance.

14 CLINICAL STUDIES

In two multi-center, randomized, double-blind, vehicle-controlled clinical trials a total of 659 subjects with psoriasis were randomized 2:1 to SORILUX Foam or vehicle; subjects applied the assigned treatment twice daily for 8 weeks. Baseline disease severity was graded using a 5-point Investigator Static Global Assessment scale (ISGA), on which subjects scored either “mild” or “moderate” as shown in Table 1.

Table 1. Investigator Static Global Assessment (ISGA) Scale for Body
Disease Severity Grade Definition
Clear 0 No evidence of scaling, erythema, or plaque thickness
Almost clear 1 Occasional fine scale, faint erythema, and barely perceptible plaque thickness
Mild 2 Fine scale with light coloration and mild plaque elevation
Moderate 3 Coarse scale with moderate red coloration and moderate plaque thickness
Severe 4 Thick tenacious scale with deep coloration and severe plaque thickness

Efficacy evaluation was carried out at Week 8 with treatment success being defined as a score of “clear” (grade 0) or “almost clear” (grade 1) and at least 2 grade improvement from the baseline score. Approximately 30% of enrolled subjects were graded as “mild” on the ISGA scale. The study population ranged in age from 12 to 89 years with 10 subjects less than 18 years of age at baseline. The subjects were 54% male and 88% Caucasian. Table 2 presents the efficacy results for each trial.

Table 2. Number and Percent of Subjects Achieving Success for Body at Week 8 in Each Trial
Trial 1 Trial 2
SORILUX FoamN = 223 Vehicle FoamN = 113 SORILUX FoamN = 214 Vehicle FoamN = 109
Number (%) of Subjects with Treatment Success 31 (14%) 8 (7%) 58 (27%) 17 (16%)

In one trial, subjects graded as “mild” at baseline showed a greater response to vehicle than SORILUX Foam.

Table 3 presents the success rates by disease severity at baseline for each trial.

Table 3. Number and Percent of Subjects Achieving Success for Body by Baseline ISGA Score and by Trial
Trial 1 Trial 2
ISGA Scores at Baseline SORILUX Foam(N = 223) Vehicle Foam(N = 113) SORILUX Foam(N = 214) Vehicle Foam(N = 109)
Mild 2/73 (2.7%) 3/34 (8.8%) 8/56 (14.3%) 4/31 (12.9%)
Moderate 29/150 (19.3%) 5/79 (6.3%) 50/158 (31.6%) 13/78 (16.7%)

In another multi-center, randomized, double-blind, vehicle-controlled clinical trial, a total of 363 subjects with moderate plaque psoriasis of the scalp and body were randomized 1:1 to SORILUX Foam or vehicle. Subjects applied the assigned treatment to the affected areas twice daily for 8 weeks.

Baseline disease severity of the scalp was graded using a 6-point ISGA; a score of “moderate” corresponded to grade 3.

The primary efficacy evaluation for scalp involvement was carried out at Week 8 with treatment success being defined as a score of “clear” (grade 0) or “almost clear” (grade 1). The study population ranged in age from 12 to 97 years with 11 subjects less than 18 years of age at baseline. The subjects were 60% male and 87% Caucasian. Table 4 presents the efficacy results for the trial.

Table 4. Number and Percent of Subjects Achieving Success for Scalp at Week 8
Trial 3
SORILUX FoamN = 181 Vehicle FoamN = 182
Number (%) of Subjects with Treatment Success 74 (41%) 44 (24%)

The contribution to efficacy of individual components of the vehicle has not been established.

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