Study Population: 12 years and older A EF Calcipotriene Foam, 0.005%

Transcription

1 Study No.: CAL.203 Title: A Randomized, Open-Label Study to Assess the Bioavailability of Emulsion Formulation Foam, 0.005%, and Dovonex, 0.005%, in Patients with Mild to Moderate Plaque-Type Psoriasis Rationale: Topical medications may be used alone in mild to moderate psoriasis or in combination with systemic agents in moderate or severe psoriasis. Topical vitamin D analogs remain one of the most widely used treatment modalities for psoriasis. is a synthetic Vitamin D3 derivative that has been used effectively for many years for the treatment of plaque-type psoriasis. The study was designed to evaluate the bioavailability of EF Foam 0.005% and 0.005% in the treatment of mild-to-moderate plaque-type psoriasis. Phase: Phase 2 Study Period: 15 days Study Design: This was a single-center, comparative bioavailability, open-label study. The study consisted of two weeks of treatment. Subjects were instructed to apply approximately 3.5 grams of study drug per application and cover all affected areas (except for the face and scalp). Subjects were instructed to apply the study drug twice a day (morning and evening) at approximately the same time each day. A blood sample was taken within 1 hour prior to the first application of study drug. Additional blood samples were collected on Day 8 and Day 15. On Day 8, blood samples were taken within 1 hour prior to the application of study drug and 1, 3, 6, and 10 hours after application of study drug. The second daily application of study drug on Day 8 occurred after the 10 hour blood sampling. On Day 15, blood samples were collected within 1 hour prior to the application of study drug and 1 hour after the application of study drug. Centres: 1 /United States Indication: mild to moderate plaque-type psoriasis Treatment: EF Foam, 0.005%, and, 0.005%, Objectives: The objective of this study was to evaluate the bioavailability of Emulsion Formulation Foam, 0.005% (EF Foam) and, 0.005% ( ), as measured by circulating plasma levels of in subjects with mild-to moderate plaque-type psoriasis. Primary Outcome/Efficacy Variable: Measurement of plasma levels of calcipotriene at Day 8 and Day 15 (to evaluate bioavailability and systemic exposure). Secondary Outcome/Efficacy Variable(s): Measurements of calcium and albumin-adjusted calcium levels at Day 8 and Day15 (to evaluate calcium metabolism). Statistical Methods: This was a single center, randomized, open-label study of subjects with mild-to moderate plaque-type psoriasis. Approximately 30 subjects were to be enrolled. Subjects were randomized to 1 of 2 parallel dose groups in a 1:1 ratio (EF Foam: ). No hypothesis testing was conducted. Sample size was selected to provide adequate information to assess the bioavailability of in subjects with mild-to-moderate plaque-type psoriasis receiving EF Foam or. Plasma levels of circulating were measured at the following time points: Prior to study product application on Days 1, 8, and 15 At 1, 3, 6, and 10 hours after morning study product application on Day 8 At 1 hour after morning study product application on Day 15 Albumin-adjusted serum calcium levels were obtained to evaluate the effect of EF Foam and on calcium metabolism. Individual subject data was listed. Plasma concentrations and pharmacokinetic parameters were to be summarized by dose group using descriptive statistics (N, mean, standard deviation [SD], median, minimum, and maximum. If possible, 10-hour AUC, Tmax and Cmax at Day 8 were calculated. Study Population: 12 years and older A EF Foam, 0.005% B 0.005% Number of Subjects: Planned, N Randomised, N 16 (100%) 16 (100%) Completed, n (%) 16 (100%) 16 (100%) Total Number Subjects Withdrawn, n (%) 0 0 Withdrawn due to Adverse Events, n (%) 0 0 Withdrawn due to Lack of Efficacy, n (%) 0 0 Withdrawn for Other reasons, n (%) 0 0 1

2 Demographics A B N (ITT) Females: Males, n (%) 6 (38%): 10 (63%) 7 (44%): 9 (56%) Mean Age, years (SD) 50.6 (18.3) 42.2 (13.9) Race, n (%) Asian 0 (0%) Black 0 (0%) Caucasian 11 (69%) Hispanic or Latino 4 (25%) Native Hawaiian or Other Pacific Islander 1 (6%) Asian 1 (6%) Black 1 (6%) Caucasian 14 (88%) Hispanic or Latino 0 (0%) Native Hawaiian or Other Pacific Islander 0 (0%) Age, Min-Max

3 Baseline Characteristics Foam Dovonex Total Extent of Psoriasis (%) N mean (std) 7.1 (1.5) 7.0 (1.5) median min, max 5.0, , 9.0 Investigator's Static Global Assessment Score Clear 0 0 Almost Clear 0 0 Mild (score of 2) 6 (38%) 6 (38%) Moderate (score of 3) 10 (63%) 10 (63%) Severe (score of 4) 0 0 Primary Efficacy Results: Efficacy was not analyzed in this study Pharmacokinetics Results: EF foam was expected to have minimal systemic exposure, and therefore a validated bioanalytical assay was developed using technology with the highest level of sensitivity (reversed-phase highperformance liquid chromatography and mass spectroscopy). The lower limit of detection was 10 pg/ml. Only 6 of the 32 subjects had measurable levels of (all below 25ng/mL) at various time points during the study. Consequently, pharmacokinetic parameters including Cmax, Tmax, and AUC could not be computed. Plasma concentration data suggest that twice daily application of 3.5 grams of foam or ointment for 2 consecutive weeks results in low systemic absorption of. Plasma Concentrations (pg/ml) of in Human Subject (one column per subject) 3

4 Pharmacodynamic Results: Summary of Serum Albumin (g/dl) Foam Baseline mean (std) 4.5 (0.21) 4.5 (0.18) median min, max 4.1, , 4.8 Day 8 mean (std) 4.4 (0.15) 4.4 (0.25) median min, max 4.2, , 5.0 Day 15/End of Treatment mean (std) 4.4 (0.19) 4.5 (0.26) median min, max 4.1, , 5.0 Summary of Serum Calcium (mg/dl) Foam Baseline mean (std) 9.2 (0.34) 9.2 (0.35) median min, max 8.5, , 9.8 Day 8 mean (std) 9.1 (0.43) 9.2 (0.30) median min, max 8.6, , 9.6 Day 15/End of Treatment n mean (std) 9.2 (0.36) 9.2 (0.31) median

5 min, max 8.7, , 9.7 Summary of Albumin Adjusted Calcium (mg/dl) Foam Baseline mean (std) 8.8 (0.24) 8.8 (0.39) median min, max 8.4, , 9.5 Day 8 mean (std) 8.8 (0.38) 8.8 (0.25) median min, max 8.2, , 9.2 Day 15/End of Treatment mean (std) 8.9 (0.31) 8.8 (0.26) median min, max 8.2, , 9.1 Out of Range Laboratory Results Actual Treatment Visit Test Name Test Result * Normal Range Foam Screening Adjusted Calcium 7.7 L Foam Screening Adjusted Calcium 7.9 L Screening Adjusted Calcium 8.0 L Foam Screening Adjusted Calcium 8.2 L Foam Screening Adjusted Calcium 8.3 L Baseline Adjusted Calcium 8.3 L Day 8 Adjusted Calcium 8.2 L Foam Screening Adjusted Calcium 8.2 L Day 8 Adjusted Calcium 8.2 L Day 15 Adjusted Calcium 8.2 L Screening Adjusted Calcium 8.3 L Foam Screening Adjusted Calcium 8.5 L Baseline Adjusted Calcium 9.0 L

6 Day 8 Adjusted Calcium 8.9 L Day 15 Adjusted Calcium 8.8 L Screening Adjusted Calcium 8.2 L Baseline Adjusted Calcium 7.9 L Day 15 Adjusted Calcium 8.3 L * L indicates below the normal range and H indicates above the normal range. Safety Results: Median daily product usage was higher (6.80 g) in subjects receiving EF Foam than in subjects receiving (5.55 g). This disparity may be due in part to the willingness of subjects to apply a large, fixed dose of foam versus a large, fixed dose of an ointment. The number of missed applications and the mean % BSA affected were similar for both groups. One subject (EF Foam group) reported an adverse experience during the study: a sinus infection of mild severity that was assessed by the investigator to be unrelated to study product. No deaths, other SAEs, or other significant AEs were reported during the conduct of the study. One subject became pregnant during the study and delivered a healthy baby 219 days after applying the last dose of study product. Albumin-adjusted calcium levels were measured in all subjects. There were no readings that were above the normal limit or that were deemed clinically significant. A B Most Frequent Adverse Events On-Therapy 1 (6%) 0 (0%) Subjects with any AE(s), n(%) Sinusitis 1 (6%) 0 (0%) Serious Adverse Events - On-Therapy: No Serious Adverse Events occurred. Subjects with non-fatal SAEs, n (%) 0(0%) 0(0%) Subjects with fatal SAEs, n (%) 0(0%) 0(0%) Conclusion: Both EF Foam and appeared to be safe and well tolerated when administered to subjects 12 years of age and older with mild-to-moderate plaque-type psoriasis. The pharmacokinetics of EF Foam and showed no significant difference in the systemic exposure and accumulation of either topically administered foam and ointment formulations of. 6