Patient Tolerability of tazarotene foam, 0.1%, and Impact on Patient Compliance A multicenter, open-label, Phase 1 study of the safety, tolerability, systemic exposure, pharmacodynamics, and treatment effect of calcipotriene foam, 0.005% in pediatric subjects (ages 2 to 11 years) with plaque psoriasis. Adelaide A. Hebert, MDa; Debbie Glaab MSN, CPNP-ACb; Rhonda Schreiber MSRNb , Calcipotriene foam, 0.005%, was well tolerated with a low incidence of adverse events in the pediatric population. There were no quantifiable systemic concentrations of calcipotriene nor effect seen on calcium metabolism with repeated application. While this study was not designed as an efficacy study, the % of subjects who were ISGA responders was found to be consistent with the efficacy in the treatment of body and scalp in adults. Overall, the results in this pediatric population are consistent with previously reported clinical findings for adolescents and adults indicating that calcipotriene foam, 0.005% is safe, well tolerated, and effective treatment option for pediatric psoriasis patients. CONCLUSIONS • Phase 1 multicenter, open-label, repeat-dose study with 36 subjects ages 2 to 11 years from 16 sites. • Two cohorts: • Maximum use cohort defined as ISGA score of 3 or higher at screening and at least 3% Body Surface Index (BSA) with some scalp involvement. • General use cohort defined as ISGA score of 2 or 3 at screening with no BSA minimum • Subjects or their caregivers applied a thin layer of study product twice a day to the treatment areas (excluding the face) for 8 weeks: • In the event that the lesions cleared prior to the end of the study, subjects or their primary caregivers were to continue to apply study product to treatment areas originally affected by psoriasis. • Any new psoriatic lesions which appeared in treatment areas during the treatment period were also treated with the study product. • Safety assessments (adverse event and serious adverse event query) occurred at all study visits. • Treatment effect, urine calcium metabolism, and application site tolerability assessments were performed for all subjects at all in-clinic visits. • Blood samples were taken from all subjects at Screening for evaluation of pharmacodynamic (PD) assessments and 25-OH vitamin D levels at baseline, and an additional blood draw for PD parameters was taken at Week 2 for the maximum-use cohort only. • The % of subjects who were ISGA responders was compared to the Phase III adult clinical trial results using Bayesian analysis. METHODS RESULTSSYNOPSIS Primary Objective: • To evaluate the safety and tolerability of calcipotriene foam, 0.005%, in pediatric subjects, ages 2 to 11 years, with mild to moderate plaque psoriasis. Secondary Objectives: • To evaluate the pharmacodynamic effect on calcium metabolism of calcipotriene foam 0.005%, in pediatric subjects, ages 2 to 11 years, with mild to moderate plaque psoriasis. • To describe the plasma concentrations of calcipotriene following administration of calcipotriene foam, 0.005% in pediatric subjects, ages 2 to 11 years, with moderate plaque psoriasis. • To describe the treatment effect of calcipotriene foam, 0.005%, in pediatric subjects, ages 2 to 11 years, with mild to moderate plaque psoriasis. OBJECTIVES • PD markers showed a general lack of change over time and there were no quantifiable systemic concentrations of calcipotriene observed. The average values of corrected calcium, magnesium and phosphorus were consistent over time. The iPTH and alkaline phosphatase showed some variability across time, but no consistent trends and similar values at screening and day 15. The variability in these values could likely be attributed to small sample size, especially in the subgroups. There was no relationship seen between urinary calcium/creatinine ratio and %BSA treated or age. • No serious adverse events were reported. Of the 29 adverse events that were reported; 7 were considered related to the treatment. These adverse events presented themselves as mostly topical in nature. Local tolerability results remained 0 from baseline to study end in 22 subjects (61.11%). • No evidence of a drug effect was noted for body weight, height, or vital signs. • ISGA scores improved with treatment, but differences between treatments could not be assessed because of the small number of subjects receiving vehicle and the study was not designed to show efficacy. However, response rates (% of subjects with an ISGA score of 0 or 1 for body or scalp at week 8) were consistent with that observed in the double-blind, vehicle controlled Phase III studies in adults. PD Marker Visit Calcipotriene (CAL) Vehicle n Mean (SD) Min - Max n Mean (SD) Min - Max Corrected Calcium (mmol/l) Screening 21 9.3 (0.22) 8.8 - 9.7 2 9.4 (0.14) 9.3 - 9.5 Day 1 3 9.1 (0.17) 9.0 - 9.3 2 9.1 (0.07) 9.0 - 9.1 Day 13 - 16 7 9.2 (0.24) 8.9 - 9.6 2 9.4 (0.35) 9.1 - 9.6 Day 56 - 59 3 9.3 (0.35) 9.0 - 9.7 2 9.4 (0.14) 9.3 - 9.5 iPTH (pmol/l) Screening 19 29.0 (10.54) 12.0 - 46.0 2 54.0 (53.74) 16.0 - 92.0 Day 1 3 45.0 (23.00) 22.0 - 68.0 2 49.0 (26.87) 30.0 - 68.0 Day 13 - 16 7 32.1 (23.58) 16.0 - 84.0 2 25.0 (9.90) 18.0 - 32.0 Day 56 - 59 3 49.7 (49.10) 16.0 - 106.0 2 26.5 (0.71) 26.0 - 27.0 Alkaline Phosphatase (µ/l) Screening 21 274.4 (69.43) 160.0 - 415.0 2 267.0 (69.30) 218.0 - 316.0 Day 1 3 357.7 (121.18) 221.0 - 452.0 2 272.0 (77.78) 217.0 - 327.0 Day 13 - 16 6 292.3 (99.83) 184.0 - 446.0 2 296.0 (106.07) 221.0 - 371.0 Day 56 - 59 3 316.7 (110.59) 190.0 - 394.0 2 279.0 (28.28) 259.0 - 299.0 Magnesium (mmol/l) Screening 21 1.8 (0.10) 1.6 - 1.9 2 1.6 (0.00) 1.6 - 1.6 Day 1 3 1.7 (0.21) 1.5 - 1.9 2 1.7 (0.21) 1.5 - 1.8 Day 13 - 16 6 1.7 (0.15) 1.5 - 1.9 2 1.7 (0.14) 1.6 - 1.8 Day 56 - 59 3 1.8 (0.15) 1.6 - 1.9 2 1.6 (0.00) 1.6 - 1.6 Phosphorus (mmol/l) Screening 21 5.0 (0.47) 3.5 - 5.8 2 4.6 (0.42) 4.3 - 4.9 Day 1 3 5.1 (0.06) 5.0 - 5.1 2 4.3 (0.42) 4.0 - 4.6 Day 13 - 16 6 4.8 (0.56) 4.1 - 5.6 2 4.4 (0.49) 4.0 - 4.7 Day 56 - 59 3 5.3 (0.46) 5.0 - 5.8 2 4.8 (0.21) 4.6 - 4.9 Calcium/Creatinine (mg/g creat) Screening 18 77.0 (43.57) 11.0 - 172.0 2 101.5 (64.35) 56.0 - 147.0 Day 1 21 66.9 (76.84) 7.0 - 286.0 2 101.5 (64.35) 56.0 - 147.0 Day 13 - 16 18 72.5 (56.57) 7.0 - 220.0 2 67.0 (29.70) 46.0 - 88.0 Day 56 - 59 19 90.2 (80.83) 5.0 - 285.0 2 61.0 (36.77) 35.0 - 87.0 PD Marker at Screening, Day 1, Day 13-16 and Day 56-59 a. UT Health McGovern Medical School-Houston, Houston, TX; b. Mayne Pharma, Greenville, NC. This study and analysis was sponsored by Mayne Pharma. All research funding was paid to UT Health McGovern Medical School- Houston, Houston, TX. AFFILIATIONS AND DISCLAIMERS REFERENCES TEAE Type n (%) # of Events OVERALL 6 (16%) 7 Application site pain 2 (6.3%) 2 Contact Dermatitis 2 (6.3%) 2 Psoriasis 3 (9.4%) 3 Relative Change from Day 1 to Day 15 and Day 22 for PD Markers Summary of Treatment emergent Adverse Events* *No AEs reported in Vehicle control group PD Marker Treatment n Geometric Mean 95% CI 90% CI Corrected Calcium (mmol/l) CAL 7 0.997 0.976 - 1.018 0.971 - 1.024 Vehicle 2 0.994 0.898 - 1.101 0.810 - 1.220 iPTH (pmol/l) CAL 7 1.069 0.697 - 1.639 0.624 - 1.831 Vehicle 2 0.626 0.015 - 25.445 0.000 - 1083.9 Alkaline Phosphatase (u/l) CAL 6 0.955 0.872 - 1.045 0.851 - 1.071 Vehicle 2 1.091 0.686 - 1.734 0.429 - 2.772 Magnesium (mmol/l) CAL 6 0.971 0.923 - 1.021 0.910 - 1.035 Vehicle 2 1.061 0.731 - 1.538 0.502 - 2.242 Phosphorus (mmol/l) CAL 6 0.991 0.907 - 1.082 0.885 - 1.109 Vehicle 2 0.945 0.857 - 1.041 0.777 - 1.148 Body n (%) Scalp n (%) Calcipotriene Foam, 0.005% 14 (45.16) 19 (61.29) Vehicle Foam 1 (33.3) 1 (33.3) % Subjects with ISGA Score 0 or 1 at Week 8 DEMOGRAPHICS Calcipotriene Foam, 0.005% n=32 Vehicle Foam n=4 DEMOGRAPHICS Calcipotriene Foam, 0.005% n=32 Vehicle Foam n=4 Age (yrs) Mean (SD) Median Min, Max 8.6 (2.06) 9 4,11 8.5 (2.65) 9 5,11 Baseline BSA: (%) Mean (SD) Median Min,Max 12.2 (9.94) 7.8 0.5,36.5 16.5 (8.26) 19.1 5,23 Race: n (%) Caucasian African American Asian Native American/Alaskan Other 25 (78) 4 (13) 0 1 (3) 2 (6) 3 (75) 0 1 (25) 0 0 Baseline ISGA Body Mean SD Median Min,Max Baseline ISGA Scalp Mean SD Median Min,Max 2.5 (0.92) 3 0,4 1.9 (1.34) 2 0,4 3 (0) 3 3,3 2.8 (0.50) 3 2,3 Gender: n (%) Male Female 15 (47) 17 (53.) 2 (50) 2 (50) Height (cm) Mean SD Median Min,Max 136.2 (13.91) 137.2 104,159 129.2 (11.59) 124.2 122,147 Ethnicity: n (%) Hispanic/Latino Not Hispanic/Latino 13 (42) 18 (58) 1 (25) 3 (75) Weight (kg) Mean SD Median Min,Max 42.1 (15.56) 41.6 17.8,77.1 36.2 (12.23) 35.3 22.7,51.3 1. National Psoriasis Foundation. (2019, July 31). About Psoriasis. Retrieved from Psoriasis.Org: www.psoriasis.org/parents/about-psoriasis. 2. Silverberg, N. B. (2009). Pediatric Psoriasis: An Update. Therapeutics and Clinical Risk Management, 5, 849- 856. 3. Kimball, A., Gold, M., Zib, B., Davis, M., & Clobetasol Propionate Emulsion Formulation Foam Ph. (2008). Clobetasol propionate emulsion formulation foam 0.05%: review of phase II open-label and phase III randomized controlled trials in steroid-responsive dermatoses in adults and adolescents. JAAD, 59(3), 448-454. 4. Shah, K. N. (2013). Diagnosis and Treatment of Pediatric Psoriasis: Current and Future. American Journal of Clinical Dermatology, 14, 195. 5. Wolverton, S. E. (2001). Comprehensive Dermatologic Drug Therapy (XlX ed.). Philadelphia, PA: Saunders. 6. Feldman , S. R., Mills, M., Brundage, T., & Eastman, W. J. (2013, March). A multicenter, randomized, double-blind study of the efficacy and safety of calcipotriene foam, 0.005%, vs vehicle foam in the treatment of plaque-type psoriasis of the scalp. JDD, 12(3), 300-306. 7. Hebert, A., Glaab, D., & Schrieber, R. (2019). A Phase 1 Open Label Multicenter Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Calcipotriene Foam, 0.005% Applied Under Maximum Use Conditions in Adolescent Subjects with Plaque Psoriasis. SKIN: The Journal of Cutaneous Medicine, 3(2). Response Rates for Pediatric and Adults from Previous Studies According to the National Psoriasis Foundation approximately 150,000 new psoriasis patients are diagnosed in the United States each year.1 Almost 20,000 (13%) of newly diagnosed patients are children under the age of 10 with most manifesting with plaque psoriasis (68.6%) with lesions localized to the scalp, post auricular region, elbows, and knees.2 Although the relative frequency of plaque psoriasis differs between adults and children, the etiology is thought to be the same as evidenced by similar response rates to therapies.3,4 There are few therapeutic options for the pediatric population that have proven safety and efficacy and that have FDA approval in the pediatric population. Calcipotriene is a synthetic vitamin D3 derivative that has been used effectively for many years for the treatment of plaque-type psoriasis.5 The efficacy and safety of calcipotriene foam, 0.005%, was established in Phase III clinical trials for the treatment of adults and recently the FDA adjusted the indication to include treatment in patients 12 years and older due to proven safety in a Phase I study in adolescents.6,7 The data presented here highlight the results of an additional Phase I clinical study in pediatric subjects aged 2 to 11 years.