The Treatment Toolbox for Severe Pediatric Psoriasis Dr. Kim A. Papp, MD, PhD, FRCPC, FAAD K Papp Clinical Research and Probity Medical Research
Objectives: Treating severe pediatric psoriasis 1. Challenges of current treatment options 2. Conditions that may impact treatment decisions 3. Adalimumab in the treatment of severe pediatric psoriasis 4. Evidence for treatment success
Commentary safety severity
The good old days
Diabetes Cyclosporine Arterial Hypertension Hyperlipidemia Methotrexate
BIOLOGIC TREATMENT OPTIONS Treating by the Evidence
Etanercept: Phase III clinical trial in pediatric psoriasis Trial design Double blind trial Escape group Etanercept weekly Open label treatment Randomized double blind Withdrawal Retreatment Eligible for additional topical therapy Etanercept weekly Screening PASI score worsening of >50% Etanercept weekly 1:1 Placebo weekly PASI 50 not achieved Etanercept weekly PASI 75 not achieved Etanercept weekly 1:1 Placebo weekly Loss of PASI 75 Retreatment with etanercept weekly Randomization 5 Day 1 4 12 24 36 48 WEEK TRIAL POPULATION Patients aged 4 17 years with stable moderate to severe chronic plaque psoriasis DOSING Etanercept 0.8mg/kg (to maximum intended dose of 50mg) or matching placebo administered subcutaneously once weekly Paller AS, et al. N Engl J Med. 2008;358:241 251.
Etanercept: PASI responses at week 12 PATIENTS (%) 100 90 80 70 60 50 40 30 20 10 0 Placebo Etanercept PASI 50 P ASI 50 PASI 75 P ASI 75 PASI 90 P ASI 90 47 44 P<0.001 P<0.001 P<0.001 27 19 11 23 11 13 P<0.005 9 P<0.005 5 3 7 0 2 4 1 6 8 2 10 12 WEEK 71 P<0.001 75 P<0.001 57 Proportions of patients with improvements over baseline in PASI of 50%, 75%, and 90% Paller AS, et al. N Engl J Med. 2008;358:241 251.
Ustekinumab CADMUS Study design = Injection visits Half standard = 60 kg, 0.375 mg/kg; >60 to 100 kg, 22.5 mg; >100 kg, 45 mg Standard = 60 kg, 0.75 mg/kg; >60 to 100 kg, 45 mg; >100 kg, 90 mg Early escape: At week 8, patients with a PASI increase 50% from BL were eligible to start treatment with moderate to high potency topical steroid preparations through week 12 Landells I, et al. JAAD 2015;73(4): 594 603
Ustekinumab: Phase III clinical trial in adolescent psoriasis (CADMUS) RESULTS: % OF PATIENTS 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% PASI75 AT WEEK 12 78.4% 80.6% UST HSD UST SD P<0.001 10.8% PBO SAFETY: Through wk 12: 1 AE: combined UST 47.9% vs 56.8% PBO 1 SAE: UST combined 1.4% vs. 0% PBO Through wk 60: 1 AE: combined UST 81.8% 1 SAE: UST combined 5.5% Discontinuation rates: wk 12 0% and wk 40 8.2% Most common reason: lack of efficacy in 5 patients (4.5%) in combined UST group No dose response observed Landells I et al. J Am Acad Dermatol 2015;73:594 603. No malignancies, MACE, TB, opportunistic infections, anaphylactic reactions, or serum sickness like reactions
ADALIMUMAB IN PEDIATRIC PSORIASIS RESULTS FROM PHASE III CLINICAL TRIAL
Phase 3 Study M04 717: 1 st Head to Head Study in Pediatric Psoriasis A total of 114 subjects were recruited at 38 sites in Canada, the EU, and rest of world (Chile, Mexico, Switzerland, and Turkey). Screening 3 30 days PERIOD A Double blind primary treatment 16 wks PERIOD B Withdrawal no medication up to 36 wks PERIOD C Double blind retreatment 16 wks 1:1:1: randomization ADA 0.8 mg/kg ADA 0.4 mg/kg Subjects who achieved both a PASI 75 and a PGA 0,1 at week 16 were withdrawn from treatment ADA 0.8 mg/kg ADA 0.4 mg/kg Early escape option up to wk 8 A MTX Non responders at wk 16 A Responders with loss of disease control in Period B, proceed to Period C Responders with no loss of disease control wks 0 B 36 B ADA 0.8 mg/kg Completed 16 wks retreatment wks 0 C 16 C PERIOD D Long term Follow up Ada 0.4mg/kg or 0.8 mg/kg Loading dose of Ada at week 0 and eow at week 1; Oral MTX: 0.1 mg/kg at Week 0 and up to 0.4 mg/kg weekly (maximum dose of 25 mg/week) for the duration of Period A; all patient received folic acid Loss of disease control was defined as a worsening of PGA scores in comparison to Week 16A by at least 2 grades after treatment withdrawal Papp K. et al., 23rd World Congress of Dermatology; June 8 13, 2015; Vancouver, Canada ADA: adalimumab; MTX: methotrexate; Wk: week
Patient demographics (Period A) Adalimubab AE, n (%) MTX (n=37) 0.4 mg/kg (n=39) 0.4 mg/kg (n=39) Total (N=114) Female, n (%) 26 (70.3) 18 (46.2) 21 (55.3) 65 (57.0) White, n (%) 34 (91.9) 34 (87.2) 35 (92.1) 103 (90.4) Mean (SD) age, y 13.4 (3.5) 12.6 (4.4) 13.0 (3.3) 13.0 (3.8) BMI percentile, n (%) <5 th (underwight) 1 (2.7) 1 (2.6) 3 (7.9) 5 (4.4) 5 th to 85 th (normal weight) 22 (59.5) 25 (64.1) 21 (55.3) 68 (59.6) 85 th to 95 th (overweight) 6 (16.2) 4 (10.3) 7 (18.4) 17 (14.9) 95 th (obese) 8 (21.6) 9 (23.1) 7 (18.4) 24 (21.1) Mean (SD) Ps duration, y 5.1 (3.8) 4.8 (3.3) 5.0 (3.8) 5.0 (3.6) Family history of Ps, n (%) 11 (30.6)* 15 (38.5) 11 (28.9) 37 (32.7) Mean (SD) %BSA affected 30.3 (21.2) 26.0 (16.2) 27.7 (20.4) 27.9 (19.3) Mean (SD) PASI 19.2 (10.0) 16.9 (5.8) 18.9 (10.3) 18.3 (8.8) PGA, n (%) Clear/minimal 0 1 (2.6) 0 1 (0.9) Mild 1 (2.7) 3 (7.7) 3 (7.9) 7 (6.1) Moderate 19 (51.4) 18 (46.2) 17 (44.7) 54 (47.4) Marked 17 (45.9) 15 (38.5) 17 (44.7) 49 (43.0) Severe 0 2 (5.1) 1 (2.6) 3 (2.6) BMI, body mass index; BSA, body surface area; MTX, methotrexate; PASI, Psoriasis Area and Severity Index; PGA, Physicians s Global Assessment; Ps, Psoriasis. *Data missing for one patient. Papp K. et al., 23rd World Congress of Dermatology; June 8 13, 2015; Vancouver, Canada
Pediatric Study Patient Population INCLUSION CRITERIA Subjects 4 and <18 years of age with severe plaque psoriasis Weight 13 kg Failure to respond to topical therapy; failure, intolerance, contraindication to, or not be candidate for heliotherapy or phototherapy Papp K. et al., 23rd World Congress of Dermatology; June 8 13, 2015; Vancouver, Canada
INCLUSION CRITERIA Subject needed systemic treatment to control his/her disease and met one of the following: PGA 4, OR BSA involved >20%, OR Very thick lesions with BSA >10%, OR PASI >20, OR PASI >10, and at least one of the following: oactive PsA unresponsive to nonsteroidal anti inflammatory drugs (NSAIDs) oclinically relevant facial, genital or hand/foot involvement ocdlqi >10 Papp K. et al., 23rd World Congress of Dermatology; June 8 13, 2015; Vancouver, Canada
Primary Efficacy Endpoints in Period A: PASI 75 and PGA 0/1 Response at Week 16 PASI 75 PGA 0/1 70 60 57.9* 70 60 60.5 PASI 75 RESPONSE, % 50 40 30 20 32.4 43.6 PGA 0/1 SCORE, % 50 40 30 20 40.5 41.0 10 10 0 MTX (n=37) ADA 0.4 mg/kg (n=39) ADA 0.8 mg/kg (n=38) 0 MTX (n=37) ADA 0.4 mg/kg (n=39) ADA 0.8 mg/kg (n=38) *P<0.05 ADA 0.8 mg/kg vs. MTX. Non responder imputation. ADA, adalimumab; MTX, methotrexate; PASI75, 75% improvement in Psoriasis Area and Severity Index; PGA, Physician s Global Assessment. PGA 0/1 is defined as PGA clear or minimal Papp K. et al., 23rd World Congress of Dermatology; June 8 13, 2015; Vancouver, Canada
PASI90/100 Responses at Week 16 (Period A) PASI RESPONSE, % 80 70 60 50 40 30 20 10 0 MTX (n=37) ADA 0.4 mg/kg (n=39) ADA 0.8 mg/kg (n=38) 30.8 28.9 21.6 PASI90 80 70 60 50 40 30 20 10 0 18.4 10.3 2.7 PASI100 ADA, adalimumab; MTX, methotrexate; PASI90/100. 90%/100% improvement in Psoriasis Area and Severity Index Papp K. et al., 23rd World Congress of Dermatology; June 8 13, 2015; Vancouver, Canada
Percentage Achieving >PASI 75 100 80 60 40 58.3 50.0 50.0 47.2 38.9 47.2 30.6 75.0 77.8 66.7 47.2 MTX PerA, n=37 ADA 0.8 PerD, n=36 86.1 61.1 61.1 55.6 50.0 83.3 80.6 69.4 77.8 55.6 ADA 0.8 PerA, n=39 ADA 0.8 PerD, n=36 58.3 ADA 0.4 PerA, n=38 ADA 0.4 PerD, n=36 77.8 75.0 52.8 86.1 72.2 47.2 Week 16A 32.4 57.9 43.6 20 27.8 27.8 0 Week 0D 1D 4D 8D 11D 16D 20D 28D 40D 52D Dose groups defined as dose received in Periods A/D. Intent to treat; non responder imputation. Papp K., 24 th EADV congress, 7 11 October 2015, Copenhagen, Denmark
How safe is it?
Summary Few clinical & scientific evidence with current treatment options Different conditions may impact treatment decisions
Summary Efficacy of adalimumab 0.8 mg/kg has been demonstrated in children and adolescents from 4 years and up with moderate severe psoriasis