Update on systemic therapies and emerging treatments How do I choose a systemic agent?

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1 Update on systemic therapies and emerging treatments How do I choose a systemic agent? Amy S. Paller, M.D. Walter J. Hamlin Professor and Chair of Dermatology Professor of Pediatrics Northwestern University Feinberg School of Medicine Chicago, Illinois Session: F025 Investigator: Abbvie; Celgene; Eli Lilly, Janssen, Leo Foundation; Novartis Consultant with honorarium: Amgen; Celgene; Eli Lilly; Novartis

2 When should a child with pediatric plaque psoriasis advance to a systemic medication? Generally moderate to severe disease Sometimes more limited disease, such as severe, recalcitrant nail involvement/ palmoplantar Not responding or tolerant of topical medications Having an impact on quality of life Highly visible Time of developing of self-esteem, social interactions Feeling control is critical: importance of adherence

3 Systemic interventions for children and adolescents with plaque psoriasis Phototherapy Compliance in kids is difficult Methotrexate [69.2%] Retinoids [14.6%] Cyclosporine [7.7%] Fumaric acid [4.9%; not in N. America] Biologics [27.2%] - Etanercept: Approved by FDA 11/16 - Adalimumab: Not yet FDA-approved - Ustekinumab: Approved by FDA 10/17 [ %] = % using this drug 12/90-9/14 Europe and US; N=390 children Bronckers et al. JAMA Derm 2017;153:1147

4 What about a Retinoid? Usually acetretin: First-line agent for pustular psoriasis in children, but also a favorite agent in some sites for plaque and palmoplantar psoriasis Most effective in study of 154 children in France (PASI 75=33.1% in 3 months) Charbit et al. BJD 2016;174:1118 Study in Turkey of 4 centers/ 61 patients on retinoids: PASI 50 in 65.5% and PASI 75 in 47.5% (no duration given) Ergun et al. J Dermatol Dec [Epub] Study of 18 patients in Italy: 44.4% with PASI 75 at wk 16 Di Lernia et al. Pediatr Dermatol 2016;33:530

5 What about a Retinoid? Dosage: mg/kg/d (max 0.6 mg/kg/d) Maintain at lowest effective level after taper No immunosuppression Can stop and start without loss of efficacy Many potential side effects, but primarily skin and mucosal dryness Higher drug survival than CsA and Mtx (36% 1 yr, 13% 3 year) with mucocutaneous issues tolerated Ergun et al. J Dermatol Dec [Epub] May be used adjunctively w/ photorx, Mtx, CsA or biologics

6 Would you use Cyclosporine? Good responses for plaque, pustular and erythrodermic psoriasis in children Generally well tolerated, but greatest potential toxicity leaves it lower on therapeutic ladder Lowest drug survival at 1 (15%), 2 (5.5%) and 3 (0) years among 80 patients on CsA (vs. Mtx/acetretin): Risk of immunosuppression, renal and liver disease, hypertension Ergun et al. J Dermatol Dec [Epub]; Pereira et al. JEADV 2006;20:651 Ergun et al. J Dermatol Dec [Epub] Dosage 3-5 mg/kg/d; can titrate up based on levels and tolerance Mean 12 weeks to improve; 40-50% with PASI 75

7 Methotrexate is most commonly used Dosage: mg/kg/wk; adjust upwards for increased efficacy; maintain at lowest effective level after taper for safety Decades of experience in children Recent study of 85 children: 34.1% achieved PASI 75 (time course not given) and drug survival 21.1% (1 yr) and 6.8% (2 yrs) Be prepared: update vaccines, warnings, check labs Ergun et al. J Dermatol Dec [Epub] For all immunosuppressants: baseline and annual TB testing; pregnancy counseling

8 Tips on Use of Methotrexate May take many months for best effect Single-site prospective study in 25 children PASI 50 PASI 75 ~40% achieved PASI 50 at 12 wks ~40% and 80% achieved PASI 75 and PASI 50 by 36 wks PASI 90 Van Geel et al. J Derm Treat 2015;26:406

9 Folate during MTX therapy International retrospective chart review of 20 US and European sites = 390 well-characterized patients treated with systemics Methotrexate most common (69.2%) > Biologics (27.2%; 76% etanercept) Daily or 6d/wk folic acid lowers risk of GI issues (nausea, dyspepsia) vs. weekly folic acid (usu. day after Mtx) GI AEs OR = 0.21 (95% CI, ) for daily and OR= 16 (95% CI, ) for 6x/wk Not related to route (eg, po vs sc) or maximum Mtx dose, but increased OR with longer duration on Mtx (p=0.006) Other AEs: Transaminitis 13.3%; fatigue 6.3%, infections (esp skin, airway) 4.4%, leukopenia 3.3% Bronckers et al. JAMA Derm 2017;153:1147

10 Biologics tested and available for children *Th17/ Th17R inhibition not tested in children

11 Percentage of Patients Etanercept trial 211 children (4-17 years) 12 weekly injections of placebo vs. 0.8 mg/kg/wk etanercept (50=max) 24 weeks open-label etanercept Baseline 12 weeks Placebo (n = 105) Etanercept 0.8mg/kg QW (n = 106) PASI 50 PASI 75 PASI 90 spga "clear"/ "Almost clear" wk PASI 75: 68% and 65% No significant safety issues Paller et al. NEJM 2008;358:21

12 5-year safety and efficacy 60-70% 30-40% Open-label extension of dbl-blind trial (4-17 yrs) in patients who achieved at least PASI 50, no AE/SAE Of 181 enrolled, 69 completed 5 years 1 patient with cellulitis No malignancy, deaths Paller et al. JAAD 2016;74: % Etanercept: Approved 2016 for 6 years and above Financial assistance program Home nurse program

13 Adalimumab vs. Methotrexate 114 patients (not US) with moderate-severe psoriasis Ages 4-8 years; mean 13 y/o, 21% obese and 15% overweight Family history psoriasis in 33% Mean duration 5 y/ %BSA 28/ mean PASI 18 Rules: could have been on etanercept >4 wks ago and on Mtx with response and tolerance >1 year ago Randomized to 16 wks Mtx ( mg/kg/wk, max 25 mg) vs. standard dose Ada (0.8 mg/kg qowk, max 40) vs. half-dose Ada (0.4 mg/kg qowk, max 20) Papp et al. Lancet 2017;390:40

14 Weeks 4-16 PASI 75 Comparable incidence of adverse events Papp et al. Lancet 2017;390:40

15 Tips on Use of TNF Inhibitors May require higher dosing for older, obese children Efficacy may be lost over years: do not have durability studies in children Does not prevent psoriatic arthritis, but most are also helpful for arthritis Most common side effect is injection site reaction May be more infections than methotrexate but need more careful data collection/ monitoring - No reported lymphoma; follow long-term

16 Tips on Use of TNF Inhibitors Baseline hx, PE, vaccines, TB testing Annual TB tests; No consensus for other labs Rheum: CBC, LFTs, Cr every 3 6 months - Level of evidence: D Beukelman et al. Arthritis Care Res 2011;63:465 Survey (n=51): 40% of pedi derms do no other labs; no lab abnormalities found Delphi study to gain consensus among pedi derms planned

17 Proportion of Subjects (%) Ustekinumab in 110 adolescents: CADMUS trial 12 wk RDBC, multicenter trial Dosing 1 mo, then open q 3 mo. (total 60 wks) 12 y, moderate to severe disease Primary endpoint: PGA of Clear (0) or Minimal (1) at Week 12 *p< /37 25/37 25/36 Placebo UST Half-Standard UST Standard 0.75 mg/kg/d Landells et al. JAAD 2015;73:

18 Secondary Endpoints: PASI 75 and PASI 90 Responders at Week 12 PASI 75 PASI 90 *p< wk etanercept PASI 75 57% and PASI 90 27% Landells et al. JAAD 2015;73:594

19 Proportion of Subjects (%) Other Secondary Analyses: PGA Clear (0) and PASI 100 at Week 12 PGA clear *p<0.001 PASI100 *p<0.001 **p=0.014 * * * ** 1/37 Placebo 12/37 17/36 UST HStd UST Std 1/37 Placebo 8/37 14/36 UST HStd UST Std Landells et al. JAAD 2015;73:

20 Mean (SD) Change from Baseline Change from Baseline in Children s Dermatology Life Quality Index (CDLQI) Score at Week 12 (3.18) (6.43) (5.63) Placebo p=0.003 UST Half Standard p<0.001 UST Standard No significant side effects Approved in US >12 y/o October, 2017

21 Tip: Ustekinumab may be choice for CARD14 mutation (may present as PRP, plaque psoriasis, erythrodermic psoriasis with pustules) CARD14 IL8 IL36 VEGF

22 Comparison among systemic medications Infrequent dosing with biologics = convenience; fewer labs Significant side effects unusual with biologics Potential issues with anti-drug antibody; no drug holidays Unknown long-term risk of biologics Etanercept use could prevent enrollment in trials Cost and response Mtx < acitretin < CsA << biologics Adjusted PASI-75 response rate (adults): 31.9% apremilast; 52.6% etanercept; 65.9% adalimumab; 68.6% ustekinumab 45mg and 74.0% 90mg* Cost per responder (PASI-75, adults) at 16 wks: $18.9K apremilast; $33.5K etanercept; $29.3K adalimumab; $21.5K and $39.9K 45mg/90mg ustekinumab* May not be covered by insurance; access an issue; biosimilars 20-30% less *Feldman et al. Presented AAD, 2015

23 Future considerations US trial ongoing for apremilast in children: case report in 14 y/o boy Ongoing effort to make adalimumab available for US children US trial ongoing for ustekinumab in children <12 years US trial ongoing for ixekizumab in adolescents and younger children Trials planned for other Th17/IL-23 inhibitors Pathogenesis-based therapy Smith. JAAD Case Rep 2016;2:89 Study using flow analysis of pediatric plaque psoriasis (n=10) suggested increased IL-17A and IL-22 T cells in skin from pediatric psoriasis vs. healthy children and vs adult psoriasis Could IL-22 be a better target in children than adults? Cordoro et al. J Am Acad Dermatol 2017;77:417