Topical Therapies for Psoriasis. Linda Stein Gold, MD Henry Ford Hospital Detroit, MI

Transcription

1 Topical Therapies for Psoriasis Linda Stein Gold, MD Henry Ford Hospital Detroit, MI

2 DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY Anacor Bayer Eli Lilly Foamix Galderma LEO Medimetrix Novartis Pfizer Taro

3 What do Psoriasis Endpoints Mean? Body surface area (BSA) National Psoriasis Foundation psoriasis.org; Accessed Oct 21, 2015.

4 Investigators Global Assessment IGA has no correlation to amount of disease, only the severity of the individual plaques

5 Psoriasis area and severity index PASI Composite index of both extent and severity of disease Measures average erythema, scaling and thickness of lesions Weighted by area of involvement Commonly used in clinical trials but not in clinical practice PASI-75 common clinical trial endpoint Mentor, JAAD. 2008;58,

6 Strength of Recommendations J Am Acad Dermatol 2009;60: Menter A, J Am Acad Dermatol 2009;60:643-59

7 Potency: Vehicles Matter Traditional thinking was that drugs had to be occlusive (ointment) in order to get the best penetration and efficacy Newer vehicles have changed our mindset Changing vehicles can affect efficacy

8 Topical Steroids: Potency Class I Ultra-High Potency II High Potency III Mid-Potency Selected Preparations Augmented betamethasone dipropionate 0.05% ointment, gel, lotion Clobetasol propionate 0.05% cream, ointment, lotion, foam Fluocinonide 0.1% cream Desoximetasone 0.25% Spray Halobetasol propionate 0.05% cream, ointment, LOTION Augmented betamethasone dipropionate 0.05% cream Betamethasone dipropionate 0.05% cream, ointment, foam and solution Desoximetasone 0.25% cream, ointment Fluocinonide 0.05% cream, ointment Mometasone furoate 0.1% ointment Fluticasone propionate 0.005% ointment Halcinonide 0.1% ointment Betamethasone dipropionate emollient spray, 0.05% Vasoconstriction test correlates with clinical psoriasis activity and is thus a relevant measure of topical corticosteroid potency IV Mometasone furoate 0.1% cream Triamcinolone acetonide 0.1% cream, ointment V Fluocinolone acetonide 0.025% cream, ointment Hydrocortisone valerate 0.2% ointment VI Low Potency Desonide 0.05% cream, ointment, lotion, gel, foam Alclometasone dipropionate 0.05% cream, ointment VII Hydrocortisone 1% cream, ointment Hydrocortisone 2.5% cream, ointment a Vasoconstriction assay. Boguniewicz M. Immunol Allergy Clin North Am. 2004;24(4): Leung DY et al. Ann Allergy Asthma Immunol. 2004;93(3 suppl 2):S1-21. Merck & Co. Inc. Accessed December 10, Vanos (fluocinonide cream 0.1%) prescribing information. Accessed November 20, Betamethasone dipropionate gel (Augmented*), 0.05% prescribing information. Accessed March 19, 2008.

9 Topical Steroids: Potency Class I Ultra-High Potency II High Potency III Mid-Potency Selected Preparations Augmented betamethasone dipropionate 0.05% ointment, gel, lotion Clobetasol propionate 0.05% cream, ointment, lotion, foam Fluocinonide 0.1% cream Desoximetasone 0.25% Spray Halobetasol propionate 0.05% cream, ointment Augmented betamethasone dipropionate 0.05% cream Betamethasone dipropionate 0.05% cream, ointment, foam and solution Desoximetasone 0.25% cream, ointment Fluocinonide 0.05% cream, ointment Mometasone furoate 0.1% ointment Fluticasone propionate 0.005% ointment Halcinonide 0.1% ointment Betamethasone dipropionate emollient spray, 0.05% Vasoconstriction test correlates with clinical psoriasis activity and is thus a relevant measure of topical corticosteroid potency IV Mometasone furoate 0.1% cream Triamcinolone acetonide 0.1% cream, ointment V Fluocinolone acetonide 0.025% cream, ointment Hydrocortisone valerate 0.2% ointment VI Low Potency Desonide 0.05% cream, ointment, lotion, gel, foam Alclometasone dipropionate 0.05% cream, ointment VII Hydrocortisone 1% cream, ointment Hydrocortisone 2.5% cream, ointment a Vasoconstriction assay. Boguniewicz M. Immunol Allergy Clin North Am. 2004;24(4): Leung DY et al. Ann Allergy Asthma Immunol. 2004;93(3 suppl 2):S1-21. Merck & Co. Inc. Accessed December 10, Vanos (fluocinonide cream 0.1%) prescribing information. Accessed November 20, Betamethasone dipropionate gel (Augmented*), 0.05% prescribing information. Accessed March 19, 2008.

10 Topical Steroids: Potency Class I Ultra-High Potency II High Potency III Mid-Potency Selected Preparations Augmented betamethasone dipropionate 0.05% ointment, gel, lotion Clobetasol propionate 0.05% cream, ointment, lotion, foam Fluocinonide 0.1% cream Desoximetasone 0.25% Spray Halobetasol propionate 0.05% cream, ointment Augmented betamethasone dipropionate 0.05% cream Betamethasone dipropionate 0.05% cream, ointment, foam and solution Desoximetasone 0.25% cream, ointment Fluocinonide 0.05% cream, ointment Mometasone furoate 0.1% ointment Fluticasone propionate 0.005% ointment Halcinonide 0.1% ointment Betamethasone dipropionate emollient spray, 0.05% Vasoconstriction test correlates with clinical psoriasis activity and is thus a relevant measure of topical corticosteroid potency IV Mometasone furoate 0.1% cream Triamcinolone acetonide 0.1% cream, ointment V Fluocinolone acetonide 0.025% cream, ointment Hydrocortisone valerate 0.2% ointment VI Low Potency Desonide 0.05% cream, ointment, lotion, gel, foam Alclometasone dipropionate 0.05% cream, ointment VII Hydrocortisone 1% cream, ointment Hydrocortisone 2.5% cream, ointment a Vasoconstriction assay. Boguniewicz M. Immunol Allergy Clin North Am. 2004;24(4): Leung DY et al. Ann Allergy Asthma Immunol. 2004;93(3 suppl 2):S1-21. Merck & Co. Inc. Accessed December 10, Vanos (fluocinonide cream 0.1%) prescribing information. Accessed November 20, Betamethasone dipropionate gel (Augmented*), 0.05% prescribing information. Accessed March 19, 2008.

11 Optimized penetration of Betamethasone dipropionate emollient spray, 0.05% more efficacious than augmented BD % Subjects achieving IGA 0 or 1and 2 grade reduction from baseline 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% IGA Results p<0.001 p<0.001 p=0.010 Day 4 Day 8 Day 15 Day 29 DFD-01, n=356 AugBD, n=90 Vehicle, n=182 Treatment success was defined as an IGA=0 or 1 and 2 grade reduction from baseline Stein Gold, Winter Clinical poster

12 SIDE EFFECTS OF TOPICAL CORTICOSTEROIDS: WHAT ARE THE FACTS?

13 Epidermal Atrophy 13 healthy women. Clobetasol Propionate BID X 28 days. Optical coherence tomography. Dashed line: reference zone. Histology showed 22% epidermal thinning after 28 days. Josse G, Skin Res Technol. 2009

14 Dermal Atrophy Treatment with Clobetasol Propionate BID X 28 days. Demal thickness measured by ultrasound. Dashed line: reference zone. 12% average decrease at day 28. Thickness increased with D/C of treatment Josse G, Skin Res Technol. 2009

15 Steroid Induced Atrophy- Prevention? Tazarotene Gel 0.1% Taz + DD reduced atrophy by 37% Ammonium lactate (AL) AL + CP 35% decrease, 15% decrease occluded Calcipotriene ointment C + BP Minimized atrophy in animal model Kaidbey K, Int J Dermatol 2001 Lavker RM JAAD 1992 H. Norsgaard 1, P. Descargues 5, S. Kurdykowski et al, poster EADV, 2012

16 Maintenance Therapy: Standard dosing or PRN? OBJECTIVE: To investigate maintenance strategies of a C/BD suspension for the treatment of scalp psoriasis. MATERIALS AND METHODS: 885 patients, treat daily until clear or almost clear then maintenance as two groups X 12 weeks total: two applications per week on-demand therapy CONCLUSIONS: Twice-weekly application more effective and is associated with a lower rate of relapse. (19.5% vs 41.7%; P<.001) J Dermatolog Treat 2014;25:30-33.

17 Calcipotriene: Vehicle Matters Ointment (8 weeks) 70% marked improvement Skin irritation 10-15% 11% clear Cream 50% marked improvement Skin irritation 10-15% 4% clear Solution 31% marked improvement Skin irritation 1-5% 14% clear Foam 41% clear/almost clear scalp Skin irritation 2% 14-27% clear/almost clear body

18 Genesis of Combination Therapy Rationale: Efficacy While Managing Steroid Risks Combined Treatment Halobetasol QD Calcipotriene QD (n=42) 71%* Halobetasol BID Only (n=43) 57% Calcipotriene BID Only (n=42) 30% Halobetasol Calcipotriene Clear or Almost Clear (% patients) at Day 14 of Treatment 80 * P<0.001 vs calcipotriene. Mean global assessment. Lebwohl M, et al. J Am Acad Dermatol. 1996;35:

19 Calcipotriene/Betamethasoe Dipropionate Ointment: Efficacy Mean Change in PASI Score (%) % -23.4% -33.3% * -39.2% BD/Cal Ointment QD (n=490) Betamethasone dipropionate QD (n=476) Calcipotriene QD (n=480) Vehicle QD (n=157) -22.7% -46.1% -57.2% -71.3% Time (weeks) * *Safety data for 1 year of use *P<0.001 for Combo Ointment vs vehicle, betamethasone dipropionate, and calcipotriene. Kaufmann R, et al. Dermatology. 2002;205: Reprinted with permission from S. Karger AG, Basel

20 Is it possible to enhance penetration with a cosmetically acceptable vehicle? Cal/BD Ointment more efficacious than suspension but less cosmetically elegant Cal/BD Aerosol Foam Formulation explored for enhanced efficacy + enhanced elegance.

21 Calcipotriol + Betamethasone Fixed Combination Foam: Phase III Study (PSO-FAST) 4-week, double-blind, randomized, vehicle-controlled study 426 patients 18 to 87 years of age with mild to severe plaque psoriasis Randomized 3:1 to receive cal/beta foam or vehicle only 1 x day Primary efficacy endpoints at week 4 Clear or almost clear with at least a 2 grade improvement Leonardi C, et al. J Am Acad Dermatol. 2015;72(5):AB232.

22 Adverse Events Cal/BD aerosol foam (n=323) Vehicle (n=103) Total number of AEs Total subjects reporting: AE ADRs SAEs* AE leading to withdrawal from trial AE leading to discontinuation of treatment 51 (15.8%) 10 (3.1%) 2 (0.6%) 0 (0.0%) 1 (0.3%) 12 (11.7%) 2 (1.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) *A total of 2 SAEs were reported by 2 subjects in the Cal BD aerosol foam group; 1 event of substance induced psychotic disorder, severe, and 1 event of bipolar disorder, severe. Both were characterized as unrelated to study drug. 22 Cal BD aerosol foam prescribing information. J Drugs Dermatol. Dec 2015 (ahead of print)

23 Efficacy of the fixed combination C/BP in an aerosol foam VS ointment in patients with psoriasis vulgaris Methods A multicenter, prospective, randomized trial 2-30% BSA IGA > mild 376 patients were randomized in 3:1:3:1 ratio to receive once-daily treatment for 4 weeks Cal B/D aerosl foam Cal B/D vehicle Calcipotriene plus BDP ointment Ointment vehicle Investigator-only blinded Full double-blinding was not possible because of the difference in formulation Koo J J Dermatolog Treat Oct 7:1-8. [Epub ahead of print]

24 Phase 2 MUSE Trial: Safety 35 patients with extensive psoriasis body and with total BSA of 30% (range: 15%- 30%) with Cal BD qd X 4 weeks Average aerosol foam = 62 g/wk; approximately twice the average exposure from typical Cal BD trials None showed adrenal suppression, as indicated by a 30-minute post-stimulation cortisol level 18 mcg/dl at day 28 There was no evidence of an effect of Cal BD aerosol foam on calcium metabolism, based on evaluation of serum and 24-hour urinary calcium parameters Cal BD aerosol foam was safe and well tolerated No SAEs, discontinuation of investigational product due to AEs, or other significant AEs were reported in this trial Taraska et al. J Cutan Med Surg Jul 29. pii: [Epub ahead of print]..

25 Tazarotene Available in 0.1% and 0.05% cream and gel Topical retinoid, Pregnancy Category X Side effects occurring in 10 to 30% of patients: pruritus, burning/stinging, erythema, worsening of psoriasis, irritation, and skin pain Combination with topical CS improves efficacy while minimizing SE s

26 Topical Tazarotene Gel in Combination With Topical Steroids Treatment Success Patients (%) * * * * * * Taz / Placebo Taz / Low Taz / Mid Taz / High Posttreatment Period Week Lebwohl, JAAD:1998 Oct;39(4 Pt 1): *P < 0.05 vs tazarotene 0.1% gel plus placebo cream

27 A Phase 3, Multicenter, Double-Blind, Randomized, Vehicle Controlled Clinical Study to Assess the Safety and Efficacy of IDP-118 in the Treatment of Plaque Psoriasis IDP-118 Lotion-halobetasol propionate 0.01%, tazarotene 0.045% Vehicle lotion Age 18 and over with moderate-severe plaque psoriasis Clinicaltrials.gov

28 A Dose-Finding Study of GSK Cream in Subjects With Plaque Psoriasis Phase 2 JAK 1 inhibitor Multicenter (United States, Canada, and Japan) Evaluate the efficacy and safety of two concentrations (0.5 % and 1%) and two application frequencies (qd and BID) Randomized, double-blind, vehicle-controlled, 6-arm, parallelgroup, dose-finding study. Plaque psoriasis (except on the scalp) for 12 weeks. 270 adult with 30 subjects in Japan Clinicaltrials.gov

29 In phase II trials: Novel Molecules in the Pipeline PDE4 inhibitor ointment Integrin inhibitor cream Jak1/Jak 3 inhibitor (tofacitinib) ointment Jak1/Jak 2 inhibitor (ruxolitinib) cream Tyrosine kinase inhibitor cream & ointment Dihydrofolate reductase inhibitor (methotrexate) proprietary vehicle Feely MA, et al. Cutis. 2015;95: , 170.

30 Conclusion Cutaneous atrophy occurs commonly but is generally reversible Vitamin D is an important addition to topical steroid treatment Complimentary efficacy targets Counteracts steroid side effects Tazarotene still hold an important place in psoriasis topical therapy There is an active future in new molecules for topical therapy