Topical Therapies for Psoriasis - American Academy of ... S008... · Topical Therapies for...
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Topical Therapies for Psoriasis
Linda Stein Gold, MDHenry Ford Hospital
Detroit, MI
DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY
Anacor Bayer Eli Lilly Foamix Galderma LEO Medimetrix Novartis Pfizer Taro
What do Psoriasis Endpoints Mean?
Body surface area (BSA)
National Psoriasis Foundation psoriasis.org; Accessed Oct 21, 2015.
Investigators Global Assessment
IGA has no correlation to amount of disease, only the severity of the individual plaques
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, 826-850
Strength of Recommendations
J Am Acad Dermatol 2009;60:643-59
Menter A, J Am Acad Dermatol 2009;60:643-59
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
Topical Steroids: PotencyClass Selected Preparations
IUltra-High Potency
• 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
IIHigh Potency
• 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
IIIMid-Potency
• Fluticasone propionate 0.005% ointment• Halcinonide 0.1% ointment• Betamethasone dipropionate emollient spray, 0.05%
IV • Mometasone furoate 0.1% cream• Triamcinolone acetonide 0.1% cream, ointment
V • Fluocinolone acetonide 0.025% cream, ointment• Hydrocortisone valerate 0.2% ointment
VILow 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
aVasoconstriction assay.Boguniewicz M. Immunol Allergy Clin North Am. 2004;24(4):631-644. Leung DY et al. Ann Allergy Asthma Immunol. 2004;93(3 suppl 2):S1-21. Merck & Co. Inc. http://www.merck.com/media/mmpe/pdf/Table_110-1.pdf. Accessed December 10, 2007. Vanos™ (fluocinonide cream 0.1%) prescribing information. http://www.medicis.com/products/pi/pi_vanos.pdf. Accessed November 20, 2007. Betamethasone dipropionate gel (Augmented*), 0.05% prescribing information. http://www.taro.com/media/oMedia/1123_6_1416.pdf. Accessed March 19, 2008.
‒Vasoconstriction test correlates with clinical psoriasis activity and is thus a relevant measure of topical corticosteroid potency
Topical Steroids: PotencyClass Selected Preparations
IUltra-High Potency
• 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
IIHigh Potency
• 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
IIIMid-Potency
• Fluticasone propionate 0.005% ointment• Halcinonide 0.1% ointment• Betamethasone dipropionate emollient spray, 0.05%
IV • Mometasone furoate 0.1% cream• Triamcinolone acetonide 0.1% cream, ointment
V • Fluocinolone acetonide 0.025% cream, ointment• Hydrocortisone valerate 0.2% ointment
VILow 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
aVasoconstriction assay.Boguniewicz M. Immunol Allergy Clin North Am. 2004;24(4):631-644. Leung DY et al. Ann Allergy Asthma Immunol. 2004;93(3 suppl 2):S1-21. Merck & Co. Inc. http://www.merck.com/media/mmpe/pdf/Table_110-1.pdf. Accessed December 10, 2007. Vanos™ (fluocinonide cream 0.1%) prescribing information. http://www.medicis.com/products/pi/pi_vanos.pdf. Accessed November 20, 2007. Betamethasone dipropionate gel (Augmented*), 0.05% prescribing information. http://www.taro.com/media/oMedia/1123_6_1416.pdf. Accessed March 19, 2008.
‒Vasoconstriction test correlates with clinical psoriasis activity and is thus a relevant measure of topical corticosteroid potency
Topical Steroids: PotencyClass Selected Preparations
IUltra-High Potency
• 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
IIHigh Potency
• 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
IIIMid-Potency
• Fluticasone propionate 0.005% ointment• Halcinonide 0.1% ointment• Betamethasone dipropionate emollient spray, 0.05%
IV • Mometasone furoate 0.1% cream• Triamcinolone acetonide 0.1% cream, ointment
V • Fluocinolone acetonide 0.025% cream, ointment• Hydrocortisone valerate 0.2% ointment
VILow 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
aVasoconstriction assay.Boguniewicz M. Immunol Allergy Clin North Am. 2004;24(4):631-644. Leung DY et al. Ann Allergy Asthma Immunol. 2004;93(3 suppl 2):S1-21. Merck & Co. Inc. http://www.merck.com/media/mmpe/pdf/Table_110-1.pdf. Accessed December 10, 2007. Vanos™ (fluocinonide cream 0.1%) prescribing information. http://www.medicis.com/products/pi/pi_vanos.pdf. Accessed November 20, 2007. Betamethasone dipropionate gel (Augmented*), 0.05% prescribing information. http://www.taro.com/media/oMedia/1123_6_1416.pdf. Accessed March 19, 2008.
‒Vasoconstriction test correlates with clinical psoriasis activity and is thus a relevant measure of topical corticosteroid potency
Optimized penetration of Betamethasone dipropionate emollient spray, 0.05% more efficacious than augmented BD
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Day 4 Day 8 Day 15 Day 29
% S
ubje
cts
achi
evin
g IG
A 0
or 1
and
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e re
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DFD-01, n=356 AugBD, n=90 Vehicle, n=182
11Treatment success was defined as an IGA=0 or 1 and ≥2 grade reduction from baseline
IGA Results p<0.001
p<0.001
p=0.010
Stein Gold, Winter Clinical poster 2016
SIDE EFFECTS OF TOPICAL CORTICOSTEROIDS: WHAT ARE THE FACTS?
Epidermal Atrophy
Josse G, Skin Res Technol. 2009
13 healthy women. Clobetasol Propionate BID X 28 days. Optical coherence tomography. Dashed line: reference zone.
Histology showed 22% epidermal thinning after 28 days.
Dermal AtrophyTreatment with Clobetasol Propionate BID X 28 days. Demal thickness measured by ultrasound. Dashed line: reference zone.
Josse G, Skin Res Technol. 2009
12% average decrease at day 28. Thickness increased with D/C of treatment
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 2001Lavker RM JAAD 1992H. Norsgaard1, P. Descargues5, S. Kurdykowski et al, poster EADV, 2012
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.
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
Genesis of Combination Therapy
*P<0.001 vs calcipotriene.†Mean global assessment.Lebwohl M, et al. J Am Acad Dermatol. 1996;35:268-269.
30%
57%
71%*
0 10 20 30 40 50 60 70
Calcipotriene BID Only (n=42)
Halobetasol BID Only (n=43)
Combined TreatmentHalobetasol QD
Calcipotriene QD (n=42)
Clear or Almost Clear (% patients)†
at Day 14 of Treatment
Halobetasol
Calcipotriene
80
Rationale: Efficacy While Managing Steroid Risks
‐80
‐70
‐60
‐50
‐40
‐30
‐20
‐10
0
0 1 2 3 4
*P<0.001 for Combo Ointment vs vehicle, betamethasone dipropionate, and calcipotriene.
Mea
n C
hang
e in
PA
SI S
core
(%)
Vehicle QD (n=157)Calcipotriene QD (n=480)
BD/Cal Ointment QD (n=490)Betamethasone dipropionate QD (n=476)
*
*
-18.1%-23.4%
-33.3%
-39.2%
-22.7%
-46.1%
-57.2%
-71.3%
Time (weeks)
Kaufmann R, et al. Dermatology. 2002;205:389-393. Reprinted with permission from S. Karger AG, Basel
Calcipotriene/Betamethasoe Dipropionate Ointment: Efficacy
*Safety data for 1 year of use
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.
Calcipotriol + Betamethasone FixedCombination Foam: Phase III Study (PSO-FAST)
Leonardi C, et al. J Am Acad Dermatol. 2015;72(5):AB232.
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 4Clear or almost clear with at least a 2 grade improvement
Adverse Events
Cal/BD aerosol foam
(n=323)Vehicle
(n=103)
Total number of AEs 64 15
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%)
0.290.52
*A total of 2 SAEs were reported by 2 subjects in the Cal BD 90100 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)
Efficacy of the fixed combination C/BP in an aerosol foamVS 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. 2015 Oct 7:1-8. [Epub ahead of print]
35 patients with extensive psoriasis body and with total BSA of 30% (range: 15%-30%) with Cal BD 90100 qD X 4 weeks
Average 90100 aerosol foam = 62 g/wk; approximately twice the average exposure from typical Cal BD 90100 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 90100 on calcium metabolism, based on evaluation of serum and 24-hour urinary calcium parameters
Cal BD aerosol foam 90100 was safe and well tolerated – No SAEs, discontinuation of investigational product due to AEs, or other significant AEs
were reported in this trial
Phase 2 MUSE Trial: Safety
Taraska et al. J Cutan Med Surg. 2015 Jul 29. pii: 1203475415597094. [Epub ahead of print]..
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
Treatment Success
Topical Tazarotene Gel in Combination With Topical Steroids
*P < 0.05 vs tazarotene 0.1% gel plus placebo cream
Patients (%)
0
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0 2 4 8 12 16
PosttreatmentPeriod
**
**
*
*
Taz / PlaceboTaz / LowTaz / MidTaz / High
WeekLebwohl, JAAD:1998 Oct;39(4 Pt 1):590-6.
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
A Dose-Finding Study of GSK2894512 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, parallel-
group, dose-finding study. Plaque psoriasis (except on the scalp) for 12 weeks.
270 adult with 30 subjects in Japan Clinicaltrials.gov
Novel Molecules in the Pipeline
In phase II trials: 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;95:164‐168, 170.
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