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

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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

10

20

30

40

50

60

70

80

90

100

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