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Medical therapeutics: 2013 update!

Pacific Dermatologic Association !65th annual meeting 2013!

Kanade Shinkai, MD PhD Assistant Professor of Clinical Dermatology

University of California, San Francisco!

Disclosure of relationships with industry!

I have no conflicts of interest to disclose.!

I will be discussing off-label use of medications during this lecture.!

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Learning objectives!

• Recognize new strategies for treating common diseases that we see in the clinic!

• Describe new therapeutics that are available or coming soon to your clinical practice!

What’s new in 2013!

Rosacea Urticaria Psoriasis

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What’s new in 2013!

Urticaria

Maurer M et al (2013) NEJM, 368:924-935

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A new treatment for chronic urticaria!

• Chronic urticaria often fails treatment!!- antihistamine stacking (3-4x over licensed doses)!!- many other treatments are not FDA-approved!

• Omalizumab -> anti-IgE monoclonal antibody!

• Is currently approved as add-on therapy for moderate-to-!!severe allergic asthma!

• Good safety profile!

Maurer M et al (2013) NEJM, 368:924-935

How does it work?!

• Chronic urticaria: !blood basopenia!! ! ! !recruitment of basophils to tissues!! ! ! !suppression of high-affinity IgE-R (FcεRI)!

• Omalizumab downregulates mast cell/ basophil FcεRI!!- reduce free IgE!!- reduces mast cell/ basophil degranulation!! ! ! !!

Maurer M et al (2013) NEJM, 368:924-935 Vonakis & Saini (2008) Curr Opin Immun, 20:709-716

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What’s the evidence?!• Phase 3 clinical trial !• Study funded by Genentech and Novartis Pharma!

• 323 patients !!- symptomatic despite H1 antihistamine use!!- randomized to 3 weekly subcutaneous injections of!! !- placebo!! !- 75, 150, or 300 mg!!- 12 week end point followed by 16 week observation!!- continue antihistamine (x2) + diphenhydramine rescue!

Maurer M et al (2013) NEJM, 368:924-935

What’s the evidence?!• Therapeutic effect @ 1 week!

• Omalizumab @ 150mg, 300mg effective versus placebo!!- itch severity score (primary outcome)!!- reduced weekly # of hives!!- combined score @ 6 weeks (placebo 19% v. 66% 300mg)!!- improved Dermatology QOL scores!

• No difference in angioedema-free days!

• Almost no serious adverse events, no deaths!

Maurer M et al (2013) NEJM, 368:924-935

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Important considerations!• Highest dose (300mg) works best but!!- clear: !10% placebo!! ! !18% pts on 75 mg!! ! !23% pts on 150 mg!! ! !53% pts on 300 mg!!- partial improvement of symptoms and signs!

• Not clear who the best candidates are!

• The bottom line: !continue antihistamine stacking!! ! ! !consider omalizumab for worst cases !

What’s new in 2013!

Rosacea

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2 new treatments for rosacea!

• Treating erythema with !

• Targeting GI flora !

Treating erythema with brimonidine 0.5% gel !

• No approved medications for erythema 2/2 rosacea!

• What we tell patients: !avoid triggers!! ! ! ! !consider laser!

• Brimonidine !!- highly-selective α2-adrenergic agonist!!- vasoconstrictive!!- known efficacy and safety profile in glaucoma!

Fowler J et al (2011) BJD, 166:633-641!

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What’s the evidence?!

• 2 Galderma-funded studies!• 391 total patients: !!- brimonidine 0.5%, 0.18%, 0.07% or placebo!!- clinician-rated, patient-rated, meter-rated erythema!!- also looked at inflammatory lesions!

• Key findings:!!- reduces erythema for 12 hours (dose-dependent)!!- 2 grade improvement in clinical ratings also found by meter-rating!

Fowler J et al (2011) BJD, 166:633-641!

Fowler J et al (2011) BJD, 166:633-641!

No treatment! 30 minutes! 3 hours! 10 hours!

Single-application of brimonidine 0.5% gel!

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Important considerations!

• Reduced erythema at 30 minutes, max at 4-6 hours!

• Well-tolerated!

• No tachyphylaxis (8 weeks study) or disease worsening!

• Head to head trials versus vascular laser not done yet!

• Several cases of mild, transient, decrease in IOP!

• Limited long-term efficacy and safety profiles!

Targeting GI flora in rosacea!

Parodi et al (2008) Clin Gastroent Hep, 6: 759-764!Steinhoff et al (2011) JID Symp Proc, 15:2-11!

Westal FC (2006) J Clin Microbiol, 44:2099-2104!

• 2008 reports 46% patients with rosacea have small intestinal bacterial overgrowth (SIBO) versus 5% controls!

• SIBO -> !increase TNFα ! ! !suppress IL-17!! ! !increase Th1!

• Gut bacteria -> molecular mimicry that leads to extraintestinal disease?!

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Rifaximin for rosacea!

• 2 studies of rifaximin for rosacea!!- most cases confirmed by dermatologist!!- mixed clinical subtypes of rosacea!!- lactulose +/- glucose breath test as surrogate for SIBO!!- 10 day course of rifaximin (400mg TID)!

• Study 1: 78% of patients with SIBO were clear!

• Study 2: 46% clear, mild (11%) or moderate (25%) improvement!

Parodi et al (2008) Clin Gastroent Hep, 6: 759-764 Weinstock & Steinhoff (2013) JAAD, 68:875-876!

Parodi et al (2008) Clin Gastroent Hep, 6: 759-764!

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Important considerations!

• What about recurrence? !!- Study 1: 96% remained clear up to 9 months!!- 2 cases of recurrence of both rosacea and SIBO!

• Study 2: 18% of patients did not improve!

• Jejunal aspirate is the gold standard for SIBO!

• The bottom line: Very promising but we still need double-blind study with greater # of patients!

Parodi et al (2008) Clin Gastroent Hep, 6: 759-764 Weinstock & Steinhoff (2013) JAAD, 68:875-876!

What’s new in 2013!

Psoriasis

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2 new treatments for psoriasis!

• A new topical treatment!

• A brief update and note on IL-17 antagonists!

A new topical treatment for psoriasis!

• Tofacitinib: Janus kinase inhibitor!!- small molecule inhibitor!!- oral agent!!- indications: RA (Xeljanz)!!- under development for psoriasis, transplantation, IBD!!- trial as topical ointment for plaque psoriasis !

Ports WC et al (2013) BJD 169:137-145!

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How does it work?!

• Inhibits Jak kinases:!!- tyrosine kinase!!- involved in signalling of !! !IL-2, IL-6, IL-12, IL21, IL-23, EPO!!- utilized by almost all immune cells!! ! ! !!

Ports WC et al (2013) BJD 169:137-145!

What’s the evidence?!

• Pfizer-funded investigation!• Multi-center, double-blind trial!• 71 patients!• 4 weeks!• Statistically-significant improvement from baseline (54%)!• Efficacy as early as week 1 with ongoing improvement!• 2nd endpoints: itch severity, plaque size also improved!

• Side effects: well-tolerated, very rare/ mild side effects!• Minimal systemic absorption!

Ports WC et al (2013) BJD 169:137-145!

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Ports WC et al (2013) BJD , 169:137-145!

Tofacitinib!ointment!

vehicle!

Baseline! Week 4!

Leg lesion!

Important considerations!

• The bottom line: Data is not amazing but it does offer a new topical approach to psoraisis!

• Systemic form can result in neutropenia (none in topical)!

• Systemic form in RA: tofacitinib is superior to adalimumab in head to head trial!

• May not be long before we see more use of this systemic form for psoriasis!

Ports WC et al (2013) BJD 169:137-145!Kyttaris V (2012) Drug Des Dev Ther 6:245-250!

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Targeting IL-17 pathway in psoriasis!

• 2 new monoclonal antibodies that target IL-17:!!- secukinumab!!- ixekizumab!

• 1 new monoclonal antibody that targets IL-17 RA!!- brodalumab (human)!

Leonardi C et al (2012) NEJM 366:1190-1199!Papp KA et al (2012) NEJM 366:1181-1189!

Rich P et al (2012) BJD 168:402-411

Important considerations!

• Data are relatively comparable between treatments!

• Safety profile is excellent!

• Safety issue: IL-17 role in neutrophil homeostasis?!

• Targeting IL-17 pathway may provide an important advantage of selective immunosuppression!! !- TNFa and IL-23: more central immune roles!! !- less side effects!

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Conclusions!

• Very promising treatments are here, and on the horizon!

Q&A!