DERMATOLOGICAL DRUGS UPDATE 2018 Fall Dermatology Update 2018 Montreal, Quebec Thursday, November 15th 2018

Charles W. Lynde, MD, FRCPC Diplomate American Boards, Dermatology Associate Professor, Department of Medicine, University of Toronto CONFLICTS OF INTEREST

3M Glaxo Smith Kline Abbott H3 Pharmaceuticals AbbVie Innovaderm Akros Janssen Allergan L’Oreal Amgen Leo Pharma Astellas Merck Aralez Novartis Basilea Ortho Biotech Bausch Health Pediapharm Boehringer Ingelheim Pfizer Celgene Roche Cipher Sanofi Aventis Eli Lilly Stiefel EMD Serono Sunpharma Galderma TEVA Glaxo Smith Kline Tribute H3 Pharmaceuticals UCB Pharmaceuticals Innovaderm Valeant Janssen Westwood Squibb Wyeth OBJECTIVES

1.To be familiar with the key dermatological therapeutics of 2018 and what’s in the pipeline 2.To translate this information into changing dermatologic clinical practice

IS IT THE RENAISSANCE?

The Mona Lisa IS IT THE AGE OF ENLIGHTENMENT?S DERMATOLOGY

Weimar’s Courtyard of the Muses, a tribute to The Enlightenment and the Weimar Classicism depicting German poets Schiller, Wieland, Herder and Goethe IS IT THE AGE OF THE INDUSTRIAL REVOLUTION?

Industrial Revolution WHATEVER AGE IT IS IN 2018 DERMATOLOGY IS IMMUNOLOGY ….

IMMUNOLOGY IS DERMATOLOGY ? – WE ARE MAKING GREAT STRIDES IN OUR TREATMENT OF SKIN DISEASES…

IS IT THE AGE OF DERMATOIMMUNOLOGY

THE FIRE IS ON…. AND IT’S GETTING HOTTER AS OF NOVEMBER 8TH 2018 THERE WERE 745 TRIALS LISTED UNDER ON CLINICALTRIALS.GOV

“Search of: Unknown Status Studies | Atopic+Dermatitis - List Results.” Search of: Unknown Status Studies | Atopic+Dermatitis - List Results - ClinicalTrials.gov, clinicaltrials.gov/ct2/results?cond=atopic%2Bdermatitis&Search=Apply&recrs=m&age_v=&gndr=&type=&rslt=. TARGET IL-4/IL-13 PATHWAY

IL-4/IL-13 signaling is needed for Th2 responses

Modified from: Simpson EL, Bieber T, Guttman-Yassky E, et al. (2016). Poster EADV Vienna Seegraber M, Smour J, Walter A., Knop M., Woldenberg, A. (2018). Expert Rev Clin Pharmacol 11: 457-474 DUPILUMAB (REGENERON/SANOFI/GENZYME)

 Indication: moderate-to-severe AD  Safety, Pharmacokinetics and Efficacy of Dupilumab in Patients ≥6 Months to <6 Years With Severe Atopic Dermatitis (Liberty AD PRESCHOOL) – recruiting  Phase 2/3  MoA: IL-4, IL-13 inhibitor  Other indications being investigated: allergic rhinitis, , eosinophilic esophagitis, nasal polyps, food allergy  US Launch: March 2017  Canadian Launch: December 2017

Safety, Pharmacokinetics and Efficacy of Dupilumab in Patients ≥6 Months to <6 Years With Severe Atopic Dermatitis (Liberty AD PRESCHOOL). (2018). Retrieved from https://clinicaltrials.gov/ct2/show/NCT03346434?term=Safety%2C+Pharmacokinetics+and+Efficacy+of+Dupilumab+in+Patients+%E2%89%A56+Months+to+%3C6+Years+With+Severe+Atopic+Dermatitis+%28Liberty+ AD+PRESCHOOL%29&rank=1 (NCT03346434) TRALOKINUMAB (LEO)

 Tralokinumab in Combination With Topical Corticosteroids for Moderate to Severe Atopic Dermatitis - ECZTRA 3 (ECZemaTRAlokinumabTrial no. 3) – recruiting  Phase 3  Indication: moderate-to-severe AD  MoA: IL-13 inhibitor  Expected launch: ?2020 (US)  Other indications being investigated: Asthma, AA, UC

Tralokinumab in Combination With Topical Corticosteroids for Moderate to Severe Atopic Dermatitis - ECZTRA 3 (ECZema TRAlokinumab Trial no. 3). (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03363854?term=Tralokinumab+in+Combination+With+Topical+Corticosteroids+for+Moderate+to+Severe+Atopic+Dermatitis+- +ECZTRA+3+%28ECZema+TRAlokinumab+Trial+no.+3%29&rank=1 (NCT03363854) GBR 830 (GLENMARK)

 Phase 2b Study to Evaluate the Efficacy and Safety of GBR 830 in Adults With Moderate to Severe Atopic Dermatitis - recruiting  Phase 2b  Indication: moderate-to-severe AD  MoA: GBR 830 is a humanized, immunoglobulin G1 (IgG1) antibody specific for OX40 (CD134)  Subcutaneous Injection (biologic)  Expected launch: ?  Other indications being investigated: n/a

Phase 2b Study to Evaluate the Efficacy and Safety of GBR 830 in Adults With Moderate to Severe Atopic Dermatitis. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03568162?term=Phase+2b+Study+to+Evaluate+the+Efficacy+and+Safety+of+GBR+830+in+Adults+With+Moderate+to+Sev ere+Atopic+Dermatitis&rank=1(NCT03568162) NEMOLIZUMAB (CHUGAI/GALDERMA)  Indication: moderate-to-severe AD  Status: Phase IIb (first patient enrolled on July 25th 2017)  Announced that it made its endpoints  MoA: Anti-IL-31 receptor A  Launch?: Late 2019 or 2020 (US)

“Dose-Ranging Study of Nemolizumab in Atopic Dermatitis - Full Text View.” Full Text View - ClinicalTrials.gov, Galderma R&D, clinicaltrials.gov/ct2/show/NCT03100344?term=Nemolizumab&rank=1. ANB020

 A Study Investigating the Efficacy, Safety, and PK Profile of ANB020 Administered to Adult Subjects With Moderate-to- Severe AD (ATLAS)- recruiting  Phase 2  Indication: moderate-to-severe AD  MoA: IL-33 inhibitor  Other indications being investigated: eosinophilic asthma, peanut allergy, chronic rhinosinusitis

A Study Investigating the Efficacy, Safety, and PK Profile of ANB020 Administered to Adult Subjects With Moderate-to-Severe AD (ATLAS). (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03533751?term=A+Study+Investigating+the+Efficacy%2C+Safety%2C+and+PK+Profile+of+ANB020+Administered+to+Adult+Subjects+With+ Moderate-to-Severe+AD+%28ATLAS%29-&rank=1. (NCT03533751) IL-31 CYTOKINE (THE ITCH CYTOKINE)

Adapted from SIMID Meeting Verona, Italy Fall 2018 ATOPIC DERMATITIS SYSTEMIC TREATMENTS

Adapted from SIMID Meeting Verona, Italy Fall 2018 ORAL JANUSKINASE (JAK INHIBITORS)

 Baricitinib – JAK 1, JAK 2 (under development for AD)  Upadacitinib – JAK 1 (under development for AD)  Tofactinib – JAK 3, JAK 1 (currently used in RA)

 ASN002 – broad JAK/SYK inhibitor (under development for AD)  Pf04965842 – JAK 1 (under development for AD)

Adapted from SIMID Meeting Verona, Italy Fall 2018 UPADACITINIB / ABT-494 (ABBVIE)

 Indication: moderate-to-severe AD  A Study to Evaluate ABT-494 (Upadacitinib) in Adult Subjects With Moderate to Severe Atopic Dermatitis  Status: Phase 3  MoA: JAK1 selective inhibitor  Once daily 30mg oral, quickly decreases pruritis/skin signs (as early as week I)  Other indications being investigated: AS, PsA, RA, Ulcerative Collitis, Crohn’s Disease

“A Study to Evaluate ABT-494 (Upadacitinib) in Adult Subjects With Moderate to Severe Atopic Dermatitis - Full Text View.” Full Text View - ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT02925117?term=Upadacitinib&cond=Atopic%2BDermatitis&rank=1 BARICITINIB / LY3009104 (ELI LILLY)

 Indication: moderate-to-severe AD  A Study of Baricitinib (LY3009104) in Adults With Moderate to Severe Atopic Dermatitis (BREEZE-AD1) – recruiting  A Study of Long-term Baricitinib (LY3009104) Therapy in Atopic Dermatitis (BREEZE- AD3) - recruiting  Status: Phase 3  MoA: JAK1/2 inhibitor  4 mg PO daily  Other indications being investigated: RA, Giant Cell Areritis, Liver Disease, AA

A Study of Baricitinib (LY3009104) in Adults With Moderate to Severe Atopic Dermatitis (BREEZE-AD1). (2018). Retrieved from https://clinicaltrials.gov/ct2/results?cond=&term=A+Study+of%C2%A0Baricitinib%C2%A0%28LY3009104%29+in+Adults+With+Moderate+to+Severe%C2%A0Atopic+Dermatitis%C2%A0% 28BREEZE-AD1%29+&cntry=&state=&city=&dist= (NCT03334396) PF-04965842 (PFIZER)

 Study to Evaluate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-1) - recruiting  Study Evaluating Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-2) – not yet recruiting  Study to Investigate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years and Over With Moderate to Severe Atopic Dermatitis With the Option of Rescue Treatment in Flaring Subjects - recruiting  Indication: moderate-to-severe AD  Status: Phase 3  MoA: JAK1 inhibitor  Other indications being investigated: hepatic impairment, psoriasis

“Search of: PF-04965842 - List Results.” Search of: PF-04965842 - List Results - ClinicalTrials.gov, clinicaltrials.gov/ct2/results?cond=&term=PF-04965842&cntry=&state=&city=&dist=. JAK

….. JACK LYNDE Drs. Lynde are now in the process of renaming all of our grandchildren after dermatology drugs ATOPIC DERMATITIS TOPICALS CRISABOROLE (PFIZER)

 Indications: mild-to-moderate atopic dermatitis  Indications being investigated: children aged 3- 24 months with AD, seborrheic dermatitis, plaque type psoriasis  Standard dosing: twice daily to the affected areas  Issued NoC June 2018 Canada  MoA: PDE4  Available in Canada on November 5th 2018

“EUCRISA™ (CRISABOROLE) NOW AVAILABLE IN CANADA.” Pfizer Canada, 7 Nov. 2018, www.pfizer.ca/eucrisa%E2%84%A2-crisaborole-now-available-canada. https://www.researchgate.net/profile/Emma_Guttman-Yassky/publication/299940027/viewer/AS:353144941891584@1461207723753/background/3.png FUSIDIC ACID/BETAMETHASONE VALERATE CREAM (LEOPHARMA)

 Indication: mild-to-moderate atopic dermatitis secondarily infected  Standard dosing: twice daily  MoA: combo antibiotic and topical steroid  Old drug, available in Europe now in Canada as of Fall 2018 ATI-502 (ACLARIS)

 A Study of ATI-502Topical Solution for the Treatment of Atopic Dermatitis  Indications: moderate or severe atopic dermatitis in adults  Phase: 2  MoA: Topical JAK1/3 inhibitor  Other indications being investigated: AA

A Study of ATI-502 Topical Solution for the Treatment of Atopic Dermatitis. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03585296?term=A+Study+of+ATI- 502+Topical+Solution+for+the+Treatment+of+Atopic+Dermatitis&rank=1. (NCT03585296) RVT-501 TOPICAL OINTMENT (DERMAVANT)

 Current Trials: patients 2-11 y/o with extensive atopic dermatitis  Dosing: RVT-501 0.5% topical ointment twice daily (BID) for 4 weeks.  Phase: 2 – recruiting  Previously studied in adults and adolescents  RVT-501 0.2% vs. RVT-501% vs placebo  MoA: PDE4 inhibitor

Open-Label Study of RVT-501 Topical Ointment in Pediatric Patients With Atopic Dermatitis. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03415282?term=RVT-501&cond=Atopic+Dermatitis&rank=2. (NCT03415282) INCB018424 (RUXOLITINIB) PHOSPHATE CREAM

 Current Trials: An Open-Label, Pilot Pharmacokinetic Study of INCB018424 Phosphate Cream in Pediatric Subjects With Atopic Dermatitis  Population: pediatric patients between 12 to 17 years  Dosing: INCB018424 phosphate cream 0.5%. vs INCB018424 phosphate cream 1.5%.  Phase: 1 (recruiting)  N=20  Previously studied in adults  Phase 2 completed March 2018  A Phase 2, Randomized, Dose-Ranging, Vehicle-Controlled and Triamcinolone 0.1% Cream-Controlled Study to Evaluate the Safety and Efficacy of INCB018424 Phosphate Cream Applied Topically to Adults With Atopic Dermatitis  MoA: selective JAK inhibitor

A Pharmacokinetic Study of INCB018424 Phosphate Cream in Pediatric Subjects With Atopic Dermatitis. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03257644?term=An+Open- Label%2C+Pilot+Pharmacokinetic+Study+of+INCB018424+Phosphate+Cream+in+Pediatric+Subjects+With+Atopic+Dermatitis&rank=1. (NCT03257644) FUSIDIC ACID AND BETAMETHASONE VALERATE CREAM (FUCIBET) LEOPHARMA

 Topical antibiotic/corticosteroid for eczematous dermatoses with secondary bacterial infection caused by S. aureus  Highly effective against S. aureus including methicillin resistant strains  Available in Europe for years, now available in Canada PSORIASIS PSORIASIS PATHOGENESIS 2018 VIEW

Lynde, Charles W., et al. “ 17A: Toward a New Understanding of Psoriasis Pathogenesis.” Journal of the American Academy of Dermatology, vol. 71, no. 1, 2014, pp. 141– 150., doi:10.1016/j.jaad.2013.12.036. IS PASI 100 A REASONABLE TREATMENT GOAL

Psoriasis: increase in drug potential

Before 2004: PASI 50 – clinically meaningful response

PASI 90 PASI 100 PASI 75 Near Complete Significant complete resolution response resolution

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 BIOLOGICS APPROPRIATE TREATMENT: BIOLOGICS

 Etanercept   Certolizumab  (2019)

Used with the permission of Dr. Yves Poulin PASI RESPONSE, SHORT TERM

PASI 75 Week 10, 12 or 16 PASI 90 Week 10, 12 or 16 PASI 100 Week 10, 12 or 16

Etanercept 49% Etanercept 22% Etanercept 11% Infliximab 80% Infliximab 57% Infliximab N/A Adalimumab 73-80% Adalimumab 45-51.3% Adalimumab 20% Certolizumab 80.1% Certolizumab 52.2% Certolizumab 14.4% Ustekinumab 67-76% Ustekinumab 42-50% Ustekinumab 18% Secukinumab 77.1-81.6% Secukinumab 59% Secukinumab 30% Ixekizumab 87-89% Ixekizumab 70% Ixekizumab 40% Brodalumab 86.3% Brodalumab 86.3% Brodalumab 86.3% 86.3-91.2% Guselkumab 70-73.3% Guselkumab 34.1-37.4% Risankizumab 86.8-88.8% Risankizumab 73.2-75.3% Risankizumab 35.9-50.7% Adapted from: Used with permission of Dr. Yves Poulin ETANERCEPT: Leonardi, C et al. N. Engl J Med 2003: 349:2014-22; Papp K et al Br J Dermatol 2005: 152:1304-1312: USTEKINUMAB PHOENIX 1. Leonardi C. Lancet 2008: 371: 1665-74; PHOENIX 2: Papp, K. Lancet 2008;371 :1675-87. SECUKINUMAB: Langley RG et al N Engl Med 2014;371:326-38. IXEKIZUMAB Gordon K et al NEJM 2016;345-356. RISANKIZUMAB: Gordon KB et al. Lancet Aug 2018 IL-17 BLOCKERS SECUKINUMAB

 Indications: PsO, PsA, AS  Standard dosing: 300mg SC at weeks 0, 1, 2, 3, and 4 followed by 300mg every 4 weeks  MoA: human IgG1 that selectively binds IL-17A and inhibits its interaction with the IL-17 receptor  Launch: March 2015

1. Cosentyx Product Monograph 2015 IXEKIZUMAB  Indications: adults with moderate-to-severe plaque psoriasis  Standard dosing: 160mg SC (2 80mg injections) at week 0, followed by 80mg (one injection) at Weeks 2, 4, 6, 8, 10 and 12, then one 80mg every 4 weeks  MoA: IgG4 monoclonal antibody that has the binding affinity of <3pM to IL-17A  Launch: June 2016

1. Ixekizumab Product Monograph 2017 BRODALUMAB

 NEW  Indications: moderate-to-severe PsO  Standard dosing: 210mg SC at weeks 0, 1 and 2 followed by 210mg every 2 weeks  MoA: human monoclonal IgG2 antibody that selectively binds to human IL-17RA and inhibits its interactions with cytokines IL- 17A, IL-17F, IL-17C, IL-17A/F heterodimer and IL-25  Launch: July 2017 (US)  Canadian Launch: March 2018

1. Siliq Product Label 2017 (UCB)

 A Study to Assess the Safety, Tolerability and Efficacy of Bimekizumab in Adult Subjects With Moderate to Severe Chronic Plaque Psoriasis (BE BRIGHT)  Indications: moderate-to-severe PsO  MoA: Dual IL-17A and IL17F inhibitor  Launch: ?  Canadian Launch: ?  Other indications being investigated: AS, PsA, HS, RA

A Study to Assess the Safety, Tolerability and Efficacy of Bimekizumab in Adult Subjects With Moderate to Severe Chronic Plaque Psoriasis (BE BRIGHT). (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03598790?term=A+Study+to+Assess+the+Safety%2C+Tolerability+and+Efficacy+of+Bimekizumab+in+Adult+Subjects+With+Moderate+to+Severe+Chr onic+Plaque+Psoriasis+%28BE+BRIGHT%29&rank=1 (NCT03598790) GUSELKUMAB (JANSSEN)

 Indications: moderate-to-severe PsO  Standard dosing: 100 mg SC at Week 0, Week 4 and every 8 weeks thereafter  MoA: human IgG1λ antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor  Launch: July 2017 (US)  Canadian Launch: November 2017

1. Tremfya Product Label 2017 MOA: USTEKINUMAB VS. GUSELKUMAB

Ustekinumab Guselkumab

A. Blauvelt, et al. EADV 2016. VIE16LAT-0080.

TILDRAKIZUMAB (SUNPHARMA)

 Indication: moderate-to-severe PsO  Status: Phase 3  MoA: IL-23 inhibitor  Launch: available in the US  Status: whether they will launch in Canada is unknown at present

“Efficacy and Safety Study of SUNPG1623 - Full Text View.” Full Text View - ClinicalTrials.gov, Sun Pharma Global FZE, clinicaltrials.gov/ct2/show/NCT02980692?term=Tildrakizumab&cond=psoriasis&rank=4. RISANKIZUMAB (ABBVIE)

 Indications being investigated: PsO, PsA, Crohn’s  MoA: humanized IgG1 monoclonal antibody that selectively inhibits IL- 23 by specifically targeting p19  Launch?: US launch expected 2019  Canadian Launch: second quarter 2019

“A Study Comparing the Safety and Efficacy of Risankizumab to Methotrexate in Subjects With Moderate to Severe Plaque Psoriasis - Full Text View.” Full Text View - ClinicalTrials.gov, AbbVie, clinicaltrials.gov/ct2/show/NCT03219437?term=BI%2B655066&cond=psoriasis&draw=1&rank=10. (ELI LILLY)

 A Study to Evaluate the Efficacy and Safety of Mirikizumab (LY3074828) in Participants With Moderate-to- Severe Plaque Psoriasis (OASIS-1) – recruiting  Indication: Moderate-to-Severe PsO  MoA: IL-23 inhibitor  Other indications being investigated: UC, Crohn’s Disease,

A Study to Evaluate the Efficacy and Safety of Mirikizumab (LY3074828) in Participants With Moderate-to-Severe Plaque Psoriasis (OASIS-1). (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03482011?term=A+Study+to+Evaluate+the+Efficacy+and+Safety+of+Mirikizumab+%28LY3074828%29+in+Participants+With+Moderate-to- Severe+Plaque+Psoriasis+%28OASIS-1%29&rank=. (NCT03482011) (UCB)

 Indication: moderate-to-severe PsO  MoA: TNF± inhibitor  Used in rheumatology for many years, only recently used for dermatology  Other indications: Crohn’s, RA, AS  Advantage: pegolated doesn’t cross the placental barrier and thus can be used in pregnant females

“FDA Approves Cimzia for Plaque Psoriasis.” National Psoriasis Foundation | Locations: Hands, Feet & Nails, National Psoriasis Foundation, www.psoriasis.org/advance/fda-approves-cimzia-for-plaque- psoriasis. BIOSIMILARS: WHAT ARE THEY?

 Copy version of original biologic whose data protection has expired  Not a generic  Not entirely identical  Highly similar reference product re: physiochemical function characteristics/clinical performance  Extrapolation of efficacy and safety data to other indications require scientific justification  Risk management should be include plan for post-licensing surveillance  Only biosimilar available in Canada is Inflectra (infliximab) however, adalimumab biosimilar likely to hit market 2021 SYSTEMICS APREMILAST (OTEZLA)

 Indications: PsO/PsA  Indications being investigated: AD, RA, Acne, , HS, Uveitis, Rosacea, Vitiligo, Prurigo Nodularis, Female Genital Erosive Lichen Planus, Frontal Fibrosing Alopecia, Chronic Itch, AS  Standard dosing: 30mg twice daily (titrated over 6 days from 10mg  30mg)  MoA: small molecule inhibitor of PDE4  Soon to be studied in >5% BSA

1. Otezla Product Monograph 2017 2. ClinicalTrials.gov 3. http://www.otezla.se/plaque-psoriasis/novel-moa/ TOPICALS CALCIPOTRIENE AND BETAMETHASONE DIPROPIONATE FOAM, 0.005%/0.064% (LEO)

 Calcipotriol and betamethasone dipropionate aerosol foam  Applied to the affected area once daily for 4 weeks Enhanced drug delivery and penetration vs Dovobet® ointment  Superior efficacy compared to calcipotriol and betamethasone dipropionate alone & and calcipotriol + betamethasone dipropionate combination products (Dovobet gel and ointment)  Fast and effective itch relief  Safety and tolerability consistent with other fixed combination products. No clinically relevant impact on HPA axis and calcium homeostasis.

Enstilar Product Monograph, 08 Sep 2016, LEO Pharma Inc 1. Hollesen Basse, et al. J Invest Dermatol 2014;134:abst 192; 2. Queille-Roussel et al. Poster #915; AAD 2015, San Francisco, CA, USA; 3. Lebwohl et al. J Clin Aesthet Dermatol. 2016 Feb; 9(2): 34–41. 4. Koo et al. J Dermatol Treat 2015;1-8; 5. Queille-Roussel et al. Clin Drug Investig. 2015;35:239–245; 6. Paul et al. JEADV 2016 Aug 17; 7. Leonardi et al. J Drugs Dermatol 2015;14:1468–1477; 8. Taraska V, et al. J Cutan Med Surg. 2016;20(1):44-51. HALOBETASOL PROPIONATE AND TAZAROTENE (BAUSCH HEALTH)

 consistently more effective than vehicle in achieving treatment success demonstrating statistically significant superiority by week four (in Study 1) and week two (in Study 2)  At week eight, 35.8 percent (Study 1) and 45.3 percent (Study 2) had achieved the primary efficacy outcome, compared to 7.0 percent and 12.5 percent on vehicle (both p<0.001)  The majority of patients maintained treatment success over the four-week post treatment period.  Likely to be available in Canada in late 2018?

Valeant Pharmaceuticals International, Inc. “FDA Issues Complete Response Letter For DUOBRII™ (Halobetasol Propionate and Tazarotene) Lotion.” PR Newswire: News Distribution, Targeting and Monitoring, 18 June 2018, www.prnewswire.com/news-releases/fda-issues-complete-response-letter-for-duobrii-halobetasol-propionate-and-tazarotene-lotion-300667565.html. ALOPECIA AREATA Adapted from SIMID Meeting Verona, Italy Fall 2018 JANUS-KINASE (JAK) INHIBITORS (ORAL)

 Responses  30-50% of patients had at least 50% hair regrowth  Relapses during treatment  Tofacitinib: 12.3% of the 90 patients had a relapse during treatment  Relapses after drug withdrawal  Loss of hair within 3 months (leading to regression to SALT score = or > than before therapy)  Maintenance therapy may be required to sustain remission

Adapted from SIMID Meeting Verona, Italy Fall 2018 JANUS-KINASE (JAK) INHIBITORS (TOPICAL)

 Ruxolitnib 0.6% cream twice daily: 1 case hair growth after 12 weeks  Tofactinib 1% and ruxolitnib 2% in liposomal base or cream: 6 children some regrowth in 4 cases  Ruxolitnib 1% ointment vs. Tofactinib vs. clobetasol priopionate vs ointment (placebo): eyebrows/parietal areas for 12 weeks JANUS-KINASE (JAK) INHIBITORS

 Tofactinib: reduces hemoglobin levels, red blood cells, neutrophil and eosinophil counts in a dose dependent manner  Ruxolitinib: disseminated molluscum contagiosum reactivation of herpes simplex virus

Adapted from SIMID Meeting Verona, Italy Fall 2018 Shreberk-Hassidim R et al. J Am Acad Dermatol. 2017; 76: 745-753 Adapted from SIMID Meeting Verona, Italy Fall 2018 HIDRADENITIS SUPPURATIVA Adapted from SIMID Meeting Verona, Italy Fall 2018 INCB54707-203 (RUXOLITINIB)

 A Placebo-Controlled Study of the Safety of INCB054707 in Participants With Hidradenitis Suppurativa – recruiting  Immediate release (IR) tablets in 3mg and 5 mg  Indication: HS  MoA: Oral JAK inhibitor

A Placebo-Controlled Study of the Safety of INCB054707 in Participants With Hidradenitis Suppurativa. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03607487?term=A+Placebo- Controlled+Study+of+the+Safety+of+INCB054707+in+Participants+With+Hidradenitis+Suppurativa&rank=1. (NCT03607487) VACCINES SHINGRIX VACCINE (GSK) FOR PREVENTION OF HERPES ZOSTER SHINGRIX VACCINE (GSK VACCINE) FOR PREVENTION OF HERPES ZOSTER

Dosing: 0 and then 2-6 months later (ie. 2 injections) IMPETIGO 72

OZENOXACIN (CIPHER) Ozenoxacin prevents DNA replication and causes cell death1. Basal function Basal function with Ozenoxacin (without Ozenoxacin) DNA-gyrase Topoisomerasa IV DNA-gyrase Topoisomerase IV A A A A

Separation Relaxation Topoisomerase of replicated DNA-gyrase of DNA IV cannot chains cannot uncoil supercoiling DNA separate replicated chains

Inhibition of DNA replication and cell death: BACTERICIDAL EFFECT

1. Yamakawa T, Mitsuyama J, Hayashi K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolona. J Antimicrob Chemother 2002;49:455-465. 2. Drlica K. Mechanism of fluoroquinolone action. Curr Opin Microbiol 1999;2(5):504-8. OZENOXACIN 1% (CIPHER)

 Ozenoxacin is an antibiotic that is effective against S. aureus and S. pyogenes  Indications: one application twice daily for 5 days  Presentation: 10g tube of cream for topical application  Indication: treatment of impetigo in adults and children 2 months and older

1. Cipher Pharmaceuticals Inc. OzanexTM Product Monograph. May 11, 2017. CHRONIC URTICARIA URTICARIA: PATHOGENESIS

Mast cells are the key effector cells in the induction of urticaria symptoms

IL-1, IL-2, Activation PRURITUS IgE Fc ε RI SCF Kit IL-3, IL-4, IL-5, IL-6, IgG Fcγ R LPS TLRs IL-8, IL-10, Complement CR1/2, CR3 IL-13, TNF, C Anaphylatoxins C3aR, C5aR MIPs, IFN-γ, Neuropeptides NK1 GM-CSF, Vasodilation ERYTHEMA β A Endothelin-1 ETA /ETB TGF- , Bacteria CD48 bFGF, IL-3,4,15R VPF/VEGF, U Chemokines CCR3 MC PGD , LTB , 2 4 Oxytocine OTRs LTC4, PAF, Extravasation Leukotriene CysLT1R histamine, S POMCs MC-1/MC5 serotonin, WHEAL Prostaglandins EP 1/EP3 heparin, E Cannabinoids CB1/CB2 chondroitin- Adenosine A2b/A3 sulfate, Urokinase uPAR chymase, Capsaicin VR tryptase, CPA ? PIR A/PIR B Recruitment INFILTRATE

Courtesy of Prof. Marcus Maurer. BILASTINE (ARALEZ/TRIBUTE)

 Indication: CSU > 18 years of age  Other indications: seasonal allergic rhinitis (>12 years)  MoA: principal effects are mediated via selective inhibition of peripheral H1 receptors  Dosing: 20 mg tablet qd for oral administration

Blexten Product Monograph 2017 RUPTATADINE (PEDIAPHARM)

 Indication: CSU (>2 years of age)  Other indications: seasonal allergic rhinitis (>2 years)  MoA: second-generation antihistamine, long-acting histamine antagonist with selective peripheral H1-receptor and platelet activating factor (PAF) antagonistic activities  Dosing: 10 mg tablet qd for oral administration

Rupall Product Monograph 2017

 MoA: Humanized monoclonal IgG anibody against IgE  Dosing: 150mg or 300mg administered SC every 4 weeks

Xolair Product Monograph 2017 FENEBRUTINIB (NOVARTIS)

 A Study to Evaluate the Long-term Safety and Efficacy of Fenebrutinib in Participants Previously Enrolled in a Fenebrutinib Chronic Spontaneous Urticaria (CSU) Study – not yet recruiting  Intervention: 200mg BID  Phase: 2  MoA: BTK inhibitor

A Study to Evaluate the Long-term Safety and Efficacy of Fenebrutinib in Participants Previously Enrolled in a Fenebrutinib Chronic Spontaneous Urticaria (CSU) Study. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03693625?cond=A+Study+to+Evaluate+the+Long- term+Safety+and+Efficacy+of+Fenebrutinib+in+Participants+Previously+Enrolled+in+a+Fenebrutinib+Chronic+Spontaneous+Urticaria+%28CSU%29+Study&rank=1. (NCT03693625) PEMPHIGUS VULGARIS Adapted from SIMID Meeting Verona, Italy Fall 2018 RITUXIMAB

 Anti-CD20 monoclonal antibody  Intravenous rituximab 2x 1000 mg (2 weeks apart) or 4x 375 m2/1 week apart  Treatment can be repeated with 500 mg rituximab in case of clinical relapse or as early as 6 months after treatment  Rituximab can be combined with short term (<4mo) systemic corticosteroids and long term (>12 mon) immunosuppressive treatment  Unforeseen fatal infections such as progressive multifocal leukencephalopathy (PML) cannot be estimated due to the rarity of pemphigus

Adapted from SIMID Meeting Verona, Italy Fall 2018 RITUXUMAB

 A Study to Evaluate the Efficacy and Safety of RituximabVersus Mycophenolate Mofetil (MMF) in Participants With PemphigusVulgaris (PV) – active, not recruiting  Status: Phase 3  The study will consist of three periods:  a screening period of up to 28 days  a 52-week double-blind treatment period  48-week safety follow up period that begins at the time of study treatment completion or discontinuation..  Approved in the US  Available in Canada with special authorization

https://clinicaltrials.gov/ct2/show/NCT02383589?term=rituximab&cond=pemphigus&rank=5 PRN1008 (BIOPHARMA)

 A Study of PRN1008 in Adult Patients With Pemphigus Vulgaris – recruiting  Indication: pemphigus vulgaris  Phase: 2  MoA: BTK inhibitor

A Study of PRN1008 in Adult Patients With Pemphigus Vulgaris. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT02704429?term=A+Study+of+PRN1008+in+Adult+Patients+With+Pemphigus+Vulgaris&rank=1. (NCT02704429) DENOSUNAB (AMGEN) FOR OUR LONG TERM STEROID PATIENTS

 Fully human IgG2 monoclonal antibody RANKL  High-affinity and highly specific targeting RANKL  No detectable binding to TNF-α, TNF-β, TRAIL, or CD40 ligand  Inhibition of osteoclast formation, function, and survival  Properties of a monoclonal antibody to inhibit RANKL Denosumab  Is not incorporated into bone  Fast action, reversible effect  No dose adjustment required for patients with renal impairment

Bekker et al J Bone Miner Res. 2004; 19:1059. Kostenuik PJ, et al. J Bone Miner Res. 2009;24:182, Prolia Product Monograph , Amgen Canada 2010 NEW ANTAGONIST (IL-36 FAMILY)

And now being looked at for generalized pustular psoriasis and pustular psoriasis of the palms and soles Adapted from SIMID Meeting Verona, Italy Fall 2018 OTHER CONDITIONS RESPONDING TO IL-1 FAMILY

Adapted from SIMID Meeting Verona, Italy Fall 2018 ANTI IL-1 AGENTS ACNE ADAPALENE AND BENZOYL PEROXIDE TOPICAL GEL, 0.3%/2.5% W/W (GALDERMA)  Study Design:  Phase III, multi-center, randomized, double-blind, parallel-group, vehicle- and active- controlled study  Stratification: 50% moderate (IGA 3, n=251) + 50% severe (IGA 4, n=252)  Randomization: 3:3:1 (TactuPump Forte: TactuPump: topical vehicle gel)  Scarring has not been addressed by another marketed topical  The synergistic effect of the fixed dose combination increases the anti-inflammatory response, potentially reducing the risk of scarring  This therapy should be considered for patients who are prone to or at risk for scarring (? All our patients)

1. Czernielewski J, Michel S, Bouclier M, Baker M, Hensby C. Adapalene biochemistry and the evolution of a new topical retinoid for the treatment of acne. J Eur Acad Dermatol Venereol. 2001;15(suppl 3):5-12; 2. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997;36:S96-S103; 3. Hensby C, Cavey D, Bouclier M, et al. The in vivo and in vitro anti-inflammatory activity of CD271: a new retinoid-like modulator of cell differentiation. Agents Actions. 1990;29:56-58; 4. Kircik LH. The role of benzoyl peroxide in the new treatment paradigm for acne. J Drugs Dermatol. 2013;12(6)(suppl):S73-S76; 5. Tanghetti E. The evolution of benzoyl peroxide therapy. Cutis. 2008;82(suppl 5):5-11; 6. Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986;25(10):664-667; 7. TactuPump™ Forte data on file, Galderma Canada Inc; 8. Michel S, Jomard A, Demarchez M. Pharmacology of adapalene. Br J Dermatol. 1998;139(suppl 52):3-7; 9. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne Group. J Am Acad Dermatol. 2009;60(5 Suppl):S1-S50; 10. TactuPump™ Forte Product Monograph, Galderma Canada Inc., November 20, 2015. OLUMACOSTAT GLASARETIL GEL (DERMIRA)

 MoA: pro-drug of TOFA, sarcosine ester, as a topically applied sebum inhibitor  Status: Phase 3 – complete  Did not make primary endpoints  Program closed

“A Dose-Ranging Study of DRM01 in Subjects With Acne Vulgaris - Full Text View.” Full Text View - ClinicalTrials.gov, Dermira Inc., clinicaltrials.gov/ct2/show/NCT02431052?term=DRM01&cond=acne&rank=1. IDP 126 (BAUSCH HEALTH)

 Open-Label, Randomized Study Evaluating the Absorption and Systemic Pharmacokinetics of Topically Applied IDP-126 Gel in Comparison With Control Gel  Active ingredients: clindamycin and adapalene  Indication: moderate-to-severe acne  Phase: moving into Phase 3 studies

Open-Label, Randomized Study Evaluating the Absorption and Systemic Pharmacokinetics of Topically Applied IDP-126 Gel in Comparison With Control Gel. (2018). Retrieved from: https://clinicaltrials.gov/ct2/show/NCT03653403?term=Open-Label%2C+Randomized+Study+Evaluating+the+Absorption+and+Systemic+Pharmacokinetics+of+Topically+Applied+IDP- 126+Gel+in+Comparison+With+Control+Gel&rank=1. (NCT03653403) ROSACEA ORACEA SOOLANTRA (GALDERMA)

 Oracea Soolantra Association in Patients With Severe Rosacea (ANSWER) – completed  Ivermectin 1% topical cream associated with doxycycline 40mg modified release (MR)  Combination treatment  Indication: severe rosacea  Status: Phase 4

“Oracea Soolantra Association in Patients With Severe Rosacea - Full Text View.” Oracea Soolantra Association in Patients With Severe Rosacea - Full Text View - ClinicalTrials.gov, Galderma R&D, clinicaltrials.gov/ct2/show/NCT03075891?term=modified%2Brelease&cond=rosacea&rank=1. HYDROGEN PEROXIDE TOPICAL SOLUTION 40% (W/W)

 Indicated for: SKs that are raised  High concentration (40%) hydrogen peroxide based topical solution  Applied to SK lesions 4x, approximately 1 minute apart  Trade Name: ESKADA (Cipher) – already available in the USA, coming to Canada soon

Questions? [email protected]