dermatological drugs update 2018 · ad3) - recruiting status: phase 3 moa: jak1/2 inhibitor 4 mg po...

DERMATOLOGICAL DRUGS UPDATE 2018Fall 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

Glaxo Smith KlineH3 PharmaceuticalsInnovadermJanssenL’OrealLeo PharmaMerckNovartisOrtho BiotechPediapharmPfizerRocheSanofi AventisStiefelSunpharmaTEVATributeUCB Pharmaceuticals ValeantWestwood SquibbWyeth

3MAbbottAbbVieAkrosAllerganAmgenAstellasAralezBasileaBausch Health Boehringer IngelheimCelgeneCipherEli LillyEMD SeronoGaldermaGlaxo Smith KlineH3 PharmaceuticalsInnovadermJanssen

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?SDERMATOLOGY

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 2018DERMATOLOGY 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 ATOPIC DERMATITIS

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=.

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

TARGET IL-4/IL-13 PATHWAY

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

DUPILUMAB

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, asthma, 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


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+Severe+Atopic+Dermatitis&rank=1(NCT03568162)

NEMOLIZUMAB (CHUGAI/GALDERMA)


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


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


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)


UPADACITINIB / ABT-494 (ABBVIE)


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)


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


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. “Interleukin 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

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

PASI 75Significant response

PASI 90Near

complete resolution

PASI 100Complete resolution

BIOLOGICS

APPROPRIATE TREATMENT: BIOLOGICS

Adalimumab

Etanercept

Infliximab

Certolizumab

Ustekinumab

Secukinumab

Ixekizumab

Brodalumab

Risankizumab (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%

Guselkumab 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%Used with permission of Dr. Yves Poulin Adapted from:

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 monoclonal antibody 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

BIMEKIZUMAB (UCB)

A Study to Assess the Safety, Tolerability and Efficacy of Bimekizumab in Adult Subjects With Moderate to Severe Chronic Plaque Psoriasis (BE BRIGHT)


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+Chronic+Plaque+Psoriasis+%28BE+BRIGHT%29&rank=1 (NCT03598790)

GUSELKUMAB (JANSSEN)


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: USTEKINUMABVS. GUSELKUMAB

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

Ustekinumab Guselkumab

TILDRAKIZUMAB (SUNPHARMA)

Indication: moderate-to-severe PsO

Status: Phase 3


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.

MIRIKIZUMAB (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


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)

CERTOLIZUMAB PEGOL (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, Ulcerative Colitis, 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 20172. 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

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


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

Adapted from SIMID Meeting Verona, Italy Fall 2018Shreberk-Hassidim R et al. J Am Acad Dermatol. 2017; 76: 745-753

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

HIDRADENITIS SUPPURATIVA

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

SHINGRIXVACCINE (GSK) FOR PREVENTION OF HERPES ZOSTER

SHINGRIXVACCINE (GSKVACCINE) FOR PREVENTION OF HERPES ZOSTER

Dosing: 0 and then 2-6 months later

(ie. 2 injections)

IMPETIGO

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 prevents DNA replication and causes cell death1.

Inhibition of DNA replication and cell death:BACTERICIDAL EFFECT

DNA-gyrase

DNA-gyrasecannot uncoil

DNA

Topoisomerase IV

A

Ozenoxacin

A

Topoisomerase IV cannot separate

replicated chains

DNA-gyraseA

Relaxation of DNA

supercoiling

Topoisomerasa IV

Separation of replicated

chains

A

Basal function(without Ozenoxacin)

OZENOXACIN (CIPHER)

72

Basal function with

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

Recruitment

Extravasation

Vasodilation

Activation PRURITUS

ERYTHEMA

WHEAL

INFILTRATE

CAUSE

Fc εRIKit

FcγRTLRs

CR1/2, CR3C3aR, C5aR

NK1ETA /ETB

CD48IL-3,4,15RCCR3OTRs

CysLT1RMC-1/MC5

EP 1/EP 3CB1/CB2

A2b/A3uPAR

VRPIR A/PIR B

IgESCF

IgGLPS

ComplementAnaphylatoxinsNeuropeptidesEndothelin-1

BacteriaInterleukinsChemokines

OxytocineLeukotriene

POMCsProstaglandins

CannabinoidsAdenosine

UrokinaseCapsaicin

?

MC

IL-1, IL-2, IL-3, IL-4, IL-5, IL-6,

IL-8, IL-10, IL-13, TNF,

MIPs, IFN-γ, GM-CSF, TGF-β, bFGF,

VPF/VEGF, PGD2, LTB4, LTC4, PAF, histamine, serotonin,heparin,

chondroitin-sulfate,

chymase, tryptase, CPA

Courtesy of Prof. Marcus Maurer.

URTICARIA: PATHOGENESIS

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

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

OMALIZUMAB

MoA: Humanized monoclonal IgG anibodyagainst 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

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


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

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

Is not incorporated into bone

Fast action, reversible effect

No dose adjustment required for patients with renal impairment

Denosumab

RANKL

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

OTHER CONDITIONS RESPONDING TO IL-1 FAMILY


ANTI IL-1 AGENTS

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, GaldermaCanada 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

[email protected]

dermatological drugs update 2018 · ad3) - recruiting status: phase 3 moa: jak1/2 inhibitor 4 mg po...

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