Disclosures. Activity Information. Updates in Psoriasis Therapy. Ustekinumab Guselkumab Tildrakizumab. Secukinumab Ixekizumab Brodalumab

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1 Disclosures Faculty: Teri Greiling, MD, PhD, has disclosed the following conflicts of interest: research funding: Eli Lilly. Updates in Psoriasis Therapy 12 October 2018 St. Charles Medical Center Teri Greiling, MD, PhD Assistant Professor Department of Dermatology School of Medicine Oregon Health & Science University Portland, Oregon Content Development: Jashin J. Wu, MD, has disclosed the following conflicts of interest: research funding: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Regeneron. Abby Van Voorhees, MD, has disclosed the following conflicts of interest: Consultant - Dermira, AstraZenica, Novartis, Allergan, Pfizer, Eli Lilly, Celgene, Allergan, and AbbVie. Pension, ex-spouse Merck Planning Committee: Andi Agnew, National Psoriasis Foundation, has disclosed no relevant financial relationships with any commercial interests. Activity Information Provided by the National Psoriasis Foundation Supported by educational grants from Celgene Corporation, Mallinckrodt Pharmaceuticals, Eli Lilly, and Valeant Pharmaceuticals Ustekinumab Guselkumab Tildrakizumab IL 23 Etanercept Adalimumab Infliximab TNF IL 17 Secukinumab Ixekizumab Brodalumab

2 Goals of this lecture The old biologic medications Updates of the following: What s new with the old biologics Newly approved systemic therapies Treat to target goals Etanercept Adalimumab Infliximab Ustekinumab TNF inhibitors IL 12/IL 23 inhibitor Drug survival Combination of factors: 1. Drug effectiveness 2. Safety 3. Real world issues insurance & copay issues, compliance, etc 4. Patient education Drug survival of 4 biologics Prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)) Survival rates of the first course of biologics for 3,523 biologic naïve patients adalimumab (n = 1879) etanercept (n= 1098) infliximab (n = 96) ustekinumab (n= 450) Warren RB, et al. Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol Nov;135(11):

3 Drug survival of 4 biologics Drug survival Compared to adalimumab, patients on etanercept (HR 1.63; 95% CI: ) infliximab (HR 1.56; 95% CI: ) were more likely to discontinue therapy Whereas patients on ustekinumab were more likely to persist on therapy HR 0.48; 95% CI: Ustekinumab had the highest first-course drug survival Drug retention Drug retention Predictors of good retention PASI 75 at wk 16 PASI 90 at wk 16 Ustekinumab usage Predictors of poor retention Obesity ( 23 mo versus 37.4 mo) Etanercept usage Strict adherence to approved dosing Vilarrasa E, et al, J Amer Acad Dermatol 2016 Vilarrasa E, et al, J Amer Acad Dermatol 2016

4 Adherence patterns in U.S. Medicare population Ustekinumab- the winner in drug survival Ustekinumab treatment prolonged drug survival Vilarrasa E, et al. ORBIT (Outcome and Retention Rate of Biologic Treatments for Psoriasis): A retrospective observational study on biologic drug survival in daily practice. J Am Acad Dermatol Jun;74(6): Of the 4 older biologics, ustekinumab had the lowest odds of discontinuation Doshi JA, et al. Biologic therapy adherence, discontinuation, switching, and restarting among patients with psoriasis in the US Medicare population. J Am Acad Dermatol Jun;74(6): e4. Doshi JA, et al, J Am Acad Dermatol 2016 Drug survival of adalimumab 53.2% (42 of 79) of patients persisted on adalimumab therapy from 13 months to as long as 6.8 years before the end of study Mean drug survival was 1337 days, or 3.7 years (95% confidence interval, days) Median drug survival was 1259 days (3.5 years) J Invest Dermatol Feb;137(2) Spanish registry, n=2153 Reddy SP, Lin EJ, Shah VV, Wu JJ. Persistence and failure rates of adalimumab monotherapy in biologic naïve patients with psoriasis: A retrospective study. J Am Acad Dermatol Mar;74(3):575 7.

5 Infection rates in Spanish registry Infection (Crude RR) Serious infection (Crude RR) Acitretin Methotrexate Etanercept 1.2 (N.S.) 0.2 Adalimumab 1.2 (N.S.) 0.9 (N.S.) Infliximab (N.S.) Ustekinumab 0.9 (N.S.) 0.6 (N.S.) Etan + Mtx 1.0 (N.S.) 0.4 (N.S.) Ada + Mtx (N.S.) Inflix + Mtx 1.1 (N.S.) 2.1 (N.S.) Ust + Mtx 1.4 (N.S.) 1.0 Cyclosporine Infection rates in British registry Infliximab vs non biologic therapy: hazard ratio 1.95 Infliximab vs methotrexate: hazard ratio 2.96 Yiu ZZN, Ashcroft DM, Evans I, McElhone K, Lunt M, Smith CH, Walton S, Murphy R, Reynolds NJ, Ormerod AD, Griffiths CEM, Warren RB; BADBIR Study Group. Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the United Kingdom and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Br J Dermatol Aug 2. Etanercept: long term safety in children Apremilast Approved in 2014 for both psoriasis and psoriatic arthritis Small molecule phosphodiesterase 4 inhibitor No labs needed Paller A, et al, J Amer Acad Dermatol 2015

6 Highlights of prescribing information Recommended dose is 30 mg once BID after 5 days of up titration If severe renal impairment, dose at 30mg QD AEs diarrhea and nausea ( 5%) Warnings Depression Weight loss of 5 10% decrease in body weight in 10% of patients Pregnancy category C Apremilast Two multicenter, randomized, double blind, placebo controlled trials with 1257 subjects PSOR 1: 33.1% reached PASI75 at week 16 PSOR 2: 28.8% reached PASI75 at week 16 Biologics + apremilast Special situations May be better for mild to moderate disease May be helpful for immunosuppressed patients (i.e. HIV, organ transplant) Mohn d AbuHilal, Scott Walsh, and Neil Shear, J Cut Med Surg 2016 Reddy SP, Shah VV, Wu JJ. Apremilast for a psoriasis patient with HIV and hepatitis C. Journal of the European Academy of Dermatology and Venereology Nov;31(11):e481 e482.

7 Ustekinumab Guselkumab Tildrakizumab IL 23 Secukinumab Secukinumab is a IgG1 monoclonal antibody that inhibits IL 17A Approved on January 21, 2015 for psoriasis Approved on January 15, 2016 for psoriatic arthritis and ankylosing spondylitis Etanercept Adalimumab Infliximab TNF IL 17 Secukinumab Ixekizumab Brodalumab Complex inflammatory pathways in psoriasis are mediated by Th1, Th17 and Th22 cells Secukinumab prescribing information NKT cell plasmacytoid Dendritic cell keratinocyte TNF IFN IFN macrophage IL 1 IL 6 TNF activation TIP DC TNF IL 12 IL 23 Th22 Th1 Th17 IL 22 TNF IFN keratinocyte IL 17A/F IL 21 Antimicrobial peptides IL 1 IL 6 TNF S100 CXCL8 CXCL9 CXCL10 CXCL11 CCL20 Recommended dose is 300 mg by subcutaneous injection at weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks 2 injections of 150mg pens or syringes For some patients, a dose of 150 mg may be acceptable Screen for tuberculosis Be careful if prescribing to those with active inflammatory bowel disease as flares may occur Live vaccines should not be given Pregnancy category B adapted from: Nestle et al. N Engl J Med 2009

8 Secukinumab study overview Secukinumab ERASURE Results Two phase 3 trials to assess induction (at week 12) and maintenance therapy (at week 52) with secukinumab 300 mg or 150 mg subq Vs placebo (n=738), ERASURE Vs placebo or etanercept (n=1301), FIXTURE Study population Patients 18 years of age with chronic moderate to severe plaque psoriasis for 6 months prior to randomization Patients with PASI score 12 and BSA 10% Langley RG, et al. Secukinumab in plaque psoriasis results of two phase 3 trials. N Engl J Med Jul 24;371(4): Secukinumab FIXTURE Results AEs in ERASURE Candida infections 11 subjects: 7 in the 300 mg group; 3 in the 150 mg group; 1 in the placebo group All infections were localized, mild or moderate, and self resolved or responsive to standard therapy None led to treatment discontinuation

9 Why candida? Nature s example: Chronic Mucocutaneous Candidiasis Disease Children with severe recurrent candida infections Inherited IL 17 receptor deficiency AEs in FIXTURE Candida infections more common with secukinumab than etanercept during entire treatment 22 subjects (4.7%) in the secukinumab 300 mg group and 11 (2.3%) in the 150 mg group all were localized, mild or moderate, and resolved on their own or with standard therapy none led to treatment discontinuation 4 (1.2%) subjects in the etanercept group; two subjects had infections graded severe Secukinumab vs ustekinumab CLEAR trial Compare efficacy and safety of secukinumab versus ustekinumab 52 week, double blind study 676 subjects were randomized 1:1 to subcutaneous injection of secukinumab 300 mg or ustekinumab per label Primary end point was PASI90 at week 52 Blauvelt A, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis up to 1 year: Results from the CLEAR study. J Am Acad Dermatol Jan;76(1):60 69.e9.

10 Ixekizumab Ixekizumab is a humanized IgG4 monoclonal antibody that neutralizes IL 17A (IL 17 A antagonist) Approved in 2016 for psoriasis and 2017 for psoriatic arthritis Ixekizumab prescribing information Recommended dose is 160 mg (two 80 mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12 then 80 mg every 4 weeks Screen for tuberculosis Be careful if prescribing to those with active inflammatory bowel disease as flares may occur Live vaccines should not be given Pregnancy category NA Ixekizumab phase 3 trials Three prospective, double blind, multicenter, phase 3 studies (UNCOVER 1, 2, 3) for 3736 patients UNCOVER 1: placebo, 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2 wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4 wk dosing group) UNCOVER 2 and UNCOVER 3: as above plus some received 50 mg of etanercept twice weekly Coprimary efficacy endpoints were proportions of patients achieving spga score 0 or 1 and PASI75 at week 12 Gordon KB, et al. Phase 3 trials of ixekizumab in moderate to severe plaque psoriasis. N Engl J Med June 8 [Epub]

11 Kapp KA, et al, Br J Dermatol, 2017 Reich K, et al, Br J Dermatol, 2017

12 Safety All patients with ixekizumab exposure: Candida infection: 128 events, 3.7/100 patient years Crohn s disease: 4 events, 0.1/100 patient years Ulcerative colitis: 7 events, 0.2/100 patient years Brodalumab Brodalumab is a human anti interleukin 17 receptor A monoclonal antibody Approved on February 15, 2017 for psoriasis Only biologic where needs to have failed other systemic therapies Lebwohl M et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med Oct;373(14): Brodalumab prescribing information Recommended dose is 210 mg at weeks 0, 1, and 2 followed by 210 mg every 2 weeks Screen for tuberculosis Contraindication Crohn s disease (no warning on ulcerative colitis) Live vaccines should not be given Pregnancy category NA Brodalumab cautions Boxed Warning about suicidal ideation and behavior (SIB) Drug is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) Prescribers must be certified with the program and counsel patients about SIB risk Patients must sign a Patient Prescriber Agreement Form and be made aware of the risk for SIB Pharmacies must be certified with the program

13 Brodalumab In two phase 3 studies (AMAGINE 2 and AMAGINE 3), primary aims were to evaluate: superiority of brodalumab over placebo at week 12 in PASI75 and spga superiority of brodalumab over ustekinumab at week 12 in PASI100 Lebwohl M et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med Oct;373(14): Infections in both trials up to week 52 Candida infections Risk of infection: brodalumab Ustekinumab 210 mg Q2W after ustekinumab Mixed Dosing 140 mg Q2W/ 210 mg Q2W 140 mg Q2W 210 mg Q2W 14 (2.8) 4 (5.3) 42 (4.3) 55 (6.8) 7 (4.3) 43 (5.6) Ustekinumab Guselkumab Tildrakizumab IL 23 Cellulitis 1 (0.2) 0 (0.0) 1 (0.1) 3 (0.4) 0 (0.0) 2 (0.3) Pneumonia 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 1 (0.1) Sepsis 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 1 (0.1) Urinary tract infection 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 1 (0.1) Etanercept Adalimumab Infliximab TNF IL 17 Secukinumab Ixekizumab Brodalumab

14 Guselkumab Complex inflammatory pathways in psoriasis are mediated by Th1, Th17 and Th22 cells Guselkumab is a fully human IgG lambda monoclonal antibody that selectively binds and neutralizes the P19 subunit of IL23 (IL23P19 antagonist) Approved for psoriasis July 2017 NKT cell keratinocyte TNF IFN IFN IL 1 IL 6 TNF activation TIP DC TNF IL 12 IL 23 Th22 Th1 IL 22 TNF IFN keratinocyte Antimicrobial peptides IL 1 IL 6 TNF S100 CXCL8 CXCL9 CXCL10 CXCL11 CCL20 plasmacytoid Dendritic cell IL 17A/F IL 21 macrophage Th17 adapted from: Nestle et al. N Engl J Med 2009 Guselkumab prescribing information Recommended dose is 100 mg at week 0, week 4 and then every 8 weeks 100 mg/ml in a single dose prefilled syringe Screen for tuberculosis Live vaccines should not be given Pregnancy category NA no available data in pregnant women no data on lactation Guselkumab VOYAGE 1 phase 3 trial Two prospective, double blind, multicenter, phase 3 studies (Voyage 1 & 2) for 837 patients 48 week study, 837 were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks) (n = 329) placebo/guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks) (n = 174) adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47) (n = 334) Blauvelt A, et al. Efficacy and safety of guselkumab, an anti interleukin 23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double blinded, placebo and active comparator controlled VOYAGE 1 trial. J Am Acad Dermatol Mar;76(3):

15 AEs in Voyager trials Tildrakizumab Tildrakizumab is a fully human IgG kappa monoclonal antibody that selectively binds and neutralizes the P19 subunit of IL23 (IL23P19 antagonist) Approved for psoriasis March 2018

16 Tildrakizumab prescribing information Recommended dose is 100 mg at week 0, week 4 and then every 12 weeks 100 mg/ml in a single dose prefilled syringe Screen for tuberculosis Live vaccines should not be given Pregnancy category NA no available data in pregnant women no data on lactation Tildrakizumab resurface 1/2 phase 3 trials Two prospective, double blind, multicenter, phase 3 studies (resurface 1 & 2) for 772 and 1090 patients respectively Tildrakizumab 100 mg vs tildrakizumab 200 mg vs placebo vs etanercept PASI75 PGA0/1 Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, Nograles K, Mehta A, Cichanowitz N, Li Q, Liu K, La Rosa C, Green S, Kimball AB. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (resurface 1 and resurface 2): results from two randomised controlled, phase 3 trials. Lancet Jul 15;390(10091): Tildrakizumab AEs 9 biologics and 4 oral meds which to pick? Oral: acitretin, cyclosporine, methotrexate, apremilast Ustekinumab Guselkumab Tildrakizumab IL 23 Etanercept Adalimumab Infliximab TNF IL 17 Secukinumab Ixekizumab Brodalumab

17 Drug Dosage frequency PASI-75 response State of Psoriasis Treatment Infliximab 5mg/kg week 0, 2, 6 then q8 weeks IV 76-80% Adalimumab 80mg loading dos, 40mg week 1, then q2 weeks SC 71-80% Etanercept 50mg twice weekly x 3mo, then 50mg weekly SC 49% Psoriasis is a chronic inflammatory disease with debilitating effects on multiple organ systems. Ultimately patients have poor long term health outcomes, the significance of which we are continuing to realize. 1 Age at Death Ustekinumab < 100kg: week 0, 4 then q12 weeks SC 100kg: week 0, 4 then q12 weeks SC 66 76% Secukinumab 300mg weekly x 5 weeks, then mg q % Ixekizumab 160 mg (two 80 mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12 then 80 mg every 4 weeks 87% Brodalumab 210 mg at weeks 0, 1, and 2, followed by 210 mg every 2 weeks 85-86% Guselkumab 100 mg at weeks 0 and 4, followed by 100 mg every 8 weeks 83% Tildrakizumab 100 mg at weeks 0 and 4, followed by 100 mg every 12 weeks 64% Despite the consequences, NPF surveys show that many patients continue to undertreat and are dissatisfied. 2 Many factors contribute to this, including access issues, fear of side effects, and lack of defined treatment goals in the US. 1. Abuabara, K., et al. British Journal of Dermatology (2010): Armstrong, April W., et al. JAMA dermatology (2013): Case for treatment targets: RA Case for treatment targets: PsA T2T approach improves joint outcome OR of ACR 20 in tight vs standard control 1.91 OR of ACR 50 in tight control was 2.36 OR of ACR Coates, LC, et al, Lancet 2015

18 Treat to Target Approach in PsA: TICOPA Trial Tight Control was Associated with Significantly Greater Improvements in Signs and Symptoms and Quality of Life at Week 48 Radiograph hands/feet Radiograph hands/feet Safety visit Tight control DMARD naive early PsA (n=206) TC: Start on MTX (n=101) StdC (n=105) Wk TC (n=101) R: 1:1 StdC (n=105) MDA MDA MDA MDA MDA MDA MDA MDA T2T: Treatment escalation if MDA not reached MTX to 25 mg at Wk 6 if tolerated Blinded assessment of clinical and PROs To combination DMARDs if MDA not reached To anti-tnf if 3 tender/swollen joints or alternative DMARD + MTX if no MDA but with <3 active joints Treatment at rheumatologist s discretion; no set protocol Assessments Q12 wks in both groups; Additional review Q4 wks in tight control only Patients (%) p=0.02 p=0.015 p= p= ACR20 ACR50 ACR70 PASI 75 PASI 90 Median change from baseline Standard care PsAQoL HAQ MDA, minimum disease activity; MTX, methotrexate; R, randomisation; StdC, standard care; TC, tight control; T2T, treat to target Coates LC, et al. BMC Musculoskelet Disord. 2013;14:101 Intention to treat (ITT) with multiple imputations ACR, American College of Rheumatology Coates LC, et al. BMC Musculoskelet Disord. 2013;14:101; Coates LC, et al. Lancet. 2015;386: Goal Define treatment targets for both patients and clinicians in order to: 1. Aid in treatment decisions 2. Reduce disease burden 3. Improve outcomes

19 Methods Treatment Targets Preferred assessment instrument: Body Surface Area (BSA) 1. Literature Review 2. Patient Focus Group (n = 4) Time Post Initiation Target Acceptable 3 Months BSA 1% BSA 3% or 75% Improvement 3. Survey to Practicing Dermatologists (n = 19) 4. Four Rounds of Expert Delphi (n =25) Every 6 Months BSA 1% x T2T Most preferred treat to target instrument: BSA Fulfillment of a single criteria (not multiple criteria) is sufficient for achieving the treatment target. Time to initial assessment following therapy initiation: 3 months. Treatment target at the end of the initiation phase: BSA 1% Acceptable response at end of initiation phase: 75% reduction from baseline PASI BSA< 3 % Assessment time interval for maintenance therapy: 6 months Treatment target during maintenance phase: BSA 1% Sanctity of patient provider relationship Which therapy for psoriasis has the best drug survival? a) Adalimumab b) Apremilast c) Etanercept d) Infliximab e) Ustekinumab

20 Which therapy for psoriasis has the highest risk of infection? a) Adalimumab b) Apremilast c) Etanercept d) Infliximab e) Ustekinumab Which therapy for psoriasis does not require laboratory monitoring and can be combined with other biologic therapies? a) Adalimumab b) Apremilast c) Etanercept d) Infliximab e) Ustekinumab Which class of medications for psoriasis has an increased risk of candida infections? a) IL 17 inhibitors b) IL 23 p19 subunit inhibitors c) IL 23 p40 subunit inhibitors d) Phosphodiesterase 4 inhibitors e) TNFalpha inhibitors Which IL 17 inhibitor has a black box warning for suicidality? a) Brodalumab b) Guselkumab c) Ixekizumab d) Secukinumab e) Tildrakizumab

21 What is the treat to target goal after 6 months of therapy? a) PASI75 b) PASI90 c) <1% body surface area d) <3% body surface area e) <10% body surface area Take home points Ustekinumab has the best drug survival of the old biologics Safety issues may be less in those with psoriasis Apremilast is very safe with no monitoring needed, augment efficacy IL 17 inhibitors are very effective for psoriasis and psoriatic arthritis Risk for Candida infections Avoid in those with IBD Guselkumab is a highly effective agent in psoriasis, not approved for PsA at this time Treat to target: BSA< or equal to 1 Navigators provide ongoing support and guidance to patients coping with the range of issues related to disease management, access to care, and adherence Open to all people with psoriatic disease, their families and caregivers Communicate via phone, text, , and instant messaging and Skype