Held in conjunction with AMCP Managed Care & Specialty Pharmacy Annual Meeting Jointly provided by

Transcription

1 Jointly provided by This activity is supported by independent educational grants from Sanofi Genzyme and Regeneron Pharmaceuticals Held in conjunction with AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018

2 Clinical Update: The Impact of Novel Therapies Paul Yamauchi, MD, PhD Clinical Assistant Professor of Medicine Division of Dermatology, David Geffen School of Medicine at UCLA Adjunct Associate Professor John Wayne Cancer Institute, Santa Monica

3 Learning Objectives Review recent insights into the pathophysiology of atopic dermatitis (AD) Discuss the safety, efficacy and attributes of emerging therapies for the treatment of AD

4 Atopic Dermatitis: A Chronic Inflammatory Disease Estimated prevalence in the US 1 Adults: 18 million (7.2%) Children (<18 years): 9.6 million (13%) Onset typically occurs before age 5 Onset may also occur during adulthood 2,3 Characterized by pruritus and xerosis 4 Follows a waxing and waning course 2 Significantly impairs quality of life 4 Atopic comorbidities 4 Asthma Allergic rhinitis 1. Eczema Facts. National Eczema Association Web site. facts/. Accessed March Margolis JS, Abuabara K, Bilker W, Hoffstad O, Margolis DJ. JAMA Dermatol. 2014;150(6): Nutten S. Ann Nutr Metab. 2015;66 Suppl 1: Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(1):

5 Genes and the Environment Influence the Natural History of AD AD is complex and multifactorial, characterized by genetic mutations, immune dysregulation, skin barrier dysfunction, and abnormal itch response Environmental factors Scratching Environmental factors (e.g., soap, dust mite) Allergens Genes linked to AD 1,2 FLG (encodes profilaggrin, a skin barrier protein) CARD11 Genes that encode inflammatory cytokines (eg, IL 4, IL 5, IL 12, IL 13)11 gene Epigenetic regulation Genetics Impaired epithelial barrier Skin barrierrelated genes Barrier hypothesis: 70% before 1 year old Staphylococcus aureus Non AD dermatitis (non IgE Associated) Acquired sensitization Immune (atopy) related genes AD (IgE Associated) Immunologic hypothesis: 30% before 1 year old 1. Ma CA, Stinson JR, Zhang Y, et al. Nat Genet. 2017;49(11): Nutten S. Ann Nutr Metab. 2015;66 Suppl 1: Guttman yassky E, Dhingra N, Leung DY. Expert Opin Biol Ther. 2013;13(4): ~80% of patients with AD have personal or family history of atopy (elevated IgE) 3

6 Immunologic Dysregulation in AD Skin barrier dysfunction and Th2/Th22 deviated immune reactions are the fundamental abnormality in AD Antigen mediated Th2 cell activation leads to cytokine release (eg, IL 4, IL 13) leading to: Further disruptions in the skin barrier by decreased expression of FLG IL 31 activation of nerve terminals that mediate itch Increased Th2 differentiation drives inflammation and immune activation IL 22 FLG mutations Other mutations Lipid defects PDE4 Th22 cells B cells Cytokines JAK STAT Irritants ph changes Trauma/ scratching Proteases camp=cyclic adenosine monophosphate; FLG=filaggrin gene; IgE=immunoglobulin E; IL=interleukin; PDE4=phosphodiesterase 4; Th2=T helper cell 2; TSLP=thymic stromal lymphopoietin Furue M, Chiba T, Tsuji G, et al. Allerg Int. 2017;66(3): Lee DE, Clark AK, Tran KA, Shi VY. J Dermatolog Treat. 2017;19. Accessed March IL 4 IL 13 IgE Th2 cells IL 31 Allergens PDE4 camp Sensory neurons Bacteria TSLP Itch

7 Mechanisms of Pruritus in AD Pruritus in AD is induced by a variety of histamine dependent and independent pruritogens including IL 4, IL 13, IL 31 Proteases IL 31 and nerve growth factors stimulate an increase in the number of epidermal sensory nerve fibers Novel AD therapies such as IL 4, IL 13, and IL 31 inhibitors exhibit antipruritic properties IL 31 RA Ab IL 31 Ab IL 4R Ab H1R H4R antagonist antagonist IL 4 Histamine Protease IL 13 Substance P IL 31 H1R H4R Neurons JAKi NK1R antagonist Capsaicin ROS PAR2 IL 4R IL 31R NK1R TRPV1 TRPA1 Histaminedependent Histamineindependent C Fibers Paller AS, Kabashima K, Bieber T. J Allergy Clin Immunol. 2017;140(3): H1R = histamine receptor type 1; H4R = histamine receptor type 4; JAK = Janus kinase; NK1R = neurokinin 1 receptor

8 Comorbidities More Likely to Occur in the AD Population vs Non AD Controls Adjusted Odds Ratio of comorbidities stratified by disease severity in a Commercial population Adult patients with a diagnosis of AD in a Commercial claims database* (n=83,106) vs non AD controls AD patients were stratified by disease severity Comorbidity burden evaluated during a 12 month follow up *Optum Health, Eden Prairie, MN Allergic rhinitis Asthma Food allergy Chronic pulmonary disease Chronic rhinosinusitis Allergic urticarial Autoimmune disorders Conjunctivitis Esophagitis Nasal polyps Bacterial infections Fungal infections ADHD Anxiety Depression Sleep disorder Obesity Shrestha S, Miao R, Wang L, Chao J, Yuce H, Wei W. Adv Ther. 2017;34(8):

9 Treatment of AD Has Historically Been Focused on Symptomatic Relief Nonpharmacologic Topical Agents Systemic Agents Skin moisturizers Emollients Occlusive agents Humectants Bathing practices Bleach baths Wet wrap towels Light therapy* Corticosteroids Calcineurin inhibitors Antimicrobial and antiseptics Antihistamines *Not FDA approved for AD treatment Systemic corticosteroids Cyclosporine* Methotrexate* Azathioprine* Mycophenolate mofetil* Tacrolimus* Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(1): Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2):

10 New and Emerging Therapies Target Specific Steps in the Th2 Pathway Integral to AD Pathogenesis Allergens MHC class II TCR Dendritic cell IL 4 T H 0 cell IL 4 specific blockers Dual IL 4 and IL 13 specific blockers IL 5 specific blockers IL 5 T H 2 cell IL 4 PDE 4 specific blockers PDE 4 IL 13 IL 13 specific blockers JAK JAK specific blockers 1. Vakharia PP, Silverberg JI. BioDrugs. 2017;31(5): Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Nat Rev Drug Discov. 2016;15(1): Lee DE, Clark AK, Tran KA, Shi VY. J Dermatolog Treat. 2017; Accessed March B cell IgE IgE specific mabs Basophil Mast cell Histamine

11 Recently Introduced Targeted Therapies Approved for the Treatment of AD Systemic Therapy 1 Topical Therapy 2 Agent: Dupilumab (Dupixent) MOA: IL 4 receptor alpha antagonist Approval: March 2017 Indication: Treatment of adults with moderate to severe AD uncontrolled with topical therapies Administration: Subcutaneous injection (every other week) Agent: Crisaborole (Eucrisa 2% ointment) MOA: Phosphodiesterase (PDE) 4 inhibitor Approval: December 2016 Indication: Topical treatment of mild tomoderate AD in patients 2 years Administration: Topical use only (twice daily) 1. Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc; 2016.

12 Recently Approved Therapy: Dupilumab Indication: Dupilumab is indicated for the treatment of adults ( 18 years) with moderate to severe atopic dermatitis uncontrolled with topical therapies.

13 Dupilumab Inhibition of IL 4 Intracellular Signaling Fully human IL 4 monoclonal antibody 1 Binds to the IL 4 receptor α chain, a component of receptors for both IL 4 and IL 13 1 Blocks both IL 4 and IL 13 signaling, cytokines that drive Th2 mediated inflammation Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Nat Rev Drug Discov. 2016;15(1): Vakharia PP, Silverberg JI. BioDrugs. 2017;31(5): Lee DE, Clark AK, Tran KA, Shi VY. J Dermatolog Treat. 2017;19. Accessed March Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; Dupilumab is indicated for the treatment of adults ( 18 years) with moderate to severe atopic dermatitis uncontrolled with topical therapies. JAK1 IL 4 IL 4 STAT6 JAK3 Type I receptor B cells T cells Monocytes Eosinophils Fibroblasts IL 4 JAK1 STAT6 IL 13 IL 13 IL 4Rα γc IL 4Rα IL 13Rα1 TYK2 STAT3 Type II receptor Epithelial cells Smooth muscle cells Fibroblasts Monocytes Activated B cells

14 Dupilumab Phase 3 SOLO Trials Patients with Moderate to Severe AD Treated with Dupilumab Experienced Significant Skin Clearing by Week 16 Patients (%) Placebo Dupilumab 300 mg (q2 weeks) Dupilumab 300 mg (q week) Primary Endpoint IGA of 0 or 1 and 2 points decrease from baseline at Week 16 *p<0.001 vs placebo * * * * n=224 n=224 n=223 n=236 n=233 n=239 n=224 n=224 n=223 n=236 n=233 n=239 0 SOLO 1 SOLO 2 IGA=Investigator s Global Assessment; EASI 75=75% improvement in the Eczema Area and Severity Index. IGA 0 = clear ; IGA =1 = almost clear Simpson EL, Bieber T, Guttman yassky E, et al. N Engl J Med. 2016;375(24): Patients (%) *p<0.001 vs placebo 51.3 Key Secondary Endpoint EASI 75 at Week 16 * * SOLO 1 SOLO 2 Dupilumab is indicated for the treatment of adults ( 18 years) with moderate to severe atopic dermatitis uncontrolled with topical therapies. * * 48.1

15 Dupilumab Phase 3 CHRONOS Trial Combined Treatment with Dupilumab + TCS Elicited Significant Skin Clearing at Week 16 Which Was Maintained Through Week 52 Patients (%) Placebo + TCS Dupilumab 300 mg (q2 weeks) + TCS Dupilumab 300 mg (q week) + TCS Primary Endpoint IGA of 0 or 1 and 2 points decrease from baseline at Week 16 *p<0.001 vs placebo + TCS * * * * Week 16 Week 52 Week 16 Week 52 IGA=Investigator s Global Assessment; EASI 75=75% improvement in the Eczema Area and Severity Index; TCS=topical corticosteroids. IGA 0 = clear ; IGA =1 = almost clear Blauvelt A, De bruin weller M, Gooderham M, et al. Lancet. 2017;389(10086): Dupilumab is indicated for the treatment of adults ( 18 years) with moderate to severe atopic dermatitis uncontrolled with topical therapies. Patients (%) n=315 n=106 n=319 n=264 n=89 n= n=315 n=106 n=319 n=264 n=89 n= *p<0.001 vs placebo +TCS * Key Secondary Endpoint EASI 75 at Week 16 * * *

16 Dupilumab Safety Profile Warning and Precautions Hypersensitivity Discontinue treatment Conjunctivitis and keratitis Report new onset or worsening eye symptoms Comorbid asthma Advise patients with comorbid asthma not to adjust or stop their asthma treatment without consultation with their physician Most Common Adverse Reactions (>1% in Phase 3 Trials) Injection site reactions Conjunctivitis Blepharitis Oral herpes Keratitis Eye pruritus Other herpes simplex virus Dry eye Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; Dupilumab is indicated for the treatment of adults ( 18 years) with moderate to severe atopic dermatitis uncontrolled with topical therapies.

17 Dupilumab Phase 2a Data Treatment with Dupilumab Resulted in Extensive Skin Clearing in Children and Adolescents EASI in Children (6 11 years) with Severe AD EASI in Adolescents (12 17 years) with Moderate to Severe AD Dupilumab 2 mg/kg (n=18) Dupilumab 4 mg/kg (n=19) Dupilumab 2 mg/kg (n=20) Dupilumab 4 mg/kg (n=20) EASI 75=75% improvement in the Eczema Area and Severity Index. Cork MJ, et al. Abstract 5279: Pharmacokinetics, Safety and Efficacy of Dupilumab in a Pediatric Population with Moderate to Severe Atopic Dermatitis: Results from an Open Label Phase 2a Trial. Oral presentation at: American Academy of Dermatology Annual Meeting; March 2017; Orlando, FL. Dupilumab is indicated for the treatment of adults ( 18 years) with moderate to severe atopic dermatitis uncontrolled with topical therapies.

18 Recently Approved Therapy: Crisaborole Indication: Topical treatment of mild to moderate atopic dermatitis in patients 2 years.

19 Crisaborole A Non steroidal Phosphodiesterase (PDE) 4 Inhibitor PDE 4 modulates production of inflammatory cytokines by its action on camp Healthy Skin Atopic Dermatitis PDE 4 Inhibition Low PDE 4 high camp low cytokine release low inflammation Increase PDE 4 low camp increase cytokine release increase inflammation PDE 4 inhibition increases camp and reduces cytokine release PDE4 = phosphodiesterase 4; camp = cyclic adenosine monophosphate; AMP = adenosine monophosphate. Jarnagin K, Chanda S, Coronado D, et al. J Drugs Dermatol. 2016;15(4): Crisaborole is indicated for the topical treatment of mild to moderate atopic dermatitis in patients 2 years.

20 Crisaborole Patients with Mild to Moderate AD Treated with Crisaborole Experienced Significant Skin Clearing and Reduction of Itch Patients Achieving Success at Day 29 (%) Two identically designed, vehicle controlled, double blind studies enrolled patients 2 years with mild or moderate AD Vehicle 25.4 Primary Endpoint* Crisaborole p=0.038 AD p<0.001 n=256 n=503 n=250 n=513 AD 302 ISGA = Investigator s Static Global Assessment *ISGA of 0 [clear] or 1 [almost clear] with 2 grade improvement from baseline. Paller AS, et al. J Am Acad Dermatol. 2016;75: Patients Achieving Improvements in Pruritus (%) Improvement in Pruritus Vehicle Crisaborole Baseline Day 8 Day 15 Day 22 Day 29 Crisaborole is indicated for the topical treatment of mild to moderate atopic dermatitis in patients 2 years.

21 Crisaborole Safety Profile Warnings and precautions Hypersensitivity reactions No treatment related serious adverse events were reported in patients treated with crisaborole Majority of adverse events (AEs) were mild Most common AE (occurring in >1% of subjects) was application site pain Adverse event Application site pain (%) Upper respiratory tract infection (%) Crisaborole (n=502) Study AD 301 Vehicle (n=252) Crisaborole (n=510) Study AD 302 Vehicle (n=247) Crisaborole (n=1012) Pooled Vehicle (n=499) Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc; Crisaborole is indicated for the topical treatment of mild to moderate atopic dermatitis in patients 2 years.

22 Agents in Late Phase Development for the Treatment of Atopic Dermatitis

23 Topical Agents in Development for the Treatment of AD Target Compound Target Population Current Status (Phase) AhR Tapinarof/Benvitimod Moderate to severe 3 PDE 4 Roflumilast Mild to moderate 2 PDE 4 RVT 501 Mild to moderate 2 JAK1, JAK2 Tofacitinib Moderate to severe 2 JAK1, JAK2 Ruxolitinib Moderate to severe 2 JAK1, JAK3 LEO /JTE 052 Moderate to severe 2 AhR=aryl hydrocarbon receptor; PDE 4=phosphodiesterase 4; JAK=Janus kinase Paller AS, et al. J Allerg Clin Immunol. 2017;140:

24 Biologic Agents in Development for the Treatment of AD Target Compound Target Population Current Status (Phase) IL 13 Tralokinumab Moderate to severe 3 IL 13 Lebrikizumab Moderate to severe 3 TSLP Tezepelumab Moderate to severe 2 IL 4 Pitrakinra Moderate to severe 2 IL 5 Mepolizumab Moderate to severe 2 IgE Ligelizumab Moderate to severe 2 IL 12/IL 23 Ustekinumab Moderate to severe 2 IL 22 Fezakinumab Moderate to severe 2 IL 17A Secukinumab Moderate to severe 2 Il 31 Nemolizumab Moderate to severe 2 TSLP=thymic stromal lymphopoietin; IgE=immunoglobulin E Paller AS, et al. J Allerg Clin Immunol. 2017;140:

25 Tralokinumab The IL 13 Inhibitor Tralokinumab + TCS Elicited Improvement in EASI in Patients with Moderate to Severe AD: Phase 2 Results Adjusted mean change in EASI Phase 2b Results 1 EASI Mean Change from Baseline Time (weeks) Placebo + TCS Tralokinumab 150 mg + TCS Post treatment Tralokinumab 45 mg + TCS Tralokinumab 300 mg + TCS Adults with moderate to severe AD (n=204); protocol mandated b.i.d. use of TCS Tralokinumab dosed every 2 weeks Adverse events were similar between groups ECZTRA Phase 3 Trial Program Evaluate the efficacy and safety of tralokinumab in patients with moderate to severe AD who are candidates for systemic therapy ECZTRA 1 Tralokinumab vs placebo (n=780) ECZTRA 2 Tralokinumab vs placebo (n=780) ECZTRA 3 Tralokinumab + topical corticosteroids (n=369) EASI=Eczema Area and Severity Index; TCS=topical corticosteroids; ECZTRA= ECZema TRAlokinumab Trial. Wollenberg A, Howell MD, Guttman Yassky E, et al. Abstract 4496: A phase 2 b dose ranging efficacy and safety study of tralokinumab in adult patients with moderate to severe atopic dermatitis (AD). Poster presented at: American Academy of Dermatology Annual Meeting; March 2017; Orlando, FL.

26 Lebrikizumab The IL 13 Inhibitor Lebrikizumab + TCS Elicited Skin Clearance in Patients with Moderate to Severe AD: Phase 2 TREBLE Trial Patients (%) Primary Endpoint EASI 50 *p= vs placebo * 82.4 Adults with moderate to severe AD; protocol mandated b.i.d. use of topical corticosteroids Lebrikizumab dosed every 4 weeks Adverse events were similar between groups Patients (%) EASI 75 SD=single dose Q4W=every 4 weeks Simpson EL, Flohr C, Eichenfield LF, et al. [published online ahead of print January 15, 2018]. J Am Acad Dermatol. doi.org/ /j.jaad n=53 n=52 n=53 n= n=53 n=52 n=53 n= n=53 n=52 n=53 n=51 Placebo 125 mg SD 250 mg SD 125 mg Q4W Placebo 125 mg SD 250 mg SD 125 mg Q4W Placebo 125 mg SD 250 mg SD 125 mg Q4W Patients (%) IGA 0 or

27 Nemolizumab The IL 31 Inhibitor Nemolizumab Significantly Reduced Itch in a Phase 2 Trial Primary Endpoint Percent Change From Baseline in the Pruritus Score at Week 12 0 Weekly Change in Pruritus Score Percent change in pruritus score, baseline to Week Placebo 0.1 mg/kg 0.5 mg/kg 2.0 mg/kg p=0.002 p<0.001 p<0.001 Change in pruritus (%) Adults with moderate to severe AD (n=264) Nemolizumab dosed every 4 weeks Ruzicka T, Hanifin JM, Furue M, et al. N Engl J Med. 2017;376(9): Placebo 0.5 mg/kg q4wks Time (weeks) 0.1 mg/kg q4wks 2.0 mg/kg q4wks

28 Small Molecules in Development for the Treatment of AD Target Compound Target Population Current Status (Phase) PDE 4 Apremilast Moderate to severe 2 H4R ZPL389 Moderate to severe 2 JAK1, JAK2 Baricitinib Moderate to severe 3 JAK1 PF Moderate to severe 3 JAK1 Upadacitinib Moderate to severe 3 (breakthrough therapy) NK1R Tradipitant Moderate to severe 2 NK1R Serlopitant Moderate to severe 2 PDE=phosphodiesterase; H4R=histamine receptor type 4; JAK=Janus kinase; NK1R=neurokinin 1 receptor Paller AS, et al. J Allerg Clin Immunol. 2017;140:

29 Upadacitinib The Oral, Selective JAK1 Inhibitor Upadacitinib Elicited Significant Skin Clearing and Reduction in Itch: Phase 2 Results Mean % Change in EASI 50 at Week Phase 2b dose ranging study in adults patients with moderate to severe AD Primary Endpoint Pruritus Rating Scale Mean % Change in EASI 50 From Mean % Change in Itch From Baseline vs Placebo at Week 16 Baseline vs Placebo at Week 16 *p<0.05 vs placebo **p<0.001 vs placebo 23% * 39% n=39 n=42 ** 62% ** 74% n=42 n=42 0 n=39 n=42 n=42 n=42 0 Placebo 7.5 mg 15 mg 30 mg Placebo 7.5 mg 15 mg 30 mg Most common AEs: upper respiratory tract infection, atopic dermatitis worsening and acne; Serious AEs occurred in 0/1/2 patients in the 30/15/7.5 mg groups vs 1 patient on placebo. No herpes zoster, malignancies, deaths or cases of pulmonary embolism or deep vein thrombosis occurred in the first 16 weeks of the study. EASI 50=50% improvement in the Eczema Area and Severity Index. Guttman Yassky E, et al. Primary Results from a Phase 2b, Randomized, Placebo Controlled Trial of Upadacitinib for Patients with Atopic Dermatitis. Oral presentation at: American Academy of Dermatology Annual Meeting. February Mean % Change in Pruritus Score at Week *p<0.01 vs placebo **p<0.001 vs placebo 10% * 40% ** 48% ** 69%

30 Baricitinib The Oral, Selective JAK1/2 Inhibitor Baricitinib Elicited Significant Skin Clearing at Week 16: Phase 2 Results Phase 2 randomized, double blind, placebo controlled study in adult patients with moderate to severe AD* Primary Endpoint % of Patients Achieving EASI 50 at Week 16 Scoring Atopic Dermatitis (SCORAD) Total % of Patients Achieving EASI 50 at Week 16 Patients Achieving EASI 50 at Week 16 (%) p<0.027 baricitinib 4 mg vs placebo 37% 57% 61% 10 0 n=49 n=37 n=38 Placebo Baricitinib 2 mg + Baricitnib 4 mg + TCS TCS *Topical corticosteroids (TCS) were applied for 4 weeks before randomization; use of TCS permitted during the study. Treatment emergent AEs reported in 49%, 46%, and 71% of placebo, baricitinib 2 mg, and baricitinib 4 mg treated patients, respectively. EASI 50=50% improvement in the Eczema Area and Severity Index. Guttman yassky E, Silverberg JI, Nemoto O, et al. [published online ahead of print September 14, 2017]. J Am Acad Dermatol doi: /j.jaad % 39% 47% Last observation *p<0.05 **p 0.01 ***p 0.001

31 Integrating New Therapies to Improve Disease Control

32 Where Do Targeted Therapies Fit into the Treatment Algorithm? Disease Severity Severe Moderate Mild Non pharmacologic treatments Moisturizers Emollients Phototherapy Eichenfield LF, et al. J Am Acad Dermatol. 2014;70: Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2): Topical agents Corticosteroids Calcineurin inhibitors Phosphodiesterase 4 inhibitors Systemic treatments Cyclosporine Azathioprine Methotrexate Mycophenolate mofetil IL 4/IL 13 inhibitors IL 31 inhibitors* JAK inhibitors* *investigational

33 Improving Disease Control in AD Traditionally, AD has been treated reactively, adjusting treatment in response to symptoms Accumulating evidence suggests AD is a chronic systemic disease active even when symptoms are absent Approaches to improving disease control while minimizing treatment related AEs include Preventive therapy Scheduled intermittent therapy Alternating therapy Targeted therapies may remove a barrier to proactive systemic treatment for moderate to severe AD Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(1): Eichenfield LE, Simpson, EL, Guttman yassky E. Perspectives from the American Academy of Dermatology Meeting 2017: Clinical Strategies and Scientific Advances in Atopic Dermatitis. Elsevier Office of Continuing Medical Education. June 9, 2017 June 8, Accessed March 2018.

34 Summary AD is a chronically relapsing inflammatory skin disease with a complex pathogenesis involving epidermal barrier dysfunction and immune mediated cutaneous inflammation Improved understanding of AD pathogenesis has led to targeted treatment strategies for moderate to severe disease A wide range of biologic agents are under investigation for treatment of AD The availability of targeted biologics may provide additional flexibility and personalization in the treatment in moderate to severe AD Proactive treatment has the potential to result in better disease control

35 Care Management Strategies to Improve Clinical and Economic Outcomes Edmund Pezalla, MD, MPH CEO Enlightenment Bioconsult, LLC

36 Learning Objectives Evaluate strategies to align diagnosis and treatment strategies with current evidence based guidelines Apply practical approaches to improve adherence to AD treatment

37 Moderate to Severe Atopic Dermatitis Affects More Than the Skin Sleep Disruption 32.4% had 1 4 nights of disrupted sleep per week 55% had 5 7 nights of disrupted sleep per week Time to access care Inconvenience Cost Managing side effects Burden of Care Persistent Itch 62.9% had itching lasting at least 12 hours a day 60.5% had severe or unbearable itching 55% had itching for at least 10 years Psychological Distress 22% had Hospital Anxiety and Depression Scale (HADS) scores suggesting clinically relevant anxiety or depression n=380 patients with moderate to severe AD Simpson EL, Bieber T, Eckert L, et al. J Am Acad Dermatol. 2016;74(3):491 8.

38 A Diagnosis of AD is Associated with Increased Use of Health Care Resources Adjusted mean annual number of health care visits and number of prescriptions per patient in AD patients and matched non AD controls in a commercial population Mean annual use AD Non AD *p<0.05 vs non AD population * * * Inpatient visits ER visits Outpatient visits Specialist visits Prescription medication * * Optum Health, Eden Prairie, MN n=83,106 Shrestha S, Miao R, Wang L, Chao J, Yuce H, Wei W. Adv Ther. 2017;34(8):

39 Disease Severity in Children and Adults with AD Children 1 (0 to 17 years) National Survey of Children s Health 26% 7% 67% Adults 2 4 ( 18 years) Robust population based estimates of the prevalence of moderate to severe AD in adults are lacking Extrapolation from other reports: Approximately million adults with diagnosed severe AD are receiving treatment 25% of adults with AD do not seek treatment for their condition Mild Moderate Severe 1. Silverberg JI, Simpson EL. Dermatitis. 2014;25(3): Silverberg JI, Hanifin JM. J Allergy Clin Immunol. 2013;132(5): Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. J Invest Dermatol. 2015;135(1): Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):

40 Assessing the Severity of Atopic Dermatitis >20 disease severity scales exist No gold standard scale Most commonly used is the Scoring Atopic Dermatitis index (SCORAD) Others include: Eczema Area and Severity Index (EASI) Patient Oriented Eczema Measure (POEM) Investigator s Global Assessment (IGA) Scales are primarily research tools; rarely used in clinical practice In clinical practice, severity determined by Duration of disease Thickness of skin lesions Duration and intensity of pruritus Body surface area involved Impact on quality of life (sleep, school/work, social life, etc) Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):

41 The SCORAD is the Only AD Severity Scale that Includes Patient Reported Subjective Symptoms Clinical Variables Scale Erythema Edema / Papulation Oozing / Crusts Excoriation Lichenification Body Surface Area Affected Subjective Symptoms Endpoint SCORAD EASI IGA SCORAD 50 % of pa ents with 50% EASI 50 % of pa ents with 50% % of patients with IGA 0 (clear) or 1 (almost clear) Pruritus Patient reported itch severity 0 = no itch; 10 = worst imaginable itch SCORAD = Scoring Atopic Dermatitis; EASI = Eczema Area and Severity Index; IGA = Investigator s Global Assessment Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):

42 Atopic Dermatitis is a Clinical Diagnosis No universally accepted biomarker(s) to define disease stages, severity, or clinical success Essential Features: Rajka Hanifin Criteria (must be present) Important Features (seen in most cases, adding support to the diagnosis) Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2): Associated Features (suggestive of AD, but too nonspecific to be definitive on their own) Pruritus Early age of onset Atypical vascular response Scabies Exclusionary Conditions (diagnosis of AD depends on excluding these conditions) Eczema Atopy Keratosis pilaris Seborrheic dermatitis Typical morphology and age specific patterns Chronic or relapsing history Personal and/or family history Immunoglobulin E reactivity Ocular/periorbital changes Contact dermatitis Perifollicular accentuation/ lichenification/prurigo lesions Ichthyoses Xerosis Cutaneous T cell lymphoma Psoriasis Immunodeficiency disorders Erythroderma of other causes

43 Management of AD Has Historically Focused on Symptom Relief Reduce symptoms (eg, itch, degree of skin involvement) Reduce inflammation Reduce frequency and severity of exacerbations (flares) Avoid triggers Treatment Goals Minimize treatment related adverse events Follow severity directed treatment Family history of AD Early age of onset Body surface area involved Atopy Factors Associated with Poor Prognosis Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):

44 Treatment of AD is Evolving Rapidly Treatment has consisted of nonspecific anti inflammatory agents (eg, topical corticosteroids and systemic immunosuppressants*) Two targeted therapies (crisaborole, dupilumab) are now approved These agents target the immune dysfunction underlying the pathogenesis of AD *oral immunosuppressants are being used off label Tacrolimus Pimecrolimus Approved Crisaborole Topical corticosteroids in different vehicles (ointment, cream, lotion, spray, foam) Dupilumab Roflumilast Tralokinumab Lebrikizumab Nemolizumab Investigational Topical Injection Oral Ustekinumab Upadacitinib Baricitinib Apremilast Paller AS, Kabashima K, Bieber T. J Allergy Clin Immunol. 2017;140(3):

45 Current Guideline Recommended Approach to AD Treatment Non pharmacologic Topical Therapy Systemic Agents* Emollients Moisturizers Light therapy Corticosteroids Calcineurin inhibitors Cyclosporine Azathioprine Methotrexate Mycophenolate mofetil Mild Disease Severity Severe There is a need for practical guidance on the management of patients with moderate to severe AD requiring systemic therapy *not indicated for the treatment of atopic dermatitis Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2): Lynde CW, Bourcier M, Gooderham M, et al. J Cutan Med Surg. 2018;22(1):78 83.

46 Evidence Assessment for Systemic Treatments for Adults Inadequately Controlled on Topical Therapy Size of RCT Efficacy (short term) Efficacy (long term) Safety (short term) Phototherapy Small Caution or insufficient evidence Safety (long term) Required Monitoring Moderately frequent and/or extensive Methotrexate Moderate Frequent and/or extensive Cyclosporine Moderate Positive effects Frequent and/or extensive Azathioprine Moderate Negative effects Frequent and/or extensive Mycophenolate Small Caution or insufficient evidence Frequent and/or extensive Prednisone Small Caution or insufficient evidence Moderately frequent and/or extensive Dupilumab Large Positive effects Infrequent Investigational targeted agents N/A Ongoing studies N/A Desirable attributes of systemic treatments for adult AD include: 1) reduction in the signs/symptoms of disease, 2) established short and long term safety, 3) regulatory approval for treatment of AD, and 4) minimal laboratory monitoring Lynde CW, Bourcier M, Gooderham M, et al. J Cutan Med Surg. 2018;22(1):78 83.

47 Identifying Candidates for Systemic Therapy Is the diagnosis of moderate to severe AD correct? Have topical therapies failed? Characteristics of patients who are candidates for systemic therapy Itch that disrupts sleep Significant body surface area involvement (BSA 10%) Impaired quality of life Low risk for opportunistic infection Is the patient adherent to treatment? Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2): Lynde CW, Bourcier M, Gooderham M, et al. J Cutan Med Surg. 2018;22(1):78 83.

48 Comparative Clinical Effectiveness of Crisaborole and Dupilumab Methodology Meta analysis of evidence from randomized controlled trials, comparative observational studies, and high quality systematic review Focused on key clinical outcomes common to AD trials as well as symptoms and burden of the disease Included two assessments Comparative clinical effectiveness of crisaborole for its indication in the treatment of mild to moderate AD in children and adults Evaluation of the comparative clinical effectiveness and value of dupilumab for the treatment of moderate to severe AD in adults Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

49 Analytic Framework of the Analyses Interventions Crisaborole or Dupilumab Adverse Events Systemic Dermatologic Ophthalmic Endocrine Pulmonary Others Population 1. Adults and children with mildto moderate AD 2. Adults with moderate tosevere AD Intermediate Outcomes EASI 50, 75, 90 IGA SCORAD Key Measures of Clinical Benefit Health related quality of life Functional outcomes Other patient reported outcomes Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

50 Results: Dupilumab Offers Important Clinical Benefits for Adults with Moderate to Severe AD Outcome Dupilumab Crisaborole IGA Successful outcomes in 30% 44% of patients vs 1% 12% placebo Dosing schedule and concomitant use of topical corticosteroids (TCS) had no impact on results Modestly increased the likelihood of achieving success at 4 weeks vs vehicle EASI Increased likelihood of achieving EASI 75 vs placebo Dosing schedule and concomitant use of TCS had no impact on results PROs Improved quality of life, symptoms scores, and measures of anxiety and depression Harms Well tolerated; AEs were rare during treatment up to 16 weeks Injection site reactions, nasopharyngitis, and headache were the most common AEs Summary Appears to be at least as efficacious as cyclosporine (typically the preferred systemic therapy currently available) and more efficacious than phototherapy Not reported Improved quality of life as measured by DLQI and CLQI, however the differences were smaller than those usually considered clinically meaningful Modestly reduced pruritus Reduce caregiver burden Well tolerated; AEs were rare during all clinical trials Inadequate evidence to assess the relative efficacy of crisaborole vs topical calcineurin inhibitors and TCS Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

51 Modeling the Long term Cost Effectiveness of Dupilumab A Markov model was developed to estimate the cost effectiveness of dupilumab for moderate to severe AD vs usual care over a lifetime horizon Health state was categorized by the percent decrease in EASI after initiating dupilumab or usual care All patients entered the model in the non responder state Patients could then transition to responder states one cycle after initiation of treatment Utility values for quality of life and costs were applied to each health state An annual list price for dupilumab used in the model: $37,000 An estimate of the annual cost of care was also included Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

52 Base Case Results: Dupilumab is Cost Effective Usual Care Dupilumab Incremental Total costs $271,461 $466,168 $194,708 Drug costs* $224,372 $244,372 Other health care costs $271,461 $241,796 $29,665 QALYs Cost per additional QALY $101,830 *Based on the net price for dupilumab. Dupilumab provided an additional 1.91 QALYs over the remaining lifetime of patients, leading to an incremental cost effectiveness ratio of $101,800 per additional QALY gained Cost per additional QALY was lower for patients with severe AD ($78,300) vs those with moderate AD ($130,800) Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

53 Dupilumab Offers Good Long term Value for Adults with Moderate to Severe AD Moderate Severe Usual Care Dupilumab Incremental Usual Care Dupilumab Incremental Total costs $271,356 $482,861 $211,506 $271,579 $447,344 $175,765 Drug costs $243,786 $243,786 $202,480 $202,480 Other health care costs $271,356 $239,075 $32,281 $271,579 $244,864 $26,715 QALYs Cost per additional QALY $130,807 $78,295 Patients with moderate disease had lower health care costs but higher drug costs vs the total population Patients with moderate disease gained fewer QALYs with dupilumab treatment vs severe patients Patients with severe disease had higher health care costs but lower drug costs vs the total population Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

54 Determining the Cost Per Additional QALY for Dupilumab vs Usual Care Sensitivity analysis was used to demonstrate the effects of uncertainty on health care cost and outcomes Key drivers of the base case population included Utility values for quality of life (particularly for non responders) Price of dupilumab Probability of dupilumab being cost effective vs usual care at the $150,000 per QALY threshold 88% overall 70% in patients with moderate AD 95% in patients with severe AD Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

55 The ICER for Dupilumab is At or Below Commonly Cited Thresholds for Cost Effectiveness Total Dupilumab Usual Care Incremental Mean Credible Range Mean Credible Range Mean Credible Range Total costs $466,886 $364,604 $714,037 $271,334 $238,690 $303,910 $195,553 $101,073 $436,399 Total QALYs ICER $105,764 $49,805 $247,604 Moderate Total costs $485,099 $363,682 $883,929 $271,107 $232,554 $312,740 $213,993 $103,512 $612,720 Total QALYs ICER $129,299 $52,763 $492,019 Severe Total costs $446,446 $349,393 $723,588 $271,605 $233,140 $313,696 $174,841 $87,420 $447,697 Total QALYs ICER $80,772 $36,184 $208,567 Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac Atopic Dermatitis Draft Evidence Report pdf Published May Accessed March 2018.

56 Threshold Analysis Results Suggests Patients Who May Benefit From Dupilumab Are Able to Access It Annual Net Price of Dupilumab that Would Achieve Cost Effectiveness Threshold Annual Net Price of Dupilumab $50,000/QALY gained $17,307 $100,000/QALY gained $30,516 $150,000/QALY gained* $43,726 *The price of dupilumab would have to increase to reach the $150,000 per QALY costeffectiveness threshold. For moderate patients, the threshold prices to reach $50,000, $100,000, and $150,000 per QALY would be $14,385, $24,665, and $34,946 respectively, vs $21,275, $38,460, and $55,646, respectively, for severe patients Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

57 Budgetary Impact: Dupilumab is Priced In a Way That Aligns Well With the Benefit It Provides Patients Annual price $50,000 $45,000 $40,000 $35,000 $30,000 $25,000 $20,000 $15,000 $10,000 $5,000 $0 $43,726 $37,000 $31,000 $17,307 0% 5% 10% 15% 20% 25% Uptake among eligible patients at five years ~4% of eligible patients could be treated in a given year without crossing the ICER budget impact threshold of $915 million at WAC ($37,000) The low proportion of AD patients that could be treated at each price point reflects the impact that a new treatment may have in a condition with few current treatments Because dupilumab is not displacing a current therapy, there are fewer offsetting treatment costs for these patients Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. review.org/wpcontent/uploads/2016/10/mwcepac_atopic_dermatitis_draft_evidence_report_ pdf Published May Accessed March 2018.

58 Summary AD is a chronic relapsing remitting inflammatory skin disease associated with a significant clinical, humanistic, and economic burden AD is a clinical diagnosis based on lesion thickness, duration and intensity of pruritus, body surface area involved, and impact on quality of life Treatment is dependent on disease severity, but no uniform measure of severity is currently available Treatment guidelines are available, but do not include recently approved therapies A comparative effectiveness analysis indicated dupilumab appears to be at least as efficacious as cyclosporine whereas there was insufficient evidence to assess the relative efficacy of crisaborole vs other topic therapies An economic modeling analysis indicates that dupilumab improves health outcomes compared to usual care, but with additional costs

59 Benefit Design and Specialty Pharmacy Services for Optimal Management Jeffrey D. Dunn, PharmD, MBA Vice President, Clinical Strategy and Programs and Industry Relations Magellan Rx Management

60 Learning Objective Assess benefit design strategies to improve overall patient outcomes for AD

61 Atopic Dermatitis (AD) is Associated with Significant Burden Characterized by intense itching and recurrent eczematous lesions 1 Typically starts in infancy, but also highly prevalent in adults 1 Associated with acute flares, intractable pruritus, and comorbid health conditions which may prompt urgent care visits 2 Among the top 4 reasons for a visit to a dermatologist or other 1 specialist Itchy, sore, painful, stinging skin Enmbarassed/self conscious Interfered with activities of daily living Influenced clothes worn Affected social activities Affected work/study Affected relationships Impact of treatment Impact of AD on Quality of Life 3 Not at all A little A lot or very much 87.6% 61.6% 39% 57.9% 43.9% 41.8% 26.6% 40% 1. Silverberg JI. JAMA Dermatol. 2015;151(7): Kwa L, Silverberg JI. Abstract 7021: Emergency department visits are common and costly in atopic dermatitis in the United States. Oral presentation at American Academy of Dermatology; February 2018; San Diego, Calif. 3. Simpson EL, Bieber T, Eckert L, et al. J Am Acad Dermatol. 2016;74(3): Patients (%) (n=380)

62 Managed Care Perspective on the Economic Impact of AD Burden of AD Poorer overall health Higher out of pocket costs More physician visits More lost work days Impact High demand for care High utilization of care Need for utilization management strategies To guide appropriate use of therapy To ensure predictable spend Delayed care Silverberg JI. JAMA Dermatol. 2015;151(7):

63 Introduction of Specialty Drugs for AD Requires Careful Consideration of the AD Pharmacy Benefit Crisaborole and dupilumab have the potential to change AD care These agents are likely to improve health outcomes vs usual and existing care, but at an additional cost With ~400,000 adults potentially eligible for treatment with dupilumab, appropriate management strategies will be needed to manage costs Cost of Treating Atopic Dermatitis $30/month Methotrexate $150/month Topical Corticosteroids New specialty drug for atopic dermatitis. Insights Feature. CVS Health Web site. health payor solutions insightsfeature new specialty drug for atopic dermatitis october 2016.pdf. Published October Accessed March Massimiliano A, et al. Drug Design Dev Ther. 2017;11: Special Pharmacy Times. fdaapproved for treatment of atopic dermatitis. Accessed March $500/month Topical Immunosuppressants $2,500 $3,000/month Dupilumab

64 Robust Pipeline of Targeted AD Drug Candidates Ensures the Specialty Spend Will Continue to Increase Historic and Projected Specialty Drug Spend % 70% 50% 50% 60% 40% Traditional Specialty Focus on Trend. Prime Therapeutics Web site. insights/2017 insights/insights specialtyinfographic.html. Published March Accessed March 2018.

65 Specialty Drug Trend: Forecasted PMPY Drug Spend Forecasted PMPY net drug spend ($) Traditional Specialty $514 $425 $348 $290 $845 $722 $612 $665 $675 $694 $722 $751 $789 $ Specialty Drug Trend Across the Pharmacy and Medical Benefit. Artemetrx Web site. content/uploads/2014/08/artemetrxspecialty drug trends.pdf. Published Accessed March 2018.

66 Costs Can Be Effectively Managed by Aligning Distribution, Plan Design and Pharmacy Care Management Cost and Distribution Management Plan Design Pharmacy Care Management Output Better Outcomes Lower cost Incentives and Copay Assistance Technology and Support Tools

67 Basic Tenets of the Specialty Drug Benefit Utilization Management Preferred Drug Management Contract Management Channel Management Care Management Reduce costs by aggressively managing drug utilization Establish preferred products and formulary tiers Use cost sharing to drive use of preferred products, but not limit adherence Aggressively negotiate rebates Incent providers to utilize the most cost effective drugs For pharmacy, optimize the distribution network Optimize site of care Provide counseling and education to patients and caregivers Incent coordinated care Starner CI, Alexander GC, Bowen K, Qiu Y, Wickersham PJ, Gleason PP. Health Affairs. 2014;33(10):

68 Elements Typically Found in the AD Benefit Design Incentive Programs Members Prescribers Patient Access Support Programs Patient assistance Copay coupons AD Benefit Special Pharmacy Integration Case Management Efforts to increase patient ownership of their care Coordination Data management Integrated IT

69 Value = Cost Effectiveness Efficacy Price Cost per event avoided Cost per % improvement Helps compare agents When there are no head to head trials E Intervention less effective and more costly than 0 Clear Loser Intervention less effective and less costly than 0; Depends how much effectiveness you are willing to trade to reduce costs Cost Difference C+ 0 Intervention more effective and more costly than 0; Depends how much effectiveness you are willing to pay for increased effectiveness Intervention more effective and less costly than 0 Clear Winner E+ Effect Difference C

70 Elements of the AD Benefit Design: Formulary Tiers Trend is toward multi tier formularies Patient cost is dependent on the formulary tier Tier 1 Generic Tier 2 Preferred Tier 3 Non preferred Tier 4 Specialty Tier 1: lowest cost Tier 2: slightly higher cost Tier 3: higher cost Tier 4 (specialty drugs): highest cost Formulary positioning depends on the demonstrated value of the drug as assessed by the plan sponsor Least expensive, including all generics and select brands Brand name drugs proven to be most effective in their class Non preferred brand names not considered to be the most effective as well as preferred specialty drugs The most expensive drugs; typically nonpreferred, branded specialty drugs 2017 Aetna Pharmacy Drug Guide. Aetna Web site Published December Accessed March 2018.

71 New Formulary Design Example Pharmacy Benefit Medical Benefit Tier Drug Cost Tier Drug Cost Preferred generic $5 Non preferred generic $10 Preferred brand $50 Non specialty NA Non preferred brand $100 Preferred specialty 10% Preferred specialty 10% Non preferred specialty 20% Non preferred specialty 20%

72 Traditional Versus Potential Value based Contracting 45% of private payers were involved in pay for performance and risk sharing programs in 2010; the number rose to 62% in 2013, and usage of these programs was estimated to be as high as 75% in 2016 Traditional Contracting Value Based Contracting Flat, Volume, or Share Based Indication Based Regimen Based Outcomes Based Concessions may depend on volume or share Rebate %s for Purchased Brand A 4% 3% 2% 1% 0% vials vials vials ILLUSTRATIVE Rebate specific to an indication Rebate paid when two products used in combination Concessions depend on how well the drug works for a patient/cohort Drug manufacturers will increasingly find themselves involved in such arrangements with payers when applicable Long G, Mortimer R, Sanzenbacher G. J Med Econ. 2014;17: Increasing Data & Complexity

73 Manufacturers Are Using Buy Downs to Offset Increasing Patient Cost Exposure Prescription Cost Sharing US$ $150 $100 $50 Buy Down Final out of pocket cost Initial cost of exposure $0 Q1 Q1 Q1 Q1 Q Medicines Use and Spending in the U.S. IMS Institute for Healthcare Informatics Web site. content/uploads/2016/04/ims Institute US Drug Spending 2015.pdf. Published April Accessed March 2018.

74 Copay Coupons Are Used to Reduce Patient Costs But May Potentially Circumvent Formulary Controls Rx (millions) Growth of Copay Coupon Use In 2015, the pharmaceutical industry spent upward of $7 billion to fund coupons. 2 75% of members prescribed a Tier 3 drug are using a copay coupon 3 Coupon use is expected to increase to 500 million prescriptions by How Copay Coupons Could Raise Prescription Drug Costs By $32 Billion Over the Next Decade. Pharmaceutical Care Management Association. content/uploads/2016/08/visantecopay coupon study nov 2011.pdf. Published November Accessed March Koons C, Langreth R. Bloomberg Businessweek /that drugcoupon isn t really clipping costs. Published December 23, Accessed March Sandu A, Avey S. Copay Coupons for Specialty Drugs: Strategies for Health Plans and PBMs. Washington, DC: Atlantic Information Services, Inc; pdf. Accessed March Cahn L. Managed Care. combat pharma s costly coupon programs. Published June 1, Accessed March 2018.

75 Coupons May Be Beneficial for Certain Preferred Drugs For traditional drugs and non preferred specialty drugs, coupons often lead to use of therapies with higher net costs Coupons may be beneficial for the subset of members who have high deductible health plans or high coinsurance prescribed certain preferred specialty drugs Coupon programs that reduce monthly cost sharing to >$250 are associated with a lower risk for patient abandonment of biologic anti inflammatory therapy However, as a way to drive greater savings for plan sponsors, two new specialty copay card programs were introduced in 2017: accumulator adjustment and copay allowance maximization These programs may have unintended consequences Starner CI, Alexander GC, Bowen K, Qiu Y, Wickersham PJ, Gleason PP. Health Affairs. 2014;33(10):

76 Real Savings Come From Providing Optimal Clinical Support and Care Management Total Pharmacy Cost = +

77 Components of Care Management Assess Safety Adverse events Allergies Drug interactions Verify Clinical Appropriateness Route of administration Strength/dose Dosing frequency REMS Adherence Access assistance Initial fill Refills Monitoring Review progress toward goals Manage therapy interruptions Patient Education Treatment expectations Medication administration Support programs Hagerman J, Freed S, Rice G. APhA Web site pharmacy unique and growing industry. Published July 1, Accessed March 2018.

78 Role of Specialty Pharmacy Specialty pharmacists can help determine coverage and service levels for individual health plans or specific products, and reimbursement rates Specialty pharmacists have a good appreciation of unique factors of value to managed care Market pressure Cost Clinical effectiveness and medical evidence Legislated mandate Medical necessity Preventive value

79 Specialty Pharmacy is Well Positioned to Support Care Management Activities Patient Education Drug Administration Drug Dosing Monitoring Therapy expectations Dosing Adverse events Follow up Shipping and storage requirements Patient access/insurance Train patients and caregivers Drug preparation Proper administration techniques Proper handling, storage, and disposal Individualization of dosing Dosing frequency Adherence support Concurrent medications Adverse events Drug interactions Comorbidities

80 Successful AD Pharmacy Management Requires Finding the Appropriate Balance Drug Dispensing Contracting Activities Specialty Drug Management Utilization Management Benefit Design (Cost Share) & Formulary Coordination of Care