Impact Education AMCP Atopic Dermatitis Activity Education AMCP … · Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2) :327‐49. *Not FDA‐approved for AD treatment

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

Clinical Update: The Impact of Novel Therapies

Paul Yamauchi, MD, PhDClinical Assistant Professor of Medicine

Division of Dermatology, David Geffen School of Medicine at UCLAAdjunct Associate Professor

John Wayne Cancer Institute, Santa Monica

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

Atopic Dermatitis: A Chronic Inflammatory Disease• Estimated prevalence in the US1

Adults: 18 million (7.2%) Children (<18 years): 9.6 million (13%)

• Onset typically occurs before age 5• Onset may also occur during adulthood2,3

• Characterized by pruritus and xerosis4

• Follows a waxing and waning course2

• Significantly impairs quality of life4

• Atopic comorbidities4

Asthma Allergic rhinitis

1. Eczema Facts. National Eczema Association Web site. https://nationaleczema.org/research/eczema‐facts/. Accessed March 2018. 2. Margolis JS, Abuabara K, Bilker W, Hoffstad O, Margolis DJ. JAMA Dermatol. 2014;150(6):593‐600. 3. Nutten S. Ann Nutr Metab. 2015;66 Suppl 1:8‐16. 4. Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(1):116‐32.

Genes and the Environment Influence the Natural History of AD

1. Ma CA, Stinson JR, Zhang Y, et al. Nat Genet. 2017;49(11):1192‐1201. 2. Nutten S. Ann Nutr Metab. 2015;66 Suppl 1:8‐16.3. Guttman‐yassky E, Dhingra N, Leung DY. Expert Opin Biol Ther. 2013;13(4):549‐61.

• AD is complex and multifactorial, characterized by genetic mutations, immune dysregulation, skin barrier dysfunction, and abnormal itch response

Genes linked to AD1,2

• FLG (encodes profilaggrin, a skin barrier protein)

• CARD11• Genes that encode inflammatory cytokines (eg, IL‐4, IL‐5, IL‐12, IL‐13)11 gene

~80% of patients with AD have personal or family history of atopy (elevated IgE)3

Environmental factors

Genetics

Epigen

etic re

gulatio

n

Scratching Allergens

AD (IgE Associated)

Environmental factors

(e.g., soap, dust mite)

Immune (atopy)‐related genes

Acquired sensitization

Non‐AD dermatitis (non‐IgE

Associated)

Impaired epithelial barrier

Staphylococcus aureus

Skin barrier‐related genes

Barrier hypothesis:

70% before 1 year old

Immunologichypothesis:30% before 1

year old

Immunologic Dysregulation in AD

Furue M, Chiba T, Tsuji G, et al. Allerg Int. 2017;66(3):398‐403.Lee DE, Clark AK, Tran KA, Shi VY. J Dermatolog Treat. 2017;19. https://www.tandfonline.com/doi/full/10.1080/09546634.2017.1373736. Accessed March 2018.

cAMP=cyclic adenosine monophosphate; FLG=filaggrin gene; IgE=immunoglobulin E; IL=interleukin; PDE4=phosphodiesterase 4; Th2=T helper cell 2; TSLP=thymic stromal lymphopoietin

• 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

↑ JAK‐STAT

↑ PDE4

FLGmutationsOther mutationsLipid defects

pH changes

ProteasesIrritants Trauma/scratching

IL‐22

Th22 cells

B cells IgE

CytokinesTh2 cells

PDE4cAMP

IL‐31Sensoryneurons

Allergens Bacteria

TSLP

ItchIL‐4IL‐13

Mechanisms of Pruritus in AD

Paller AS, Kabashima K, Bieber T. J Allergy Clin Immunol. 2017;140(3):633‐643.

• 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

H1R = histamine receptor type 1; H4R = histamine receptor type 4; JAK = Janus kinase; NK1R = neurokinin 1 receptor

H1Rantagonist

H4Rantagonist

Histamine Protease

IL‐4R AbIL‐4IL‐13

IL‐31

IL‐31 RA AbIL‐31 Ab

NK1Rantagonist

CapsaicinSubstance P ROS

H1R H4R

NeuronsJAKi

PAR2 IL‐4R IL‐31R NK1R TRPV1TRPA1

Histamine‐dependent

Histamine‐independent

C‐Fibers

Comorbidities More Likely to Occur in the AD Population vs Non‐AD Controls

Shrestha S, Miao R, Wang L, Chao J, Yuce H, Wei W. Adv Ther. 2017;34(8):1989‐2006.

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 rhinitisAsthmaFood allergyChronic pulmonary diseaseChronic rhinosinusitisAllergic urticarialAutoimmune disordersConjunctivitisEsophagitisNasal polypsBacterial infectionsFungal infectionsADHDAnxietyDepressionSleep disorderObesity

Treatment of AD Has Historically Been Focused on Symptomatic Relief

• Skin moisturizers Emollients Occlusive agents Humectants

• Bathing practices Bleach baths Wet‐wrap towels

• Light therapy*

• Corticosteroids• Calcineurin inhibitors • Antimicrobial and

antiseptics• Antihistamines

• Systemic corticosteroids• Cyclosporine*• Methotrexate*• Azathioprine*• Mycophenolate mofetil*• Tacrolimus*

Nonpharmacologic Topical Agents Systemic Agents

Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(1):116‐32.Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2):327‐49.

*Not FDA‐approved for AD treatment

New and Emerging Therapies Target Specific Steps in the Th2 Pathway Integral to AD Pathogenesis

1. Vakharia PP, Silverberg JI. BioDrugs. 2017;31(5):409‐422.2. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos

GD. Nat Rev Drug Discov. 2016;15(1):35‐50. 3. Lee DE, Clark AK, Tran KA, Shi VY. J Dermatolog Treat. 2017;19.

https://www.tandfonline.com/doi/full/10.1080/09546634.2017.1373736. Accessed March 2018.

IL‐5‐specific blockers

PDE‐4‐specific blockers

IL‐5

PDE‐4

IgE‐specificmAbs

IL‐4 IL‐4‐specific blockers

IL‐13

JAK

Dual IL‐4 and IL‐13 ‐specific blockers

IL‐13‐specific blockers

JAK‐specific blockers

IL‐4

Allergens MHC class IITCR

Dendritic cell TH0 cell

TH2 cell

B cell IgE

Mast cell

Basophil Histamine

Recently Introduced Targeted Therapies Approved for the Treatment of AD

• 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)

Systemic Therapy1 Topical Therapy2

• Agent: Crisaborole (Eucrisa 2% ointment)

• MOA: Phosphodiesterase (PDE)‐4 inhibitor

• Approval: December 2016

• Indication: Topical treatment of mild‐to‐moderate AD in patients ≥2 years

• Administration: Topical use only (twice daily)

1. Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; 2017.2. Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc; 2016.

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.

Inhibition of IL‐4 Intracellular Signaling

• Fully human IL‐4monoclonal antibody1

• Binds to the IL‐4 receptor α chain, a component of receptors for both IL‐4 and IL‐131

• Blocks both IL‐4 and IL‐13 signaling, cytokines that drive Th2‐mediated inflammation2‐4

Dupilumab

1. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Nat Rev Drug Discov. 2016;15(1):35‐50.

2. Vakharia PP, Silverberg JI. BioDrugs. 2017;31(5):409‐422.3. Lee DE, Clark AK, Tran KA, Shi VY. J Dermatolog Treat. 2017;19.

https://www.tandfonline.com/doi/full/10.1080/09546634.2017.1373736. Accessed March 2018.

4. Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; 2017.

Dupilumab is indicated for the treatment of adults (≥18 years) with moderate‐to‐severe atopic dermatitis uncontrolled with topical therapies.

IL‐4

IL‐4

IL‐13

IL‐13

JAK1 JAK3STAT6

JAK1STAT3STAT6TYK2

•B cells•T cells•Monocytes•Eosinophils•Fibroblasts

•Epithelial cells•Smooth muscle cells•Fibroblasts•Monocytes•Activated B cells

Type I receptor Type II receptor

IL‐4Rα γc IL‐4Rα IL‐13Rα1

IL‐4

Patients with Moderate‐to‐Severe AD Treated with Dupilumab Experienced Significant Skin Clearing by Week 16

Dupilumab Phase 3 SOLO Trials

IGA=Investigator’s Global Assessment; EASI‐75=75% improvement in the Eczema Area and Severity Index.IGA 0 = “clear”; IGA =1 = almost clearSimpson EL, Bieber T, Guttman‐yassky E, et al. N Engl J Med. 2016;375(24):2335‐2348.

10.3 8.5

37.9 36.137.2 36.4

0102030405060708090100

SOLO 1 SOLO 2

Patie

nts (%

)

Placebo Dupilumab 300 mg (q2 weeks) Dupilumab 300 mg (q week)

14.7 11.9

51.344.2

52.548.1

0102030405060708090100

SOLO 1 SOLO 2

Patie

nts (%

)

Primary EndpointIGA of 0 or 1 and ≥2 points decrease from

baseline at Week 16

Key Secondary EndpointEASI‐75 at Week 16

*p<0.001 vs placebo

* * * ** *

* *

*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


Combined Treatment with Dupilumab + TCS Elicited Significant Skin Clearing at Week 16 Which Was Maintained Through Week 52

Dupilumab Phase 3 CHRONOS Trial

12 13

39 3639 40

0102030405060708090100

Week 16 Week 52

Patie

nts (%

)

Placebo + TCS Dupilumab 300 mg (q2 weeks) + TCS Dupilumab 300 mg (q week) + TCS

23 22

69 6564 64

0102030405060708090100

Week 16 Week 52

Patie

nts (%

)

Primary EndpointIGA of 0 or 1 and ≥2 points decrease from

baseline at Week 16

Key Secondary EndpointEASI‐75 at Week 16

*p<0.001 vs placebo + TCS

* * * *

* * * *

*p<0.001 vs placebo + TCS

n=315 n=106 n=319 n=264 n=89 n=270 n=315 n=106 n=319 n=264 n=89 n=270

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 clearBlauvelt A, De bruin‐weller M, Gooderham M, et al. Lancet. 2017;389(10086):2287‐2303.Dupilumab is indicated for the treatment of adults (≥18 years) with moderate‐to‐severe atopic dermatitis uncontrolled with topical therapies.

Safety ProfileDupilumab

Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; 2017.

• 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

Warning and Precautions 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


Treatment with Dupilumab Resulted in Extensive Skin Clearing in Children and Adolescents

Dupilumab Phase 2a Data

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.

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)




Recently Approved Therapy:Crisaborole

Indication:Topical treatment of mild‐to‐moderate atopic dermatitis in patients ≥2 years.

• 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

Healthy Skin Atopic Dermatitis PDE‐4 Inhibition

• PDE‐4 modulates production of inflammatory cytokines by its action on cAMP

A Non‐steroidal Phosphodiesterase (PDE)‐4 InhibitorCrisaborole

PDE4 = phosphodiesterase 4; cAMP = cyclic adenosine monophosphate; AMP = adenosine monophosphate. Jarnagin K, Chanda S, Coronado D, et al. J Drugs Dermatol. 2016;15(4):390‐6..

Crisaborole is indicated for the topical treatment of mild‐to‐moderate atopic dermatitis in patients ≥2 years.

Patients with Mild‐to‐Moderate AD Treated with Crisaborole Experienced Significant Skin Clearing and Reduction of Itch

Crisaborole

25.418

32.8 31.4

0

10

20

30

40

50

60

70

80

90

100

AD‐301 AD‐302

Patie

nts Ac

hieving

Success at Day 29 (%

)

Primary Endpoint*

Vehicle

Crisaborole

n=256 n=250n=503 n=513

p=0.038 p<0.001

0

10

20

30

40

50

60

70

80

90

100

Baseline Day 8 Day 15 Day 22 Day 29Patie

nts Ac

hieving

Improvem

ents in

Pruritus (%

)

Improvement in Pruritus

Vehicle Crisaborole

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;75:494‐503.

Two identically designed, vehicle‐controlled, double‐blind studies enrolled patients ≥2 years with mild or moderate AD


Safety ProfileCrisaborole

Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc; 2016.

• 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

StudyAD‐301

Study AD‐302 Pooled

Crisaborole(n=502)

Vehicle(n=252)

Crisaborole(n=510)

Vehicle(n=247)

Crisaborole(n=1012)

Vehicle(n=499)

Application site pain (%) 6.2 1.2 2.7 1.2 4.4 1.2

Upper respiratory tract infection (%)

2.8 4.0 3.1 2.0 3.0 3.0


Agents in Late Phase Development for the Treatment of Atopic Dermatitis

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 124249/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;140:633‐643.

Biologic Agents in Development for the Treatment of AD


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


The IL‐13 Inhibitor Tralokinumab + TCS Elicited Improvement in EASI in Patients with Moderate‐to‐Severe AD: Phase 2 Results

Tralokinumab

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.

Phase 2b Results1EASI Mean Change from Baseline

Placebo + TCS

Tralokinumab 150 mg + TCS



0 2 4 6 8 10 12 16 22

0

‐5

‐10

‐15

Adjusted

mean chan

ge in

EAS

I

Post‐treatment

Time (weeks)

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)

• 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

The IL‐13 Inhibitor Lebrikizumab + TCS Elicited Skin Clearance in Patients with Moderate‐to‐Severe AD: Phase 2 TREBLE Trial

Lebrikizumab

SD=single doseQ4W=every 4 weeksSimpson EL, Flohr C, Eichenfield LF, et al. [published online ahead of print January 15, 2018]. J Am Acad Dermatol. doi.org/10.1016/j.jaad.2018.01.017.

• 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

62.369.2 69.8

82.4

0102030405060708090

100

Placebo 125 mgSD

250 mgSD

125 mgQ4W

Patie

nts (%

)

Primary EndpointEASI‐50

3438.5

49.154.9

0102030405060708090100

Placebo 125 mgSD

250 mgSD

125 mgQ4W

Patie

nts (%

)

EASI‐75

18.9 21.228.3

33.3

0102030405060708090100

Placebo 125 mgSD

250 mgSD

125 mgQ4W

Patie

nts (%

)

IGA 0 or 1

n=53 n=52 n=53 n=51 n=53 n=52 n=53 n=51 n=53 n=52 n=53 n=51

**p= 0.026 vs placebo

The IL‐31 Inhibitor Nemolizumab Significantly Reduced Itch in a Phase 2 Trial

Nemolizumab

Ruzicka T, Hanifin JM, Furue M, et al. N Engl J Med. 2017;376(9):826‐835.

Chan

ge in

pruritus (%

)

−80

−60

Time (weeks)

−40

2 71 10

−20

0

4 65 12983 110

Placebo

0.5 mg/kg q4wks

0.1 mg/kg q4wks

2.0 mg/kg q4wks

‐20.9 ‐43.7 ‐59.8 ‐63.1

‐100

‐80

‐60

‐40

‐20

0Placebo 0.1 mg/kg 0.5 mg/kg 2.0 mg/kg

Percen

t cha

nge in pruritus score,

baselin

e to W

eek 12

p=0.002

p<0.001

p<0.001

Primary EndpointPercent Change From Baseline in the Pruritus Score at Week 12

Weekly Change in Pruritus Score

• Adults with moderate‐to‐severe AD (n=264)• Nemolizumab dosed every 4 weeks

Small Molecules in Development for the Treatment of AD


PDE‐4 Apremilast Moderate‐to‐severe 2

H4R ZPL389 Moderate‐to‐severe 2

JAK1, JAK2 Baricitinib Moderate‐to‐severe 3

JAK1 PF‐04965842 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


The Oral, Selective JAK1 Inhibitor Upadacitinib Elicited Significant Skin Clearing and Reduction in Itch: Phase 2 Results

Upadacitinib

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 2018.

23%

39%

62%

74%

0102030405060708090

100

Placebo 7.5 mg 15 mg 30 mg

Mean % Cha

nge in

EASI‐50 at W

eek 16

n=39 n=42

Primary EndpointMean % Change in EASI‐50 From Baseline vs Placebo at Week 16

Phase 2b dose ranging study in adults patients with moderate‐to‐severe ADPruritus Rating Scale

Mean % Change in Itch From Baseline vs Placebo at Week 16

n=42 n=42

*p<0.05 vs placebo**p<0.001 vs placebo

*

****

10%

40%48%

69%

0102030405060708090

100

Placebo 7.5 mg 15 mg 30 mg

Mean % Cha

nge in Pruritus

Score at W

eek 16

n=39 n=42 n=42 n=42

*p<0.01 vs placebo**p<0.001 vs placebo

***

**

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.

The Oral, Selective JAK1/2 Inhibitor Baricitinib Elicited Significant Skin Clearing at Week 16: Phase 2 Results

Baricitinib

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. 2018. doi: 10.1016/j.jaad.2018.01.018.

37%

57% 61%

0102030405060708090

100

Placebo Baricitinib 2 mg +TCS

Baricitnib 4 mg +TCS

Patie

nts Ac

hieving

EASI‐50 at W

eek 16

(%)

n=49 n=37 n=38

Primary Endpoint% of Patients Achieving EASI‐50 at Week 16

Phase 2 randomized, double‐blind, placebo‐controlled study in adult patients with moderate‐to‐severe AD*

*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.

†p<0.027 baricitinib 4 mg vs placebo

†

Scoring Atopic Dermatitis (SCORAD) Total% of Patients Achieving EASI‐50 at Week 16

‐16%

‐39%

‐47%

Last observation

*p<0.05**p≤0.01***p≤0.001

Integrating New Therapies to Improve Disease Control

Where Do Targeted Therapies Fit into the Treatment Algorithm?

Non‐pharmacologic treatments• Moisturizers• Emollients• Phototherapy

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*

Mild

Moderate

Severe

Disease Severity

*investigational

Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338‐351. Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2):327‐49.

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):116‐32.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. https://courses.elseviercme.com/aad/712. June 9, 2017 – June 8, 2018. Accessed March 2018.

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

Care Management Strategies to Improve Clinical and Economic

OutcomesEdmund Pezalla, MD, MPH

CEOEnlightenment Bioconsult, LLC

Learning Objectives

• Evaluate strategies to align diagnosis and treatment strategies with current evidence‐based guidelines

• Apply practical approaches to improve adherence to AD treatment

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

Simpson EL, Bieber T, Eckert L, et al. J Am Acad Dermatol. 2016;74(3):491‐8.

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

n=380 patients with moderate‐to‐severe AD

Psychological Distress• 22% had Hospital Anxiety and Depression Scale (HADS) scores suggesting clinically relevant anxiety or depression

Burden of Care• Time to access care• Inconvenience• Cost•Managing side effects

A Diagnosis of AD is Associated with Increased Use of Health Care Resources

Shrestha S, Miao R, Wang L, Chao J, Yuce H, Wei W. Adv Ther. 2017;34(8):1989‐2006.

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†

0.20.9

12.2

1.5

11.9

0.1 0.6

6.8

0.2

7.5

0

2

4

6

8

10

12

14

Inpatient visits ER visits Outpatient visits Specialist visits Prescription medication

Mean an

nual use

AD Non‐AD

*p<0.05 vs non‐AD population

*

*

*

*

*

†Optum Health, Eden Prairie, MNn=83,106

Disease Severity in Children and Adults with AD

• Robust population‐based estimates of the prevalence of moderate‐to‐severe AD in adults are lacking

• Extrapolation from other reports: Approximately 0.7–1.2 million adults with diagnosed severe AD are receiving treatment

25% of adults with AD do not seek treatment for their condition

Children1(0 to 17 years)

Adults2‐4(≥18 years)

67%

26%

7%

Mild Moderate Severe

National Survey of Children’s Health

1. Silverberg JI, Simpson EL. Dermatitis. 2014;25(3):107‐14. 2. Silverberg JI, Hanifin JM. J Allergy Clin Immunol. 2013;132(5):1132‐8. 3. Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. J Invest Dermatol. 2015;135(1):56‐66. 4. Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):338‐51.

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

Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):338‐51.

• 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)

The SCORAD is the Only AD Severity Scale that Includes Patient‐Reported Subjective Symptoms

Scale

Clinical VariablesBody Surface Area Affected

Subjective Symptoms EndpointErythema

Edema / Papulation

Oozing / Crusts Excoriation Lichenification

SCORAD SCORAD‐50% of pa ents with 50% ↓

EASI EASI‐50% of pa ents with 50% ↓

IGA % of patients with IGA 0 (clear) or 1 (almost clear)

Pruritus Patient‐reported itch severity0 = no itch; 10 = worst imaginable itch


SCORAD = Scoring Atopic Dermatitis; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment

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)

Associated Features (suggestive of AD, but too nonspecific to

be definitive on their own)

Exclusionary Conditions(diagnosis of AD depends on excluding these conditions)

• Pruritus • Early age of onset • Atypical vascular response • Scabies

• Eczema • Atopy • Keratosis pilaris • Seborrheic dermatitis

• Typical morphology and age‐specific patterns

• Personal and/or family history • Ocular/periorbital changes • Contact dermatitis

• Chronic or relapsing history

• Immunoglobulin E reactivity

• Perifollicular accentuation/lichenification/prurigo lesions • Ichthyoses

• Xerosis • Cutaneous T‐cell lymphoma

• Psoriasis

• Immunodeficiency disorders

• Erythroderma of other causes

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

• Minimize treatment‐related adverse events

• Follow severity‐directed treatment

• Family history of AD

• Early age of onset

• Body surface area involved

• Atopy

Treatment Goals Factors Associated with Poor Prognosis


Treatment of AD is Evolving Rapidly

• Treatment has consisted of non‐specific 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

Crisaborole

DupilumabPimecrolimus

Tacrolimus

Approved Investigational

Roflumilast

Tralokinumab

Lebrikizumab

Nemolizumab

Ustekinumab

Upadacitinib

Baricitinib

Apremilast2000 2001 2016 2017

Topical corticosteroidsin different vehicles

(ointment, cream, lotion, spray, foam)

Topical

Injection

Oral

Paller AS, Kabashima K, Bieber T. J Allergy Clin Immunol. 2017;140(3):633‐643.

*oral immunosuppressants are being used off label

Current Guideline‐Recommended Approach to AD Treatment

Disease SeverityMild Severe

Non‐pharmacologic Topical Therapy Systemic Agents*• Emollients• Moisturizers• Light therapy

• Corticosteroids• Calcineurin inhibitors

• Cyclosporine• Azathioprine• Methotrexate• Mycophenolate mofetil

There is a need for practical guidance on the management of patients with moderate‐to‐severe AD requiring systemic therapy

Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70(2):338‐51.Lynde CW, Bourcier M, Gooderham M, et al. J Cutan Med Surg. 2018;22(1):78‐83.

*not indicated for the treatment of atopic dermatitis

Evidence Assessment for Systemic Treatments for Adults Inadequately Controlled on Topical Therapy

Size of RCT Efficacy (short‐term)

Efficacy (long‐term)

Safety(short‐term)

Safety (long‐term) Required Monitoring

Phototherapy Small Caution or insufficient evidence Moderately frequent and/or extensive

Methotrexate Moderate Frequent and/or extensive

Cyclosporine Moderate Positive effects

Negative effects

Frequent and/or extensive

Azathioprine Moderate 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

Lynde CW, Bourcier M, Gooderham M, et al. J Cutan Med Surg. 2018;22(1):78‐83.

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

Identifying Candidates for Systemic Therapy

Is the diagnosis of moderate‐to‐severe AD

correct?

Have topical therapies failed?

Is the patient adherent to treatment?

• 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

Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2):327‐49.Lynde CW, Bourcier M, Gooderham M, et al. J Cutan Med Surg. 2018;22(1):78‐83.

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. https://icer‐review.org/wp‐content/uploads/2016/10/MWCEPAC_Atopic_Dermatitis_Draft_Evidence_Report_032417.pdf Published May 2017. Accessed March 2018.

Analytic Framework of the Analyses


InterventionsCrisaborole

or Dupilumab

Adverse Events• Systemic• Dermatologic• Ophthalmic• Endocrine• Pulmonary• Others

Population1. Adults and children with mild‐

to‐moderate AD2. Adults with moderate‐to‐

severe AD

Key Measures of Clinical Benefit• Health‐related quality of life• Functional outcomes• Other patient‐reported

outcomes

Intermediate Outcomes• EASI 50, 75, 90• IGA• SCORAD

Results: Dupilumab Offers Important Clinical Benefits for Adults with Moderate‐to‐Severe AD


Outcome Dupilumab CrisaboroleIGA • 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

• Not reported

PROs • Improved quality of life, symptoms scores, and measures of anxiety and depression

• Improved quality of life as measured by DLQI and CLQI, howeverthe differences were smaller than those usually considered clinically meaningful

• Modestly reduced pruritus• Reduce caregiver burden

Harms • Well‐tolerated; AEs were rare during treatment up to 16 weeks• Injection‐site reactions, nasopharyngitis, and headache were the

most common AEs

• Well‐tolerated; AEs were rare during all clinical trials

Summary • Appears to be at least as efficacious as cyclosporine (typically the preferred systemic therapy currently available) and more efficacious than phototherapy

• Inadequate evidence to assess the relative efficacy of crisaborolevs topical calcineurin inhibitors and TCS

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


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 14.37 16.28 1.91

Cost per additional QALY ‐‐ ‐‐ $101,830

• 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)

*Based on the net price for dupilumab.

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 16.00 17.62 1.62 12.52 14.77 2.24

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

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

The ICER for Dupilumab is At or Below Commonly Cited Thresholds for Cost‐Effectiveness

Dupilumab and crisaborole for atopic dermatitis: evidence and value. Institute for Clinical and Economic Review. https://icer‐review.org/wp‐content/uploads/2016/10/MWCEPAC Atopic Dermatitis Draft Evidence Report 032417.pdf Published May 2017. Accessed March 2018.

Dupilumab Usual Care Incremental

Mean Credible Range Mean Credible Range Mean Credible RangeTotal

Total costs $466,886 $364,604― $714,037 $271,334 $238,690― $303,910 $195,553 $101,073― $436,399

Total QALYs 16.28 14.43―18.14 14.37 12.21―16.52 1.91 1.23―2.64

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 17.62 15.34―19.94 16.00 13.11―18.88 1.62 0.64―2.68

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 14.77 12.59―16.97 12.53 9.78―15.23 2.25 1.41―3.14

ICER ‐‐ ‐‐ ‐‐ ‐‐ $80,772 $36,184― $208,567

Threshold Analysis Results Suggests Patients Who May Benefit From Dupilumab Are Able to Access It

Threshold Annual Net Price of Dupilumab

$50,000/QALY gained $17,307

$100,000/QALY gained $30,516

$150,000/QALY gained* $43,726

Annual Net Price of Dupilumab that Would Achieve Cost‐Effectiveness

*The price of dupilumab would have to increase to reach the $150,000 per QALY cost‐effectiveness 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

Budgetary Impact: Dupilumab is Priced In a Way That Aligns Well With the Benefit It Provides Patients


• ~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

$43,726

$37,000

$31,000

$17,307

$0

$5,000

$10,000

$15,000

$20,000

$25,000

$30,000

$35,000

$40,000

$45,000

$50,000

0% 5% 10% 15% 20% 25%

Annu

al pric

e

Uptake among eligible patients at five years

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 crisaborolevs other topic therapies

• An economic modeling analysis indicates that dupilumab improves health outcomes compared to usual care, but with additional costs

Benefit Design and Specialty Pharmacy Services for Optimal Management

Jeffrey D. Dunn, PharmD, MBAVice President, Clinical Strategy and Programs and Industry Relations

Magellan Rx Management

Learning Objective

• Assess benefit design strategies to improve overall patient outcomes for AD

Atopic Dermatitis (AD) is Associated with Significant Burden• Characterized by intense itching and recurrent eczematous lesions1

• Typically starts in infancy, but also highly prevalent in adults1

• Associated with acute flares, intractable pruritus, and comorbid health conditions which may prompt urgent care visits2

• Among the top 4 reasons for a visit to a dermatologist or other1 specialist

1. Silverberg JI. JAMA Dermatol. 2015;151(7):743‐52. 2. 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):491‐8.

Impact of AD on Quality of Life3

40%

26.6%

41.8%

43.9%

57.9%

39%

61.6%

87.6%

0 50 100

Impact of treatment

Affected relationships

Affected work/study

Affected social activities

Influenced clothes worn

Interfered with activities of daily living

Enmbarassed/self‐conscious

Itchy, sore, painful, stinging skin

Patients (%)(n=380)

Not at all A little A lot or very much

Managed Care Perspective on the Economic Impact of AD

Higher out‐of‐pocket costs

Silverberg JI. JAMA Dermatol. 2015;151(7):743‐52.

Burden of AD Impact

Poorer overall health

More lost work days

More physician visits

Delayed care

• High demand for care

• High utilization of care

• Need for utilization management strategies• To guide appropriate use of

therapy

• To ensure predictable spend

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

New specialty drug for atopic dermatitis. Insights Feature. CVS Health Web site. https://payorsolutions.cvshealth.com/sites/default/files/cvs‐health‐payor‐solutions‐insights‐feature‐new‐specialty‐drug‐for‐atopic‐dermatitis‐october‐2016.pdf. Published October 2016. Accessed March 2018.Massimiliano A, et al. Drug Design Dev Ther. 2017;11:1473‐1480.Special Pharmacy Times. https://www.specialtypharmacytimes.com/news/dupilumab‐fda‐approved‐for‐treatment‐of‐atopic‐dermatitis. Accessed March 2018.

Cost of Treating Atopic Dermatitis

$30/monthMethotrexate

$150/monthTopical Corticosteroids

$500/monthTopical

Immunosuppressants$2,500‐$3,000/month

Dupilumab

Robust Pipeline of Targeted AD Drug Candidates Ensures the Specialty Spend Will Continue to Increase

70%

30%

2013

50%50%

2018

40%60%

2021

Traditional Specialty

Historic and Projected Specialty Drug Spend

Focus on Trend. Prime Therapeutics Web site. https://www.primetherapeutics.com/en/news/prime‐insights/2017‐insights/insights‐specialty‐infographic.html. Published March 2017. Accessed March 2018.

Specialty Drug Trend: Forecasted PMPY Drug Spend

Specialty Drug Trend Across the Pharmacy and Medical Benefit. Artemetrx Web site. http://www.artemetrx.com/wp‐content/uploads/2014/08/artemetrx‐specialty‐drug‐trends.pdf. Published 2013. Accessed March 2018.

$665 $675 $694 $722 $751 $789 $836$290 $348

$425$514

$612$722

$845

0200400600800

10001200140016001800

2012 2013 2014 2015 2016 2017 2018

Forecasted

PMPY

ne

t drug spen

d ($)

Traditional Specialty

Costs Can Be Effectively Managed by Aligning Distribution, Plan Design and Pharmacy Care Management

Plan Design Pharmacy Care Management

Better OutcomesLower cost

Technology and Support

Tools

Incentives and Copay Assistance

Output

Cost and Distribution Management

Basic Tenets of the Specialty Drug Benefit

• Reduce costs by aggressively managing drug utilizationUtilization

Management

• Establish preferred products and formulary tiers• Use cost sharing to drive use of preferred products, but not limit adherence

Preferred Drug Management

• Aggressively negotiate rebates• Incent providers to utilize the most cost‐effective drugs

Contract Management

• For pharmacy, optimize the distribution network• Optimize site of care

Channel Management

• Provide counseling and education to patients and caregivers• Incent coordinated care

Care Management

Starner CI, Alexander GC, Bowen K, Qiu Y, Wickersham PJ, Gleason PP. Health Affairs. 2014;33(10):1761‐69.

Elements Typically Found in the AD Benefit Design

AD Benefit

Incentive Programs• Members• Prescribers

Special Pharmacy Integration

Case Management• Efforts to increase patient ownership of their care

Coordination • Data management• Integrated IT

Patient Access Support Programs

• Patient assistance • Copay coupons

Value = Cost Effectiveness

• Efficacy

• Price

• Cost per event avoided

• Cost per % improvement

• Helps compare agents – When there are no head‐to‐head trials

Cost DifferenceC+

E+

Effect Differen

ce

C‐

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

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

0

Elements of the AD Benefit Design: Formulary Tiers • Trend is toward multi‐tier formularies

• Patient cost is dependent on the formulary tier• 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

2017 Aetna Pharmacy Drug Guide. Aetna Web site https://fm.formularynavigator.com/MemberPages/pdf/2017AetnaCommercialFourTierOpenFullyInsuredFormulary_9824_Full_0.pdf. Published December 2017. Accessed March 2018.

Tier 1Generic

Tier 2Preferred

Tier 3Non‐preferred

Tier 4Specialty

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 non‐preferred,branded

specialty drugs

New Formulary Design Example

Pharmacy Benefit Medical BenefitTier Drug Cost Tier Drug Cost

Preferred generic $5

Non‐specialty NANon‐preferred generic $10

Preferred brand $50

Non‐preferred brand $100

Preferred specialty 10% Preferred specialty 10%

Non‐preferred specialty 20% Non‐preferred specialty 20%

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

Long G, Mortimer R, Sanzenbacher G. J Med Econ. 2014;17:883‐893.

Concessions may depend on volume or

share

Increasing Data & Complexity

Value‐Based ContractingTraditional Contracting

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

Indication‐Based Regimen‐Based

“Outcomes”Based

Flat, Volume, or Share‐Based

4%3%2%1%0% 100

vials200vials

ILLUSTRATIVE

Rebate %s forPurchased Brand A

400vials

Drug manufacturers will increasingly find themselves involved in such arrangements with

payers when applicable

Manufacturers Are Using “Buy Downs” to Offset Increasing Patient Cost Exposure

Medicines Use and Spending in the U.S. IMS Institute for Healthcare Informatics Web site. https://morningconsult.com/wp‐content/uploads/2016/04/IMS‐Institute‐US‐Drug‐Spending‐2015.pdf. Published April 2016. Accessed March 2018.

$0

$50

$100

$150

Prescriptio

n Co

st Sha

ring US$

Buy Down Final out‐of‐pocket cost Initial cost of exposure

Q1 Q1 Q1 Q1 Q1

2011 2012 2013 2014 2015

Copay Coupons Are Used to Reduce Patient Costs But May Potentially Circumvent Formulary Controls

1. How Copay Coupons Could Raise Prescription Drug Costs By $32 Billion Over the Next Decade. Pharmaceutical Care Management Association. https://www.pcmanet.org/wp‐content/uploads/2016/08/visante‐copay‐coupon‐study‐nov‐2011.pdf. Published November 2011. Accessed March 2018. 2. Koons C, Langreth R. Bloomberg Businessweek. http://www.bloomberg.com/news/articles/2015‐12‐23/that‐drug‐coupon‐isn‐t‐really‐clipping‐costs. Published December 23, 2015. Accessed March 2018. 3. Sandu A, Avey S. Copay Coupons for Specialty Drugs: Strategies for Health Plans and PBMs. Washington, DC: Atlantic Information Services, Inc; 2014. https://aishealth.com/sites/all/files/file_downloads/gc4p04_08‐14.pdf. Accessed March 2018. 4. Cahn L. Managed Care. https://www.managedcaremag.com/archives/2012/5/how‐combat‐pharma’s‐costly‐coupon‐programs. Published June 1, 2012. Accessed March 2018.

• 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 coupon3

• Coupon use is expected to increase to 500 million prescriptions by 20214

0

50

100

150

200

250

300

350

400

450

2009 2010 2011 2012 2013 2014

Rx (m

illions)

Growth of Copay Coupon Use1

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):1761‐69.

Real Savings Come From Providing Optimal Clinical Support and Care Management

= +Total Pharmacy

Cost

Components of Care Management

Hagerman J, Freed S, Rice G. APhA Web site http://www.pharmacist.com/specialty‐pharmacy‐unique‐and‐growing‐industry. Published July 1, 2013. Accessed March 2018.

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

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

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

Successful AD Pharmacy Management Requires Finding the Appropriate Balance

Specialty Drug Management

Drug Dispensing

Utilization Management

Coordination of Care

Contracting Activities

Benefit Design (Cost Share)

&Formulary

Summary

• The AD treatment landscape is evolving rapidly with the introduction of two novel products and several others in late‐stage development

• While many patients stand to gain with the growth in the number of therapeutic options, these benefits will come at a higher cost

• To ensure patient access to these innovative therapies, the AD benefit must evolve to maintain a balance between access, appropriate use, and cost management

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

Documents

Impact Education AMCP Atopic Dermatitis Activity Education AMCP … · Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(2) :327‐49. *Not FDA‐approved for AD treatment