Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies

Faculty

Jeffrey D. Dunn, PharmD, MBAChief Clinical Officer/Senior Vice President

VRx Pharmacy ServicesSalt Lake City, Utah

Raymond Cross, MD, MSProfessor of Medicine

Division of Gastroenterology and HepatologyDirector, IBD Program

University of Maryland School of MedicineCo-Director, Digestive Health Center

University of Maryland Medical CenterBaltimore, Maryland

Learning Objectives

• Describe the clinical progression of IBD and the clinical and economic consequences of undertreatment, including hospital and surgery costs

• Outline unmet patient needs and treatment shortfalls of conventional IBD pharmacotherapies

• Evaluate the safety, efficacy, mechanisms of action, and pharmacoeconomic profiles of newer IBD treatment modalities

• Develop or augment health plan policies that improve patient access to individualized IBD care

Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies

Jeffrey D. Dunn, PharmD, MBAChief Clinical Officer/Senior Vice President

VRx Pharmacy ServicesSalt Lake City, Utah

Introduction and Issues

• IBD is a broad disease state that is not often well understood– Huge clinical and financial implications

• IBD biologic class of medication is the #1 specialty spend– Multiple drugs with different MOA, indications, routes of administration

• Contracts are by drug, not disease state

– Price and price increases• Lack of useful guidelines, measures, start/stop rules

• Biosimilars coming to market

• There is a need for education

• New evidence outlining best practices– Data and treatment approaches

– Care coordination

– Benefit design

– Specialty strategies

IBD = inflammatory bowel disease; MOA = mechanism of action.Inflammatory Bowel Disease (IBD), US Centers for Disease Control and Prevention Web site. Available at http://www.cdc.gov/ibd/. Accessed December21, 2015.

IBD vs IBS

• What it is?

• What it is not: IBS– The cause of IBS remains unknown,

although symptoms may be explained, at least in some patients, by

• Alterations in intestinal motility

• Visceral hypersensitivity

• Brain response to visceral stimuli

– Activation of the mucosal immune system increases the number of lymphocytes in the GI tract

• These lymphocytes can release mediators that stimulate the enteric nervous system, increase abdominal pain, and increase inflammation

– Rome III criteria are used to differentiate between IBS and other GI disorders

– There is no gold standard for the treatment of IBS-D

• Treatment is geared toward symptoms

IBS = irritable bowel syndrome; GI = gastrointestinal; IBS-D = irritable bowel disease with diarrhea as the primary bowel dysfunction.Ford AC, et al. Am J Gastroenterol. 2014;109:S2-S26; doi:10.1038/ajg.2014.187.

Rome III Criteria

Recurrent abdominal pain or discomfort for at least 3 days/month in the past 3 months associated with two of the following

• Improvement with defecation

• Onset associated with a change in frequency of stool

• Onset associated with a change in form (appearance) of stool

Criteria must be fulfilled for the past 3 months with symptom onset at least 6 months prior to diagnosis

Option Quality of Evidence

Nonpharmacologic options (eg, diet and increased fiber)

Range from very low to moderate

Antispasmodics andpeppermint oil

Antispasmodics: Low Peppermint oil: Moderate

AntidepressantsTricyclic antidepressants:High

Loperamide Very low

Serotonergic agents Moderate

IBD: What It Is

UC

• Characterized by recurring episodes of inflammation limited to the mucosal layer of the colon

– Commonly involves the rectum and may extend in a proximal and continuous fashion to involve other parts of the colon

– Associated symptoms: Colicky abdominal pain, urgency, tenesmus

• Patients may also have fever, fatigue, and weight loss

– Associated complications: Severe bleeding, toxic megacolon, perforation, strictures, development of dysplasia and colorectal cancer

• Patients may have a slightly higher mortality vs general population

CD

• A disorder of uncertain etiology characterized by transmural inflammation of the gastrointestinal tract

– May involve the entire gastrointestinal tract from the mouth to the perianal area

– Hallmarks: Prolonged diarrhea with abdominal pain, with or without gross bleeding, fatigue, weight loss

• Patients can present with symptoms secondary to the transmural involvement of the bowel, including fistulas, phlegmon, abscess, perianal disease, and/or malabsorption

• Extraintestinal manifestations, such as arthritis, eye and skin disorders, biliary tract involvement, and kidney stones, may occur and tend to be more frequent with colonic involvement

• Typically involves small and/or large intestine, intermittent exacerbations of symptoms, periods of remission

UC = ulcerative colitis; CD = Crohn’s disease.www.UptoDate.com/IBD. Accessed July 22, 2016.

Clinical Progression of IBD and the Clinical and Economic Consequences of Undertreatment

• Treatment expenses make up a significant portion of the cost of IBD

• Studies show that inappropriate treatment, lack of adherence to therapeutic regimens, or suboptimal treatment increases the cost burden

• Costs for IBD: Hospitalizations, eventual need for surgery due to disease complications, physician visits

• Economic burden makes early diagnosis, coupled with effective treatment at onset, imperative

• Management must evolve beyond symptom control and toward sustained control of GI inflammation

– Measured by endoscopic, radiologic, and laboratoryparameters

• Compared to costs for those with mild or moderateUC, inpatient costs for those withsevere disease were more than 4 times higher

AJMC.com. Report: economic implications of inflammatory bowel disease and its management. Published online March 16, 2016. http://www.ajmc.com/journals/supplement/2016/Importance_of_Selecting_Appropriate_Therapy_Inflammatory_Bowel_Disease_Managed_Care_Environment/Importance_of_Selecting_Appropriate_Therapy_Inflammatory_Bowel_Disease_Managed_Care_Environment_Report_Economic_Implications_IBD/#sthash.MsHkOZ91.dpuf. Accessed July 22, 2016. AJMC.com. Report: economic implications of inflammatory bowel disease and its management, page 3. Published online March 16, 2016. http://www.ajmc.com/journals/supplement/2016/importance_of_selecting_appropriate_therapy_inflammatory_bowel_disease_managed_care_environment/importance_of_selecting_appropriate_therapy_inflammatory_bowel_disease_managed_care_environment_report_economic_implications_ibd/P-3#sthash.yTiHdcJY.dpuf. Accessed July 22, 2016.

Health Plan Paid Costsby Cost-Driver Category and

Pharmacy Costs for Crohn’s Disease

Pharmacy 45.5%

Inpatient Hospital 23.1%

Outpatient Hospital 15.7%

Emergency Department 2.6%

MD Office 8.2%

Home 1.4%

Other 3.2%

Adalimumab 32.5%

Infliximab Injection 27.0%

Certolizumab Pegol 5.9%

Mesalamine 8.3%

Budesonide 3.2%

Other Injectables 3.2%

Infusion Sets 0.9%

Other Drugs 19.0%

Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies

Raymond Cross, MD, MSProfessor of MedicineDirector, IBD Program

University of Maryland School of MedicineCo-Director, Digestive Health Center

University of Maryland Medical CenterBaltimore, Maryland

Goals of Therapy

• Induce clinical remission (absence of symptoms)

• Avoid short- and long-term toxicity of treatment

• Enhance quality of life

• Maintain corticosteroid-free remission

– Avoid repeated courses of corticosteroids!

• Induce “deep” remission

– Biologic remission (normalization of biomarkers)

– Mucosal healing

• Prevent complications and decrease unnecessary healthcare utilization (eg, hospitalizations, surgery)

Step-Up vs Top-Down Approach

TNF = tumor necrosis factor; 5-ASA = 5-aminosalicylic acid.Sandborn WJ. Gastroenterol Hepatol (N Y). 2007;3(1):16-17.

Corticosteroids

Immunesuppressants

Surgery

Anti-integrins

Anti-TNFs

Antibiotics and 5-ASAs

Short-Term and Long-TermResponse to Prednisone: 30-Day Outcomes

Faubion WA, Jr, et al. Gastroenterology. 2001;121(2):255-260.

DiseaseActivity

0 30 Days

Complete Response

CD (n=43) (58%)UC (n=34) (54%)

DiseaseActivity

0 30 Days

DiseaseActivity

0 30 Days

Partial Response

CD (n=49) (26%)UC (n=19) (30%)

Nonresponse

CD (n=42) (16%)UC (n=10) (16%)

Short-Term and Long-TermResponse to Prednisone: 1-Year Outcomes

Faubion WA, Jr, et al. Gastroenterology. 2001;121(2):255-260.

DiseaseActivity

1 Year

DiseaseActivity

1 Year

DiseaseActivity

1 Year

DiseaseActivity

1 Year

Prolonged Response

CD (27/74) (32%)UC (31/63) (49%)

Corticosteroid Dependency

CD (21/74) (28%)UC (14/63) (22%)

Duration of Trial (months)

80

60

40

20

0

Pat

ien

ts N

ot

Fa

ilin

g T

rial

(%

)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

100

58% fail to achieveremission

42%

7%

Efficacy of AZA as Maintenance Therapyin Patients with Active CD

AZA = azathioprine.Candy S, et al. Gut. 1995;37(5):674-678.

AZA 2.5 mg/kg/d (n = 33)

Placebo (n = 30)

P = .001

Moderate-to-Severe CD: Maintenance of Remission with MTX

• Multicenter, randomized,controlled trial

• 76 corticosteroid-dependent patients

• In remission following MTX 25 mgx 16 weeks

• Randomized to MTX15 mg or placebox 40 weeks

MTX = methotrexate.Feagan BG, et al. N Engl J Med. 2000;342(22):1627-1632.

30

0 4 12 2816 208 24 32 36 40

Weeks since Randomization

65% of 45% Responders = 30% Overall

80

70

100

90

60

50

40

Re

mis

sio

n (

%)

MTX

Placebo

n = 40

65%

n = 36

39%

Long-Term Maintenance ofRemission in CD

EOW = every other week; CDAI = Crohn’s disease activity index.Hanauer SB, et al. Lancet. 2002;359(9317):1541-1549. Colombel JF, et al. Gastroenterology. 2007;132(1):52-65. Sandborn WJ, et al. N Engl J Med. 2007;357(3):228-238.

60

40

20

10

0

Pa

tie

nts

(%

)

Reduction(≥70 Patients and≥25% in CDAI)

Response(∆100)

Remission(CDAI <150)

80

Certolizumab 400 mg every 4 weeks (PRECiSE 2) Placebo

27

5150

30

70

Weeks 26-30

26

52

36

63

21

39

17

40

29

48

Infliximab 5 mg/kg (ACCENT I) Adalimumab 40 mg EOW (CHARM)

N = 172 N = 215N = 113 N = 172 N = 215N = 113

51.8

69.4

54.6

18.7

38.8

18.5

43.2

62.0

46.9

Clinical Response, Clinical Remission, and Mucosal Healing Rates at 8 Weeks among Anti-TNFs

Rutgeerts P, et al. N Engl J Med. 2005;353(23):2462-2476. Reinisch W, et al. Gut. 2011;60(6):780-787. Sandborn, WJ, et al. Gastroenterology. 2014;146(1):85-95.

60

40

20

10

0

Pa

tie

nts

(%

)

Response Remission Mucosal Healing

80

IFX ADA Golimumab

50

30

70

Accent II:Fistula Response at Week 54

*P < .05.Sands BE, et al. N Engl J Med. 2004;350(9):876-885.

40

20

5

0

Pa

tie

nts

(%

)

Fistula Response Complete Response

50

30

10

23

46

35

15

45

25

19

36

*

*

PBO IFX

Factors Contributing to Non-Response or Loss of Response to Treatment

• No inflammation (irritable bowel syndrome, psychiatric disease)

• Complicated disease

• Other factors (bile-salt diarrhea, bacterial overgrowth, loss of ileocecal valve, short bowel syndrome, celiac disease)

• “Different” mechanism of inflammation

• “Deep-seated” or intractable disease

• Smoking

• Under treatment (dose, number of drugs)

• Pharmacokinetic issues

Long-Term Course of CD

N = 2002 patients with CD since diagnosis of the disease. Cosnes J, et al. Inflamm Bowel Dis. 2002;8(4):244-250.

Cu

mu

lati

ve

Pro

ba

bil

ity

(%)

Months

Probability of remaining free of complications

0 24 48 72 96 120 168 192 216 240144

100

90

80

70

60

50

40

30

20

10

0

Penetrating

Stricturing

Probability of Surgeryfor Patients with CD

Munkholm P, et al. Gastroenterology. 1993;105(6):1716-1723.

Years after Diagnosis

Patients (%)

NoSurgery

1Surgery

≥2Surgeries

5 51 37 12

10 39 39 23

15 30 34 36

62.5

18.2

Early Biologic Treatment Results in Higher Rates of Endoscopic Healing at 2 Years

D’Haens G, et al. Lancet. 2008;371(9613):660-667. Baert FJ, et al. Gastroenterology. 2010;138(2):463-468.

60

40

20

0

Pa

tie

nts

(%

)

Top-down

100

Simple Endoscopic Score 0

Simple Endoscopic Score 1-9

80

Complete EndoscopicHealing at 2 Years …and These Patients Did Better

in the Next 2 Years!

73

30

Step-up

P = .0028

60

40

20

0

Pa

tie

nts

in

Re

mis

sio

n (

%)

RemissionOff Corticosteroids

100

8070.8

27.3

Off Corticosteroids,No Anti-TNF

43.9

16.5

30.1

P < .001

P = .02

P = .06

47/10718/109 28/93

Comparative Effectiveness Study in CD (SONIC)

PBO = placebo; IFX = infliximab.Colombel JF, et al. N Engl J Med. 2010;362(15):1383-1395.

60

40

20

0

Pa

tie

nts

(%

)

AZA+

PBO

100

80

Clinical Remission

60

40

20

0

100

80

Mucosal Healing

IFX+

PBO

IFX+

AZA

56.8

30.0

44.4

P < .001

P = .006

P = .02

96/16951/170 75/169

AZA+

PBO

IFX+

PBO

IFX+

AZA

Combination Therapy Achieves High Mucosal Healing Rates in Early CD

*Statistical significance based Bonferroni correction for multiple comparisons (P ≤ .016).Early CD: Disease duration ≤18 months after diagnosis, no previous use of immunosuppressants and biologics, and no fistulas.IMM = immunomodulator; CRP = C-reactive protein.Colombel JF, et al. Aliment Pharmacol Ther. 2015;41(11):1211.

60

40

20

0

Pro

po

rtio

n o

f P

ati

en

ts (

%)

100

Infliximab Monotherapy Combination TherapyAzathioprine Monotherapy

80

Mucosal Healing in IMM andBiologic-Naïve CD Patients

(n=188)

29.6

43.6

65.3

12.9

25.6

52.3

60

40

20

0

100

80

30.8

43.5

70.4

10.0

25.0

64.7

Mucosal Healing inEarly CD

(n=63)

P < .001*

MucosalHealing

54n = 62 72

Clinical Remission+ CRPnorm +

Mucosal Healing

31 43 44

MucosalHealing

13 23 27

Clinical Remission+ CRPnorm +

Mucosal Healing

10 16 17

P < .001*

P = .038

P = .014*

P = .015*

P = .015*

P = .085

P = .037

P = .129

P = .245

P = .501

P = .617

UC SUCCESS: Corticosteroid-free Clinical Remission and Mucosal Healing at Week 16

*P < .05 compared to IS and IFX mono; **P < .05 compared to IS.Panaccione R, et al. Gastroenterology. 2014;146(2):392-400.e3.

70

40

20

10

0

Pa

tie

nts

(%

)

Clinical Remission Mucosal Healing

80

50

30

60

24 22

*40

37

55

**63

AZA + PBO IFX + PBO IFX + AZA

Vedolizumab Selectively Targets Leukocyte Adhesion in the Gut

• Natalizumabblocks both α4β1-and α4β7-mediated trafficking, resulting in systemic effects

• Vedolizumabonly targets α4β7 integrin, blocking lymphocytes trafficking to the gut

Rutgeerts P, et al. Gastroenterology. 2009;136(5):1844.

Vedolizumab

NatalizumabNatalizumabNatalizumab

Natalizumab

MLN-0002

PF-00547659,rhuMab-beta7

Integrins

Addressins

BrainBone MarrowOther Organs Gut

Endothelium

4741

VCAM-1 MadCAM-1

Leukocyte

†

25.6

Vedolizumab in CD: Second Induction Study Clinical Remission (CDAI ≤150) at Week 10

(Secondary Endpoint)

TNF = tumor necrosis factor ; VDZ = vedolizumab.*P < .0001; †P < .0012 based on the Cochran-Mantel-Haenszel chi-square test.Sands BE, et al. Gastroenterology. 2014;147(3):618-627.e3.

30

20

10

5

0

Pro

po

rtio

n o

f P

ati

en

tsA

ch

iev

ing

Cli

nic

al

Re

mis

sio

n (

%)

Overall Population

(PBO, n = 207; VDZ, n = 209)

Anti-TNF-Failure Population

(PBO, n = 157; VDZ, n = 158)

35

PBO

VDZ

25

15 13.0

*28.7

12.1

21.6

39.036.4

30.1

43.5 45.5

15.9

31.728.8

14.4

21.4

16.2

GEMINI II: Vedolizumab in CD through Week 52, Maintenance Intention to Treat

Q8W = every 8 weeks; Q4W = every 4 weeks.Sandborn WJ, et al. N Engl J Med. 2013;369(8):711-721.

60

40

20

10

0

Pa

tie

nts

(%

)

ClinicalRemission

CDAI-100Response

Durable ClinicalRemission

80

50

30

70

P < .001

Vedolizumab Q8W (N = 154) Vedolizumab Q4W (N = 154)Placebo (N = 153)

Glucocorticoid-FreeRemission

P = .004

P = .01

P = .005

P = .02

P = .04

Vedolizumab in UC:Clinical Response, Clinical Remission, and

Mucosal Healing at 6 Weeks

CI = confidence interval.Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.

Vedolizumab (n = 225)Placebo (n = 149)

60

40

20

10

0

Pa

tie

nts

(%

)

Clinical Response Clinical Remission Mucosal Healing

80

50

30

70

25.5

47.1

∆ 21.7(95% CI: 11.6, 31.7)

5.4

16.9

∆ 11.5(95% CI: 4.7, 18.3)

24.8

40.9

∆ 16.1(95% CI: 6.4, 25.9)

Vedolizumab in UC:Clinical Outcomes at 52 Weeks by Prior TNF

Antagonist Exposure

Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.

60

40

20

10

0

Pa

tie

nts

(%

)

ClinicalRemission

80

Vedolizumab Q8W Vedolizumab Q4WPlacebo

50

30

70

Prior Anti-TNFAntagonist Exposure

(n = 149)

10.6

36.040.4

19.1

44.0 46.2

Durable ClinicalResponse

60

40

20

10

0Clinical

Remission

80

50

30

70

19.1

45.8 47.9

26.6

63.5

56.2

Durable ClinicalResponse

Patients without TNFAntagonist Exposure

(n = 224)

Historical Management Strategies for IBD Are Flawed

• Non-biologic therapies have not modified the natural history of the disease

• Symptoms do not correlate well with inflammation in patients with CD

• Treatment decisions have been based on symptoms alone

– Adjustments to therapy are delayed and allow progressionof disease

• Step-up approach does not distinguish betweenlow-risk and high-risk patients

AGA Clinical Pathway for CD:Stratifying Patients by Risk for Disabling Course

AGA = American Gastroenterological Association.Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95.

Low Risk

Limited anatomic involvement

Age at diagnosis >30 years

Superficial ulcerations at endoscopy

No prior surgery

Non-stricturing, non-penetrating disease

High Risk

Extensive anatomic involvement

Deep ulcers

Age at diagnosis <30 years

Perianal disease and/or severe rectal disease

History of prior resection

Complicated disease behavior

AGA Clinical Pathway for CD:

Initial Treatment

Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95.

Low-risk Patient

Ileum and/or proximal colon, none to minimal symptoms

Options

• Budesonide 9 mg/d with or without AZA

• Tapering course of prednisone with or without AZA

Diffuse or left colon,none to minimal symptoms

Option

• Tapering course of prednisone with or without AZA

Moderate/High-risk Patient

Options

• Anti-TNF monotherapy over no therapy or thiopurine monotherapy

• Anti-TNF + thiopurine over thiopurine monotherapy or anti-TNF monotherapy

• Methotrexate for patients who do not tolerate purine analog in combination with anti-TNF

AGA Clinical Pathway for UC:

Stratifying Patients by Colectomy Risk

ESR = erythrocyte sedimentation rate; CMV = cytomegalovirus.Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95.

Low Risk

Limited anatomic extent

Mild endoscopic disease

High Risk

Extensive colitis

Deep ulcers

Age <40 years

High CRP and ESR

Corticosteroid-requiring disease

History of hospitalization

Clostridium difficile infection

CMV infection

AGA Clinical Pathway for UC:

Induction and Maintenance Therapy

Dassopoulos T, et al. Gastroenterology. 2015;149:238-245.

• Short course of corticosteroids with initiation of thiopurine or

• Anti-TNF with or without thiopurines

• Vedolizumab with or without immunomodulator

• Oral 5-ASA and/or

• Rectal 5-ASA and/or

• Oral budesonide or prednisone and/or

• Rectal corticosteroids

• Maintenance with oral 5-ASA and/or rectal 5-ASA

• Taper corticosteroid over 60 days

Remission

No remission

Options

• Anti-TNF ± thiopurine

• Thiopurine (optimize 6-TGN concentrations)

• Vedolizumab ±immunomodulator

• Proctocolectomy

Maintenance Options

• Thiopurine and taper corticosteroids over60 days

• Anti-TNF with or without thiopurine

• Vedolizumab with or without thiopurine or methotrexate

No remissionRemission

Low-Colectomy-Risk Patient High-Colectomy-Risk Outpatient

What Are the Risks ofAnti-TNF Therapy?

• Increased risk of serious and opportunistic infection

• Increased risk of paradoxic autoimmune reaction

– Psoriasis

– Lupus-like syndrome

– Multiple sclerosis

• Increased risk of melanoma

• Further increased risk of infection and skin cancer and increased risk of lymphoma when combined with thiopurines

Lichtenstein GR, et al. Am J Gastroenterol. 2012;107(7):1051-1063. Toruner M, et al. Gastroenterology. 2008;134(4):929-936. Siegel CA, et al. Clin Gastroenterol Hepatol. 2009;7(8):874-881. Long MD, et al. Clin Gastroenterol Hepatol. 2010;8(3):268-274. George LA, et al. Dig Dis Sci. 2015;60(11):3424-3430.

When to Operate orStart/Switch Biologics?

Most Patients Require Surgery after Treatment for Complicated CD

Samimi R, et al. Inflamm Bowel Dis. 2010;16(7):1187-1194.

Time (years)

0.60

0.40

0.20

0

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on

0.0 0.5 1.0 1.5 2.0 2.5

1.00

Product-Limit Estimate Curve

Time to Relapse or Surgery

Postoperative complication rate32% in patients exposed to anti-TNF

Censored Observations

0.80

Cumulative Probability of Abscess Recurrencein Medically vs Surgically Treated Patients

Nguyen DL, et al. Clin Gastroenterol Hepatol. 2012;10:400-404.

Time (years)

80

60

40

20

0

Pro

ba

bil

ity

of

Ab

sc

es

s

0 2 4 6 8 10

100

Medical Surgical

Two-thirds of patientshad recurrence in first 30 days

Biologics Decrease Surgery due to“Low-Risk” Strictures in Patients with CD

• Historical cohort study of 241 patients with stricturing CD having computed tomographic enterography or magnetic resonance enterography

• 49% surgery within a median of 1 year

SSS = stricture severity score; AUC = area under the curve.Nepal S, et al. Gastroenterology. 2012;142(5):S190-S191.

• Biologics may reduce the risk of surgery by up to 44% in stricturing CD

• This benefit may be more pronounced in patients with a “low-risk” (SSS = 0) enterographic finding

0 0.5 1.5 2.5

60 34 28 22 14 4 2 0

80

100

60

Su

rger

y-fr

ee (

%)

00 0.5 1.5 2.5

40

20

39 32 30 25 17 9 6 3

1.0 2.0 3.0 3.51.0 2.0 3.0 3.5

60 36 31 23 16 9 7 247 34 26 22 13 9 5 2

Biologics

No Biologics

Years Years

SSS 0

No Biologics

SSS 1-5

Biologics

P = .007 P = .3

Development SSS Score

Internal fistula

Small bowel obstruction

Prox. dilation ≥3 cm

Abdominal mass/abscess

Mesenteric stranding

AUC = .7 for predictingsurgery at 1 year

IFX Reduces PostoperativeRecurrence after Intestinal Resection

Regueiro M, et al. Gastroenterology. 2009;136(2):441-450.

80

40

10

0

Pa

tie

nts

(%

)

Placebo IFX

100

60

20

84.6

9.1

70

30

90

50

Endoscopic Recurrence: Endoscopic Scores of i2, i3, or i4

Summary

• Look beyond symptoms in patients with IBD, particularly those with CD

• Consider early biologic therapy with or without IS in patients at high risk of disability

• Concurrent IS with an anti-TNF results in greatest efficacy

– Avoid combination therapy in older patients, those with comorbidities, and those with recent prior cancer

• Search for a reason for incomplete or loss of response to biologics

• Vedolizumab is an alternative to anti-TNF, particularly when use of anti-TNF is contraindicated or higher risk

Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies

Jeffrey D. Dunn, PharmD, MBAChief Clinical Officer/Senior Vice President

VRx Pharmacy ServicesSalt Lake City, Utah

Sales of Specialty DrugsContinue to Grow

PMPY = per member per year.Artemetrx. Specialty drug trends across the pharmacy and specialty benefit. 2015. Available at: http://www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf.

Spending on Specialty Drugs Projected toSurpass Sales of Traditional Agents by 2018

1200

800

400

200

0

Fo

rec

as

ted

PM

PY

Ne

t D

rug

Sp

en

d (

$)

2012 2015 2018

1800

Traditional Specialty

1000

600

1400

665

290

2014 20172013 2016

1600

675

348

694

425

722

514

751

612

789

722

836

845

Inflammatory Disease Remains a Key Driver of the Specialty Drug Trend

Express Scripts. Drug Trend Report 2015. Available at: http://lab.express-scripts.com/lab/drug-trend-report. Accessed April 11, 2016.

Trend

Rank Therapy Class PMPY Spend ($) Utilization (%) Unit Cost (%) Total (%)

1 Inflammatory conditions 89.10 10.3 14.7 25.0

2 Multiple sclerosis 53.31 3.5 6.2 9.7

3 Oncology 49.62 9.3 14.4 23.7

4 Hepatitis C 38.44 -2.2 9.2 7.0

5Human immunodeficiency virus

31.53 4.6 12.0 16.6

6 Growth deficiency 7.12 2.8 2.8 5.6

7 Cystic fibrosis 6.64 12.5 40.9 53.4

8 Pulmonary hypertension 5.85 13.4 4.8 18.1

9 Hemophilia 5.79 4.9 15.4 20.4

10 Sleep disorders 4.57 5.5 18.5 24.1

Total Specialty $341.21 6.8% 11.0% 17.8%

Inflammatory Disease

• Other class of drugs

– Ustekinumab and apremilast = psoriatic arthritis and plaque psoriasis

– Anakinra = RA

*Also indicated for cancer.RA = rheumatoid arthritis; IL = interleukin; TNF = tumor necrosis factor. FDA.gov. http://www.fda.gov/. Accessed July 21, 2016.

Disease Tocilizumab GolimumabCertolizumab

PegolRituximab* Abatacept Adalimumab Etanercept Infliximab Vedolizumab

Tofacitinib Citrate

MOA Anti-IL-6ra Anti-TNF Anti-TNF Anti-B Cells Anti-T Cell Anti-TNF Anti-TNF Anti-TNF Anti-Integrin Anti-TNF

Indications

RA x x x x x x x x x

Juvenile RA x x x x

Psoriatic arthritis x x x x x

Ankylosing spondylitis x x x x x

CD x x x x

Plaque psoriasis x x x

UC x ”Soon” x x x

*Infliximab, adalimumab, golimumab, or other approved anti-TNF therapy.•Anti-TNF agent or vedolizumab.6-MP = 6-mercaptopurine; AZA = azathioprine; anti-TNF = anti-tumor necrosis factor agents.https://www.uptodate.com/contents/search?source=USER_PREF&search=ulcerative+colitis+guidelines+graph&searchType=GRAPHICS.

Example of Guidelines:Corticosteroid-Dependent UC

Check serum biologic levels,check for neutralizing antibodies

RelapseFail Relapse

Low biologic level,no antibodies

Low biologic level,antibodies present

Adequate biologiclevel, no antibodies

Dose escalatebiologic

Switch to a biologicin the same class

Switch to a differentclass of biologic

Wean corticosteroids;maintain 6-MP/AZA

Relapse

FailWell FailResponse tocyclosporine

Response toinfliximab

Wean corticosteroids;maintain biologic•

SurgeryInitiate 6-MP/AZA;wean corticosteroids,

thenwean cyclosporine

Initiate 6-MP/AZA;wean corticosteroids,continue infliximab

Well Allergic; failureCyclosporineor infliximab

Previous/current6-MP/AZA failure/allergy?

Previous/current6-MP/AZA failure/allergy?

No6-MP/AZA Anti-TNF* orvedolizumab

Able/willing to remain on corticosteroids

while slow-acting agent started?

Patient responding to systemic corticosteroids

but unable to wean without relapse

NoYes

No Yes

EntryPoint“A”

Guideline: Changing Paradigm

• Step-up vs top-down therapy

• Better understanding of the disease has led to a more targeted and refined approach to using biologic agents

• Newer evidence suggests a rationale for changing the management of IBD

– Using mucosal healing as an endpoint

– Using immunosuppressive and biologic agents earlier, particularly in CD

Devlin SM, et al. Med Clin North Am. 2010 Jan;94(1):1-18. doi: 10.1016/j.mcna.2009.08.017.Source: Expert Rev Gastroenterol Hepatol © 2010 Expert Reviews Ltd.

Anti-TNF

AZA / MTX

Corticosteroids

5-ASA / SPS

Anti-TNF

AZA / MTX

Combination

Corticosteroids

Step-UpTherapy

Top-DownTherapy

UC: Updated Evidence

• Vedolizumab is effective for induction and maintenance of remission in outpatients with moderate to severe UC or CD who have not responded to conventional and anti-TNF therapy

• Infliximab was statistically superior to adalimumab after induction

• Golimumab was statistically superior to adalimumab for sustained outcomes

Thorlund K, et al. Expert Rev Gastroenterol Hepatol. 2015;9(5):693-700.

CD: Updated Evidence

• Vedolizumab is effective for induction and maintenance of remission in outpatients with moderate to severe UC or CD who have not responded to conventional and anti-TNF therapy

• No comparative trials have evaluated the relative efficacy of infliximab, adalimumab, and certolizumab

Bryant RV, et al. J Crohns Colitis. 2015;9(4):356-366. Behn BW, et al. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006893.

Medication Adherence Factors

• Effectiveness

• Adverse events

• Drug interactions

• Concomitant medications (eg, methotrexate)

• Cost/benefit

– Access to care

• Other factors

– Patient’s age

– Full-time employment

– Male gender

– Discordance between patient and provider

– Complex dosing regimens (three-times-daily dosing or a large number of tablets)

– Disease education

• Lack of counseling to patients and access to care challenges

Bokemeyer B, et al. Aliment Pharmacol Ther. 2007;26:217-225. Jackson CA, et al. Am J Gastroenterol. 2010;105:525-539.

Quality Improvement

• No specific IBD quality measures exist

– Lack of objective, easy-to-use measures

• Education

– Symptoms to“mucosal healing”

• Measures have to be standardized but individualized at thesame time

Kappelman MD, et al. Inflamm Bowel Dis. 2010;16:125-133.

• What dowe want to accomplish

• What changes might be useful

• How will we measure progress

• Carry out the plan

• Document issues

• Record chosen outcomes

• What changes should be made

• How can we improve from past experience

• Analyze data• Where were

effects insufficient• What was

learned

Specialty Pharmacy Strategy:The Equation

Specialty Drug

Manage-ment

Drug Dispensing

Utilization Management

Coordinationof Care

Contracting Activities

BenefitDesign

(Cost Share)and

Formulary

Benefit Design: Multi-Tier Structure

• All specialties are NOT created equal

• 12 of 36 health plans with specialty strategy have multi-tier specialty cost share

– Accounts for 45% of covered lives

• 93% of pharmacy benefits managers plan to increase use of specialty tier in the next 24 months

• Opportunity

– Multi-tier specialty formulary

• Generic specialty tier

• Preferred specialty tier

• Non-preferred specialty tier

• Optional to clients but structure in place for those who want to participate in specialty strategy

AMCP. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.

Multi-Tier Structure

Benefits

• Further differentiation of specialty class

– Cost management

– Ability to manage specialty classes

• Contracting benefits

• Provides a strategy solution for employer groups and health plans

Possible Challenges

• Multiple layers adds confusion

– Client

– Member

– Customer service

– Internal

• More time spent managing the formulary

Managed Care Review Board. An analysis of treatment options, comparative effectiveness research, and benefit designs for rheumatoid arthritis. http://www.impactedu.net/nexusra15/AMCP%20Nexus%202015%20RA%20Satellite%20Symposium%20Slides_Impact%20Education.pdf.

Tier Specialty “Opt In” (%) “Opt Out” (%)

4 (generic) 10 20

5 (preferred) 20 20

6 (non-preferred) 40 20

Drug Dispensing

• Site-of-care optimization

MD = medical doctor; HOPD = hospital outpatient department.Internal Utilization and Pricing Data.

Infliximab Site-of-Care Example

Place of ServiceCost per

UnitUnits

Cost per Claim

Claims per Year

Annual Cost

MD office or home infusion

$70 50 $3500 7 $24,500

HOPD (average) $111 50 $5500 7 $38,850

HOPD (highest cost hospital)

$360 50 $18,000 7 $126,000

Utilization Management

• PAs

• Step-therapy

• Quantity limits

• Reporting

PA = prior authorization.EMD Serono Specialty Digest, 9th Edition. Managed Care Strategies for Specialty Pharmaceuticals. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.

83%

85%

74%

72%

75%

68%

71%

78%

79%

78%

72%

74%

70%

68%

13%

7%

17%

16%

9%

14%

11%

11%

9%

7%

11%

9%

12%

10%

GH Disorders

RA/Crohn's Disease (SC)

Hepatitis C (Oral)

MS (Oral)

Hepatitis C (SC)

ESAs

MS (SC)

RA/Crohn's Disease (IV)

Psoriasis

Botulinum Toxins

RSV

MS (IV)

Immune Globulin (IV)

Immune Globulin (SC)

96%

83%

83%

85%

88%

89%

82%

82%

84%

88%

91%

92%

82%

78%

Use of Prior Authorizations by Disease State (%)

50 60 70 80 90 100

2011 % Change from 2011 2012

Utilization Management (cont)

Analysis

• Review specialty database for clinically appropriate quantity limits and PAs

– Opportunities exist to further control utilization by implementing PAs and QLs on medications

• Evaluate effectiveness of PA/step-therapy

Outcomes

• PAs may not help and may increase work and costs to

– Client

– Member

– Customer service

– Internal

• Evaluate requests and approvals/denials/appeals

QL = quantity limits.EMD Serono Specialty Digest, 9th Edition. Managed Care Strategies for Specialty Pharmaceuticals. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.

Care Management

Opportunity

• Costs will continue to increase

– How to get the most out of drug spend

• Fill the specialty pharmacy “gap”

– Education on use

– Education on side effects

– Adherence

– Site-of-care optimization

AMCP. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.

80

40

10

0

Pla

ns

(%

)

EnsureDose

Accuracy

100

60

20

88

57

70

30

90

50

Specialty Pharmacy Services

Most Valuable Services (top 4+5) Satisfaction with Services (top 4+5)

85

46

76

44

76

61

75

58

75

41

73

50

69

36

ManageDrug

Waste& Abuse

AdherenceMeasurement

LimitedDistribution

DrugAccess

AdherencePrograms

SavingsMeasurement

TrackPatient

Interventions

TrackOutcomesof Patient

Interventions

Specialty Care Management

Program

• Specialty pharmacy medication therapy management

– Integrate with care management

– Coordinate site of care

– Ensure appropriate dosing

– Ensure adherence

– Provide education on use

– Ensure expectation management

– Address barriers

Actions

• Design program workflow and integration with care management

• Analyze utilization to select targeted drugs/disease states

• Train personnel

– Specialty diseases

– Medications

– Site-of-care logistics

Traditional Management Approach

• Many available programs focus on proper utilization and improving the quality of care

– Programs tend to be fragmented with little to no collaboration

Internal Data. VRx.

Chronic

Disease

Management

Acute Care

Management

Medication

Therapy

Management

Utilization

Review

Mental

Health

Management

Integrated Care Management

• Patient care is complex

• Integration

– Unites different viewpoints

– Allows management of every aspect of patient care

MENTALHEALTHCARE

MANAGER

Incorporatessocial

and behavioralcomponents of care

PHARMACISTCARE

MANAGER

Approaches carefrom a treatment-based

perspective focusedon disease and drug

information

NURSE CAREMANAGER

Supports and advocatesfor patients,

helping them navigatethe healthcare system

and obtainappropriate care

Other Strategies for Improving Management, Education, and Adherence

• Encourage pay-for-performance

– Offers incentives for medication compliance

– Can be either patient or provider targeted

• Strengthen patient-provider relationships

– As prescription costs increase, medication underuse increases

– In patients grouped by level of trust for their physician, the low-trust group was less likely to be adherent than the high-trust group

• Empower the patient

– Address the complex interaction of motivations, cues to action, perception of benefits and consequences, expectancies, environmental and cultural influences, self-efficacy, state of readiness to change, ambivalence, and implementation intentions

• Integrate communication channels

– Communicate respect for the patient's perspective of his/her condition

– Provide rationale for any recommended treatment

– Negotiate a plan and anticipate and address problems

– Discuss adherence at every visit in a nonjudgmental way

– Establish a collaborative process of problem-solving

Butterworth SW. J Manag Care Pharm. 2008;14(6)(suppl S-b):S21-S25. Piette JD, et al. Arch Intern Med. 2005;165:1749-1755.

15

10

5

0Pat

ien

ts w

ith

Co

st-R

elat

ed U

nd

eru

se (

%)

<$51

35

25

$51-$100

High-Trust Group (n=557)

Low-Trust Group (n=355)

Monthly Prescription Cost

30

20

>$100

Comparative Effectiveness Research

• Pharmacists, physicians, payers, policy makers, and patients most often rely on incomplete data when making healthcare decisions

• Lack of head-to-head comparisons of competing treatment alternatives can lead to a “trial-and-error” approach todecision-making

• If effectively designed and conducted, CER can help fill data gaps

– Used to compare drug therapies in the absence of head-to-head data

– Applicable to a variety of practice settings and diversity of patients

CER = comparative effectiveness research.Brixner DI, et al. J Manag Care Pharm. 2012;18(Suppl 4-a):S3-S4.

Benefit Design

Formulary Positioning

Coverage Decisions

CAN IT WORK? DOES IT WORK? IS IT WORTH IT?

RandomizedControlled Trials

AccumulatedEvidence

Health TechnologyAssessments

ComparativeEffectiveness

Research

Informed Decision Making

Clinical GuidelinesTreatment Pathways

CER Used to Differentiate the Effectiveness vs Efficacy of Treatment Alternatives

Drummond MF, et al. Int J Technol Assess Health Care. 2008;24:244-258.

CER in Formulary and Benefit Design: How to Evaluate without Head-to-Head Trials

• Identify and target key trials with similar patient characteristics, outcome measures, inclusion/exclusion criteria, etc

• Evaluate drug benefit minus placebo benefit over defined time frame of defined and appropriate outcome measure(s)

• Determine appropriate costs over same period

• Divide cost into drug benefit

• Compare cost to achieve predefined response

– “How much do we pay for an outcome with all of the drugs?”

• Hold industry accountable

Diagnosis Criteria: CDAI

• CDAI scores are frequently used to assess disease severity

– Score 0 to >600 based on a diary of symptoms kept by the patient for 7 days

• Remission: <150

• Response: Decrease >70

– >100 in recent clinical trials

• Mild disease: 150-220

• Moderate to severe disease: 220-450

• Severe disease: >450

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0048967/. Accessed July 22, 2016.

Variable Scale Weight

Liquid or very soft stool

Daily stool count is summed for 7 days 2

Abdominalpain

Sum of 7 days of daily ratings as 0=None, 1=Mild, 2=Moderate, 3=Severe

5

General well-being

Sum of 7 days of daily ratings as 0=Generally well, 1=Slightly below par, 2=Poor, 3=Very poor, 4=Terrible

7

Features of extraintestinal disease

Presence of any of the following in the previous 7 days

• Arthritis or arthralgia• Skin or mouth lesions (erythema nodosum,

aphthous ulcers, pyoderma gangrenosum)• Iritis or uveitis• Anal fissures, fistulas, perianal abscess• Other external fistulas• Fever >100˚F

20each

Opiates for diarrhea

0=No, 1=Yes 30

Abdominal mass

0=None, 2=Questionable, 5=Definite 10

HematocritMen 47% hematocritWomen 42% hematocrit

6

Body weight 100 x [1-(body weight/standard weight)] 1

Summary of Clinical Trials: UC

Note: Values in parentheses indicate placebo values.SQ = subcutaneous; EOW = every other week; BIW = biweekly; W = week.FDA.gov. http://www.fda.gov/. Accessed July 21, 2016. Reinisch W, et al. Gut. 2011;60(6):780-787. Sandborn WJ, et al. Gastroenterology. 2012;142:257-265.

Parameter Adalimumab Etanercept Infliximab Golimumab Vedolizumab

Dose40 mg SQ

EOW 25 mg SQ

BIW5 mg/kg IVevery 8 W

100 mg SQevery 4 W

300 mg IVevery 8 W

Clinicalremission at 8 weeks

18.5%(9.2%)

Not indicated34%(6%)

18%(6%)

17%(5%)

Clinical remission at 8 and52 weeks

16.5%(9.3%)

Not indicated35%

(17%)28%

(16%)42%

(16%)

Summary of Clinical Trials: CD

Note: Values in parentheses indicate placebo values.FDA.gov. http://www.fda.gov/. Accessed July 21, 2016.

Parameter Adalimumab Etanercept Infliximab Certolizumab Vedolizumab

Dose40 mg SQ

EOW 25 mg SQ

BIW5 mg/kg IVevery 8 W

400 mg SQevery 4 W

300 mg IVevery 8 W

Clinicalremission at 4 weeks

36%(12%)

Not indicated22%

(17%)15%(7%)

Clinical remission at 26 weeks

40%(17%)

Not indicated39%

(25%)29%

(18%)

Clinical remission at 52 weeks

36%(12%)

Not indicated NR39%

(22%)

CER in Formulary and Benefit Design: How to Evaluate without Head-to-Head Trials (Recap)

• Identify and target key trials with similar patient characteristics, outcome measures, inclusion/exclusion criteria, etc

– CDAI: Choose appropriate studies

• Evaluate drug benefit minus placebo benefit over defined time frame of defined and appropriate outcome measure(s)

• Determine appropriate costs over same period

– Rebates

• Divide cost into drug benefit

• Use comparative effectiveness research

• Compare cost to achieve predefined response

– “How much do we pay for an outcome with all of the drugs?”

Biologic = Specialty Drug

Close, but… What have we learned in 8 years?

What is abiosimilar?

Biosimilar Issues

• Cost

• Rating / interchangeability

– States to determine

– Batch variance???

– Naming?

• Data extrapolation/ indications

• Safety

• Manufacturing

• Provider acceptance

– Depends on disease state

– Risk (financial vs clinical)

• Experience

– In Europe since 2006

Biosimilar Pipeline

www.biopharma.com/biosimilars/pipeline.pdf.

Summary

• IBD is a significant cost driver

• Education is needed

• Strategies to improve cost and care include

– Utilization management

– Site-of-care/channel management

– Coordinated and integrated care management

• Contracting and pricing have to change

• Biosimilars may play an important role

– But are we ready?

Questions?