Assessing the Cost/Benefit of Oral MS Therapies on Patient Health and Resource Utilization

Presenters

Jeffrey D. Dunn, PharmD, MBASenior Vice President

VRxSalt Lake City, Utah

Stephen Krieger, MDAssistant Professor of Neurology

Neurology Residency Program DirectorIcahn School of Medicine at Mount Sinai

Attending NeurologistCorinne Goldsmith Dickinson Center for MS

New York, New York

Learning Objectives

• Discuss the impact of inadequate disease control on the clinical and economic burden of MS

• Define treatment success of MS therapy in terms of clinical and radiographic outcomes

• Outline the safety, efficacy, and pharmacoeconomics of available and emerging oral MS therapies

• Apply emerging clinical evidence on oral MS therapies to formulary discussions and review

• Promote patient-centric and model-driven strategies to improving adherence to MS therapies

MS = multiple sclerosis.

The Burden of MS and Defining Treatment Success

Stephen Krieger, MD

Epidemiology of MS

• Most common neurological medical cause of disability in young adults

• Between 350,000 and 400,000 cases in the United States

• The chances of developing MS are 1:750 in the general population

• More than 2.1 million cases worldwide

• Highest incidence in Caucasians

• Higher incidence in women (~3:1)

• Roughly 75% of cases present between 20 years to 50 years of age

National MS Society. Who gets MS? http://www.nationalmssociety.org/What-is-MS/Who-Gets-MS. Accessed May 21, 2014. Compston A, et al. Lancet. 2002;359(9313):1221-1231. Frohman EM. Med ClinNorth Am. 2003;87(4):867-897.

Clinically Isolated Syndrome

• CIS is the term used to describe a first episode of neurologic symptoms that lasts at least 24 hours caused by inflammation and demyelination as seen on the brain or spinal cord MRI

• Clinical features indicative of CIS:

– Appropriate age

• Excludes too young and too old

– Characteristic syndrome

– Optic neuritis: typically unilateral, retrobulbar, and painful in nature; some recovery expected

– Brainstem dysfunction: most commonly ocular motor syndromes (nystagmus), hemisensory and hemiparesis, or trigeminal neuralgia

– Myelitis: partial sensory more common than partial motor; bladder and bowel dysfunction is common; presence of Lhermitte’s sign; presence of band-like abdominal or chest pressure

CIS = clinically isolated syndrome; MRI = magnetic resonance imaging.Frohman EM, et al. Neurology. 2003;61(5):602-611.

Brain Cervical Spine

Characteristic MRI Findings in CIS/MS

Major Outcomes in MS

Relapsing Forms

Time

Incr

easi

ng

Dis

abili

ty

Subclinical CIS Relapsing-Remitting Secondary Progressive

Initialdemyelinating

event

Clinicallydefinite MS

Relapse

Brain Volume

Accumulated MRI Lesion Burden

Cognitive Dysfunction

Level of DisabilityAcute (New and Gd+)MRI Activity

RELAPSES

MRI LESIONS

DISABILITY

When to Treat MS?“Relapsing Forms”

• CIS with MRI lesions is MS from a treatment perspective

– MS can be diagnosed at the time of CIS with 1 MRI by the McDonald 2010 Criteria if certain imaging conditions are met

– Overwhelming and consistent evidence for treating CIS from numerous Phase 3 trials of MS agents across classes

• Relapsing-remitting MS

• SPMS with relapses

• Progressive relapsing MS

SPMS = secondary progressive multiple sclerosis.

Actuarial analysis of disability: Percentage of patients not having reached EDSS 6: Difference between groups is significant (P<.0001)

Early Relapses Affect Long-Term Disability

Time from Onset of MS (years)

50403020100

Low (0–1 attacks in 2 years)Intermediate (2–4 attacks in 2 years)High (≥5 in 2 years)

Pat

ien

ts (

%)

20

0

40

60

80

100

Tintoré M. J Neurol. 2008;255(suppl 1):37-43. Weinshenker BG, et al. Brain. 1989;112(Pt 6):1419-1428.

The Importance of Early Treatment

• MS may be active in the absence of clinical symptoms

• Lesions may occur early and may be associated with irreversible damage

• Evidence suggests that degenerative changes can occur in normal-appearing white matter

• Early treatment with DMTs may help slow the accumulation of damage

DMTs = disease modifying therapies.Trapp BD, et al. N Engl J Med. 1998;338(5):278-285. Ruiz-Peňa JL, et al. BMC Neurol. 2004;4:8. LosseffNA, et al. J Neurol. 2001;248(6):517-521. De Stefano N, et al. Arch Neurol. 2001;58(1):65-70. Ferguson B, et al. Brain. 1997;120(Pt 3):393-399. Filippi M, et al. Brain. 2003;126(Pt 2):433-437. Coyle PK, et al. Mult Scler. 2002;8(1):2-9. Narayanan S, et al. J Neurol. 2001;248(11):979-986.

Expectations on Treatment Responsefrom Clinical Experience

Time

Preclinical CIS RRMS SPMS

Clinical Threshold

Treatment ofRRMS

Treatment after a first event

RRMS = relapsing-remitting multiple sclerosis.

The Evolving MS Treatment Landscape

1995 2000 2005 2009 2010 2011

Aubagio®

(teriflunomide)

Tecfidera™(dimethyl fumarate, BG-12)

Lemtrada™(alemtuzumab)

Extavia®

(IFNβ-1b)

Gilenya™(fingolimod)

Tysabri®

(natalizumab)Betaseron®

(IFNβ-1b)

Copaxone®

(glatiramer acetate)

Avonex®

(IFNβ-1a)

Rebif®

(IFNβ-1a)

Novantrone®

(mitoxantrone)

Approval Date

2012 2013

Phase 3 Data Released

FDA-Approved Therapies

PEG-IFNb-1a(q2wks, q4wks)

Copaxone® 40 mg TIW

IFN = interferon.

GA = glatiramer acetate; SQ = subcutaneous; IM = intramuscular; IV = intravenous; PO = by mouth.National MS Society. Treating MS. http://www.nationalmssociety.org/Treating-MS/Medications. Accessed May 21, 2014.

Disease-Modifying Therapies

GA

– Given by SQ injection at a dose of 20 mg daily or 40 mg 3 times per week

IFN-1a

– Given by SQ injection at a dose of 22 to 44 mcg 3 times weekly

IFN-1a

– Given by IM injection at a dose of 30 mcg weekly

IFN-1b

– Given by SQ injection at a dose of 250 mcg every other day

Natalizumab

– Given by IV infusion at a dose of 300 mg every 4 weeks

Fingolimod

– Given PO at a dose of 0.5 mg daily

Teriflunomide

– Given PO at a dose of 7 mg or 14 mg daily

Dimethyl fumarate (BG-12)

– Given PO at a dose of 240 mg twice daily

Mitoxantrone

– Given by IV infusion at a dose of 12 mg/m2 every 3 months

Fingolimod

Fingolimod: First Oral Agent, 2010 Mechanisms of Action

• Binds to 4 of 5 sphingosine 1-phosphate receptor subtypes

• Results in inhibition of lymphocyte egress from lymph nodes account for effect on MS

• Reduced infiltration of cells into the CNS

• May be direct action in CNS in light of positive effects on brain atrophy

CNS = central nervous system.

*Additional results from open-label Phase 3 extension and 7-year Phase 2 extension studies showed sustainedlow disease activity on clinical and MRI measures in patients continuing on treatment with fingolimod.TRANSFORMS = Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing Remitting Multiple Sclerosis; ARR = annualized relapse rate; EDSS = expanded disability status scale; GdE = gadolinium-enhanced; FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis.Cohen JA, et al. N Engl J Med. 2010;362(5):412-415. Kappos L, et al. N Engl J Med. 2010;362(5):387-401. Kappos L, et al. Presented at: 64th Annual Meeting of the AAN; April 21-28, 2012; New Orleans, Louisiana. Abstract P41.004. Antel J, et al. Presented at: 64th Annual Meeting of the AAN; April 21-28, 2012; New Orleans, Louisiana. Abstract P01.129.

Fingolimod: Clinical Trial Summary*

Study Treatment Arms Outcomes Fingolimod

TRANSFORMS

• N=1292; RRMS

• Aged 18-55 years

• EDSS 0-5.5

• 12-month study

(1) Fingolimod 0.5 mg

(2) Fingolimod 1.25 mg

(3) IFN β-1a 30 μg

Reduction (vs IFN) 0.5 mg 1.25 mg

ARR-52%

(P<.001)-38%

(P<.001)

Active T2-35%

(P=.004)-42%

(P<.001)

GdE lesions-55%

(P<.001)-73%

(P<.001)

FREEDOMS

• N=1272; RRMS

• Aged 18-55 years

• EDSS 0-5.5

• 24-month study

(1) Fingolimod 0.5 mg

(2) Fingolimod 1.25 mg

(3) Placebo

Reduction (vs Placebo) 0.5 mg 1.25 mg

ARR-54%

(P<.001)-60%

(P<.001)

Enlarging T2-74%

(P<.001)-74%

(P<.001)

GdE lesions-82%

(P<.001)-82%

(P<.001)

AE = adverse effect; AV = atrioventricular; FEV1 = forced expiratory volume over 1 second; DLCO = diffusion capacity of the lung for carbon monoxide.Gilenya (fingolimod) 0.5 mg capsules. Risk Evaluation and Mitigation Strategy. http://www.fda.gov/downloads/Drugs /DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf. Accessed May 21, 2014.

Current Strategies for Mitigating the Potential Risks Associated with Fingolimod

Potential AE or Risk Mitigation Strategy

Bradycardia/AV block

• Cardiac contraindications

• All patients must be observed for 6 hours after initial dose for signs and symptoms of bradycardia

• If patients go off medication for prolonged time period, they must be observed when restarting therapy

Macular edema • Ophthalmologic exam at baseline and 3-4 months after treatment initiation

Infection

• Patients should be vaccinated for varicella zoster virus

• Consider stopping therapy if serious infection develops

• Avoid live attenuated vaccines for at least 2 months after stopping therapy

↓FEV1 and ↓DLCO • Spirometric evaluation when indicated

LFT elevations • Monitor regularly, as needed

Pregnancy risk category C

• Counsel patients about fetal risks

• Use effective contraception on treatment and for at least 2 months after stopping therapy

Teriflunomide

Teriflunomide Immune Effects

• In in vitro and animal studies, teriflunomide:

– Selectively and reversibily inhibits mitochrondrial enzyme DHO-DH

– Is cytostatic for proliferative T and B cells

– Lowers phospholipid synthesis protein glycosylation (immune cell membrane effects)

– Interferes with T cell – APC interaction

– Blocks TNF-induced NF-K activation

– Lowers oxygen free radicals, neutrophil chemotaxis, increases TGF, lowers COX-2 activity

– Lowers protein tyrosine kinase activity (at higher doses)

• In patients with rheumatoid arthritis, teriflunomide:

– Lowers cell adhesion molecules, matrix metalloproteinases

DHO-DH = dihydroorotate dehydrogenase; TNF = tumor necrosis factor; NF = nuclear factor; TGF = transforming growth factor; COX-2 = cyclooxegenase-2.Losy J, et al. J Neuroimmunol. 2011;231(1-2):15-22. Warnke C, et al. Neuropsychiatr Dis Treat. 2009;5:333-340. Kraan MC, et al. Arthritis Rheum. 2000;43(8):1820-1830.

Teriflunomide Phase 3 Study (TEMSO): Primary Endpoint

*Statistically significant compared to placeboTESMO = Teriflunomide Multiple Sclerosis Oral; RRR = relative risk reduction.O’Connor P, et al. N Engl J Med. 2011;365(14):1293-1303.

0.4

0.3

0.6

0.5

0.2

0.1

0

Placebo(n=363)

Teriflunomide7 mg

(n=365)

Teriflunomide14 mg

(n=358)

Ad

jus

ted

AR

R

0.54

0.37 0.37

31.5%RRR

31.2%RRR

TEMSO: Disability Progression

O’Connor, et al. N Engl J Med. 2011;365(14):1293-1303.

Weeks to Progression

1087248240

12-W

eek

Su

stai

ned

-D

isab

ility

Pro

gre

ssio

n (

% P

atie

nts

)

0

10

20

30

40

96603612

27.3% (Placebo)

21.7% (Teriflunomide 7 mg)20.2% (Teriflunomide 14 mg)

7 mg vs placebo: 23.7% reduction; (P=.08)14 mg vs placebo: 29.8% reduction; (P=.03)

Teriflunomide 14 mgTeriflunomide 7 mgPlacebo

84

5

15

25

35

Teriflunomide Efficacy: TOWER

• Multicenter, randomized, double-blind, placebo-controlled, phase 3 study

• 1169 RRMS patients received teriflunomide 7 mg, 14 mg, or placebo

• Primary endpoint, ARR, was reduced by:

– Teriflunomide 14 mg: 36.3% (P<.0001)

– Teriflunomide 7 mg: 22.3% (P=.02)

• 12-week sustained disability progression reduced by 31.5% with 14 mg teriflunomide compared with placebo (P=.04), not significant for 7 mg dose

TOWER = Teriflunomide Oral in People with Relapsing-Remitting Multiple Sclerosis.Miller AE, et al. Neurology. 2013;80(Meeting Abstracts 1):S01.004.

Teriflunomide Efficacy: TENEREHead-to-Head

• Phase 3, 1-year trial involving teriflunomide 7 mg (n=109) and 14 mg (n=111) vs SQ IFNβ-1a (n=104)

• No difference on primary outcome:

– Treatment failure, defined as confirmed relapse or permanent discontinuation was the same in teriflunomide and interferon-treated patients

– 48.6% and 37.8% vs 42.3%

• ARR 0.41 and 0.259 vs 0.216

• Discontinuation due to AE 8.2% and 10.9% vs 21.8%

TENERE = Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis.Vermersch P, et al. J Neurol. 2012;259(suppl 1):1-236.

Teriflunomide Adverse Effects

• No treatment-related fatalities in either phase 3 trial

• Hair thinning – reversible

• Gastrointestinal (nausea, diarrhea)

• Elevation in aminotransferases

– LFTs checked monthly x6

• Neutropenia – rare

• PPD or Quantiferon Gold check prior to initiation

• Pregnancy Category X (note for male and female patients)

LFTs = liver function tests; PPD = purified protein derivative.Aubagio [package insert]. Cabridge, MA: Genzyme Corporation; 2012.

Dimethyl Fumarate

Dimethyl Fumarate (BG-12) Mechanisms of Action

• Dimethyl fumarate rapidly metabolized to active metabolite, MMF

• MMF releases the transcription factor Nrf-2 from its usual binding to Keap-1

• Nrf-2 inhibits translocation of NF-κB into the nucleus

• Ultimately leads to a decrease in inflammatory cytokines, chemokines, and adhesion molecules

• Induces a Th1 to Th2 shift

• Decreases circulating T cells

• Possible neuroprotective effects

MMF = monomethylfumarate.Gold R, et al. Clin Immunol. 2012;142(1):44-48. Linker RA, et al. Brain. 2011;134(Pt 3):678‐692.

DEFINE: Cumulative Probability of Relapse (Primary Endpoint)

DEFINE = Determination of Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.Gold R, et al. Presented at: 5th Joint Triennial Congress of ECTRIMS/ACTRIMS; October 19-21, 2011; Amsterdam, Netherlands. Abstract 95. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107.

Time (weeks)

96724824BL

Pro

bab

ility

of

Rel

apse

0

0.1

0.3

0.5

603612

Hazard Ratio:BG-12 BID vs Placebo = 0.51 (P<.0001)BG-12 TID vs Placebo = 0.50 (P<.0001)

BG-12 TID (n=416)BG-12 BID (n=410)Placebo (n=408)

84

0.2

0.4

Number of Patients at Risk:

PlaceboBG-12 BIDBG-12 TID

406410416

358353348

321324322

282303301

224287270

243288288

205255251

190243244

Patients were censored if they withdrew from study or switched to alternative MS medication without a relapse

DEFINE: ARR

Gold R, et al. Presented at: 5th Joint Triennial Congress of ECTRIMS/ACTRIMS; October 19-21, 2011; Amsterdam, Netherlands. Abstract 95. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107.

0.4

0.3

0.6

0.5

0.2

0.1

0

Placebo(n=408)

BG-12 BID(n=410)

BG-12 TID(n=416)

AR

R0.364

0.172 0.189

48%Reductionvs Placebo

P<.0001

53%Reductionvs Placebo

P<.0001

Gold R, et al. Presented at: 5th Joint Triennial Congress of ECTRIMS/ACTRIMS; October 19-21, 2011; Amsterdam, Netherlands. Abstract 95. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107.

DEFINE: Time to 12-WeekConfirmed Disability Progression

Time (weeks)

96724824BL

Pro

po

rtio

n o

f P

atie

nts

wit

h12

Wee

ks D

isab

ility

Pro

gre

ssio

n

0

0.1

0.3

0.5

603612

Hazard Ratio:BG-12 BID vs Placebo = 0.62 (P=.0050)BG-12 TID vs Placebo = 0.50 (P=.0128)

BG-12 TID (n=416)BG-12 BID (n=410)Placebo (n=408)

84

0.2

0.4

Number of Patients at Risk:

PlaceboBG-12 BIDBG-12 TID

408409416

375359360

345333346

319328325

285290291

291304324

242278276

224267265

DEFINE: MRI Outcomes – 2 Years

Gd+ Lesions New or Newly Enlarging T2 Lesions

Arnold DL, et al. Presented at: 5th Joint Triennial Congress of ECTRIMS/ACTRIMS; October 19-21, 2011; Amsterdam, Netherlands. Abstract P831. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107.

1.5

1.0

2.5

2.0

0.5

0

Placebo(n=165)

BG-12 BID(n=152)

BG-12 TID(n=152)

Mea

n N

um

ber

of

GD

+ L

esio

ns

1.8

0.5

73%ReductionP<.0001

0.1

90%ReductionP<.0001

12

8

20

16

4

0

Placebo(n=165)

BG-12 BID(n=152)

BG-12 TID(n=152)

Ad

jus

ted

Mea

n N

um

ber

of

New

or

New

ly E

nla

rgin

g T

2 L

esio

ns

17.0

4.4

74%ReductionP<.0001

2.6

85%ReductionP<.0001

DEFINE: Adverse Events

AE n (%)Placebo (n = 408)

BG-12 240 mg BID (n = 410)

Flushing*

MS relapse

Nasopharyngitis

Headache

Diarrhea*

Fatigue

Upper respiratory tract infection

Urinary tract infection

Nausea*

Back pain

Upper abdominal pain*

Proteinuria*

Abdominal pain*

Arthralgia

Influenza

Pruritus*

Vomiting*

20 (5)

189 (46)

101 (25)

80 (20)

55 (13)

54 (13)

53 (13)

53 (13)

38 (9)

57 (14)

28 (7)

34 (8)

22 (5)

39 (10)

39 (10)

19 (5)

24 (6)

154 (38)

111 (27)

108 (26)

81 (20)

62 (15)

57 (14)

63 (15)

55 (13)

53 (19)

59 (14)

40 (10)

38 (9)

46 (11)

46 (11)

34 (18)

42 (10)

40 (10)

*Incidence ≥3% higher in either BG-12 group.Gold R, et al. N Engl J Med. 2012;367(12):1098-1107.

Understanding Treatment Options and Assessing Outcomes

Multiple Treatment Options

• “All of these FDA-approved agents should be included in formularies and covered by third-party payers so that physicians and patients can determine the most appropriate agent on an individual basis; failure to do so is unethical and discriminatory.”

• “Patients’ access to medication should not be limited by the frequency of relapses, age, or level of disability.”

• “Treatment is not to be stopped while insurers evaluate for continuing coverage of treatment, as this would put patients at increased risk for recurrent disease activity.”

National MS Society. Disease management consensus statement. http://www.nationalmssociety.org /NationalMSSociety/media/MSNationalFiles/Brochures/ExpOp_Consensus.pdf. Accessed June 6, 2014.

The Canadian Treatment Optimization ModelAssessing Concern Whether to Modify a Treatment Regimen

Each gauge represents a continuum from no concern (0 on the dial)through low, medium, or highlevels of concern

Consider:• 1 ‘low’• 2 ‘medium’ or • 3 ‘high’as an indication of possible sub-optimal treatment that might warrant a change in management

Freedman MS, et al. Can J Neurol Sci. 2013;40(3):307-323.

MRI

ProgressionRelapse

What MRI Criteria Defines aSuboptimal Response?

• Radiologic/MRI signs

• New or recurrent brain stem or spinal cord lesions

• Increasing lesion number on MRI

– 3 enhancing lesions in 1 year

– >3 new T2 lesions in 1 year

– ≥2 new T2 lesions on each repeated scan performed at ≤3 month intervals

• Increasing lesion size on MRI, most notably

– In more than 2 types of lesions

– In presence of EDSS worsening independent of attacks

Cohen BA, et al. Neurology. 2004;63(12 suppl 6):S33-S40. Coyle PK. J Neurol. 2008;255(suppl 1):44-50. Freedman MS, et al. Can J Neurol Sci. 2004;31(2):157-168. National MS Society. http://www .nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/ExpOp_ChangingTherapy_2004.pdf. Accessed May 21, 2014.

Relationship between Early MRI and Response to Treatment

• MRI changes during the first year of IFNβ treatment may have prognostic value for identifying patients with increased disability after 2 years of therapy

• Only the presence of more than 2 active lesions on MRI (new or newly enlarging T2 lesions + 1 Gd lesion) at year 1 was related to an increase in disability after 2 years of therapy

Río J, et al. Mult Scler. 2008;14(4):479-484.

6 12 18

1.0

0.9

0.8

0.6

0.7

3 9 15 21 24

Pro

bab

ility

of

Rem

ain

ing

Fre

e o

f P

rog

ress

ion

Months

P<.0001

≤2 Active Lesions

>2 Active Lesions

Relationship between Nonadherence and Risk of Severe Relapse

• MS patients who initiated DMT treatment (N=2388) were evaluated to examine the association between DMT adherence and the likelihood of patients experiencing a severe relapse

• Adherence measures, including treatment gaps and MPR, were evaluated for 24 months following treatment initiation of a self-injectable DMT

– Patients with gaps in treatment of 90 days or greater had an increased risk of severe relapse relative to patients with gaps of 0-10 days (OR=1.925; P=.007)

– Nonadherent patients (MPR <80%) were twice as likely to have experienced a severe relapse (OR=1.976; 95% CI, 1.46-2.69) compared with adherent patients (≥80%)

• Findings of relationships between measures of adherence and severe MS relapse are associative and not necessarily causal

MPR = medication-possession ratio; OR = odds ratio.Okuda DT, et al. Presented at: The Consortium of Multiple Sclerosis Centers 22nd Annual Meeting; May 28-31, 2008; Denver, Colorado. Abstract S55. Meletiche D, et al. Presented at: The Consortium of Multiple Sclerosis Centers 22nd Annual Meeting; May 28-31, 2008; Denver, Colorado. Abstract S47.

Economic Impact of MS

• Impact in the workplace (MS vs non-MS)

– Higher percentage of employees claiming short- or long-term disability (21.4% vs 5.2%; P<.0001)

– More disability days per year (29.8 vs 4.5; P<.0001)

– Average annual costs for disability $3868 vs $414 US (P<.0001)

• Health-related costs: $35,000/patient/year in 2008

– Total cost to US economy: $16 billion/year

• MS is leading cause of disability in young women and the second leading cause of disability in young men in the United States

Ivanova JL, et al. Pharmacoecomonics. 2009;27(8):681-691. Edlin M, et al. PT. 2008;33(10):611-614.

Pricing ofMS Disease Modifying Therapies

ABCR = Avonex, Betaseron, Copaxone, Rebif.Credit Suisse Equity Research, May 2014.

40

30

$70K

50

20

10

0

An

nu

aliz

ed P

rice

($K

)

6059

17

58

17

62

16

63

21

61

18

63

27

54

24

61

35

60

25

US currency

EU currency

Association of Prescription Abandonment with Cost Share for DMTs: Summary

• 1 in 4 members with an OOP expense greater than $200 abandoned their DMT prescription

– These members were 6 times more likely to abandon their DMT prescription compared with members with OOP expense ≤$100

• Member cost share impacts DMT prescription abandonment

OOP = out-of-pocket.Gleason PP, et al. J Manag Care Pharm. 2009;15(8):648-658.

To Be Successful…

• Must be ready to begin therapy

– Patient desire

• Must believe that therapies can make a difference

– Expectation management

• Must be willing to make a commitment

– Adherence assessments

• Must be well educated

– Regarding MS

– Regarding therapies for MS

Comprehensive Care Model for the MS Patient

Personal medical filesMedical insurance carriers

Nonprofit organizationsMedical informatics

Continuing patient education Researchers

RadiologistsDermatologistsPsychologistsPsychiatrists

Primary care physiciansNeurologistsUrologists

OphthalmologistsCardiologists

Physical therapistsOccupational therapists

PhysiatristsSocial workers

NursesNurse practitioners

Physician assistantsPharmacists

Speech therapists

MSPatient

Direct and Indirect Costs That Should Be Considered in Direct Patient Care Services

Direct Costs*

• Medication costs (eg, prescription, nonprescription)

• Costs of medical devices and equipment and other healthcare supplies

• Hospitalizations and inpatient care

• Ambulatory care costs (clinic use)

• Healthcare provider office or clinic visits

• Emergency department visits

• Preventive care (eg, screenings, immunizations, vaccinations)

• Auxiliary services (eg, dental services, self-management training, ophthalmology and optometry services, podiatry services, chiropractic services)

• Costs of laboratory tests and procedures

Indirect Costs†

• Rehabilitation

• Occupational therapy and physical therapy

• Long-term care or nursing home care

• Hospice or palliative care

• Home healthcare services

• Mental healthcare services

• Transportation

• Days of work lost

• Time of healthcare providers

• Caregiver time

• Time for medical treatment

• Time for and costs of treatment of side effects or adverse events

*Expenses that can be directly attributed to an object such as a product, service, or condition; †Expenses not directly related to an object such as a product, service, or condition but that may be incurred as a consequence of a product, service, or condition.Chisholm-Burns MA, et al. Am J Health Syst Pharm. 2010;67(19):1624-1634.

Benefit Design and Utilization Management Strategies

• Mandatory/exclusive specialty pharmacy distribution

• Distribution channel management

• Pay-for-performance/guidelines/quality measures

• Prior authorization

– Should be intended to constrain off-label use

• Step therapy only if supported by guidelines or label

• Specialty pharmacy-developed therapy management programs

Summary: Implications of Individualized MS Therapy and Care

• Early onset of effective MS immune therapy can alter long-term natural history

• Because individuals may differ in their response to a particular agent, optimal therapy requires monitoring effectively for a suboptimal response and switching of therapy as needed

• Expansion of the therapeutic armamentarium and investigation of potential synergies based on mechanisms of action may further optimize treatment results, particularly when applied in early MS

• A comprehensive care model, including contributions from care providers, pharmaceutical companies/patient support programs, specialty pharmacies, and insurance providers, is needed to ensure compliance and best outcomes

Incorporating Oral MS Therapies into Formularies

Jeffrey D. Dunn, PharmD, MBA

Sales of Specialty DrugsContinues to Grow

PMPY = per-member per-year.Artemetrx. Specialty drug trends across the pharmacy and specialty benefit. 2013. http://www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf. Accessed May 21, 2014.

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

SpecialtyTraditional

Fo

reca

sted

PM

PY

Net

Dru

g S

pen

d (

$)

2018

836

845

1800

1400

1000

600

200

0

2012 2013 2014 2015 2016 2017

665

290

675

348

694

425

722

514

751

612

789

722

1600

1200

800

400

Top 10 Specialty Categories under Pharmacy Benefit

55

Transplant

Respiratory conditions

Pulmonary hypertension

Anticoagulant

Growth deficiency

Hepatitis C

HIV

Cancer

MS

Inflammatory conditions

$37.98

$31.98

$20.78

$7.82

$7.41

$6.74

$5.71

$5.56

$4.92

$50.62

PMPY ($)

Express Scripts. Drug Trend Report. 2013. http://lab.express-scripts.com/~/media/pdfs/drug%20trend %20report/express%20scripts%202013%20drug%20trend%20report.ashx. Accessed May 21, 2014.

600 10 30 5020 40

In 2013, MS Treatments Made Up 18% of Specialty Spend under the Pharmacy Benefit

56

Trend

Rank Therapy Class PMPY Spend Utilization Unit Cost Total

1 Inflammatory conditions $50.62 9.0% 14.0% 23.0%

2 MS $37.98 0.5% 17.3% 17.8%

3 Cancer $31.98 3.4% 22.3% 25.8%

4 HIV $20.78 -2.1% 11.1% 9.0%

5 Hepatitis C $7.82 28.9% 4.8% 33.7%

6 Growth deficiency $7.41 1.7% 7.7% 9.5%

7 Anticoagulant $6.74 1.7% 0.3% 2.1%

8 Pulmonary hypertension $5.71 5.1% 6.2% 11.3%

9 Respiratory conditions $5.56 1.5% 25.7% 27.2%

10 Transplant $4.92 2.2% -6.9% -4.7%

Other $27.68 -24.9% 43.7% 18.8%

TOTAL SPECIALTY $207.19 -0.4% 18.7% 18.4%

Express Scripts. Drug Trend Report. 2013. http://lab.express-scripts.com/~/media/pdfs/drug%20trend %20report/express%20scripts%202013%20drug%20trend%20report.ashx. Accessed May 21, 2014.

The EvolvingMS Treatment Landscape

Phase 3 Data Released

FDA-Approved Therapies

1995 2000 2005 2009 2010 2011

Aubagio®

(teriflunomide)

Extavia®

(IFNβ-1b)

Gilenya™(fingolimod)

Tysabri®

(natalizumab)Betaseron®

(IFNβ-1b)

Copaxone®

(glatiramer acetate)

Avonex®

(IFNβ-1a)

Rebif®

(IFNβ-1a)

Novantrone®

(mitoxantrone)

Approval Date

2012 2013

Cladribine

X

Alemtuzumab

Laquinimod

Dimethyl fumarate(BG-12)

Potential Factors inFormulary Decision Making

DECISIONWillingness to Pay

Cost-Effectiveness

Efficacy

Safety

Productivity, Satisfaction, and QoL

PBM, Physician, and Pharmacist contracts

Budget Impact

Physician Support

Discounts and Rebates

Politics & Public Image

Acquisition Costs

HEDIS, JCAHO, and NCQA

Disease Management Programs

HEDIS = Healthcare Effectiveness Data and Information Set; JCAHO = Commission on Accreditation of Healthcare Organizations; NCQA = National Committee for Quality Assurance; PBM = pharmacy benefit manager.Academy of Managed Care Pharmacy. Format for forumlary submissions. Version 2.0. October 2002. http://amcp.org/WorkArea/DownloadAsset.aspx?id=16276. Accessed May 21, 2014.

Benefit Design and Utilization Management Strategies

• Mandatory/exclusive specialty pharmacy distribution

• Distribution channel management

• Pay-for-performance/guidelines/quality measures

• Prior authorization

– Off-label use

– Genetic-based testing and companion diagnostics

• Step therapy if supported by guidelines or label

• Specialty pharmacy-developed therapy management programs

Medical Benefit Cost Sharing

Zero Cost Sharing in Medical Benefit May Disappear

MA-PDs = Medicare Advantage Prescription Drug Plans.EMD Serono Specialty Digest 8th edition. Managed care strategies for specialty pharmaceuticals. 2012. http://www.amcp.org/WorkArea/DownloadAsset.aspx?id=15229. Accessed May 21, 2014.

Single Tier Cost ShareNo Cost Share Multi-Tier Cost Share

100

80

60

40

20

0

2008(n=57)

2009(n=64)

2010(n=75)

2011(n=83)

2008(n=47)

2009(n=58)

Pla

ns

(%)

Commercial

2010(n=65)

2011(n=78)

MA-PDs

70 63 47 48 64 48 40 45

25 34 41 52 32 47 51 52

5 3 12 4 5 9 3

Specialty Cost Sharing

*Significantly higher than comparison group.Pharmacy Benefit Management Institute. 2013 Specialty Drug Benefit Report.

Specialty Cost Sharing Structure

Coinsurance (fixed percentage of each prescription)

Copay (flat dollar amount for each prescription)

Coinsurance with a minimumand/or maximum copay

100

80

60

40

20

0

2012(n=306)

2011(n=122)

2012(n=306)

2011(n=122)

Per

cen

t o

f P

lan

s (%

)

Under thePharmacy Benefit

Under theMedical Benefit

55 49 26 17

3232

18

11

226 29

Not Sure

Other

None

1112

2528

4

9

4

26

Cost Efficacy

• Population-based study of MS drugs published in Neurology in 2011

• Authors reported that using MS drugs resulted in modest health gains (all drugs) compared with nontreatment

• The cost-effectiveness of all agents far exceeded $800,000/quality-adjusted life year

• The conclusion was that use of MS drugs results in health gains that come at a very high cost

Noyes K, et al. Neurology. 2011;77(4):355-363.

MS Specialty Management

• Managed care is using traditional management strategies, customized for specialty medications

– Prior authorization – 78% of plans

• Based on indication, monitor response, drive preferred, failure of other drug

– Preferred products – 63% of plans prefer MS drugs

• National Drug Code block – 19% of plans block nonpreferred

– Cost sharing – 27% of plans use tiered copay

– Step-edits – 36% of plans use online edits

– Mandatory specialty pharmacy provider

• Pharmacy and medical benefit responsibility

– Case/therapy management – 22%, often by speciality pharmacy provider

– Cost-effectiveness analysis – eg, fingolimod

– REMS programs

M. Zitter, MBA, The Zitter Group, written communication.

Comparative Effectiveness Research

• Defined as the conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat, and monitor health conditions in “real-world” settings

• Decision makers need comparative information to support informed treatment choices

• CER produces information that decision makers can use to make informed treatment and coverage decisions

• Value of CER

– Generates data comparing the effectiveness of competing therapies

– Provides insights on use of therapies in “real-world” patients

– Supports selection of the most effective and safe drug

– Results can be applied to an individual patient

CER = comparative effectiveness research.Federal Coordinating Council for Comparative Effectiveness Research. Report to the President and the Congress. US Department of Health and Human Services; June 30, 2009. National Pharmaceutical Council. Making informed decisions: assessing the strengths and weaknesses of study designs and analytic methods for comparative effectiveness research. http://www.npcnow.org/system/files /research/download/experimental_nonexperimental_study_final.pdf. Accessed May 21, 2014. Oderda GM, et al. J Manag Care Pharm. 2011;17(9 suppl B):S19-S24.

Specialty Is a Prime Target for Comparative Effectiveness Research

High Budget Impact and Lack of Clear Clinical Superiority among Biologic Alternatives Make Specialty an Attractive Target for CER

Tuttle E, et al. Pharmaceutical Exec. 2010;30(11):78-87.

Comparable Alternatives(Number of agents, degree of genericization)

Gaucher’s

Migraine

Fabry

NSCLC

ADHD

GERDChronic Pain

Schizophrenia

RheumatoidArthritis

Diabetes

AsthmaDyslipidemia

Depression

HIV Infection

Hypertension

AllergicRhinitis

ColorectalCancer

MultipleSclerosis

Alzheimer’s(Dementia)

SeizureDisorders

Treatment Experience Assisting with Formulary Decision Making to CER

• Expert opinion

– Should involve key opinion leaders

• Anecdotal support

– Geographical considerations

– Plan-specific considerations

• Literature evidence

– Comparative trials are relatively rare

– Need to understand how clinical trials were designed as well as how outcomes were measured

• Guideline concordant care

– Reduces variability in outcomes

– Reduces variability in costs

– Invests in patients’ health and improves health outcomes

– Reduces wasteful spending by using evidence to optimize efficacy and minimize toxicity

CER in Formulary and Benefit Design: Current Reality

• Impact of drug-formulary or benefit design decisions on health outcomes is generally not measured

– Most likely reflects a lack of real-world CER data at a product’s launch

• Patients are not currently part of the formulary decision-making chain

– Increasing availability of PCOR will allow more patient-centered decision making in the future

• Reassessments of drugs for inclusion, exclusion, or change in position in the drug formulary are currently rarely performed

– Real-world CER can only effectively add value if reassessments of formulary decisions are conducted throughout the life cycle of a product

• Evaluation of the real-world ability of drugs to improve outcomes requires technology that effectively integrates all stakeholders

PCOR = patient-centered outcomes research.Biskupiak JE, et al. J Manag Care Pharm. 2012;18(5 suppl A):S19-S29.

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 time 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?”

Other Benefit Design Issues

• Specialty tiers

– OOP limitations

• Closed formularies

• Price protection

• Payment reform

– How quickly does it get to specialty?

• Patient assistance

• Medicaid expansion and exchanges

– Cost partially borne by commercial

Future of Emerging and New Therapies: Key Points

• The field of MS therapy is rapidly changing

• Newer therapies may supplant currently available DMTs

• Newer therapies will have both known and unforeseen complications

• Future treatment options will be more complex than those currently available to us

• Budgetary constraints will play major role in the decision-making process

• Why don’t we have guidelines?

Polman CH. Presented at: 28th Congress of ECTRIMS; October 9-13, 2012; Lyon, France. Abstract 149.

Definitions and Issues

• Poor compliance: not taking medication as prescribed

• Nonadherence: discontinuation of medication (short-term)

• Lack of persistency: failure to continue medication over long-term; not realizing long-term clinical benefit

• Often these factors are influenced by unrealistic expectations (including cost) and adverse effects

Not Remembering to Inject Is the Main Reason for Missing the Injections: >50% of Noncompliant Patients

Tend to Forget to Administer Their DMT Injections

No one available to administer injection

Dosing schedule inconvenient/difficult

Reasons for Missed DMT Injections Noncompliant Patients (%) (n=798)

Headache

Injection anxiety

Skin reaction

Fatigue

Financial reasons

Forgot to administer injection

Not sure about treatment benefits

Depression

Pain at injection site

Did not feel like taking injection

Flu-like symptoms

Tired of taking injections

Weakness

Other

Did not refill

0 10 30 50 7060 8020 40

Patients (%)

2

3

5

12

4

4

58

3

4

7

22

5

8

16

2

23

6

More than a third ofpatients reported an

injection-related reason for missing their DMT dose

(32%)

Treadaway K, et al. J Neurol. 2009;256(4):568-576.

Adherence

• Between 17% and 40% of patients stop taking DMT within 1 year of initiation

• Multifactorial

– Perceived lack of efficacy

– Adverse effects

– Depression

• 41% of patients had new or increased depression within 6 months of treatment initiation

• Decreased adherence in patients with depression

Rio J, et al. Mult Scler. 2005;11(3):306-309. Daugherty KK, et al. J Am Pharm Assoc. 2005;45(3):371-375.Mohr DC, et al. Arch Neurol. 1997;54(5):531-533. Clerico M, et al. J Neurol Sci. 2007;259(1-2):104-108.

Association of Prescription Abandonment with Cost Share for DMTs: Summary

• 1 in 4 members with an OOP expense greater than $200 abandoned their DMT prescription

– These members were 6 times more likely to abandon their DMT prescription compared with members with OOP expense ≤$100

• Member cost share impacts DMT prescription abandonment

Gleason PP, et al. J Manag Care Pharm. 2009;15(8):648-658.

Relationship between Nonadherence and Risk of Severe Relapse

• MS patients who initiated DMT treatment (N=2388) were evaluated to examine the association between DMT adherence and the likelihood of patients experiencing a severe relapse

• Adherence measures, including treatment gaps and MPR, were evaluated for 24 months following treatment initiation of a self-injectable DMT

– Patients with gaps in treatment of 90 days or greater had an increased risk of severe relapse relative to patients with gaps of 0-10 days (OR=1.925; P=.007)

– Nonadherent patients (MPR <80%) were twice as likely to have experienced a severe relapse (OR=1.976; 95% CI, 1.46-2.69) compared with adherent patients (≥80%)

• Findings of relationships between measures of adherence and severe MS relapse are associative and not necessarily causal

MPR = medication-possession ratio.Okuda DT, et al. Presented at: The Consortium of Multiple Sclerosis Centers 22nd Annual Meeting; May 28-31, 2008; Denver, Colorado. Abstract S55. Meletiche D, et al. Presented at: The Consortium of Multiple Sclerosis Centers 22nd Annual Meeting; May 28-31, 2008; Denver, Colorado. Abstract S47.

MS Management Challenges:Drug and Disease Cost Issues and Trends

• Drug costs– Drug acquisition

• Pipeline burgeoning with novel biologic agents

• Price increases vs rebates

• Administrative burden– Elusiveness of data to determine total costs due to lack of

transparency driven by medical/pharmacy benefit designs

– Parity laws

– Patient education/health management programs

– Management of safety monitoring

• Total costs need to be evaluated– Direct and indirect

– Contract implications of indications

– Role of patient assistance programs

Compliance, Persistency, Adherence

• Patient factors

– Depression, anxiety, phobia

– Fatigue

– Cognitive status

– Patient attitude and beliefs (realistic therapeutic expectations)

– Active lifestyles

– Patient-physician relationship/teamwork

• Physician factors

– Physician intervention

• 1 month following therapy initiation, then every 3 months thereafter

– Appropriate patient education

• Setting appropriate expectations for therapy

– Managing symptoms and side effects

• Aggressive management of side effects

• Monitoring of MS symptoms and timely management

– Multidisciplinary approach to care

• Easy access to OTs, PTs, social workers, psychologists, urologists, nurses, etc, with a firm understanding of MS

OT = occupational therapists; PT = physical therapists.

What Can Be Done?

Drug Therapy Management$$$

(High-touch patient care management)

Channel Management$$$

(Medical to Pharmacy)

Utilization Management$$

(Prior Authorization/Step Therapy)

Formulary Management$$

(Preferred Drugs)

Drug Cost Management

$(Discount

Improvement)

Best Practice Strategies

Strategies for Improving Medication Compliance: MTM

• Steps can be taken to:

– Target drug therapy problems

– Establish focused medication management interventions

– Develop a framework that is patient-centered

• Keys

– Education

– Set expectations

– Follow up/evaluate

Fleming WK. J Manag Care Pharm. 2008;14(6 suppl B):S16-S20.

MTM = medication therapy management.MTM Core Elements. Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version 2.0. American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008. http://www.accp.com/docs/positions/misc/CoreElements.pdf. Accessed May 21, 2014.

The MTM Core ElementsService Model

How the MTM Core Elements () Interface with the Patient Care Process to Create an MTM Service Model

Interviewpatient

and createa database

withpatient

information

Reviewmedications

forindication,

effectiveness,safetyand

adherence

Listmedication-

relatedproblem(s)

&prioritize

Createa plan

Personal

Medicationrecord(PMR)

Medication-

relatedaction plan

(MAP)

Documentation

& follow-up

Implementplan

Create/Communicate

Create/Communicate

Create/Communicate& Conduct

Medication TherapyReview

Possible referralof patient tophysician,

anotherpharmacist

or otherhealthcare

professional

Interventionsvia

collaboration

Physician andother healthcare

professionals

Interventions directlywith patients

Intervention and/or Referral

To Be Successful…

• Must be ready to begin therapy

• Must believe that therapies can make a difference

• Must be willing to make a commitment

• Must be well educated

– Regarding MS

– Regarding therapies for MS

Potential Strategies

• Better case management

• Guidelines?

• More formulary control

– Data

– Contracts

• Work with pharmacists refunding costs of therapy if a member is compliant and has “x” number of relapses within “x” time frame

• Outcome-based

• Net effective pricing

– Mandatory patient support programs

• Incentive programs

– Member

– Physician – differential reimbursement, pay-for-performance

• Benefit design

– Tiers, evaluating OOP expenses and distribution

– Biosimilars

Strategies for Improving Medication Compliance: Integrated Communication Channels

• Multiprovider level communication with patients regarding the importance of medication compliance

– Physicians

– Pharmacists

– Nurses

– Case managers

• Providers must:

– 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

Roter D. J Pharmacoepidemiol. 1995;3:37-48.

Role of Pharmacists in MS Management

Educational Opportunities for Pharmacist/Allied Health Involvement in MS Therapy

Optimal MS Management

DiseaseModification

SupportSystem

Symptom Management

ClinicalFindings

MRIFindings

Wellness

Ross AP. Neurology. 2008;71(24 suppl 3):S21-S23.

Therapy Selection Issues: Lifelong Treatment of MS

• Every patient with MS is unique and must be managed differently

• Clinicians who treat MS must actively plan for the long-term management of disease

– Monitoring progression with MRI

– Managing the symptoms that come with progression

– Monitoring compliance and adherence to treatment

– Handling breakthrough disease

• Cost considerations

• Administration considerations

Establish Realistic Expectations

• DMTs decrease relapses, reduce MRI activity, and attenuate disease activity

• Attenuated disease activity may lead to more patients retaining employment

• Patients with MS must also realize that DMTs

– Only work if patients take them

– Do not “cure” MS

– May not eliminate MS symptoms

– Do not completely eliminate future disease activity

Cerghet M, et al. Presented at: 60th Annual Meeting of the AAN; April 12-19, 2008; Chicago, Illinois. Abstract P05.073. Putzki et al Presented at: 60th Annual Meeting of the AAN; April 12-19, 2008; Chicago, Illinois. Abstract P05.076.

Proper Injection Technique Promotes Adherence

• Rotate injection sites

• Use an autojector (available at no charge from manufacturer)

• Inject medication at room or body temperature

• Ice the area before and after injecting the medication

• Massage the area before and after injecting the medication

Ryan M, et al. J Am Pharm Assoc. 2002;42(5):753-766.

Full Circle:The Importance of Adherence

• Statistics:

– Relative ↓ in ARR: 30% to 80%

– Relative ↓ in sustained progression: 31% to 42%

• Clinical significance:

– Untreated MS patients: relapse ~every 6 months

– Treated MS patient: relapse ~every 2 to 5 years

FDA.gov. http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm. Accessed May 31, 2014.

Patient Cost-Share Assistance

• Most pharmaceutical manufacturers of MS drugs provide member with financial assistance if cost sharing is an adherence barrier

– The Partnership for Prescription Assistance also offers financial support assistance

• Patient cost-share assistance programs may provide 100% cost share without limitation

• Others provide assistance for a limited time or maximum monthly amount

• How do we factor these programs into benefit design?

Savings Opportunities

Savings Tactic Financial Impact

Drug Cost Management(AWP Discount Improvement)

$(1%-2% of Total Spend)

Formulary Management(Preferred Drugs)

$$(2%-3% of Total Spend)

Utilization Management(Prior Authorization/Step Therapy)

$$(2%-5% of Total Spend)

Channel Management (Medical to Pharmacy)

$$$(5%-10% of Total Spend)

Drug Therapy Management (High-Touch Patient Care Management)

$$$(5%-10% of Total Spend)

AWP = average wholesale price.Data on file. VRx Pharmacy.

Generic Copaxone

• AB-rated

• Contract implications

• Not currently FDA approved – under review

Conclusion

• Specialty trend continues to exponentially grow

• MS is a complex disease

– No guidelines

• CER

– Many reasons for poor compliance and poor outcomes

• MS treatment needs to be individualized

– Tools exist to improve compliance and outcomes

• Healthcare reform (whatever it looks like) will affect what we do

• Benefit design needs to be addressed

• The pharmacist plays a key role in each of these issues