Page 1Optum www.optum.com

Drug ClassInsight

HEMOPHILIABackground, new developments, key strategies

INTRODUCTION

Hemophilia is a rare, inherited bleeding disorder in which

the blood does not clot properly.

• 20,000 patients in the US1

• Occurs in 1 of 5,000 male births1

• Affects MALES almost exclusively1

• Extremely rare, but extremely expensive:

Ranks 8th most costly for employers for all specialty diseases2

MISSING LINK

Lack of clotting factor reduces the body’s ability to control bleeding.

Hemophilia is caused by a mutation that disrupts the body’s ability to produce clotting factor proteins. There are two main forms of the disease, labeled A and B.1

Low levels of clotting factor can lead to spontaneous bleeding in the joints or internal organs, or even inside the skull. Uncontrolled bleeding can cause joint disease, seizures and paralysis or death.1

Hemophilia can be mild, moderate, or severe. The lower the amount

of the factor, the more likely it is that bleeding will occur.1

Injury to blood vessel results in bleeding.

Vessel constricts and clotting factors are activated.

Natural clotting factor helps form a strong platelet plug.

A stable fibrin mesh forms a sealed clot over the platelet plug to stop the bleeding.

Lack of natural clotting factor means only a weak platelet plug can form.

Incomplete fibrin mesh allows bleeding to continue.

Injury Occurs

Natural clotting factor

Damaged area

Normal Hemophilia

Adapted from: Human Disease: Blood Clot Disease (Hemophilia). Jan 26, 2015. Accessed at: http://humansanatomy.org/2015/01/26/blood- clot-disease-hemophilia/ on 02.26.2015.

Less clotting factor

Hemophilia Insight Report

Optum www.optum.com Page 2

All but the mildest forms of hemophilia are extremely expensive to treat. Unfortunately, the majority of people with hemophilia have the most severe form.

ImmunitySome patients develop immunity to their infusions

About 30% of type A and 5% of type B patients on preventive therapy develop immunity to the clotting factors called inhibitors.4 Inhibitors make treatment of bleeding episodes much more complicated, which drives up factor costs – up to or over $1 million per year is not uncommon.4

Critical Breakthrough: Replacement Clotting FactorCompact, effective forms of replacement clotting factor helps many hemophilia patients live near-normal lives.3

Hemophilia therapy consists of replacement therapy — artificially raising a patient’s level of clotting factor via infusion.3

Fresh plasma contains only trace amounts of clotting protein and huge amounts were needed to control bleeding. Researchers learned to make concentrated forms of factor, but these still required thousands of units of donated plasma to prepare just one unit of concentrate.3

Modern factor concentrates are made either with donated human blood plasma, or, beginning in the 1990’s, patients began using genetically engineered clotting factor.3

Both forms of clotting factor are easy to store, mix, and use at home, so many patients self-administer their factor. It only takes about 15 minutes to receive the factor.3

60% Severe: less than 1% of normal level of clotting factor; constant danger of bleeding episodes

25%Mild: 6-30% of normal clotting factor; may not be diagnosed until after serious injury

15%Moderate: 1-5% of normal clotting factor; some possible spontaneous bleeding, or after injury

Nature Outlook: Haemophilia. A Primer on Haemophilia. Dec 16, 2014

Of all people with hemophilia…

Factor VIII Concentrate

500Factor IX

Concentrate

500

≥$1 million

Total annual cost

Hemophilia Insight Report

UNDERSTANDING TREATMENT COSTS

Hemophilia treatment costs can be extremely variable at the individual patient level. At the aggregate level, we can expect overall treatment spending to rise over time as hemophilia patients live longer and as new treatments come into play.

Clotting factor costs

One key cost variable is how much replacement clotting factor a patient needs. Mild and moderate cases require relatively little replacement factor, while severe cases need much more. Patients on preventive therapy use the most replacement factor but also show fewer bleeding episodes and ER visits.

Journal of Medical Economics. Burden of illness: direct and indirect costs among persons with hemophilia A in the United States. Mar 9, 2015. [Epub ahead of print.] Accesses at: http://www.ncbi.nlm.nih.gov/pubmed/25660324 on 04.20.2015.

Mild

Tota

l med

ical

an

d in

dir

ect

cost

s p

er y

ear

$350k

$300k

$250k

$200k

$150k

$50k

$0k

Moderate Severe (On-demand treatment)

Severe (Preventive treatment)

$84,363$59,10154%

Nearly all spending (94%) for severe cases is due to factor costs. Compare to just over half (54%) for mild cases.

$301,392 94%

Immunity (inhibitors) to factor infusions

Health Care Costs for Hemophilia in Commercially Insured Populations$9.0k

$8.0k

$7.0k

$6.0k

$5.0k

$4.0k

$3.0k

$2.0k

$1.0k

$0k

All males with Type A

$696,279

Adults with Type A plus HIV/HCV

Total Annual Medical Cost

The chart below illustrates the explosive effect inhibitors have on costs when inhibitors and comorbidities are added.

Haemophilia (2012), 18, 268–275 DOI: 10.111 1/j.1365-2516.201 1 .02692.xPage 3

Children with Type A

$831,866$577,640

$144,306 $142,057 $188,056

Total Annual Medical CostWithout inhibitors Including inhibitors

$201,471

Hemophilia Insight Report

Costs will rise as growing numbers of patients live longer and develop additional complications (e.g., obesity, low bone density).

Ave

rag

e lif

e ex

pec

tan

cy f

or

hem

op

hili

acs.

National Hemophilia Foundation. History of Bleeding Disorders. Accessed at: https://www.hemophilia.org/Bleeding-Disorders/History-of-Bleed-ing-Disorders on 01.13.2015.National Haemophilia Council. What is the life expectancy of someone with haemophilia? Accessed at: http://www.nationalhaemophiliacouncil.ie/home/faqs/what_is_the_life_expectancy_of_someone_with_haemophilia/ on 01.13.2015.

1900 1960 Today / Newborn with

hemophilia living in a developed

nation

13

20

76

1990s / Hemophiliacs who have consistently received proper

treatment

66 ~10 years less than average

Normal U.S. male lifespan

Better treatments have increased Hemophiliac life expectancy

PREDICTING FUTURE TREATMENT SPENDING

While factor concentrate is expensive, purchase prices have remained fairly flat and are expected to remain so in the short term.5 Therefore, predicting costs over the short term means understanding the age profile of each patient. Over the longer term, overall treatment costs will go up due to demographic pressures.

Hemophilia patients experience radical changes in the cost of their disease as they age.

Payer costs change significantly by patient age

American Society of Hematology: 56th Annual ASH Meeting & Exposition. The Changing Costs of Caring for Hemophilia Patients in the U.S.: Insurers’ and Patients’ Perspectives. Dec. 9, 2014. Paper 199.

Age Years

Ann

ual H

ealth

Insu

ranc

e Ex

pend

iture

Per

Pat

ient

, $U

SD $600,000

$500,000

$400,000

$300,000

$200,000

$100,000

$0

Hemophilia A Hemophilia B

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Type B peak

Type A change

Long Term

Short Term

Optum www.optum.com Page 4

2

Hemophilia Insight Report

Page 5Optum www.optum.com

PROMISING TECHNOLOGY

Some of the highest costs for hemophilia are due to patients who develop inhibitors (resistance) to the factor itself.6 Unfortunately, treatments to overcome resistance are expensive (~$1 million) and not always effective.6 This promising research aims to prevent the immune system from producing inhibitors.

Preventing Inhibitor resistance

Genetically engineered plant cells can be coaxed to produce type A and B factor proteins as part of their normal cell machinery. While plant proteins cannot be used to directly promote clotting, they can help “desensitize” the body’s immune system and prevent rejection.7 Note: Although human figures are used below, these studies are still in the animal phase. Human trials are expected to begin sometime in 2015.7

Leaf cell diagram adapted from: University of Cincinnati – Clermont. College Biology Home page: Cells & Organelles. Sept 5, 2011. Process based on: Nature Outlook: Haemophilia. Lettuce Pills May Help Treat Haemophilia. Dec 16, 2014.

The resulting plant-based factor cannot be used directly to control bleeding.

Instead, the engineered lettuce and clotting protein is freeze dried, powdered and administered by adding to food.1Lettuce leaf chloroplasts are genetically

engineered to produce human clotting factor protein.

About 10,000 chloroplasts are in each cell.

43The leaf cells protect clotting proteins from stomach acids.

Cells release proteins once inside the intestinal tract.

Another protein is added to help clotting factor bind to the intestinal wall.

Clotting proteins are then processed by the immune system to produce tolerance.

stomach

large

intestine

The plant-based clotting protein “defuses” the immune system.

Real clotting factor infusion can proceed with no allergic reaction.

Any existing inhibitors are reversed.

chloroplasts

Engineered clotting proteincell wall

Optum www.optum.com

Hemophilia Insight Report

Page 6

SPECIALTY PHARMACY HEMOPHILIA PROGRAMThe OptumRx Specialty Pharmacy hemophilia program is designed to make patients as self-sufficient as possible. We also work closely with regional Hemophilia Treatment Centers (HTCs), that bring together specialty teams of doctors, nurses, & health professionals.

The OptumRx Specialty Pharmacy Program connects patients with the nearest local HTC which monitors each patient’s treatment.

DEDICATED CALL CENTERWe have a dedicated call center for hemophilia. The same specialty pharmacist within OptumRx Specialty Pharmacy will regularly assess each patient’s needs.

• Ongoing support to recognize and prevent bleeds

• Comprehensive assessments 2-4X per year

• Teach patients and caregivers how to “self-infuse” at home

• Ensure ready access to clotting factor

• Conduct routine compliance and adherence calls

• Supplies needed such as needles, tubing, syringes, etc.

HTCS ARE LOCATED ACROSS THE COUNTRY

OVERVIEW OF HEMOPHILIA MANAGEMENT PROGRAMIntegrated management allows for consistent management and holistic care coordination.

Clinical Management Provides individualized educational and clinical support for patients to help improve adherence to achieve optimal outcomes.

Utilization Management Ensure clinically appropriate and cost-effective utilization by using the management strategies available to each client.

Aggressive contractingLeading to better drug pricing.

Available NetworksAccess to efficient, quality care and deep discounts for many specialty drugs.

Assay Management We tightly manage how much factor medication is dispensed reduces waste and can save thousands of dollars per patient per year.

MEMBERS Better health and support and guidance

CLIENTS Total cost control and program management: clients can achieve up to $0.66 PMPM savings by exclusively using participating providers*

PROVIDERS Better health support and guidance

BenefitsOptumRx Program Goals

*Oxford Hemophilia Initiative covering FI clients during calendar 2014.

Optum www.optum.com

Hemophilia Insight Report

MEET JOHNJohn was diagnosed with severe hemophilia when he was an infant. Without effective preventive therapy he would risk spontaneous bleeding, disability or death. John was transitioned into our Hemophilia Specialty Pharmacy Program shortly after his employer switched to OptumRx.

Page 7

Connected Engagement: Every interaction is an opportunity to reduce health risk and lower costs

What does it mean to manage the total cost of John's condition?

Synchronize member touch points and data into ONE system.

Opportunities Traditional

PBM OPTIMIZED* OptumRx Connected Care

1 Prior Authorization YES 2 Assay Management NOT OPTIMIZED 3 Adherence Programs NOT OPTIMIZED 4 Clinical Management

ProgramNOT OPTIMIZED

5Connect members with quality physicians and Hemophilia Treatment Centers

MISSED

6Manage co-morbid depression with synchronized behavioral referrals

MISSED

7

Weight monitoring and healthy lifestyle programs to encourage condition-appropriate exercises and diet

MISSED

+Self Service +Outreach Inbound

Synchronized Touch Points

Pharmacy Customer

Service

Online

Health Care Advisor

Mobile

Nurse Advisor

A traditional PBM looking only at pharmacy claims or pharmacy solutions can miss opportunities. Our ONE team approach manages multiple consumer touch points to promote real behavior change, like lower cost alternatives, medication adherence or engagement in clinical management programs.

Our Connected Care model leverages all member touch points to capitalize on every opportunity to guide each member to their best next health action.

* The synchronized care management model described here depends on a minimum specific set of OptumHealth care management services, plus OptumRx pharmacy services. Please speak to your OptumRx or UnitedHealthcare representative for more information about how synchronization can work for you.

Connected Value• Care Management,

Wellness, Behavioral

Program Connections

• Advanced Nurse Advisor

• Pharmacist Consults

• 360˚ Alert System

• Connected Medical,

Pharmacy, Specialty

Hemophilia Insight Report

Connected Dataand Expertise

Connected Engagement

Connected Care

Incremental3-6% savings*

compared to total pharmacy spend

THE OPTUMRx DIFFERENCE: HEALTH CARE CONNECTED

Even ordinary PBMs can do an adequate job at the ordinary things PBMs do – negotiate discounts, pay claims, manage formularies and so on. But OptumRx is more than an ordinary PBM: We are a complete pharmacy care services company.

We focus on managing total condition spending by connecting pharmacy’s impact across all benefits.

Optum www.optum.com Page 8

Core PBM Value Like other PBMs, OptumRx delivers savings through core PBM programs

• PDL Management

• Clinical Programs

• Utilization Management

• Exclusions

• Specialty Pharmacy

• Home Delivery

• Adherence programs

• Drug cost management

• Claims processing

• Network

* Estimated additional savings over traditional core PBM services based on total pharmacy spend. Illustrative only; results may vary.

11000 Optum Circle, Eden Prairie, MN 55344

Optum and the Optum logo are registered trademarks of Optum. All other brand or product names are trademarks or registered marks of their respective owner. Because we are continuously improving our products and services, Optum reserves the right to change specifications without prior notice. Optum is an equal opportunity employer.

M33018-N 4/15 © 2015 Optum. All Rights Reserved.

www.optum.com

Hemophilia Insight Report

1. Centers for Disease Control and Prevention. Hemophilia Facts. Aug 26, 2014. Accessed at: http://www.cdc.gov/ncbddd/hemophilia/facts.html on 10.17.2014.

2. UnitedHealth Center for Health Reform & Modernization, Issue Brief. The Growth of Specialty Pharmacy. April, 2014. Accessed at: http://www.unitedhealthgroup.com/~/media/UHG/PDF/2014/UNH-The-Growth-Of-Specialty-Pharmacy.ashx on 02.13.2015.

3. National Hemophilia Foundation. History of Bleeding Disorders. Accessed at: https://www.hemophilia.org/Bleeding-Disorders/History-of-Bleeding-Disorders on 01.13.2015.

4. Specialty Pharmacy Continuum. Hemophilia: Overview and New and Emerging Treatments. May, 2014. Volume 3, Spring Issue. Accessed at: http://www.specialtyphar-macycontinuum.com/ViewArticle.aspx?d=Clinical&d_id=500&i=May+2014&i_id=1063&a_id=27523 on 01.28.2015.

5. Morningstar Healthcare Observer. The Hemophilia Market. January 2013.

6. CDMI Report. Understanding Hemophilia: A Managed Care Review. Fall 2013. Accessed at: http://www.cdmi-health.com/CDMI_Journal/Fall_2013/files/assets/FALL%202013_FINAL2.pdf on 01.30.2015.

7. Nature Outlook: Haemophilia. Lettuce Pills May Help Treat Haemophilia. Dec 16, 2014. Accessed at: http://www.scientificamerican.com/article/lettuce-pills-you-heard-that-right-may-help-treat-haemophilia/ on 02.25.2015.

References

For more information about how you can manage the cost of Hemophilia,please contact your OptumRx representative.

Page 9