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Disease State Primer: Rheumatoid Arthritis

Q1 2012: Pre-EULAR

2

Table of Contents

Slide Number

I. Introduction • Who is Lumleian and what is a disease state primer?

• What is our perspective on rheumatoid arthritis?

• 3 – 6

• 7 – 9

II. Disease Overview and Care Paradigm • What is rheumatoid arthritis?

• Presentation, diagnosis, classification

• Epidemiology by geography and patient segment

• Current care paradigm and clinical evidence

• Emerging care paradigm

10 • 11 - 12

• 13 - 14

• 15

• 16 – 27

• 28

III. Clinical Development Pipeline • Disease mechanism overview

• Clinical development pipeline mapping

• JAK Inhibitors

• Syk Inhibitors

• c-Kit Inhibitors

• Anti-Baff antibodies

• Other mechanisms

29 • 30 - 32

• 33 – 38

• 39 – 45

• 46 - 48

• 49 - 50

• 51 - 52

• 53 – 71

IV. Commercial Landscape • Global, US, EU, Japan market size and growth by brand

• Wall Street consensus forecasts for pipeline assets

• US growth decomposition: Rx volume, pricing, product mix

• US promotional spending, marketing mix and brand messaging

72 • 73 – 78

• 79

• 80 – 81

• 82 – 90

V. Appendix • Table of Acronyms

• More about Lumleian

91 • 92 – 93

• 94 – 96

3

Lumleian offers the requisite scale and depth of life science expertise required for our client’s

most critical investment decisions; We offer universal information and real time knowledge.

• Data Mining

- Regulatory filings

- Scientific literature

- Patent filings

- Company filings

and press releases

• Secondary Data

- Industry pipelines

- Wall Street analysis

- US TRx, pricing,

promotional spend

• Primary Research

- Key opinion leaders

- Practicing physicians

- Reimbursement

Expertise Based

Teams

• Experience

- Academic faculty

- Bio-pharmaceutical

- Equity research

- Strategy consulting

• Expertise

- 30+ clinicians

and Ph.D. scientists

• Analytics

- 5 Ph.D. economists

and statisticians

Universal

Information

Real-Time

Knowledge

• Disease State Primers

- Disease overview

and care paradigm

- Clinical development pipeline

- Commercial landscape

• Functional Drill Downs

- In licensing assessments

- Early and late stage

- Preliminary due dilligence

- Real-time clinical data

• Proprietary Analytics

- Asset valuation

- Epidemiologic forecasts

- Industry benchmarks

• Drug Development

and commercial

- Patient segment valuations

- Promotional response models

• Healthcare professional

and direct to consumer

• Academic and

Research Institutions

- Portfolio optimization

• Early stage

- Out licensing strategy

• Asset valuation

• Transaction support

• Royalty monetization

• Bio-pharmaceutical Companies

- Asset valuation

- Clinical strategy

- In licensing strategy

• Early and late stage

- Portfolio optimization

• Early and late stage

- Preliminary due dilligence

• Life Science Investors

- Asset valuation

- Clinical strategy

- In licensing strategy

Life Science

Client Base

Decision

Support

4

Notes: 1These are a representative sub-set of the publicly available data sources

To ensure real-time knowledge, across disease states, our team of 30+ clinicians and Ph.D.

scientists maintain a comprehensive knowledge management platform, leveraging novel data

mining technology and proprietary analytics.

Data Mining

and Analytics

• Company presentations

• Earnings announcements

• Equity research coverage

• Investor relations transcripts

• Clinical trials

• Conference presentations

• Gene ontology

• Industry pipeline databases

• NIH grants

• Scientific literature & citations

• Business development transactions

• Venture capital investments

• Disease profiles

• Industry publications

• Sales and Rx data

• Treatment algorithms

• Advisory committee transcripts

• FDA and EMA filings

Scientific

& Clinical:

Financial:

Academic

Tech Transfer:

Competitive

Landscape:

• Early stage technologies

• Intellectual property filings

Business

Development:

Regulatory:

• Leverage data mining

technology to access

novel data sources

• Standardize, collate,

and link data sources

• Execute Lumleian’s

proprietary analytical

models

Universe of Public

Information1

• 30+ clinicians and

Ph.D. scientists

- Focused by area

of expertise

• 5 Ph.D. economists

and statisticians

Expert Validation

and Decision Support

5

Our efficient platform and our expertise based teams enable us to both deliver the highest

quality product and tailor our offer, to specific client needs: either custom decision support or

more standardized research and analytics, e.g. disease state primers.

Decision

Support

• Clinical strategy

• Portfolio optimization

- Pre-Clinical

- Clinical

• Transaction support

- In licensing

- Out licensing Disease

State Primers

Proprietary

Analytics

• Asset valuation

• Epidemiologic forecasts

• Industry benchmarks

- Commercial

- Clinical Development

• Patient segment

valuations

• Promotional

response models

- Healthcare professional

- Direct to consumer

• Royalty monetization

Functional

Drill Downs

• Real-time clinical

data

- Trial strategies

- Results

• In licensing

assessments

- Pre-clinical

- Clinical

• Preliminary

due dilligence

- Scientific

- Clinical

- Commercial

• Disease overview

and care paradigm

• Clinical development

pipeline

• Commercial

landscape Customized

Standardized

6

What information is included in a disease state primer?

• Lumleian’s objective and fact based perspective on the relative attractiveness of investing in a given disease state

• Disease overview and care paradigm - Etiology, Diagnosis and patient segmentation, Global epidemiology, Treatment algorithm, Clinical evidence, Emerging care paradigm

• Clinical Development Pipeline - Validated industry pipeline for all assets in clinical development, Select mechanism of action profiles, trial designs and evidence

• Commercial landscape - Global, US, EU, Japan market and brand revenue, Pipeline forecasts, US growth decomposition, Promotional spend and messaging

What disease states are planned for 2012? • Autoimmune: Inflammatory Bowel Disease, Lupus, Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis

• Cardiovascular: Hyperlipidemia

• Central Nervous System: Alzheimer’s Disease, Depression, Pain, Schizophrenia

• Endocrine: Type II Diabetes, Obesity

• Infectious Disease: Gram Negative Bacteria, Hepatitis C Virus

• Oncology: Breast, Colorectal, Leukemia(s), Lung, Lymphoma(s), Melanoma, Ovarian, Pancreatic, Prostate

• Pulmonary: Chronic Obstructive Pulmonary Disease, Idiopathic Pulmonary Fibrosis

Can we create custom disease state primers for customers? • Yes, based on the expertise of our team of 30+ clinicians and Ph.D. scientists, 5 Ph.D. economists and statisticians we can create a

sustome primer in appoximately 3 to 4 weeks

• We can supplement the primers with deeper analysis to help customers reach a deeper understanding of critical issues e.g. KOL

interviews, Financial Models, Survey Conduction and Analysis, Pre-Clinical Asset Assessment

• We are also developing deep drills by function, e.g. Discovery, Clinical development, Business development, Commercial

Why did we create our disease state primers? • We were frustrated by having to repeatedly validate, standardize, and collate pipeline and commercial data

• Portfolio optimization requires a standard framework to compare “apples to apples” investment decisions across disease states

• Our primers began as a training tool; We require every decision scientist create one from scratch before supporting clients

What is a Lumleian’s disease state primer?

7

Executive Summary: Rheumatoid Arthritis

• The global

Disease

Overview and

Care Paradigm

• Rheumatoid arthritis is a chronic, debilitating, systemic inflammatory condition, with multiple serious comorbidities

including cardiovascular disease, increased risk of infections, malignancies, and osteoporosis ‐ Rheumatoid arthritis is a heterogeneous disease in which response to treatment varies dramatically by patient

• Remission rates remain sub-optimal despite aggressive therapy early in disease progression: ‐ DMARDs, non-biologic first then biologics, are the backbone for therapy with novel biologics reserved for later treatment lines

‐ Methotrexate is the most common non-biologic DMARD in 1st line mono-therapy and the base for most combination therapies

‐ Anti-TNFα’s are the cornerstone biologics used in 2nd line, as mono-therapy or commonly in combination with methotrexate

• After inadequate response, 3-6 months per recent 2012 ACR guidelines, switching to a successive anti-TNFα’s is standard

• 50% of patients stop responding to a particular DMARD after five years creating substantial unmet need later in treatment

‐ Novel biologics are used 3rd line: Orencia (T Cell Costimulation Inhibitor), Actemra (IL-6 Inhibitor), and Rituxan (B Cell Inhibitor)

Clinical

Development

Pipeline

• Substantial primary need exists for agents which offer an alternative for patients who do not respond to anti-TNFα therapy

‐ ACR50 response is achieved in ~2/3 of patients, leaving ~1/3 of patients without an effective long-term treatment strategy ‐ Secondary unmet needs include providing: (1) Additional benefits such as prevention of bone erosion or cardio-protection,

and (2) An oral formulation as an alternative to sub-cutaneous and intravenous agents

• As of May 2012, Lumleian validated 82 assets in clinical development, nearly all of which focus on chronic symptom

management and cessation of structural damage

• The late stage pipeline is crowded with multiple mechanisms, including: Cytokine inhibition (TNF, IL-6), Kinase inhibition

(JAK, Syk, P38 MAPK, c-Kit CD117), B Cell inhibition (BAFF, CD-20), and T Cell inhibition (CD4, CD23) ‐ FDA precedent suggests novel mechanisms will initially be approved in later lines of treatment where they will compete for

class and asset differentiation in the eyes of payors and physicians

• Most pipeline activity is focused on the development of kinase inhibitors: ‐ Excitement exists for Pfizer’s Tofacitinib, the first oral treatment with anti-TNFα like efficacy

‐ In May 2011 an FDA advisory committee voted 8-2 in favor of approval and its PDUFA decision is set for August 2012

‐ Tofacitinib approval will most likely be in 3rd line without an inhibition of structural damage claim and with dose titration

‐ Other kinase targets have not fared so well and in particular the relative lack of efficacy of p38 MAPK was surprising

• Oral Syk Inhibitors are promising; In addition to offering impressive inflammation control, they also slow bone resorption

Commercial

Landscape

• Global ’11 brand revenue for RA was ~$14.7B and is forecast to grow by ~4.5% to ~$18.3B between ’12 and ’15 ‐ Modest growth in pipeline biologics is expected short term supported by recent ACR guidelines reinforcing anti-TNFα’s

‐ Other approved biologic classes will gain 2nd line share based on sub-cutaneous formulations and Humira head-to-head trials

‐ Novel drug classes will likely be restricted to 3rd line by regulators and will all have to compete for differentiation • Precedent exist based on Actemra’s approval in January 2010 and concerns raised at Tofacitinib’s advisory committee in May 2012

‐ Payor pressure will be acute, as evidence by recent NICE guidelines for Orencia, and bio-similars will stunt growth in Europe • An EMA decision on bio-similar Remicade is expected in ~12 months with Enbrel and Humira in clinical development

• Promotion costs are substantial and may be a deterrent for less differentiated agents - In December 2011 US marketing/sales monthly costs exceeded $40M: $17.5 on Healthcare professional s and $32.6M in DTC

- Perhaps indicative of this challenge, Simponi and Cimzia the 4th and 5th anti-TNFα’s to market have reduced promotional spend

consistently throughout 2011; Actemra, which has a label restricted to 3rd line patients, is also reducing promotional spend

8

What are the key questions for 2012?

Key

Questions

• Commercial Opportunity - What will be the impact of Pfizer terminating its co-promote arrangement for Humira in 2012?

- What will be the impact of the JAK Inhibitors, and other orals on the treatment paradigm, given Tofacitinib,

the first JAK inhibitor is likely to be approved in August ’12 in 3rd line without a structural inhibition claim? • In which line of treatment is Tofacitinib likely to be indicated at launch, given safety concerns and FDA precedent

for initially approving novel mechanisms in later lines of treatment and then staggering approvals to earlier lines?

• What will be the impact of a likely label without an inhibition of progression of structural damage claim?

• How will payors perceive Tofacitinib based on its launch label, will they perceive it to be a driver of treatment cost

or perceive it as having potential to reduce treatment cost, by reducing anti-TNFα cycling?

• What will be the rate of uptake of orals in the market by rheumatologists and potentially primary care?

- What will be the impact of anti-TNFα therapy head-to-head studies by incumbent biologics, e.g. AMPLE and ADACTA?

- Will late stage biologics provide sufficient clinical advantage over incumbents to merit moving up in the treatment

paradigm? How long will it take for the FDA, ACR/EULAR and rheumatologists to gain comfort with their safety profiles?

- Will payors be willing to pay for novel pipeline agents given the size of the commercial market, $14.7B globally?

- How will the loss of European patent exclusivity for entrenched incumbents Remicade (2014), Enbrel (2015),

and Humira (2018) impact EU revenue considering that the EMA has already approved 14 bio-similars? • How will downward pricing pressure, caused by the entry of bio-similars, affect the opportunity of, and point

of entry in the treatment paradigm for future innovative approaches?

- How will the US’s Biologics Price Competition and Innovation Act impact the commercial landscape of biologics

in the US considering patent expiry for Enbrel (2014), Humira (2016), Remicade (2018)?

• Clinical Development and Regulatory Risk - Will regulators gain comfort approving agents in earlier treatment lines or will they continue to stage approvals?

- How will efficacy and safety requirements impact the point of entry in the treatment paradigm for novel therapies?

- Will more emphasis be placed on achieving ACR50 and ACR70 endpoints versus ACR20?

- Post Tofacitinib, how will pipeline assets overcome placebo challenges in short-term structural progression studies?

Lumleian’s

Perspective

• ACR50 response is achieved in fewer than 2/3 patients, leaving at least 1/3 of the most seriously affected patients with

rheumatoid arthritis without an effective long-term treatment strategy; acute need exists in later treatment lines

• This represents an attractive long-term opportunity for companies with novel therapies that can navigate regulatory

approval and payor reimbursements, and provide patients and clinicians with demonstrable efficacy/safety benefit ‐ Incumbent anti-TNFα’s will continue to dominate the market in the short term with slow but steady uptake of new MoAs

‐ Once oral agents demonstrate long-term safety and efficacy equivalent to current SoC, they will likely challenge anti-TNFα’s

the cornerstone of RA treatment after 1st line methotrexate; this will be slow over 3-5 years; novel biologics are a wild card

• Early diagnostic and prognostic markers are needed to ensure that appropriate treatment is initiated early and to identify

inadequate responders in earlier lines of treatment, for example ACR20 and power-doppler ultrasonography

9

0

1

2

3

4

5

Level of Unmet Need Likelihood of Technical Success Regulatory Impetus Commerical Attractiveness Required Investment

The attractiveness of investing in late stage clinical development is mechanistic specific based on

likelihood of technical success; appropriately the regulatory environment is highly conservative

dictating slow uptake; with high unmet RA is very commercially attractive for the right asset.

Average

RA: Relative Attractiveness of Greenfield Investment in Late Stage Clinical Development

High

Low

Required

Investment

Phase III Investment

• 500-1000 patients, with

2-3 Phase III trials minimum

• 6 month to 2 year length ‐ Safety extensions mandatory

• Costs increase dramatically

for active comparator trial

Commercial Spend

• Total category advertising

was ~$40M in Dec ’11 ($5M

per major brand) - $17.5M on health care

professionals

- $32.6M on consumers

Phase IV Investment

• New MoA requires long term

safety studies

• Active comparator studies

vs. anti-TNFα for 2nd line ‐ Studies: AMPLE, ADACTA

• Additional indications

beyond RA are standard

Level of

Unmet Need

Clinical Unmet Need

• Need exists in Anti-TNFα

inadequate responders

• Safety is a universal

concern for all lines

of treatment

Global Epidemiology

• 1.5M US prevalence ’11

• 3.3M EU prevalence ’11

Disease Burden

• ~$20B in tangible costs

• 33% patients stop work

within 2 years

Not a Cause of Mortality

• Mortality is increased in

RA patients, mainly due

to CV causes

Commercial

Attractiveness

Market Size

• WW ~$14.7B

• US ~$7.8B

Global Epidemiology

• 1.5M US prevalence ’11

• Declining diagnosis rates

Expansion Opportunities

• 2nd line of treatment

versus Anti-TNFα’s

Generic Penetration

• Generic methotrexate

dominates 1st line

• Bio-similars are certain

in EU and likely in US ‐ Rituxan EU (Aug ‘13)

‐ Remicade EU (Aug ‘14)

‐ Enbrel EU (Oct ‘15)

Competitive Launches

• 7 regulatory review/

Phase III drugs in pipeline

• Tofacitinib Q3/Q4 2012

Likelihood of

Technical Success

Unknown Etiology

• Combination of genetic

and environmental factors

Many Late Stage Failures

• AZD5672 (AZN); CEP-37247

(Cephalon); dnaJP1

(Adeona); Doramapimod (BI);

GLPG-0259 (Galapagos);

Maraviroc (PFE);

PF-05212368 (PFE);

MLN1202 (Millenium);

MLN3897 (Millenium);

RG4934 (Roche),

Pamapimod (Roche);

Scio-323; Scio-469 (Scios);

VX-702, VX-745 (VRTX)

Statistical Challenges

• Placebo radiography

challenges

• ACR endpoints well validated

Target Patient Populations

• Treatment naïve; MTX

failure; anti-TNFα failure

Regulatory

Environment

Regulatory Pathway

• High unmet need in 2nd

and 3rd lines of treatment

• Clear and established

regulatory pathway

Historical Precedents

• In Nov ‘98 Enbrel

• In Aug ‘98 Remicade ‐ Nov ‘99 in RA

• In Dec ‘02 Humira

• In Dec ‘05 Orencia

• In Nov ‘97 Rituxan ‐ Feb ‘06 in RA

• In Apr ‘09 Simponi

• In April ‘08 Cimzia ‐ May ‘09 in RA

• In Jan ‘10 Actemra

Safety Concerns

• Acute safety concerns

have led regulators to

initially restrict agents

to later treatment lines

Advocacy

• Arthritis Foundation

Highly

MoA specific

Well defined regulatory pathway,

but conservative labeling

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Table of Contents

Slide Number



• 3 – 6

• 7 – 9






10 • 11 - 12

• 13 - 14

• 15

• 16 – 27

• 28



• JAK Inhibitors

• Syk Inhibitors




29 • 30 - 32

• 33 – 38

• 39 – 45

• 46 - 48

• 49 - 50

• 51 - 52

• 53 – 71





72 • 73 – 78

• 79

• 80 – 81

• 82 – 90



91 • 92 – 93

• 94 – 96

11

Sources: 1Lajas C et al. Costs and Predictors of Costs in Rheumatoid Arthritis: A Prevalence-Based Study. Arthritis Rheum 2003;49: 64-70; 2Verstappen SMM

et al. Working status among Dutch patients with rheumatoid arthritis: work disability and working conditions. Rheumatology 2005; 44: 202- 206

Executive Summary: Disease Overview and Care Paradigm

• The global

What is

Rheumatoid

Arthritis?

• Rheumatoid arthritis is a chronic, debilitating, inflammatory condition, with a number of serious comorbidities

including cardiovascular disease, increased rate of infections, malignancies and osteoporosis - Rheumatoid arthritis affects about 1% of adults in industrialized countries and nearly three times as many women as men

- Onset commonly occurs between the ages of 30 and 60

• Rheumatoid arthritis has no known cause, but likely results from a combination of genetic and environmental factors - Non-modifiable risk factors include gender, aging, and genetics

- Modifiable risk factors include smoking, reproductive hormonal exposures, and periodontal disease (gingivitis)

What is the

disease burden?

• In 2011 estimated prevalence was ~1.5 M in the United States and ~3.3M in Europe - Prevalence has declined in the United States over the past decade and the annual incidence is estimated to be ~114K cases

• Rheumatoid arthritis is not a direct cause of mortality, although it increases the overall mortality ratio by 1.3 to 3,

primarily due to infections, malignancies and increased cardiovascular events

• Rheumatoid arthritis represents substantial financial burden in both tangible and intangible costs for patients,

employers and payors, private and particularly public: ‐ In the US the disease is estimated to cost $19.3B (tangible costs only) and $39.2B (with intangible costs) in ‘05 dollars

‐ Average annual cost to patients is estimated at $8,000 to $13,0001

‐ Cost to employers includes decreased productivity and absenteeism; this reduces tax revenue for public payors

• ~1/3 of patients stop work within two years and ~2/3 of patients are unable to work 15 years post onset

• ~40% of patients change their working conditions within 4 years2, as defined by reduced hours and/or pace of work

What is today’s

care paradigm?

• Under the current standard of care, treatment goals are symptom control and inhibition of structural damage

• Treatment of rheumatoid arthritis is driven by ACR/EULAR guidelines with DMARDs as the backbone of therapy ‐ Methotrexate is used as 1st line in naïve patients, anti-TNFα’s are used successively in 2nd line, and novel biologics are used 3rd

‐ Substantial unmet need exists in 3rd line for patients not responding to anti-TNFα’s and in 2nd line to reduce anti-TNFα cycling

• ~50% of patients stop responding to a particular DMARD after five years creating substantial unmet need later in treatment

What is the

emerging care

paradigm?

• For the foreseeable future methotrexate will remain the dominant choice for treatment naïve patients and the-

leading anti-TNFα’s (Humira, Enbrel, and Remicade) will continue to dominate 2nd line treatment

• Currently approved novel biologics (Orencia and Actemra) and once monthly anti-TNFα ‘s (Cimzia) are conducting

head-to-head trials in 2nd line; premised on superiority these will gain more traction with anti-TNFα naïve patients

• FDA precedent suggests that novel pipeline agents will be initially approved for 3rd line patients; over time once

safety has been validated in clinical practice they will receive label expansions to earlier lines of treatment

• Despite approval of new mechanisms and formulations FDA labels and ACR/EULAR guidelines will set a slow

timetable for new product uptake in earlier treatment lines; these guidelines will be effectively enforced by payors

12

No Yes (Women)

What is Rheumatoid Arthritis?

Description

• Rheumatoid arthritis is the most common systemic autoimmune disease, and is

characterized by chronic inflammation of the joints that can damage cartilage,

tendons and bone, lead to joint deformity and disability, and affect internal organs

- Rheumatoid arthritis affects about 1% of adults in industrialized countries, nearly

three times as many women as men, with common age of onset between 30 and 60

- Common co-morbidities include: cardiovascular disease, increased rate of infection,

lymphoproliferative malignancy, osteoporosis, psoriasis, and peptic ulcers

Etiology

• Rheumatoid arthritis has no known causes but likely results from a combination of

genetic and environmental factors

- The strongest genetic associations have been found with HLA class II DRB1*0401

and DRB1*0404 alleles and the PTPN22 gene

• Gender, aging, and genetics are non-modifiable primary risk factors

• Smoking, the highest modifiable risk factor, increases onset risk by 1.3 to 2.4 times

Symptom

Progression

• Symptoms vary widely between patients, from inactive to severe

• The hallmark symptom is synovitis, the inflammation of the lining of the joints

(synovium) that causes pain, stiffness and swelling, and potential irreversible damage

to the cartilage and bone leading to loss of function ‐ Synovitis usually affects the fingers and toes in the early stage, but can spread to the

knees, wrists, ankles, neck, shoulders, elbows, and even the jaw

‐ Joints are usually affected in a symmetrical pattern

• Systemic symptoms include flu symptoms (fatigue, malaise, loss of appetite, and

muscle aches), pleural effusion, pericardial effusion, vasculitis, anemia, nerve

entrapment, and eye dryness or inflammation (Sjögren’s syndrome)

Disease

Burden

• Rheumatoid arthritis has a standardized overall mortality ratio of 1.3 to 3 versus the

population, mainly due to increased rates of infection, malignancies, and CV risk

• Rheumatoid arthritis is a significant public health problem, and cost between $19.3B

(tangible costs) and $39.2B (with intangible costs included) in ‘05 dollars in the US - Employers and patients bear the majority of cost burden in lost productivity/wages

• Cost burden: Employers (33%); Patients (28%), Government (20%); Caregivers (19%)

- Intangible costs included quality of life deterioration ($10.3B) and mortality ($9.6B)

2. Is RA a primary cause of mortality?

7. Where is RA treated, commonly?

Yes No

Out

Patient

Inpatient

Hospital

Long

Term

Care

Symptom

Relief

Disease

Treatment

Disease

Cure

3. Is RA an acute or chronic disease?

Acute Chronic

6. Which specialties treat RA, commonly?

5. What is RA’ s treatment goal?

8. Who pays for RA care (Rx), commonly?

3rd party Cash Medicare

PCP Rheumatology

4. Is RA a communicable disease?

Yes No

1. Is RA’s etiology well understood?

Yes No

9. Does RA impact a special population?

13

Note: *Presence of blood rheumatic factor and citrulline antibodies, erythrocyte sedimentation rate, and levels of C-reactive protein

Currently, rheumatoid arthritis is diagnosed by the rheumatologist, who provides the backbone

of treatment, based on physical examination and serology results*; primary care physicians and

nurse educators help patients with daily management; other specialists support complications.

Diagnosis (Current)

• Patients commonly present with symmetrical joint stiffness,

swelling, pain, redness and warmth, usually in the fingers and

toes in the early stage

Referral Pathway (Current)

• Primary Care Physician: first point of contact; referral to

rheumatologist and patient managers

• Nurse Educator: registered nurse with special training and

background in education and caring for patients on daily

management

• Physical therapist: helps patient to improve joint function

• Occupational therapist: instructs patient to protect joints,

minimize pain, and conserve energy while performing

everyday tasks

• Dietician: established diet to reduce inflammation and weight

• Rheumatologist:

- Specialized training and experience in diagnosis and

pharmacological treatment of RA and related conditions

- Rheumatologists also refer patients to other specialists

for the treatments of complications

• Other Specialists:

- Podiatrist: trained to treat foot-related pain, deformity,

and decreased motion caused by rheumatoid arthritis

- Orthopedic surgeon: specialized in treating bones, joints,

muscles, and tendons and perform procedures such as joint

injections and joint replacement

Diagnosis and Referral Pathway (Current)

Key:

Specialists for complications

Chronic management

Patient

Primary Care

Physician

Nurse Educator

Lifestyle Program

Rheumato- logist

Specialist

(Podiatrist,

Surgeon)

1

2

3

14

The American College of Rheumatology (ACR) recommends that assessment of disease activity

involve combined estimation of six different disease activity scores based on joint examination,

pain assessment, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) blood levels.

Note: 1Each instrument has advantages and disadvantages and has been used interchangeably; 2Erythrocyte Sedimentation Rate; 3 C-Reactive

Protein; 4Visual Analog Scale (measurement of pain)

Source: Saag KG et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying

antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-784

Disease Activity Score1 Criteria Score Range Low Moderate High

• DAS28: Disease Activity

Score in 28 joints

• Joint exam,

ESR2/CRP3, VAS4 • 0-9.4 • ≤3.2 • >3.2 and ≤5.1 • >5.1

• SDAI: Simplified Disease

Activity Index

• Joint exam, CRP, VAS • 0.1-86.0

• ≤11 • >11 and ≤26 • >26

• CDAI: Clinical Disease

Activity Index

• Joint exam, VAS

• 0-76.0 • ≤10 • >10 and ≤22 • >22

• RADI: Rheumatoid

Arthritis Disease Activity

Index

• Self-report of joint

pain • 0-10

• <2.2 • ≥2.2 and ≤4.9 • >4.9

• PAS: Patient Activity

Index

• Self-report of global

health • 0-10 • <1.9 • ≥1.9 and ≤5.3 • >5.3

• RAPID: Routine

Assessment Patient

Index Data

• Self-report of global

health • 0-30 • <6 • ≥6 and ≤12 • >12

15

Source: Tobon et al. The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. Autoimmune Rev 2010;35:10-14; Myasoedova E

et al. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010 June ; 62(6): 1576–

1582; Bax M et al., Genetics of rheumatoid arthritis: what have we learned? Immunogenetics 2011;63:459-465

Rheumatoid arthritis incidence and prevalence rates are higher in North America and in Northern

Europe than in Southern Europe and other countries; For reasons that are unclear US incidence,

based on rheumatoid arthritis diagnosis rates, has declined over the past decade.

Moderate

2011 Prevalent Cases (M)

• Genetics: Contributes 50-60% to the risk of developing RA ‐ The genes most strongly associated are HLA-DRB1, which

contributes by 30-50% to the risk of developing RA, and PTPN22

‐ Additional genes include TRAF1-C5, TNFAIP3, STAT4, PADI4,

CTLA-4, IL2/IL21, CD28, PRDM1, and CD2/CD58

• Gender: The female-to-male ratio in RA patients is 3:1

• Age: The peak age of onset is the 5th decade

• Smoking: The strongest environmental risk factor, especially

in rheumatoid factor (RF)+ men and heavy smokers

• Socioeconomic factors: Affect the course and outcome of

RA but are not believed to influence the risk of developing RA

• Hormones: Several lines of evidences suggest that estrogens

are a risk factor associated with RA

• Ethnicity: Some ethnic and racial groups at higher risk than

others to develop RA, including Pima Indians

• Infections: The role of several infectious agents as initiating

factors of RA is controversial

• Diet: The Mediterranean diet may protect from rheumatoid

arthritis

Primary Risk Factors Secondary Risk Factors

1.5

3.3

0.5

0

2

4

US EU Japan

2011 Incidence: Total New Cases (K)

117

185

23

0

100

200

US EU JP

Prevalence

Rate: 0.50% 0.40%

Incidence Rate:

(Cases per 100K

person per year) 38 24 18 0.44%

16

Diagnosis (Current)

• Diagnosis is based on physical examination and blood tests and

a definitive rheumatoid arthritis diagnosis is confirmed by:

‐ Blood autoantibodies: Rheumatic factor and citrulline antibodies

‐ Abnormal acute-phase response: Abnormal ESR and C-reactive protein

• X-rays are used to monitor disease progression in the joints

Treatment (Current)

• Updated ACR treatment recommendations (2012), include: ‐ Reiterating DMARDs as backbone of care

• Omits specific role for glucocorticoids and NSAIDs

‐ Shortening the treatment response window to 3-6 months

• 1st Line: Initiate treatment with non-biologic DMARDs - Use as mono-therapy or in dual/triple combination therapy:

• Methotrexate (MTX), Hydroxychloroquine (HCQ)

• Leflunomide (LEF), Minocycline, Sulfasalazine

- Add MTX, HCQ, or LEF if inadequate response after 3 months

- Switch to a non-MTX non-biologic DMARD after a year to minimize

hepatoxicity risk, for example Leflunomide

• 2nd line: Switch to anti-TNFα - Add or switch to an anti-TNFα if inadequate response

after 3-6 months; repeat anti-TNFα cycling as necessary

• 3rd line: Switch to novel biologic - Switch to Orencia, Actemra, or Rituxan if inadequate

response to multiple anti-TNFα’s

- Kineret has less attractive efficacy/safety profile

• Monitor disease progression as defined by: ‐ Tender and swollen joint counts, CRP level, and patient global

assessment of ≤1 each or a simplified DAS of ≤3.3

‐ Joint X-rays to monitor disease progression and structural damage

Source: Saag KG et al. American College of Rheumatology 2008 recommendations for the use of non-biologic and biologic disease-modifying anti-rheumatic

drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-784; Singh JA et al. 2012 update of the 2008 American College of Rheumatology

recommendations for the use of disease-modifying anti-rheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res

2012;5:625-639; Smolen JS et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying

anti-rheumatic drugs. Ann Rheum Dis 2010;69:964-975

A well established standard of care exists to treat rheumatoid arthritis: (1) Non-biologic DMARDs

are used 1st line, (2) Anti-TNFα’s are used successively in 2nd line, (3) Novel biologics are reserved

for 3rd line; Substantial unmet need exists in 3rd line for patients not responding to anti-TNFα’s.

Diagnosis:

Low Activity

with Good Prognosis

Low with Poor Prognosis

or Moderate/High Activity

Physical Examination

Blood Test

Add / Switch

NB DMARD monotherapy

Anti-TNFα

Other Anti-TNFα

Novel Biologic

Switch

Methotrexate or

NB DMARD Combination

NB DMARDs

Switch Anti-TNFα

or Novel

Biologic

Add /Switch

Anti-TNFα or Novel Biologic

Switch Switch

Switch

Stratification:

1st line:

2nd line:

3rd line:

17

Note: *Selective NSAIDs are generally considered less toxic than nonselective NSAIDs for the gastrointestinal mucosa, but there is still some

controversy. **Celebrex is the only COX-2 inhibitor approved in the US following the withdrawal of Vioxx (rofecoxib) and Bextra (valdecoxib),

which were associated with an increased risk of heart attack and stroke

Source: Product prescription information; Company press release

Dosing

Safety

Mechanism

of Action

Efficacy

Brands

Generics

• Synthetic analogues to steroid

hormones that bind to the

glucocorticoid receptor ‐ Up-regulate anti-inflammatory

proteins, and down-regulate pro-

inflammatory proteins

• Oral, or injection into the joint

Glucocorticoids

• Reduces pain and swelling as a

low-dose “bridge therapy” when

initiating DMARDs, or short-term

high-dose therapy in some patients

• Swelling/edema

• Easy bruising

• Mood swings, insomnia, euphoria

• Risk of infection

• Decadron (dexamethasone)

• Medrol (methylprednisolone)

• Deltason (prednisone)

• Orasone (prednisone)

• Meticorten (prednisone)

• Celestone (betamethasone)

• Aristopan (triamcinolone)

• Yes

• Inhibit COX-2 selectively versus

COX-1, which is constitutively

expressed in the gastrointestinal

tract, blood platelets, and blood

vessels

• Oral

Selective NSAIDs*

• Liver toxicity

• Kidney toxicity

• Ringing in the ears

• Increased cardiovascular risk

• Celebrex (celecoxib)**

• Yes

Despite omission from the ACR’s updated treatment guidelines (2012), glucocorticoids and

non-steroidal anti-inflammatory drugs are commonly prescribed for short-term symptom relief;

clinicians prescribe these judiciously, most often as a bridge therapy when initiating DMARDs.

• Inhibit both cyclooxygenase (COX)

enzyme isoforms COX-1 and COX-2,

thereby inhibiting the production

of prostaglandins

• Oral

Nonselective NSAIDs

• Dyspepsia, peptic ulcer disease

• Liver toxicity

• Kidney toxicity

• Ringing in the ears

• Aspirin

• Advil (ibuprofen)

• Motrin (ibuprofen)

• Nuprin (ibuprofen)

• Aleve (naproxen)

• Voltaren (diclofenac sodium)

• Yes

• Reduce pain and swelling at low

dose, and fully treat inflammation

at higher doses

• Reduce pain and swelling at low

dose, and fully treat inflammation

at higher doses

18


Dosing

Safety

Mechanism

of Action

Efficacy

Brands

Generic

• Mechanism of action

in RA is unknown ‐ Antimetabolite that

inhibits dihydrofolic

acid reductase

• QW Oral

Methotrexate

• Efficacious for

prolonged treatment ‐ 35-57% ACR20

at 6 months

• Teratogenic action

• Hepatotoxicity

• Myelosuppression

• Aplastic anemia

GI disorders with

NSAIDs

• Lung disease

• Severe skin reactions

• Rheumatrex

• Trexall

• Folex

• Yes

• Prevents expansion of

activated lymphocytes ‐ Inhibits pyrimidine

synthesis by inhibiting

dihydroorotate

dehydrogenase

• QD Oral

Leflunomide

• Teratogenic action

• Hepatotoxicity

• Myelosuppression

• Infections

• Anemia, bleeding

• Lung disease

• Arava

• Yes

• Mechanism of action

in RA is unknown ‐ Inhibits lysosomal

acidic proteases,

causing a diminished

proteolysis

‐ Antimalarial

• QD oral

Hydroxychloroquine

• Eye toxicity

• Plaquenil

• Yes

• Broad spectrum

tetracycline antibiotic ‐ Decreases production

of leukotriene and

prostaglandin

‐ Increases IL-10

production

• BID oral

Minocycline

• Drug reaction with

eosinophilia and

systemic symptoms

(DRESS)

• Thyroid cancer

• Minocin

• Dynacin

• Yes

• Activates liver enzyme

AMPK, which suppresses

hepatic gluconeogenesis

• Also increases Insulin

sensitivity

• BID oral

Sulfasalazine

• Hypersensitivity

• Allergic reaction

• Mild GI symptoms

• Azulfidine

• Yes

• Efficacious for

prolonged treatment ‐ 41-49% of ACR20

at 6 months

• Efficacious for

prolonged treatment

• Efficacious for

prolonged treatment ‐ 35-45% of ACR20

at 6 months

• Efficacious for

prolonged treatment

Generic non-biologic DMARDs, alone or in combination, are the standard of care in 1st line

patients who are treatment naïve; unfortunately only a third to half of patients treated with

methotrexate achieve ACR20 necessitating adding or switching to an anti-TNFα.

19

Source: Product prescription information; Company press release; Comparative effectiveness of drug therapy for rheumatoid arthritis and psoriatic

arthritis in adults (Agency for Healthcare Research and Quality, Rockville, MD, Nov. 2007)

Methotrexate is the is the most commonly prescribed 1st line DMARD, despite hepatoxicity risks

and frequent liver function tests; in year one more patients treated with methotrexate achieve

ACR20 than leflunomide patients; thereafter leflunomide is as effective with less toxicity.

Non-biologic DMARDs

Methotrexate Leflunomide

Sponsor • Pharmacia and Upjohn (Folex)

• Deva Pharmaceuticals (Rheumatrex)

• Treva Pharmaceuticals (Trexall)

• Sanofi

Formulation • Tablet (2.5 mg) • Tablet (10, 20, or 100 mg)

Dosing • Oral: QW • Oral: QD with loading dose

Indications • Treatment of adult patients with all RA durations

and for all degrees of disease activity, irrespective

of poor prognosis – 10-25 mg weekly orally

• Treatment of adult patients with all RA durations

and for all degrees of disease activity, irrespective

of poor prognosis – 10-20 mg daily orally

Adverse Events

• Liver toxicities (15%)

‐ Requires quarterly liver function tests (15%)

• Nausea/vomiting (10%)

• Stomatitis (3-10%)

• Thrombocytopenia (3-10%)

• Diarrhea (17%)

• Respiratory infection (15%)

• Hair loss (10%)

• Rash (10%)

Lumleian

Commentary

• Methotrexate is the most commonly prescribed DMARD based on its demonstrated 1st year efficacy, 35-57%

ACR20 at 6 months, despite significant hepatoxicity risks ‐ Studies indicate that more than 50% of patients who take methotrexate continue on therapy for more than

three years, which is longer than for any other DMARD

‐ More patients meet the ACR20 improvement criteria at year one with methotrexate than with leflunomide,

but statistical difference is lost after two years

• There is no difference between methotrexate and leflunomide in radiographic outcomes over two years

20



Non-biologic DMARDs

Hydroxychloroquine Minocycline Sulfasalazine

Sponsor • Sanofi (Plaquenil) • Triax (Minocin)

• Medicis (Dynacin)

• Pfizer (Azulfidine)

Formulation • Tablet (200 mg) • Capsule (50, 100 mg) • Tablet (500 mg)

Dosing • Oral: QD • Oral: BID • Oral: BID

Indications • Mono-therapy recommended for

patients without poor prognosis

features, with low disease activity,

and with disease duration ≤24 months – 400 to 600 mg daily (induction)

– 200 to 400 mg daily (maintenance)

• Mono-therapy recommended for

patients without poor prognosis

features, with low disease

activity, and with short disease

duration – 200 mg initially

– 100 mg every 12 hours thereafter

• Mono-therapy recommended for

patients with all RA durations and

for all degrees of disease activity,

irrespective of poor prognosis – 2 to 3 grams per day in a twice

daily doing regimen

Adverse Events

• CNS reactions

• Neuromuscular reactions

• Ocular reactions

• Dermatologic reactions

• Hematologic reactions

• Gastrointestinal reactions

• Allergic reactions

• Diarrhea

• Dizziness

• Drowsiness

• Indigestion

• Lightheadedness

• Loss of appetite

• Nausea

• Headache

• Hypersensitivity reaction

• Photosensitivity

• Serum sickness-like syndrome

Lumleian

Commentary

• Sulfasalazine mono-therapy is less efficacious at 2 years (ACR20 and ACR50) than Leflunomide mono-therapy

Other non-methotrexate DMARDs play second fiddle to methotrexate and leflunomide; prolonged

use of hydroxychloroquine is associated with a decrease in cardiovascular disease, which is an

acute concern for rheumatoid arthritis patients who are at higher risk than the overall population.

21

Note: *An ACR20 response is defined as a 20% reduction in the number of swollen and tender joints, and a 20% reduction in 3 out of 5 other parameters

Biologic DMARDs, most commonly used as 2nd line therapy, have revolutionized the treatment of

RA underlining the key roles of T Cells, B Cells, and cytokines in disease pathogenesis; anti-TNFα’s

are the cornerstone of biologic DMARD treatment and capture ~90% of biologic market share.


Dosing

Safety

Mechanism

of Action

Efficacy

Brands

Generic

• Block interaction of

TNFa with its

receptors, which

affects TNFa role in

inflammation and

joint destruction

• QW, QM IV or sub-c

Anti-TNFa’s

• 45 to 76% ACR20*

over 3 to 6 months

• Risk of serious

infections, including

TB reactivation, and

malignancies,

including lymphoma

• Humira (adalimumab)

• Remicade (infliximab)

• Enbrel (entanercept)

• Cimzia (certolizumab)

• Simponi (golimumab)

• No

• CTLA-4Ig fusion

protein: blocks CD80

and CD86 interactions

with CD28, which

inhibits T Cell

activation and

proliferation

• QM IV or QW sub-c

T Cell

Costimulation

Inhibitor

• 67.9% ACR20*

at 6 months

• Risk of serious

infections and

malignancies ‐ Increased with

concomitant

anti-TNFα usage

• Orencia (abatacept)

• No

• Rituxan (rituximab)

• Induces B Cell lysis by

binding to CD20,

inhibits B Cell-driven

inflammation,

autoantibody

formation, and

cytokine release

• Every 24 weeks IV

B Cell

Inhibitor

• 65 to 76% of ACR20*

at 6 months

• Risk of fatal infusion

reactions, severe

mucocutaneous

reactions, and

progressive multifocal

leukoencephalopathy

• No

• Inhibits IL-6-mediated

signaling via binding

to IL-6 receptors,

which inhibits IL-6

pro-inflammatory

actions

• QM IV

IL-6

Inhibitor

• 50 to 70% of ACR20*

at 6 months

• Risk of serious

infections

• Actemra (tocilizumab)

• No

• Blocks interaction of

IL-1 with its receptor.

which inhibits IL-1-

mediated cartilage

degradation, bone

resorption, and other

activities

• QD sub-c

IL-1

Inhibitor

• Risk of serious

infections

• Kineret (anakinra)

• No

• 38 to 43% of ACR20*

at 6 months

Key:

3rd line

(primarily)

2nd line

(primarily)

22



Anti-TNFα’s

Humira (adalimumab) Enbrel (entanercept) Remicade (infliximab)

Sponsor • Abbott • Amgen/Pfizer • Johnson and Johnson/Merck

Formulation

• Pre-filled syringe / pen (40 mg) • Pre-filled syringe (50 or 25 mg)

• Lyophilized powder (25 mg)

• Lyophilized powder (100 mg)

Dosing • Subcutaneous: QW • Subcutaneous: QW • Intravenous: Q8W

Mono-therapy • Yes • Yes • No

Combination

therapy

• Yes with methotrexate • Yes with methotrexate • Yes with methotrexate

Indications • In adult patients with moderately to

severely active rheumatoid arthritis: ‐ Reducing signs and symptoms

‐ Inducing major clinical response

‐ Improving physical function

‐ Inhibiting the progression of

structural damage

• In adult patients with moderately to





structural damage

• In adult patients with moderately to





structural damage

Adverse

Events

• Injection site reaction (20%)

• Upper respiratory tract infection (17%)

• Headache (12%)

• Rash (12%)

• Sinusitis (11%)

• Infection (27%)



• Non-upper respiratory infection (12%)


• Nausea (21%)

• Headache (18%)

• Sinusitis (14%)

Lumleian

Commentary • Clinical studies show no differences in ACR20 and ACR50 response rates among the three leading anti-TNFα’s

• In clinical practice Remicade is favored less for private patients but is the standard of care for Medicare patients ‐ It is perceived as less convenient, absent a sub-cutaneous formulation, and lacks a mono-therapy indication

• Anti-TNFα’s in combination with methotrexate are more efficacious than either anti-TNFα or methotrexate mono-therapy

Sub-cutaneous Humira and Enbrel lead the anti-TNFα’s with private payors; Remicade is used

mainly in Medicare - it is an intravenous formulation and lacks a mono-therapy indication; as a

class the Anti-TNFα’s recently received a black box serious infection/tuberculosis warning.

23

Cimzia and Simponi offer once monthly sub-cutaneous dosing; as the 4th and 5th anti-TNFα’s to

market they account for ~10% market share; clinicians question duration of effect and head-to-

head trials are ongoing; in July 2011 the FDA rejected a “structural” indication for Simponi.

Anti-TNFα’s

Cimzia (certolizumab pegol) Simponi (golimumab)

Sponsor • UCB • Johnson and Johnson/Merck

Formulation • Single-use pre-filled syringe (200 mg) • Single-use pre-filled syringe (50 mg)

Dosing • Subcutaneous: QOW (QM maintenance) ‐ 400 mg (twice 200 mg) at weeks 1, 2, and 4,

followed by 200 mg every other week

‐ For maintenance 400mg every 4 weeks can be

considered

• Subcutaneous: QM ‐ With methotrexate, 50 mg once a month

Indications • Treatment of adults with moderately to severely

active RA ‐ Reducing signs and symptoms



‐ Inhibiting the progression of structural damage

• In combination with methotrexate, treatment of adults

with moderately to severely active rheumatoid arthritis ‐ Reducing signs and symptoms



Adverse Events


• Headache (5%)

• Hypertension (5%)

• Nasopharyngitis (5%)



• Viral infection (5%)


Lumleian

Commentary

• Both Cimzia and Simponi offer more convenient dosing and greater flexibility ‐ Cimzia offers flexible dosing options and a rapid onset (1 to 2 weeks in some patients)

‐ Simponi has similar efficacy and safety as Humira and Enbrel, and can be administered less frequently than other

anti-TNFα’s (once monthly for maintenance)

• Clinically physicians question whether the longer acting effect may taper off towards the end of the month ‐ Cimzia is currently conducting the EXXELERATE trial, which is a head-to-head trial versus Humira to assess the impact

of early responder treatment after 12 weeks


24

Orencia, a CTLA4-immunoglobulin fusion protein, is the market leading non anti-TNFα biologic

based on its relatively attractive safety profile and recent subcutaneous formulation; head-to-

head data versus Humira in combination with methotrexate is scheduled for release in June ‘12.

T Cell Costimulation Inhibitor

Orencia (abatacept)

Sponsor • Bristol-Myers Squibb

Formulation • Lyophilized powder (250 mg) ‐ Intravenous dosing regimen: 30-min IV infusion (500-1000 mg per body weight ) followed by IV infusion at 2 and 4 weeks

and every 4 weeks thereafter, alone or with concomitant DMARDs other than anti-TNF

• Single-dose prefilled syringe (125 mg/ml) ‐ Subcutaneous dosing regimen: 30-min IV infusion (500-1000 mg per body weight) followed by 125 mg within a day,

and 125 mg once weekly thereafter, alone or with concomitant DMARDs other than anti-TNF

Dosing • Intravenous: QM

• Subcutaneous: QW

Indications • In adult patients with moderately to severely active rheumatoid arthritis: ‐ Reducing signs and symptoms




Adverse Events

• Headache (18%)

• Nasopharyngitis (12%)

• Dizziness (9%)

• Cough (8%)

Lumleian

Commentary

• Orencia does not have a black box warning for tuberculosis (a confirmatory test is not required), and is not

contra-indicated in patients with congestive heart failure, unlike the anti-TNFα’s ‐ Safety issues include increased risk of infections, increased COPD flares, and a contra-indication in cancer patients

• Orencia has achieved ~70% ACR20 at 6 month in anti-TNFα inadequate response patients

• To effectively compete in earlier lines of treatment versus the anti-TNFα’s Orencia will release data, in June

‘12, from its head to head trial (AMPLE) versus Humira in combination with methotrexate


25

Actemra, an IL-6 inhibitor, is disadvantaged versus Orencia as it is only approved in 3rd line for

patients refractory to anti-TNFα’s and is an intravenous formulation; Actemra’s recent phase IV

data showed superiority in 2nd line versus Humira; a sub-cutaneous formulation is being pursued.

Interleukin-6 Inhibitor

Actemra (tocilizumab)

Sponsor • Roche/Chugai

Formulation • Single-use vial (80, 200 or 400 mg)

Dosing • Intravenous: QM ‐ 60-min IV infusion once every 4 weeks, 8-12 mg/kg, alone or in combination with methotrexate, but not in combination

with any biologic DMARD

Indications • Treatment of adult patient with moderately to severely active RA who have had an inadequate response to

one or more anti-TNF agent ‐ Reducing signs and symptoms




Adverse Events

• Upper respiratory tract infection (6-8%)

• Headache (5-7%)

• Hypertension (4-6%)

• Nasopharyngitis (4-7%)

Lumleian

Commentary • Actemra appears to be as efficacious as the anti-TNFα’s but has been constrained by: (1) The FDA granting only a

3rd line indication, a 2nd line expansion is anticipated with more safety data, and (2) An intravenous formulation

• Top line data from the ADACTA phase IV trial indicated that Actemra mono-therapy achieved superiority to

Humira mono-therapy on its primary end-point (DAS28) and all secondary end-points (ACR20, ACR50, ACR70) ‐ ADACTA compared mono-therapies and Humira with methotrexate is more efficacious than Humira mono-therapy

‐ Further the majority of clinical usage is combination therapy with methotrexate

• The FDA approved Actemra as a 3rd line agent, despite having compelling 2nd line data and a strong majority vote for approval

‐ This may set precedent for other novel pipeline agents seeking approval; in their briefing the FDA stressed the number of

recently approved agents and the need to trade the relative unmet need in later lines versus safety concerns


26

Rituxan, an anti-CD20 antibody, offers strong efficacy, but is used as a last resort versus Orencia

and Actemra; it has a relatively high rate of injection site infections and patients treated with

Rituxan are at increased risk for potentially fatal viral infections of the white brain matter.

B Cell Inhibitor

Rituxan (rituximab)

Sponsor • Biogen Idec/Roche

Formulation • Single-use solution vial (100 or 500 mg)

Dosing • Intravenous ‐ With methotrexate, two 1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or

based on clinical evaluation, but not sooner than every 16 weeks

Indications • In combination with methotrexate, treatment of adult patient with moderately to severely active rheumatoid

arthritis who have had an inadequate response to one or more anti-TNF agent ‐ Combination therapy with methotrexate has been shown to yield greater response rates over 2 years (ACR20, ACR50)

than Rituxan mono-therapy

Adverse Events

• Infusion reaction (32% within 24 hours following first infusion)

‐ 11% within 24 hours following second infusion


• Nausea (8%)


• Arthralgia (6%)

Lumleian

Commentary • Rituxan has demonstrated strong efficacy in 3rd line patients: 65 to 76% of ACR20 at 6 months

• Safety issues include a relatively high risk of infusion reactions and progressive multiple focal

leukoencephalopathy (PML) infection ‐ PML, is a rare viral disease characterized by progressive inflammation of white brain matter; it is commonly fatal



27

Kineret, an IL-1 inhibitor, is rarely used to treat rheumatoid arthritis; nearly three out of four

patients experience an injection site infection; Kineret is thought to be less efficacious than

Rituxan in 3rd line anti-TNFα inadequate response patients yielding 38-43% ACR20 at 6 months.

Interleukin-1 Inhibitor

Kineret (anakinra)

Sponsor • Biovitrum

Formulation • Single-use prefilled syringe (100 mg)

Dosing • Subcutaneous: QD ‐ 100 mg daily, or every other day for patients with renal insufficiency

Indications • Treatment of adult patient with moderately to severely active RA who have had an inadequate response

to one or more anti-TNF agent ‐ Reducing signs and symptoms


Adverse Events


• Worsening of RA (19%)

• Upper respiratory infections (14%)

• Headache (12%)

Lumleian

Commentary

• Although it is effective in other auto-inflammatory diseases, Kineret has only demonstrated moderate

effectiveness in rheumatoid arthritis, achieving 38-43% ACR at 6 months in anti-TNFα inadequate responders ‐ In comparison Rituxan has demonstrated strong efficacy in 3rd line patients: 65 to 76% of ACR20 at 6 months,

albeit not in head-to-head trials

Source: Product prescription information; Company press release; Kalliolias GD and Liossis SN, Expert Opin Investig Drugs 2008;17:349-59

28

Source: Geriag DM et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study

Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis 2011 doi:10.1136; Lindstrom T and Robinson WH. Biomarkers for rheumatoid

arthritis: making it personal. Scand J Clin Lab Invest 2010;70:79-84; Duroux-Richard I et al. miRNAs and rheumatoid arthritis – promising novel

biomarkers. Swiss Med Weekly;2011:w13175

Near term Lumleian sees slow but deliberate evolution of the treatment paradigm to include

novel mechanisms, starting in 3rd line and moving forward; long term Lumleian foresees a

progression toward more personalized care based on genetic and proteomic biomarkers.

• Additional risk factors and biomarkers are needed for (1) early diagnosis, (2) assessment and prediction

of disease severity, (3) selection of therapy, and (4) monitoring response to therapy: ‐ Risk factors and biomarkers will likely enable clinicians to identify patients at risk of developing clinical rheumatoid arthritis

‐ Biomarkers will likely allow clinicians to predict the state of progression of joint destruction and the development

of extra-articular manifestations, potentially allowing for a more aggressive approach in susceptible patients

‐ Therapy is still conducted on a trial-and-error basis prognostic biomarkers will likely improve therapy selection

• Proteomic and genetic biomarkers are being pursued but are quite far from clinical practice ‐ Proteomic biomarkers will likely be more valuable, but their development presents technical challenges

‐ Genetic biomarkers are useful as risk factors, but changes in genetic sequence does not always translate into changes

in gene expression and protein activity, which limits their clinical application

• Several candidate biomarkers have been recently described: - Anti-mutated citrullinated vimentin (MCV) might allow better diagnosis than anti-cyclic citrullinated peptides (CCPs)

- Genotypes of follate enzymes may predict which patients will develop adverse side effects in response to methotrexate

- A biomarker signature of 13 auto-antibodies and 11 cytokines has been shown to predict patients’ response to anti-TNFα’s

- An IFN signature was shown to predict patients’ response to rituximab treatment

- Several microRNAs (miRNAs) were found to be up-regulated in rheumatoid arthritis, and may become valuable biomarkers

• For the foreseeable future methotrexate will remain the dominant choice for treatment naïve patients and

the-leading anti-TNFα’s (Humira, Enbrel, and Remicade) will continue to dominate 2nd line treatment

• Currently approved novel biologics (Orencia and Actemra) and once monthly anti-TNFα ‘s (Cimzia) are conducting

head-to-head trials in 2nd line; premised on superiority these will gain more traction with anti-TNFα naïve patients

• FDA precedent suggests that novel pipeline agents will be initially approved for 3rd line patients; over time once

safety has been validated in clinical practice they will receive label expansions to earlier lines of treatment

• Despite approval of new mechanisms and formulations the FDA label, ACR/EULAR guidelines will set the timetable

for new product uptake in earlier treatment lines; these guidelines will be effectively enforced by payors

• Once oral agents demonstrate long-term safety and efficacy equivalent to current SoC, they will likely challenge

anti-TNFα’s the cornerstone of treatment after 1st line methotrexate ; this will be slow over 3-5 years

Future

Diagnosis

(Long Term)

Future

Treatment

(Near Term)

29

Table of Contents

Slide Number



• 3 – 6

• 7 – 9






10 • 11 - 12

• 13 - 14

• 15

• 16 – 27

• 28



• JAK Inhibitors

• Syk Inhibitors




29 • 30 - 32

• 33 – 38

• 39 – 45

• 46 - 48

• 49 - 50

• 51 - 52

• 53 – 71





72 • 73 – 78

• 79

• 80 – 81

• 82 – 90



91 • 92 – 93

• 94 – 96

30

Executive Summary: Clinical Development Pipeline

What is in the

industry’s

clinical

development

pipeline?

• Most pipeline therapies in development focus on managing chronic symptoms and inhibiting structural damage,

similar to marketed agents

• Patient’s heterogeneous response to treatment remains a key development challenge, as highlighted by recent

pipeline failures: - AZD5672 (AZN); CEP-37247 (Cephalon); dnaJP1 (Adeona); Doramapimod (BIPI); GLPG-0259 (Galapagos); Maraviroc, PF-05212368

(PFE); MLN1202, MLN3897 (Millenium); RG4934, Pamapimod (Roche); Scio-323, Scio-469 (Scios); VX-702, VX-745 (VRTX)

• The overwhelming majority of drugs in development target the immune system including cytokines and chemokines

(TNFa,IL-6, CCR1), cell signaling (JAK, p38 MAPK, Syk), B Cell modulators (CD20, BAFF, CD19), and T Cell

modulators (CD4, CD28/80, CD3, CTLA4)

• The pipeline is very crowded and Lumleian validated 82 assets in ‘active’ clinical development ‐ 7 in US Regulatory/Phase III, 44 in Phase II, and 31 in Phase I

• Once approved US regulatory precedent suggests, Actemra, the initial label will restrict usage to later lines of

therapy, where unmet need is greatest; Subsequent label extensions expand usage to earlier treatment lines

What is the

evidence for

late stage

assets?

• Kinase Inhibitors: Although numerous kinase Inhibitors have failed in clinical trials, evidence suggests

that moving higher in the signaling cascade may provide efficacy with a more tolerable safety profile

‐ Nine JAK Inhibitors targeting various combinations of isoform subtypes are in development • Pfizer’s Tofacitinib will likely be the first orally available kinase inhibitor approved for RA; Most likely approved in 3rd line;

The FDA Arthritis Advisory Committee meeting on May 9th voted 8:2 in favor of approval and the PDUFA date is set for August 2012

• Phase IIb trial data for Baricitinib (Incyte/LLY) is anticipated at EUALR in June; Incyte CEO, Paul Friedman, suggests

that Phase III trials are expected to begin in 2012 but Lilly has not made a statement of public commitment

‐ Oral Syk Inhibitors are promising; In addition to offering impressive inflammation control, they also slow bone

resorption by osteoclasts; Three Syk Inhibitors are in development • Fostamatinib (AZN/Rigel) is leading the field with 6 month Phase III data anticipated in Q2 2012

• Cytokine Inhibitors: Anti-Il6 is a proven MoA in rheumatoid arthritis; Actemra was FDA approved in 2010, but

currently garners only modest market share and is only indicated for 3rd line patients ‐ Other late stage assets including Sarilumab (Regeneron/SNY) will need to offer clear clinical differentiation

• B Cell modulators: A number of B Cell modulators are currently in development ‐ Rituxan, the first drug to selectively target CD20 positive B Cells, is being eyed by generic manufacturers Spectrum and Teva

• Other anti-CD20 agents Ofatumumab (GSK/Genmab), Veltuzumab (Immunomedics/Takeda) and SBI-087 (Emergent Biosolutions/PFE)

will need to offer clear clinical differentiation

‐ Similarly Lilly’s anti-BAFF antibody, Tabalumab, which shares the same MoA (B Cell depletion) will need to offer clear clinical

advantage over anti-CD20 antibodies • GSK/ HGSI’s rheumatoid arthritis program for Belimumab was terminated by decision of the sponsor (unrelated to safety)

31

Sources: McInnes IB and Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007;7:429-442; Schaper F. Institute of Biology,

Otto von Guericke University Magdeburg, Germany

New therapeutics for RA are directed at a myriad of cellular and intracellular targets including

antibodies against pro-inflammatory cytokines, chemokines, adhesion molecules, T Cells, B Cells,

and small molecules targeting kinases and transcription factors involved in cell signaling.

B Cell Inhibitors: • Anti-CD20

• Anti-CD19

• Anti-BAFF

T Cell Inhibitors: • Anti-CD4

• Anti-CD3

• CTLA4-Ig

Cytokine Inhibitors: • Anti-RANKL

• Anti-IL-17

Macrophage Inhibitors

Cytokine Inhibitors: • Anti-TNF

• Anti-IL-1

• Anti-IL-6

Cytokine Inhibitors: • Anti-M-CSF

Adhesion Inhibitors: • Anti-VLA-1

• Anti-VAP-1

• Anti-chemokine

JAK Inhibitors

PI3K Inhibitors

STAT3/NFkB

Inhibitors

NFkB Inhibitors

PPARg Inhibitors

p38MAPK

Inhibitors

Cell Signaling Inhibitors:

32

Clear consensus exists on the need for new therapies based on the moderate rates of remission

achieved by approved biologics; it is also clear regulators will treat new therapies cautiously;

It is very unclear how the many alternative pipeline mechanisms will be utilized in practice.

Key

Unknowns

• Development of new drugs targeting specific pathways or cell subsets is motivated by the low rate of

remission achieved by RA patients, the lack of uniform response to biologics, and the association of

biologics with concerning adverse events, such as infections and risk of malignancies

• Regulatory precedent suggests novel therapies will initially be approved in 3rd line patients with

supplementary label expansions to early lines of treatment; this is consistent with unmet needs

Source: Lipsky PE. Are new agents needed to treat RA? Nat Rev 2009;5:521-522

• The combination of novel drugs and biomarker guidance will likely improve remission rates,

drug safety, and treatment cost

• That said it is very unclear which therapies will emerge as viable competitors to anti-TNFα’s in 2nd line

or if any will be viable alternatives to generic methotrexate in 1st line for treatment naïve patients

• Clinical pipelines are dominated by biologics targeting cytokines, chemokines, B Cells and T Cells, and

by small molecules targeting protein kinases

- Anti-BAFF antibody (Tabalumab)

- Anti-IL-17 antibodies (Ixekizumab, Secukinumab)

- Anti-GM-CSF (Mavrilimumab, MOR-103, MT-203, MORAb-022)

- Anti-CCR1 (BMS-817399, CCX354-C)

- Anti-CXCL10 (MDX-1100)

- Anti-RANKL antibodies (Prolia, ALX-0141)

- JAK Inhibitors (Tofacitinib, Baricitinib, GLPG0634, ASP 015K)

- Syk Inhibitors (Fostamatinib, GS-9973, PRT062607)

- c-Kit Inhibitors (Masitinib, PLX-3397)

• Development of biomarkers will likely inform treatment selection for future patients

- New genetic and proteomic risk factors/biomarkers will likely help to identify patients at risk to develop RA

- Prognosis biomarkers will likely inform on disease progression of the disease, and guide treatment intensity

- Biomarkers will likely enable selection of the most suitable MoA to individual patients or subsets of patients

Emerging

Consensus

33

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, pipeline presentations, analyst day transcripts); 3rd party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; CenterWatch

In RA the late stage pipeline is crowded with cytokine Inhibitors dominating: TNF, IL-6, IL-17 and

GM-CSF are the main targets; second come kinase Inhibitors with the most advanced targeting

the JAK family; B Cells, T Cells and the complement are also important targets. (1 of 2)

RA Pipeline: Recent History

• Follow on assets abound ‐ 5 follow-on anti-TNFα’s are in development,

although 5 are currently on-market

‐ Similarly, 7 anti-IL-6 agents are in development,

following Actemra which was approved in Jan 2010

• p38 MAPK Inhibitors have not held their promises ‐ ~9 assets were discontinued in Phase II due to lack of

efficacy or safety concerns

‐ These showed only transient CRP decreases

• Chemokine receptor Inhibitors have also had

mixed clinical results: 3 CCR1 Inhibitors and

3 CCR5 Inhibitors have been discontinued ‐ CCR1 may be a better target than CCR5 in RA due to its

role in monocyte migration

‐ One CCR1 inhibitor showed no efficacy over placebo in

a clinical trial, but CCR1 remains an acceptable target

‐ A possible hurdle is ineffective dosing, leading to

inappropriate level of receptor occupancy at all times

RA Pipeline: Upcoming Catalysts

• Tofacitinib (JAK inhibitor) PDUFA in August 2012

• Fostamatinib (Syk inhibitor)

• Prolia (Anti-RANKL)

• Tabalumab (Anti-BAFF) - Since the main effect of anti-BAFF agents is B Cell

depletion, it remains to be seen their relative

advantage versus anti-CD20 antibodies, e.g. Rituxan

• Iguratimod (COX-2, IL-1, IL-6, IL-8, and TNF)

• Anti-IL-17antibodies

Rheumatoid Arthritis Pipeline: Current (N=82)

Mechanism of Action US Reg/

Phase III (N=7)

Phase II

(N=44)

Phase I

(N=31)

Cyto

kin

e

Inhib

itio

n

( N

=30)

TNF Family

Inhibition

(N=9)

Anti-TNFα (N=5) 4 1

Other (N=4) 2 2

Interleukin

Inhibition

(N=12)

Anti-IL-6 (N=7) 1 5 1

Other (N=5) 4 1

CSF Inhibition (N=5) 2 3

Chemokine

Inhibition

(N=3)

CCR1 Antagonists (N=2) 2

Anti-CXCL10 (N=1) 1

Others

(N=1) Unclear Mechanisms

1

Cell S

ignaling Inhib

itio

n

(N=22)

Kinase

Inhibition

(N=17)

JAK Inhibitors (N=9) 1 7 1

p38 MAPK Inhibitors (N=3) 2 1

Syk Inhibitors (N=3) 1 2

c-Kit Inhibitors (N=2) 1 1

NFkB Inhibitors (N=2) 2

TLR Inhibition (N=1) 1

Phosphodiesterase 4 Inhibitors (N=2) 2

34


Rheumatoid Arthritis Pipeline: Current (N=82)

Mechanism of Action US Reg/

Phase III

(N=7)

Phase II

(N=44)

Phase I

(N=31)

B Cell Inhibition

(N=8)

Anti-CD20 (N=5) 1 2 2

Anti-BAFF (N=1) 1

Anti-CD19 (N=2) 2

T Cell Inhibition

(N=4)

Anti-CD4 (N=1) 1

Anti-CD28/CD80 (N=1) 1

Anti-CD3 (N=1) 1

CTLA4-Ig Fusion Protein (N=1) 1

Complement Inhibition (N=2) 1 1

Adhesion Inhibition (N=2) 2

Innunogenic Peptides (N=2) 2

NK Cell Modulation (N=1) 1

Others (N=12) 8 4

In RA the late stage pipeline is crowded with cytokine Inhibitors dominating: TNF, IL-6, IL-17 and

GM-CSF are the main targets; second come kinase Inhibitors with the most advanced targeting

the JAK family; B Cells, T Cells and the complement are also important targets. (2 of 2)

RA Pipeline: Recent History

• Follow on assets abound ‐ 5 follow-on anti-TNFα’s are in development,

although 5 are currently on-market

‐ Similarly, 7 anti-IL-6 agents are in development,

following Actemra which was approved in Jan 2010

• p38 MAPK Inhibitors have not held their promises ‐ ~9 assets were discontinued in Phase II due to lack of

efficacy or safety concerns

‐ These showed only transient CRP decreases

• Chemokine receptor Inhibitors have also had

mixed clinical results: 3 CCR1 Inhibitors and 3 CCR5

Inhibitors have been discontinued ‐ CCR1 may be a better target than CCR5 in RA due to its

role in monocyte migration

‐ One CCR1 inhibitor showed no efficacy over placebo in

a clinical trial, but CCR1 remains an acceptable target

‐ A possible hurdle is ineffective dosing, leading to

inappropriate level of receptor occupancy at all times

RA Pipeline: Upcoming Catalysts

• Tofacitinib (JAK inhibitor) PDUFA in August 2012

• Fostamatinib (Syk inhibitor)

• Prolia (Anti-RANKL)

• Tabalumab (Anti-BAFF) - Since the main effect of anti-BAFF agents is B Cell

depletion, it remains to be seen their relative

advantage versus anti-CD20 antibodies, e.g. Rituxan

• Iguratimod (COX-2, IL-1, IL-6, IL-8, and TNF)

• Anti-IL-17antibodies

35

Nota Bene: In this graph only, assets are double counted, in

the case of co-development partners


As of Q1 Lumleian validated 82 assets in ‘active’ clinical development for RA: 7 in US

Regulatory/Phase III, 44 in Phase II, and 31 in Phase I; the leading sponsors are: Pfizer (5),

Bristol-Myers Squibb (5), GlaxoSmithKline (4), Ablynx (4), Novo Nordisk (4), and Eli Lilly (3).

Rheumatoid Arthritis Assets in ‘Active’ Clinical Development

Phase III (N=5) Phase II (N=44) Phase I (N=31) US Regulatory/Phase IV (N=2)

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36

Cytokine Inhibitors account for the majority of pipeline assets; they target: TNF, IL-6, IL-17,

GM-CSF, M-CSF, lymphotoxin a, RANKL, IL-1, IL-13, IL-20, IL-21, IL-12/IL-23, and oncostatin M.

RA Pipeline: Current (N=82)

Mechanism of Action US Regulatory/Phase III

(N=7)

Phase II

(N=44)

Phase I

(N=31)

Cyto

kin

e

Inhib

itio

n (

N=30)

TNF Family

Inhibition

(N=9)

Anti-TNF (N=5)

• Ozoraluzimab (PFE/Ablynx) • CEP-37247 (Cephalon) • TNFα Kinoid (Biomedical

Diagnostics/ Neovacs) • Tinefcon (Piramal Life Sciences)

• PF-05230905 (Ablynx/ PFE)

Infliximab Biosimilar (N=1) • Infliximab Biosimilar (Celltrion/Lg

Life Sciences Ltd/Nippon Kayaku)

Anti-Lymphotoxin a (N=1) • RG-7416 (Roche)

Anti-RANKL (N=2) • Prolia (AMGN) • ALX-0141 (Ablynx)

Interleukin

Inhibition

(N=12)

Anti-IL-6 (N=7)

• Sarilumab (Regeneron/SNY)

• BMS-945429 (BMY) • Olokizumab (UCB Pharma) • PF-04236921 (PFE) • Sirukumab (GSK) • ALX-0061 (Ablynx)

• SA 237 (Roche/Chugai)

Anti-IL-17 (N=2) • Ixekizumab (LLY) • Secukinumab (NVS)

Anti-IL-20 (N=1) • NN8226 (NVO)

Anti-IL-21 (N=1) • NN8828 (NVO)

Anti-IL-12/IL-23 (N=1) • Apilimod Mesylate (Synta

Pharmaceuticals)

CSF

Inhibition

(N=5)

Anti-GM-CSF (N=4) • Mavrilimumab (AZN/CSL Ltd) • MOR-103 (Morphosys AG)

• MT-203 (Takeda) • MORab-022 (Eisai)

Anti-M-CSF (N=1) • PLX-5622 (Plexxikon)

Chemokine

Inhibition

(N=3)

CCR1 antagonists (N=2) • BMS-817399 (BMY) • CCX354 (Chemocentryx/ GSK)

Anti-CXCL10 (N=1) • MDX 1100 (BMY)

Other

(N=1) Unclear mechanism (N=1)

• Iguratimod/T-164 (Eisai)

37

RA Pipeline: Current (N=82)

Mechanism of Action US Regulatory/Phase III

(N=7)

Phase II

(N=44)

Phase I

(N=12)

Cell S

ignaling Inhib

itio

n (

N=21)

Kinase

Inhibition

(N=16)

JAK Inhibitors (N=8)

• Tofacitinib (PFE) • Baricitinib (Incyte/ LLY) • VX-509 (VRTX) • ASP 015K (Astellas) • GLPG0634 (Galapagos/ ABT) • AC430 (Ambit) • CYT387 (YM BioScience)

• SB1578 (S*Bio)

p38 MAPK Inhibitors (N=3) • BMS-582949 (BMY) • PG-760564 (PG)

• UR-13870 (Palau)

Syk Inhibitors (N=3) • Fostamatinib (AZN/Rigel) • GS-9973 (GILD)

• PRT062607 (BIIB/Portola)

c-Kit Inhibitors (N=2) • Masitinib (AB Science) • PLX-3397 (Plexxikon)

Transcription

Factors (N=2) NFkB Inhibitors (N=2)

• Triolex (Harbor Biosciences) • VGX-1027 (Inovio Pharmaceuticals)

TLR Inhibitor (N=1) • XToll (CBio Ltd)

Phosphodiesterase 4 Inhibitors (N=2) • Apremilast (CELG)

• Revamilast (Glenmark)

B C

ell Inhib

itors

(N=8)

Anti-CD20 Monoclonal Antibodies (N=5) • Ofatumumab (GSK /Genmab)

• Veltuzumab (Immunomedics/Takeda) • SBI-087 (S*Bio/ PFE)

• TL 011/ Rituxan biosimilar (Teva

Pharmaceuticals) • TX-RAD (TxCell)

Anti-BAFF Monoclonal Antibodies (N=1) • Tabalumab (LLY)

Anti-CD19 Monoclonal Antibody (N=2) • MDX 1342 (BMY)

• AMG729 (AMGN)

T C

ell Inhib

itors

(N

=4)

Anti-CD4 Monoclonal Antibodies (N=1) • Tregalizumab (Biotest AG)

CD28/CD80 Inhibitor (Small Molecule) (N=1) • RhuDex (MediGene/Active Biotech

AB)

Anti-CD3 Monoclonal Antibody (N=1) • Otelexizumab (GSK)

CTLA4-Ig Fusion Protein (N=1) • ASP 2408 (Astellas/ Maxygen/Perseid

Therapeutics)

B Cell Inhibitors include: anti-CD20, anti-BAFF, and anti-CD19 monoclonal antibodies, as well as

Iguratimod, whose MoA is undefined; T Cell Inhibitors include: anti-CD4 and anti-CD3 monoclonal

antibodies and Inhibitors of the CD28/CD80 interaction.

38

Mechanism of Action US Reg. / Phase III (N=7) Phase II (N=44) Phase I (N=31)

Complement Inhibitors (N=2) • MP-435 (Mitsubishi Tanabe)

• NN8209 (NVO)

Adhesion Molecule Inhibitors (N=2)

• BTT-1023 (Biotie) • SAN-300 (Santarus)

Innunogenic Peptides (N=2) • ARG301 (Argentis)

• Org39141 (Organon)

NK Cell Inhibitors (N=1) • NN8765 (NVO)

Other (N=12)

• PDA001 (CELG)

• CF101 (Can-Fite)

• LX2931 (Lexicon Pharmaceuticals)

• LT-NS001(Logical Therapeutics)

• RWJ-445380 (JNJ)

• NU3450 (Nuon Therapeutics)

• CH-1504 (Chelsea Therapeutics)

• CH-4051 (Chelsea Therapeutics)

• RPI-78 (Nutra Pharma)

• LAS-186323 (Almirall)

• RX-10001 (Resolvyx)

• MK50 (Mika Pharma)

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, pipeline

presentations, analyst day transcripts); 3rd party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; CenterWatch

A substantial number of early stage assets are pursuing more novel targets; Complement

Inhibitors target C5aR.

39

Sources: Goreschi K et al. Modulation of innate and adaptive immune responses by Tofacitinib (CP-690,550). J Immunol 2011;186:4234-4243.

JAK Inhibitors hold promise as an effective treatment for RA and have the potential to transform

the current SoC by providing once daily oral therapy; Within the JAK inhibitor class mechanistic

differences exist, but clinical relevance of JAK subtypes is still to be determined.

Physiology • Janus kinases (JAKs) bind to the intracellular portion of

some cell surface cytokine receptors

• Upon binding of the cytokine to its receptor, JAK is

activated and phosphorylates tyrosine motifs on the

receptor, creating binding sites for the Signal

Transducer and Activator of Transcription (STAT)

protein

• STAT is phosphorylated and translocated to the nucleus,

where it binds to DNA and promotes

gene transcription - In RA patients, the JAK-STAT pathway is over-stimulated by

some pro-inflammatory cytokines, including interleukins,

and GM-CSF

Hypothesized

Mechanism

• Tofacitinib inhibits both JAK3 and JAK1, which results in

the inhibition of IL-4-dependent Th2 cell

differentiation, expression of the IL-23 receptor and the

Th17 cytokines IL-17A, IL-17F, and IL-22 upon

stimulation with IL-6 and IL-23, activation of STAT1,

induction of T-bet, and subsequent generation of Th1

cells - JAK2 is crucial to red blood cell maturation; inhibition of

the enzyme results in anemia

- This might raise safety issues for the JAK1/JAK2 Inhibitors

- Some research suggests that JAK3 fails to mediate signaling

without active JAK1, though the reverse is not true

- If the data translates into the clinic, this may disadvantage

agents which are primarily JAK3 specific

Phase III • Tofacitinib (Pfizer): JAK3/JAK1

Phase II • Baricitinib (Incyte/Eli Lilly): JAK1/JAK2 • VX-509 (Vertex Pharmaceuticals): JAK3 • ASP 015K (Astellas): JAK3 • GLPG0634 (Galapagos/ Abbott): JAK1 • AC430 (Ambit): JAK2 • CYT387 (YM Biosciences): JAK1/ JAK2

Phase I • SB1578 (S*Bio): JAK2

Pipeline

40

Tofacitinib (Pfizer) is the most advanced JAK inhibitor having received a 8:2 vote in favor of

approval by the FDA Arthritis Advisory Committee meeting; 3rd line approval without a

“structural” claim is most likely; the August 2012 PDUFA will dictate near-term opportunity.

Clinical Results (Phase III: ORAL SOLO, ORAL SEQUEL)

Efficacy: • In ORAL SOLO, Tofacitinib showed a dose responsive and statistically significant improvements in ACR20/50/70 and

HAQ-DI scores compared to placebo at both doses, and in DAS28-4(ESR) at the 10 mg dose only

• In ORAL SEQUEL, the improvements in ACR20/50/70, DAS28-4(ESR), and HAQ-DI seen in the first 3 months were

maintained for the duration of the 24 months – ACR20s were 73.1-80.9%, ACR50s 47.0-57.4%, and ACR70s 24.3-35.0%

Safety: • A total of 2611 AEs were reported with the most common being infections, gastrointestinal disorders, and

musculoskeletal and connective tissue disorders; the most frequent class of SAEs was infections

• Several safety laboratory parameters were negatively influenced: total cholesterol, LDL, serum creatinine, AST,

ALT, and neutrophil count

Lumleian

Commentary:

• Tofacitinib will likely be initially approved as a 3rd line agent in anti-TNFα/Biologic IR patients without an

“Inhibition of progression of structural damage” claim and potentially also with titrated dosing

Phase III Program (ORAL SOLO; Completed) Phase II/III Program (ORAL SEQUEL, Completed)

Patient Segment: • Moderate to severe RA with inadequate prior response

to at least one DMARD

• Moderate to severe RA (rollover from prior Phase II or III

study)

Studies: • Single, double-blind, monotherapy (N=611) • Single, open-label, extension monotherapy (N=1070)

Comparator: • Placebo • Placebo

Dosing: • 5 mg or 10 mg twice a day, orally • 5 mg or 10 mg twice a day, orally

Duration: • 6 months • 24 months

Primary End-Points: • ACR20, mean change in HAQ-DI, and DAS28-

4(ESR)<2.6, all at 3 months

• Laboratory AEs and safety reports at 1, 2, and 3 months,

and each 3 months afterwards

Secondary End-Points:

• ACR50/70 and change in DAS 28 at 3 months • ACR20/50/70, DAS28-4(ESR) and HAQ-DI scores at 1, 2,

and 3 months, and each 3 months afterwards

Sources: Company press releases

41

Clinical Results (Phase III: ORAL SYNC, ORAL SCAN)

Efficacy: • ORAL SYNC met its primary efficacy endpoints

• In ORAL SCAN, ACR20 was improved at both doses at 6 months, but structural disease progression (measured as

change from baseline in mTSS) was only improved at the 10 mg dose at 6 months

Safety: • In ORAL SYNC, AE/SAE rates were similar with Tofacitinib and placebo at 3 months, but higher with Tofacitinib than

with placebo from 3-6 months; discontinuation rates were higher with Tofacitinib versus placebo from 3-6 months;

most frequent class of AEs were infections; in the Tofacitinib group there were 4 opportunistic infections, and 4

deaths, one of which was related to the study drug

• In ORAL SCAN, most frequent AEs were mild to moderate infections; the SAE rate was higher with Tofacitinib from 0-

3 months, and similar to placebo from months 3-6; there were 6 deaths, 4 on Tofacitinib 5 mg, 1 on Tofacitinib 10

mg, and 1 on placebo; increases in LDL, HDL, and serum creatinine, and decrease in neutrophil countswere observed

in the Tofacitinib groups

Lumleian

Commentary:

• Tofacitinib’s efficacy profile is viewed as similar to that of anti-TNFs, and its safety profile is viewed as comparable

to modestly worse to that of anti-TNFs

• Across Phase III, the frequency of serious adverse infection events is higher in the Tofacitinib groups than in the

Humira or placebo groups; there is some concerns about potential long-term side-effects, particularly cardiovascular

Phase III Program (ORAL SYNC; Completed) Phase III Program (ORAL SCAN; Completed)



• Moderate to severe RA with inadequate prior response to

at least one DMARD

Studies: • Single, double-blind, monotherapy (N=792) • Single, double-blind, monotherapy (N=797)

Comparator: • Placebo (Background: MTX) • Placebo (Background: MTX)



Primary End-Points: • HAQ-DI at 3 months

• ACR20 and DAS28-4(ESR)<2.6 at 6 months

• ACR20 at 6 months

• Structural disease progression at 6 months: radiographic

progression (total sharp score, mTSS), and erosions

Tofacitinib induces a decrease in IL-6, IL-8, MMP3, IL-17, and IFN, and an increase in IL-1; The

Phase III program includes the ORAL SOLO, ORAL SEQUEL, ORAL SYNC, ORAL SCAN, ORAL

STANDARD, and ORAL STEP studies.


42

Clinical Results (Phase III: ORAL STANDARD, ORAL STEP)

Efficacy: • In ORAL STANDARD, Tofacitinib showed statistically significant improvements in ACR20/50/70, HAQ-DI, and DAS28-

4(ESR) at both doses compared to placebo; these improvements were similar to those observed with Humira (NOTE:

Humira dosed once weekly has been shown to be more effective than dosed every other week)

• In ORAL STEP, Tofacitinib showed statistically significant improvements in ACR20/50/70, HAQ-DI, and DAS28-4(ESR)

at both doses compared to placebo

Safety: • In ORAL STANDARD, the frequencies of total AEs were similar in all treatment groups

• In ORAL STEP, the frequencies of total AEs were similar in the Tofacitinib and placebo groups

Lumleian

Commentary:

• Tofacitinib’s efficacy profile is viewed as similar to that of anti-TNFs, and its safety profile is viewed as comparable

to modestly worse to that of anti-TNFs

• Across Phase III, the frequency of serious adverse infection events is higher in the Tofacitinib groups than in the

Humira or placebo groups; there is some concerns about potential long-term side-effects, particularly cardiovascular

Phase III Program (ORAL STANDARD;

Completed)

Phase III Program (ORAL STEP, Completed)



• Moderate to severe RA patients on a stable dose of MTX

and prior TNF inhibitor failure

Studies: • Randomized, double-blind, (N=717) • Randomized, double-blind, (N=399)

Comparator: • Humira (40 mg, SQ, Q2W)

• Placebo

• Placebo (background: MTX)



Primary End-Points: • HAQ-DI at 3 months

• ACR20 and DAS28-4(ESR)<2.6 at 6 months

• Laboratory AEs and safety reports at 1, 2, and 3 months,

and each 3 months afterwards

Tofacitinib was shown in the Oral Standard trial to be comparable to Abbott’s Humira in treating

rheumatoid arthritis, but was associated with a higher rate of serious adverse events.


43

Baricitinib (Lilly/Incycte) is an oral small molecule that inhibits JAK1/JAK2 with critical 3 month

data from the Phase II trial anticipated to be released at EULAR in June, and 6 month data at

ACR in November 2012.

Clinical Results (Phase IIa)

Efficacy: • ACR20/50/70 were achieved in 59%/35%/16% of Baricitinib-treated patients vs. 32%/13%/3% of placebo-treated

patients at 3 months, and ACR20/50/70 rates incrementally increased to 72%/44%/30% at 6 months

Safety: • AEs were predominantly mild and moderate with rates similar to those observed on placebo

Lumleian

Commentary:

• Baricitinib has a level of efficacy similar to that of other biologics

• Safety might be a concern with longer-term dosing, particularly because of dose-related decreases in mean Hb,

increases in LDL levels, and several cases of uncomplicated Herpes Zoster infection

Phase IIa Program (Completed) Phase IIb Program (Ongoing)


to DMARDs, including biologic DMARDs

• Moderate to severe RA patients on background MTX

therapy

Studies: • Randomized, double-blind, placebo-controlled (N=125) • Randomized, double-blind, placebo-controlled (N=270)

Comparator: • Placebo • Placebo

Dosing: • 4, 7, and 10 mg once daily, orally • 4 mg and 8 mg, once or twice daily, orally

Duration: • 6 months • 12 weeks, then a 12-week extension, then an optional 52-

week open-label extension, and a 28-day follow up

Primary End-Points: • ACR20 response rates at 3 months

• Safety and tolerability as measured by AEs, vital signs,

clinical laboratory tests, and ECGs at 3 months

• ACR20 response rates at 12 weeks


• ACR20/50/70/90 response rates at 6 months

• Safety and tolerability as measured by AEs, vital signs,

clinical laboratory tests, and ECGs at 6 months

• ACR20/50/70/90 response rates at 2, 4, 8, 12, 14, 16, 20,

and 24 weeks; mean CRP, HAQ-DI, and DAS28 at 12 and

24 weeks; additional pain and stiffness criteria


44

VX-509 (VRTX) is a JAK3 inhibitor that has provided efficacy proof-of-concept, a Phase IIb study

in combination with methotrexate expected to begin in 1H 2012.


Efficacy: • The study met its two primary endpoints, defined as a statistically significant improvement in the proportion of

people who achieved at least an ACR20, and a statistically significant improvement from baseline in DAS28

• For the two highest dose groups, statistically significant improvements in ACR20/50/70 and DAS28 responses were

observed over placebo, and >1/3 of patients in these groups achieved clinical remission (DAS28 remission)

Safety: • At least 80% of patients in VX-509 treatment group vs. 68% in the placebo group completed the 12-week treatment

course; most frequent class of AEs was infections (17% VX-509, 17% placebo); most frequent individual AEs were

nausea (6% VX-509, 0% placebo), ALT increase (4% VX-509, 5% placebo), and headache (4% VX-509, 5% placebo)

• Dose-related low-grade HDL and LDL increases were observed in VX-509-treated patients

• SAEs occurred in 2% of placebo-treated patients vs. 0%, 2%, 13%, and 5% of VX-509-treated patients in the 25, 50,

100, and 150 mg groups, respectively; in the 100 mg dose group, one patient died of a hemorrhagic stroke, reported

as unrelated to VX-509, and one patient died of pneumonia

Lumleian

Commentary:

• The data provide proof-of-concept for VX-509’s efficacy, but the safety profile remains in question

• A 6-month Phase IIb study of VX-509 in combination with MTX is expected to begin in early 2012

Phase IIa Program (Completed)

Patient Segment: • Moderate to severe RA with inadequate prior response to at least one non-biologic DMARD

Studies: • Randomized, double-blind, placebo-controlled Phase II (N=204)

Comparator: • Placebo

Dosing: • 25, 50, 100, or 150 mg twice a day, orally

Duration: • 12 weeks

Primary End-Points: • ACR20 response rates, change from baseline in DAS28 at 12 weeks


• ACR50/70 rates, moderate to good EULAR response rates, and magnitude of improvement in ACR response at 12

weeks, and PK and PD at 6 weeks


45

In February this year, Galapagos licensed GLPG0634, a JAK1 inhibitor, to Abbott for $150M

upfront, with the potential for significant milestone payments; ACR20 results were impressive.

Clinical Results (Phase II)

Efficacy: • GLPG0634 achieved the primary endpoint of significant improvement in the signs and symptoms of RA; overall,

ACR20/50/70 were achieved by 83%/42%/21% of GLPG0634-treated patients vs. 30%/8%/0% of placebo-treated

patients; half of treated patients went into remission or showed a low disease activity

• GLPG0634 also showed impressive results in DAS28 scores, and CRP levels

Safety: • A GLPG0634 was well-tolerated, with all patients completing the trial and no safety signals reported; no anemia or

increases in lipids (LDL or cholesterol) were observed in this trial although there were modest decreases in platelets

and neutrophils; no SAEs were reported in patients receiving GLPG0634

Lumleian

Commentary:

• The long-term efficacy and safety remain to be established

• ACR20 response rates re impressive

Phase II Program (Completed)

Patient Segment: • Active RA despite methotrexate treatment



Dosing: • 100 mg twice a day, or 200 mg once a day, orally


Primary End-Points: • ACR20 response rates at 4 weeks

Secondary End-

Points:

• ACR20/50/70 response rates, time to response, and DAS28 score at every visit as a measure of efficacy

• Number of patients with AEs, abnormal lab tests, vital signs, and ECG as a measure of safety and tolerability

• Plasma levels of GLPG0634 as a measure of PK, and levels of immune- and inflammation-related parameters in blood

as a measure of PD


46

Sources: Yazici Y and Regens AL. Promising new treatments for rheumatoid arthritis. Bull NYU Hosp Jt Dis 2011;69:233-237; Braselmann S et al. R406, an

orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther

2006; 319:998-1008

Syk Inhibitors may provide a double benefit in RA treatment by not only controlling inflammation,

but also by slowing bone resorption by osteoclasts; Clinical results are promising in attractive

earlier treatment lines; Biogen Idec licensed Portola’s PRT062607 for $36M upfront.

Physiology • Syk is a cytoplasmic tyrosine kinase involved in

signaling and in the activation of Fcg receptors (FcRg)

on macrophages, neutrophils, and mast cells; Syk binds

to immunoreceptor tyrosine-based activation motifs

(ITAMs) located in the cytoplasmic tail of FcRg; this

leads to up-regulation of TNFa, IL-6 and matrix

metaloproteinases (MMPs) - In RA patients, autoantibodies and immune complexes

engage and activate FcR signaling in macrophages,

neutrophils, dendritic cells, and mast cells

Hypothesized

Mechanism

• Blocks the FcR signaling pathway - Syk Inhibitors potently inhibit immunoglobulin (Ig)E- and

IgG-mediated activation of Fc receptor signaling; It inhibits

the ITAM-dependent signaling by the Fc receptor

complexes in macrophages, neutrophils and mast cells,

and the ITAM-dependent signaling from the B Cell receptor

Phase III • Fostamatinib (AstraZeneca/Rigel Pharmaceuticals)

Phase I • GS-9973 (Gilead Sciences) • PRT062607 (Biogen Idec/Portola Pharmaceuticals)

Pipeline

47

Fostamatinib, an orally active small molecule Spleen Tyrosine Kinase (Syk) inhibitor, is in Phase

III development for the treatment of moderate to severe RA; Although safe, this drug has not

proven to be effective in patients with an inadequate response to biologic DMARDs (TASKi3).

Clinical Results (Phase IIa and TASKi2)

Efficacy: • Fostamatinib met both primary and secondary end-points at the doses of 100 and 150 mg; ACR20/50/70 were

achieved by 72%/57%/40% of patients on 150 mg fostamatinib vs. 18%/9%/2% of patients on placebo

• In TASKi2, both fostamatinib doses met the primary and secondary end-points

Safety: • In the 150 mg fostamatinib group, 47% of patients had moderate to severe GI symptoms, 21% had neutropenia lasting

one month, and 6% had ALT elevations greater than 3x normal; based on this, Rigel has discontinued the

development of 150 mg twice daily; in the 100 mg fostamatinib group, 9% had moderate to severe GI symptoms, 11%

had neutropenia lasting one month, and 4% had moderate to severe hypertension

• In TASKi2, AEs included diarrhea, transient neutropenia, elevations in ALT, and increase in blood pressure that

required adjustments or initiation of blood pressure medication in 23% of patients on 100 mg fostamitinib and 18% of

patients on 150 fostamitinib vs. 7% of patients on placebo

Lumleian

Commentary:

• Fostamatinib shows robust efficacy, but there is concern with several safety signals including infection, diarrhea,

high blood pressure/hypertension, neutropenia, and elevation in liver enzymes; potential tumor risk with long-term

use due to the tumor suppressor activity of Syk might also require close monitoring

Phase II Program (Phase IIa, Completed) Phase IIb Program (TASKi2, Completed)

Patient Segment: • Moderate to severe RA patients • Moderate to severe RA patients failing to respond

to methotrexate

Studies: • Randomized, double-blind, (N=189) • Randomized, double-blind, (N=457)

Comparator: • Placebo (background: MTX) • Placebo (background: MTX)

Dosing: • 50, 100, or 150 mg twice a day, orally • 100 twice a day or 150 mg once a day, orally

Duration: • 12 weeks • 6 months

Primary End-Points: • ACR20 • ACR20 response rates at 6 months


• ACR50/70 and DAS28<2.6 • ACR50/70, DAS28-CRP, and DAS28-ESR at 6 months

• FACIT-fatigue and SF-36 from baseline to 6 months

• Safety: liver function, neutrophils, GI side-effects


48

Clinical Results (Phase IIb: TASKi3)

Efficacy: • In TASKi3, fostamatinib missed both the primary and secondary end-points, which was attributed to unusually high

placebo response rates, and lack of response of patients with elevated ESR and normal baseline CRP levels

Safety: • In TASKi3, most common AEs were infection,diarrhea, and hypertension; AEs such as neutropenia, GI AEs,

hypertension/high blood pressure, and elevations in liver enzymes required fostamatinib dose reductions

Lumleian

Commentary:

• Fostamatinib shows robust efficacy, but there is concern with several safety signals including infection, diarrhea,

high blood pressure/hypertension, neutropenia, and elevation in liver enzymes; potential tumor risk with long-term

use due to the tumor suppressor activity of Syk might also require close monitoring

Phase IIb Program (TASKi3, Completed) Phase III Program (OSKIRA-1, -2, -3, Ongoing)

Patient Segment: • Moderate to severe RA patients who have

failed at least one biologic

• Moderate to severe RA patients who are: - MTX inadequate responders (OSKIRA-1)

- DMARD inadequate responders (OSKIRA-2)

- on MTX and anti-TNF refractory (OSKIRA-3)

Studies: • Randomized, double-blind, (N=219) • Randomized, double-blind, (N=900, OSKIRA-1 and -2;

N=450, OSKIRA-3)

Comparator: • Placebo (background: non-biologic DMARD) • Placebo

Dosing: • 100 mg twice a day, orally • 100 mg twice a day and 150 mg once a day, orally


Primary End-Points: • ACR20 response rates at 3 months • ACR20 (OSKIRA-1, -2, -3) and mTSS (OSKIRA-1) at 6 mo.


• ACR50/70, ACRn, DAS28-CRP, DAS28-ESR at 3 months

• FACIT-fatigue and SF-36 from baseline to 3 months

• Radiologic response (MRI) using the modified RAMRIS

scoring system of hands and wrists (baseline, Month 3)

• Safety: liver function, neutrophils, GI side-effects

Fostamatinib completed its Phase II program for the treatment of moderate to severe RA; it

included 3 trials: a Phase IIa study, TASKi2, and TASKi3; In TASKi3, fostamatinib missed both the

primary and secondary end-point which was attributed to unusually high placebo response rates.


49

Sources: Tebbib J et al. Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.

Arthritis Res Ther 2009;11:R9

The receptor tyrosine kinase c-Kit plays a major role in the survival and activation of mast cells

which both blocks TNF signaling and recruitment of other inflammatory cell types; a different

approach from current RA therapy with potential for synergistic efficacy with other products.

Physiology • c-Kit is a receptor tyrosine kinase whose ligand is the

stem cell factor (SCF); mast cells are the only

terminally differentiated hematopoietic cells that

express the c-Kit receptor

• c-Kit is also expressed in hematopoietic stem cells,

melanocytes, germ cells, and hematopoietic

progenitor cells including erythroblasts, myeloblasts,

and megakaryocytes

• Interaction of SCF with c-Kit promotes mast cell

adhesion, migration, proliferation, and survival

• Mast cells produce factors that regulate lymphocyte

migration, angiogenesis, inflammation, and cartilage

and bone destruction - In RA patients, the percentage of mast cells in the

synovium is increased, and mast cells are observed at the

cartilage-pannus junction, near blood vessels, and in areas

of fibrosis

Hypothesized

Mechanism

• Inhibits mast cell activation by preventing the c-

Kit/SCF interaction

Phase III • Masitinib (3AB Science)

Phase I • PLX-3397 (Plexxikon)

Pipeline

50

Orally available Masitinib targets mast cells via the inhibition of the tyrosine kinase c-Kit

(CD117) and lyn; AB’s go-to-market strategy for Masitinib was to first gain approval in animal

health for canine mast cell tumors; High AE rates and withdrawal rates are notable.


Efficacy: • Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%,

respectively, and a reduction in CRP level by greater than 50% for approximately half the population

• This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent

of initial DMARD resistance

Safety: • A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data

imputation

• Incidence of AEs was high (95%), although the majority were mild or moderate in severity with a considerable

decline in frequency observed after 12 weeks of treatment; 2 nonfatal SAEs were reported

Lumleian

Commentary:

• Incidence of adverse events was high (95%), and 31% of patients withdrew before the 12-week endpoint due to AEs;

most AEs were mild or moderate; AEs included rash (30%), edema (26%), nausea (23%) and diarrhea (18.6%); in 21%

of patients, AEs were severe

Phase IIa Program (Completed) Phase IIb/III Program (Ongoing)

Patient Segment: • Active RA patients with inadequate response to at

least one DMARD, including MTX or anti-TNF

• Active RA patients with inadequate response to MTX, any

DMARD including at least one biologic drug if patients

previously failed MTX, or MTX in combination with any

DMARD including biologic drugs

Studies: • Randomized, open-labeled, (N=43) • Randomized, double-blind, (N=450)

Comparator: • MTX

Dosing: • 3 or 6 mg/kg once daily • 3 or 6 mg/kg once daily

Duration: • 3 months • 24 weeks with possible extension

Primary End-Points: • ACR20/50/70/90 at 12 weeks • ACR50 at 24 weeks


• DAS28, ACRn, and improvement of quality of life

assessed by SF12 at 12 weeks


51

Sources: Moisin I and Davidson A. BAFF: a local and systemic target in autoimmune diseases. Clin Exp Immunol 2009;158:155-63

IV delivered, anti-BAFF agents offer an alternative approach to B Cell depletion vs. Rituxan;

B Cell depletion is thought to restore immune tolerance and provide sustained benefit over 18+

months post treatment.

Physiology • The B Cell activating factor (BAFF) is a homotrimer of

the TNF superfamily expressed on the surface of

monocytes, dendritic cells, neutrophils, stromal cells,

activated T Cells, malignant B Cells, and epithelial cells ‐ Most of the expressed BAFF is cleaved and circulates

in a soluble form

• BAFF plays a key role in B Cell survival, maturation, and

activation through its interaction with its receptors

TACI, BAFF-R, and BCMA - In RA patients, serum levels of BAFF are increased

- Pathologic concentrations of BAFF are thought to overcome

the negative selection of autoreactive B Cells

in the periphery; autoreactive B Cells then survive and

produce self-reactive antibodies

Hypothesized

Mechanism

• Reduces the concentration of circulating BAFF through

interaction with BAFF - Targeting of BAFF in patients with RA results in prompt

depletion of transitional and naive B Cells, with sparing

of memory B Cells and plasma cells, and only modest

reductions in serum Ig levels

Pipeline

Phase III • Tabalumab (Eli Lilly)

52


Efficacy: • Tabalumab met the primary end-point at all 3 doses: ACR20 was achieved in 69.7% of patients on 30 mg, 67.6% of

patients on 60 mg, and 63.6% of patients on 160 mg vs. 26.5% of patients on placebo

• B Cell (except memory B Cells) were partially depleted: CD20+ B Cell counts decreased by 33.3% (160 mg) vs. 18.3%

(placebo), and IgD+CD27- B Cell counts by 63.6% (160 mg) vs. 17.7% (placebo) at 24 weeks

Safety: • The nature and frequency of AEs were similar across groups; serious AEs were reported in 5 (4.9%) Tabalumab

treated patients and 3 (9.1%) placebo-treated patients; serious infection was reported in 1 (1.0%) Tabalumab

treated patient and 1 (3.0%) placebo-treated patient; IgM (but not IgG or IgA) levels decreased significantly more

in all Tabalumab groups combined than in the placebo group

Lumleian

Commentary:

• Clinical trials of Belimumab in RA were confirmed to be terminated in June 2011. This was cited as being the

sponsors decision, not related to safety.

Phase II Program (Completed) Phase III Program (Ongoing)

Patient Segment: • Patients with active RA despite ongoing MTX therapy • Anti-TNF refractory RA patients (FLEX V)

• RA patients on background DMARD or not (FLEX O)

• RA patients on background MTX (FLEV M)

Studies: • Randomized, double-blind, placebo-controlled, dose-

ranging Phase II (N=136)

• Randomized, double-blind, (FLEX V, O, M)

• Open-labeled, long-term safety and efficacy

Comparator: • Placebo (background: MTX) • Placebo (FLEX V, O, M)

Dosing: • 30, 60, 120 mg IV, every 3 weeks for a total of 3 doses • 90 mg every 2 weeks, or 120 mg every 4 weeks, IV

Duration: • 24 weeks • 24 weeks (FLEX V, O); 52 weeks blinded, then 48 weeks

unblinded (FLEX M); 240 weeks

Primary End-Points: • ACR20 response rates at 24 weeks • ACR20 (FLEX V, O, M), HAQ-DI and mTSS (FLEX M)

• Anti-LY2127399 antibodies, B Cells, Ig levels

Secondary End-Points: • Safety through evaluation of laboratory tests, vital signs

and ECG; PK through blood sample collections

• ACR50/70, DAS28, CRP, B Cells, Ig, antibodies, PK

Tabalumab is a fully human anti-BAFF monoclonal antibody that binds both surface and soluble

BAFF; In Phase III it currently remains the only anti-BAFF in development since GSK/ HGSI’s RA

program for Belimumab was terminated by decision of the sponsor (unrelated to safety).


53

RANKL is thought to be involved in immune activation of osteoclasts resulting in bone

resorption; anti-RANKL agents reduce the progression of bone erosion without affecting

markers of inflammatory disease activity; they do not reduce pain symptoms.

Physiology • Receptor activator of nuclear factor-kB (RANK) ligand

(RANKL), a protein that binds to RANK, is the primary

mediator of bone resorption

• RANKL/RANK interaction activates a cellular signaling

that mediates the differentiation, activation, and

survival of osteoclasts.

• Osteoprotegerin (OPG) provides an alternative binding

site for RANKL and acts as a decoy receptor by blocking

RANKL/RANK interaction

• When RANKL is bound and neutralized by OPG,

osteoclasts cannot form, function, or survive, and bone

resorption is inhibited. - Articular bone erosions by osteoclasts are a characteristic

feature of RA, and destruction of articular bone is

associated with significant morbidity and poor prognosis

Hypothesized

Mechanism

• Inhibits RANKL/RANK interaction by mimicking the

binding of OPG to RANKL

Pipeline

Phase II • Prolia (Abbott/Biotest)

Phase I • ALX-0141 (Ablynx)

Sources: Pettit AR et al. RANKL protein is expressed at the pannus–bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology

2006;45:1068–1076; Josse RG. The role of RANK/RANKL/OPG pathway in bone loss: new insights. Conference Report from the 2009 CGS Annual Scientific

Meeting: Satellite Symposium

54

Prolia is an anti-RANKL humanized monoclonal antibody that is targeting the bone

manifestations of RA; In Phase II trials it significantly reduced the increase in bone erosion

score, and modified sharp erosion score at both 6 months and 12 months versus placebo.


Efficacy: • Prolia at both doses statistically significantly reduced the increase in bone erosion score, and modified sharp erosion

score at both 6 months and 12 months versus placebo

• Prolia did not impact joint space narrowing, or measures of RA activity

• Prolia has a rapid onset of action (12-24 hours), a durable effect (out to 4+ years), and is reversible upon

discontinuation of therapy

Safety: • Side effects were similar across the three arms

Lumleian

Commentary:

• Prolia is likely to decrease the degree of structural damage, but may have a limited impact on the progression of

erosion associated with inflammation, because it is not an immunosuppressant; It will likely be adjunctive


Patient Segment: • RA patients on MTX



Dosing: • 60 mg or 180 mg every 6 months, SQ

Duration: • 1 year

Primary End-Points: • Change in baseline erosion score (MRI) at 6 months

Secondary End-

Points:

• AEs, laboratory analytes and anti-denosumab antibodies at 24 months

• Change in mTSS, radiographic erosion score (ES) and radiographic joint space narrowing score (JS) at 24 months

• Percent changes in lumbar spine, total hip and proximal femur bone mass density at 24 months

• Percent changes in bone (serum Type I C-terminal telopeptide of type I collagen (CTX) and procollagen type I N

propeptide (PINP)), and cartilage (urine Type II CTX/creatinine) markers at 24 months


55

Sources: Szekanecz Z et al. Chemokine and chemokine receptor blockade in arthritis, a prototype of immune-mediated inflammatory diseases.

Neth J Med 2011;69:356-66.

Once promising, the clinical targeting of the chemokine receptors CCR1 and CCR5 has been

disappointing; however, three chemokine-targeting assets are still being developed in Phase II:

two target CCR1, and one targets the chemokine CXCL10.

Physiology • Chemokines and their receptors can promote

leukocyte migration at sites of inflammation - In RA, leukocyte extravasation into the synovium occurs

through the vascular endothelium, via a process that

involves certain chemokines and their receptors

- CXCL10 is abundantly expressed in the sera, and synovial

fluid and tissues of RA patients; CXCL10 inhibits synovial

neovascularisation, and has a proinflammatory action

- CCR1 is a receptor for the chemokines CCL3, CCL5,

CCL7, CCL14, CCL15, and CCL16, which have been

implicated in the pathogenesis of RA

- In RA patients, CCR1-expressing monocytes and

macrophages are found at high levels in the synovium;

the C6 superagonists of CCR1 (activated highly potent

forms of certain CCR1 ligands) are detected at high

levels in synovial fluids; CCR1 may mediate osteoclast

formation

Hypothesized

Mechanism

• Inhibit leukocyte recruitment into the synovium

Potential

considerations

• 3 CCR1 Inhibitors and 3 CCR5 Inhibitors were

discontinued for lack of efficacy in RA, including

Pfizer’s HIV drug Maraviroc (CCR5 antagonist)

• CCR1 may be a better target than CCR5 in RA, due to

its role in monocyte migration

Pipeline

Phase II • BMS-817399 (Bristol-Myers Squibb)

• CCX354-C

(ChemoCentryx/GlaxoSmithKline)

• MDX-1100 (Bristol-Myers Squibb)

56


Efficacy: • ACR20 response rate was significantly higher in MDX-1100 group than in placebo group (54% vs. 17%; P=0.0024)

• ACR50/70 response rates in MDX-1100 treatment group at Day 85 were not significantly different from placebo

Safety: • Overall, 51.4% of MDX-1100-treated patients and 30.3% of placebo-treated patients experienced at least 1 AE; no

drug-related serious AEs were reported

Lumleian

Commentary:

• MDX-1100 was well tolerated and demonstrated clinical activity in RA patients who had an inadequate response to MTX

• This is the first study to demonstrate clinical activity of a chemokine inhibitor in RA and supports the potential role of CXCL10 in

the immunopathogenesis of RA


Patient Segment: • Patients with active RA receiving MTX



Dosing: • 10 mg/kg administered IV over 60 minutes every other week, in combination with MTX (10-25 mg weekly)

Duration: • 85 days

Primary End-Points: • ACR20 response rate at day 85

Secondary End-

Points:

• Safety and tolerability monitored by physical exam, laboratory tests, ECGs, chest X-ray, and AEs over 141 days

MDX-1100 is an anti-CXCL10 monoclonal antibody that has completed its Phase II Program; ACR20

response rate was moderate (54%) and ACR50/70 response rates were not statistically significant

versus placebo.

Sources: Company press releases; Yellin M et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-

1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum

2011;DOI: 10.1002/art.34330

57


Efficacy: • ACR50, ACR70, DAS28-CRP, and ACR component results indicate greatest efficacy in the 200 mg QD dose group; CTx,

PINP, and osteocalcin decreases were more pronounced in the CCX354-C groups compared to placebo and reached

statistical significance at several time points during the study

Safety: • No SAEs were reported in the 200 mg QD and placebo groups; four SAEs not deemed related to CCX354-C (syncope

due to blood draw, angina pectoris, MI, temporal lobe epilepsy) were reported in the 100 mg BID group

Lumleian

Commentary:

• CCX354-C was found to be safe and well-tolerated by RA patients in the Phase II trial, and to be clinically and

biologically active at an IV dose of 200mg once-daily

• This Phase II proof-of-concept clinical trial triggered GSK's option rights under a collaboration agreement with

ChemoCentryx; GSK exercised its option to further develop and commercialize CCX354-C in November 2011, and has

an exclusive right to initiate a Phase IIb clinical trial for CCX354-C in rheumatoid arthrtitis


Patient Segment: • Patients with moderate to severe RA partially responsive to MTX



Dosing: • 100 mg twice daily, or 200 mg once daily

Duration: • 85 days

Primary End-Points: • Subject incidence of AEs over 12 weeks

Secondary End-

Points:

• The change in DAS28-CRP from baseline to Week 12

CCX354-C, a CCR1 antagonist, was found to be safe and well-tolerated by RA patients in a

Phase II trial, and to be clinically and biologically active at an IV dose of 200mg once-daily; GSK

exercised its option to further develop and commercialize CCX354-C in November 2011.

Sources: Company press releases; Tak PP et al. Safety and efficacy of oral chemokine receptor 1 antagonist ccx354-c in a phase 2 rheumatoid

arthritis study. ACR/ARHP Scientific Meeting, Chicago, IL, Nov. 5-9, 2011

58

Sources: Burmester GR et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a

randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis 2011;70:1542-1549

Targeting of the GM-CSF/GM-CSFR interaction is a novel strategy in treating rheumatoid

arthritis; the leading agent, AstraZeneca’s mavrilimumab, has achieved positive interim

phase II results with an attractive safety profile.

Physiology • Granulocyte-macrophage colony-stimulating factor

(GM-CSF) is a soluble cytokine that binds to GM-CSFR;

GM-CSF/GM-CSFR interaction promotes the generation,

survival, and activation of neutrophils, eosinophils,

and macrophages, and regulates numerous functions of

mature tissue macrophages: cell adhesion, expression

of pathogen recognition receptors, expression of the

proinflammatory cytokines TNFa, IL-6, IL-12, IL-18,

MCP-1 and M-CSF; phagocytosis, and microbial killing;

GM-CSF is also critical in maintaining the ability of

pulmonary alveolar macrophages to clearsurfactant

lipid and proteins from the lung surface - In RA patients, levels of GM-CSF and GM-CSFR are

increased in the synovial fluid and plasma

- Administration of recombinant GM-CSF to Felty’s syndrome

patients can induce arthritic flares

Hypothesized

Mechanism

• Suppresses macrophage activity by blocking the

interaction between GM-CSF and GM-CSFR - Mavrilimumab was well tolerated and showed efficacy in

RA patients, and there were few safety signals

- Main adverse events associated with mavrilimumab were a

decrease in carbon monoxide diffusing capacity,

nasopharyngitis, and upper respiratory infections

- MOR-103 (Phase II) and MT-203 and MORAb-022 (Phase I)

are monoclonal antibodies directed against GM-CSF

Pipeline

Phase II • Mavrilimumab (AstraZeneca/Csl Ltd.) • MOR-103 (Morphosys AG)

Phase I

• MORAb-022 (Eisai) • MT-203 (Takeda)

59


Efficacy: • 55.7% of mavrilimumab subjects met the primary endpoint vs. 34.7% in the combined placebo group (P=0.003)

• The 100 mg mavrilimumab group showed significant improvement compared with placebo in the primary (P=0.001),

and secondary endpoints (P<0.05)

• The onset of response generally occurred within 2 wks

Safety: • AEs were generally mild or moderate in intensity; the most common AEs were decrease in carbon monoxide

diffusing capacity (placebo 5.1%; mavrilimumab 11.9%), nasopharyngitis (placebo 2.5%; mavrilimumab 6.3%) and

upper respiratory tract infections (placebo 5.1%; mavrilimumab 3.8%); no significant hypersensitivity reactions,

serious or opportunistic infections, or changes in pulmonary parameters were reported; SAEs were reported in 1.3%

of placebo-treated and 1.9% of mavrilimumab-treated subjects, and were not treatment related

Phase II Program (Ongoing)

Patient Segment: • Patients with moderate to severe RA

Studies: • Randomized, double-blind, placebo-controled Phase II (N=233)


Dosing: • 10, 30, 50, or 100 mg every other week, SQ


Primary End-Points: • DAS28-CRP decrease ≥1.2 from baseline at 12 weeks

Secondary End-Points: • DAS28-CRP remission, ACR20/50/70, and HAQ-DI

Mavrilimumab is an anti-GM-CSFR monoclonal antibody; positive intermediate results of an

ongoing Phase II trial were reported in November 2011.


60

Sources: Genovese M et al. s . One Year Efficacy And Safety Results Of A Phase Ii Trial Of Secukinumab In Patients With Rheumatoid Arthritis. Arthritis

Rheum 2011;63 Suppl10:401; Genovese M et al. Ixekizumab, a humanized anti–interleukin-17 monoclonal antibody, in the treatment of patients with

rheumatoid arthritis. Arthritis Rheum 2010;62:929-939

Two anti-IL-17 monoclonal antibodies are being developed, currently in Phase II; they both show

efficacy and limited safety concerns in rheumatoid arthritis patients.

Physiology • IL-17 is a proinflammatory cytokine produced primarily

by CD4+ T helper (Th) 17 cells; IL-17 provides immunity

to bacteria, fungi, and some other pathogens through

generation and reruitment of neutrophils - In RA patients, serum and synovial fluid levels of IL-17 are

elevated; RA synovial tissue explants produce biologically

active IL-17; a subset of infiltrating T Cells expressing IL-

17 has been identified in RA synovium

- IL-17 could contribute to the pathogenesis of RA in synergy

with TNFa and IL-1b, and independently from these

cytokines

Hypothesized

Mechanism

• Neutralizes the biologic effects of IL-17 - Secukinumab showed efficacy in active RA patients on MTX

over a 24-week period and a safety profile comparable to

placebo in a Phase IIb trial

- Ixekizumab was tolerated and showed efficacy in RA

patients over a 10-week period; there were few safety

signals, although leukopenia and neutropenia would

require monitoring in future trials

- Amgen had completed a Phase II trial to assess the efficacy

of the IL-17 antibody AMG-827 in RA subjects with

inadequate response to MTX, but announced in April 2011

that it was stopping that clinical program

Pipeline

Phase II • Ixekizumab (Eli Lilly)

• Secukinumab/AIN457 (Novartis)

61


Efficacy: • ACR20 responder rates at Week 16 were higher with secukinumab 75mg, 150mg and 300mg (47%, 47% and 54%,

respectively) versus placebo (36%) but did not reach statistical significance

• Responders on secukinumab maintained their ACR20 response from Week 24 to 52; improvement in ACR20 response

rates at weeks 24 and 52 were seen in patients who remained on secukinumab 150mg for the entire study; through

Week 52, responders who remained on secukinumab 150mg had further improvement in ACR50/70

• Non-responders did not gain much additional efficacy benefit after dose escalation as assessed by ACR20/50/70 and

DAS28-CRP

Safety: • AE rates were similar at Week 20 and Week 52 (60-70%); most AEs were mild to moderate in severity and did not lead

to study discontinuation (6.9%); the rate of infections was 31.9% overall; 9.7% of SAEs were reported including 6 cases

of serious infections without dose relationship; there were 3 malignancies and no deaths up to Week 52

Phase II Program (Completed) Phase III Program (Ongoing)

Patient Segment: • Patients with active RA despite ongoing MTX therapy • RA patients refractory or intolerant to anti-TNF

Studies: • Randomized, double-blind, placebo-controlled, dose-

ranging Phase II (N =237)

• Randomized, double-blind, Phase III (FLEX V, O, M)

• Open-labeled, long-term safety and efficacy (Phase

IIIb)

Comparator: • Placebo (background: MTX) • Placebo

• Abatacept (CTLA4-Ig)

Dosing: • 25, 75, 150, or 300 mg once a month, SQ • 75 or 150 mg once a month, SQ

Duration: • 52 weeks; doses escalated in non-responders at Week 20 • 24 weeks

Primary End-

Points:

• ACR20 response rates at 16 weeks • ACR20 (vs. placebo) at 24 weeks

Secondary End-

Points:

• ACR20/50/70 and DAS28-CRP at 52 weeks • ACR20 (vs. atabacept) at 24 weeks; ACR70 (vs.

placebo) at 52 weeks; HAQ-DI (vs. placebo) at 52

weeks; HAQ-DI (vs. atabacept) at 52 weeks

Secukinumab is anti-IL-17 monoclonal antibody that has completed its Phase II Program and

entered a Phase III Program; ACR20 rates at week 16 were higher than placebo but did not

attain statistical significance.

Sources: Company press releases; Genovese MC et al. One year efficacy and safety results of a Phase II trial of Secukinumab in patients with

rheumatoid arthritis. Arthritis Rheum 2011;63 Suppl 10:401

62


Efficacy: • Meaningful differences vs. placebo were seen at Week 12 for ACR20 in bDMARD-naïve patients receiving 30, 80, or

180 mg Ixekizumab, and in TNF-IR patients receiving 80 or 180 mg Ixekizumab

• CRP values showed a rapid drop with nadir values at 1 week after the first injection

• Significant differences vs. placebo were observed for other clinical measures in both populations at Week 12

Safety: • The frequency of AEs through Week 12 was similar across treatment arms in both populations (range: 45-64%)

• Infections were more frequent in Ixekizumab arms than in placebo arm in bDMARD-naïve (25 vs. 19%) and TNF-IR

patients (27 vs. 23%)

• In bDMARD-naive patients, SAEs occurred in 1.9% of placebo-treated and 3.4% of Ixekizumab-treated patients with 1

serious infection-related event in a patient receiving 80 mg Ixekizumab

• In the TNF-IR population, SAEs occurred in 1.6% of placebo-treated and 9.7% of Ixekizumab-treated patients, and

serious infections occurred in 3.2% of Ixekizumab-treated patients

Lumleian

Commentary:

• If Lilly advances Ixekizumab to phase III it would likely be its third asset targeted to later treatment lines


Patient Segment: • RA patients who are naïve to biologic therapy (bDMARD-naïve), or inadequate responders to TNF Inhibitors (TNF-IR)



Dosing: • 3, 10, 30, 80, or 180 mg at 0, 1, 2, 4, 6, 8, and 10 weeks, SQ


Primary End-Points: • Determine the dose-response relationship of Ixekizumab in bDMARD naïve pts at Week 12, based on logistic

regression of the ACR20 response rate

Secondary End-

Points:

• Additional safety and efficacy evaluations in the two populations at Week 12

Ixekizumab is an anti-Il17 monoclonal antibody that has completed its Phase II program and

achieved its primary end-point; Lilly has not publicly commented on its advancement to phase III.

Sources: Company press releases; Genovese MC et al. A Phase 2 study of multiple subcutaneous doses of Ixekizumab, an anti-IL-17 monoclonal antibody, in

patients with rheumatoid arthritis in two populations: naïve to biologic therapy or inadequate responders to tumor necrosis factor alpha Inhibitors.

ACR/ARHP Meeting, Chicago, IL, Nov. 5-9, 2011

63

Sources: Simmonds RE and Foxwell BM.. NF-kB and its relevance to arthritis and inflammation. Rheumatology 2008;47:584–590; Hara M et al.

Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter,

double-blind, parallel-group study.. Mod Rheumatol 2007;17:1-9; Hara M et al.. s Long-term safety study of iguratimod in patients with

rheumatoid arthritis. Mod Rheumatol 2007;17:10-16; Lü LJ et al. Safety and efficacy of T-614 in the treatment of patients with active

rheumatoid arthritis: a double blind, randomized, placebo-controlled and multicenter trial. Chin Med J 2008;121:615-619

Iguratimod is a small molecule compound with anti-inflammatory and immunomodulatory actions.

Physiology • The transcription factor nuclear factor kB (NF-kB)

regulates many aspects of cellular activity in response

to stress and injury, especially the inflammatory

response via induction of IL-1, TNF-a, and the adhesion

molecules E-selectin, VCAM-1, and ICAM-1

• NF-kB consists out of homo- and hetero-dimers of

different subunits: p50, p52, p65, RelB, and c-Rel; NF-

kB dimers are sequestered in the cytosol of

unstimulated cells via non-covalent interaction with

the inhibitor protein IkB; upon phosphorylation, IkB is

degraded, and NF-kB enters the nucleus and binds to

DNA to induce gene expression - In the synovial cells of patients with RA, NF-kB activation

results in the transactivation of multiple genes that

contribute to the inflammatory phenotype, including TNF-

α from macrophages, matrix metalloproteinases from

synovial fibroblasts, and chemokines that recruit immune

cells to the inflamed pannus

Hypothesized

Mechanism

• Multiple mechanisms, including inhibition of NF-kB - Iguratimod inhibits the production of immunoglobulins and

various inflammatory cytokines via suppression of NF-kB

activation without blocking NF-kB inhibitor a (IkBa)

degradation

- Iguratimod also has an anabolic effect on bone metabolism

via stimulation of osteoblastic differentiation and

inhibition of osteoclastogenesis

- Iguratimod has been SFDA-approved in China, and is

undergoing Phase IV trials for re-filing in Japan

Phase IV • Iguratimod (Eisai)

Pipeline

64

Sources: Branger J et al. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol

2002;168:4070–4077.

Three p38 MAP kinase Inhibitors are in the pipeline, but their future is uncertain as several p38

MAP kinase Inhibitors have already been discontinued for lack of efficacy in patients with RA.

Physiology • p38 mitogen-activated (MAP) kinases are responsive

to stress stimuli, such as cytokines, growth factors,

ultraviolet, irradiation, heat shock, and osmotic

shock, and are involved in cell differentiation and

apoptosis - In RA patients, abnormal activation of p38 MAPK to

prevent Fas-mediated apoptosis may represent a

common survival mechanism of RA synovial T Cells

contributing to persistent inflammation of affected

synovium

Hypothesized

Mechanism

• Inhibition of the p38 MAP kinase pathway leading to

inhibition of cytokines and adhesion molecules, and

decrease in CRP release

Potential

considerations

• BMS-582949, an oral dual-action p38 kinase inhibitor,

is a more promising asset than are most other p38

kinase Inhibitors - in a Phase I study, BMS-582949 significantly increased

the proportion of ACR20, DAS28, and HAQ-DI responders

in patients with active RA who had an inadequate

response to MTX

• The long list of failed or terminated p38MAP kinase

Inhibitors in RA includes: - doramapimod, VX-745, VX-702, AMG-548, Scio-323, Scio-

469, pamapimod and ARRY-797

Phase II • BMS-582949 (Bristol-Myers Squibb) • PG-760564 (Procter & Gamble)

Phase I • UR-13870 (Palau Pharmaceuticals)

Pipeline

65

Sources: Vergunst CE et al. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation.

Rheumatology 2007;46:1773–1778

A novel approach targeting the complement system in RA, anti-C5aR agents competitively bind

the C5a receptor which is expressed on activated immune cells, thereby blocking the action of

C5a from guiding inflammatory cells into tissue.

Physiology • All three pathways of complement lead to

formation of C5 convertase, which cleaves C5 into

C5a and C5b

• Whereas C5b is incorporated into the membrane-

attack complex, C5a exerts a predominant pro-

inflammatory activity through interactions with the

classical G-protein coupled receptor C5aR (CD88) as

well as with the non-G protein coupled receptor

C5L2, expressed on various immune and non-

immune cells

• C5a serves as a strong chemotactic factor CD88+

monocytes and neutrophils - In RA patients, monocytes and neutrophils are abundant

in the joints, and C5a is found in the synovium in levels

high enough to induce CD88+ cell chemotaxis

Hypothesized

Mechanism

• Inhibits C5a proinflammatory action by blocking the

C5aR receptor

Potential

Considerations

• MP-435 is being evaluated in combination with MTX

in a Phase II study in RA patients

• NN8209 was evaluated in a Phase I study, and RA

patients are being recruited for a Phase II study

• Cephalon’s anti-C5aR antagonist PMX53 was

discontinued after failing to show efficacy in RA

patients in a Phase II study

• Another C5aR antagonist, CCX168, is being

developed by Chemocentryx for use in vasculitis

Pipeline

Phase II • MP-435 (Mitsubishi Tanabe)

Phase I • NN8209 (Novo Nordisk)

66

Sources: Crilly A et al. Phosphodiesterase 4 (PDE4) regulation of proinflammattory cytokine and chemokine release from rheumatoid synovial

membrane. Ann Rheum Dis 2011;70:1130-1137

Orally available PDE4 Inhibitors reduce TNFα production and therefore provide a potential

alternative to approved, injectable, anti-TNF biologics; two oral phosphodiesterase-4 Inhibitors

are in Phase II.

Physiology • PDE4 is the major cyclic AMP (cAMP)-metabolizing

enzyme found in inflammatory and immune cells

Hypothesized

Mechanism

• Inhibition of PDE4-mediated cAMP metabolism,

leading to the inhibition of multiple cytokines

(TNFa, IL-12, IL-2, IFN-g, IL-5, IL-8), leukotriene B4,

and the adhesion molecule Mac-1 (CD18/CD11b)

Potential

considerations

• Apremilast is in Phase II (recruiting stage) in patients

with rheumatoid arthritis

• Revamilast is in Phase II (recruiting stage) in patients

with rheumatoid arthritis who are taking

methotrexate

Pipeline

Phase II • Apremilast (Celgene Corp.) • Revamilast (Glenmark Pharmaceuticals)

67

Sources: Söderström K et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci USA

2010;107:13028-13033; Andersson AK et al. Blockade of NKG2D ameliorates disease in mice with collagen-induced arthritis: a potential

pathogenic role in chronic inflammatory arthritis. Arthritis Rheum 2011;63:2617-2629; Park KS et al. Inhibitory NKG2A and activating NKG2D

and NKG2C natural killer cell receptor genes: susceptibility for rheumatoid arthritis. Tissue Antigens 2008:72:342-346

Assets from Novo Nordisk targeting natural killer (NK) cells constitute a new therapeutic

strategy for RA.

Physiology • Natural killer (NK) cells mediate the clearance of virus-

infected, aberrant, or transformed cells

• NK cells also release cytokines and growth factors that

might influence the initiation and development of

immune responses by T and B Cells

• The inhibitory NKG2A and activating NKG2D NK cell

receptors are expressed on subsets on NK cells and T

Cells; they might contribute to chronic inflammation

and destruction of bone and cartilage in RA - NK cells can be detected in the inflamed synovial tissue at

an early stage of RA, and they constitute up to 20% of all

lymphocytes in the synovial fluid of patients with

established RA

- Such NK cells express NKG2A, RANKL and M-CSF, and are

frequently associated with CD14+ monocytes; expression of

NKG2D was also detected on RA synovial cells

Hypothesized

Mechanism

• Modulate NK cell function via blockade of either NKG2D

or NKG2A

Potential

considerations

• The safety and tolerability of anti-NKG2A antibody

NN8765 in RA patients are currently under evaluation in

a Phase I study

• The anti-NKG2D antibody NN8555 program has been

terminated in RA, and is now only focusing on Crohn’s

Phase I • NN8765 (Novo Nordisk)

Pipeline

68

Sources: Gendron S et al. α1β1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T Cells and enhance their

osteoclastogenic function. Immunology 2008;125:359–369

Two adhesion molecule Inhibitors are in the early stage of clinical development, though two

integrin Inhibitors have been discontinued after Phase II trials; Cell adhesion molecules play a

key role in the migration, retention and proliferation of activated T Cells and monocytes.

Physiology • Integrins modulate cell adhesion via interaction with

their primary ligands, vascular cell adhesion

molecule (VCAM) and mucosal addressin cell

adhesion molecule (MAdCAM), expressed in the

affected tissue; very late activation antigen-1 (VLA-

1, or a1b1) is a collagen receptor located on T Cells

• Vascular adhesion protein-1 (VAP-1) is required for

leukocyte rolling and transmigration through the

endothelium - In RA patients, activation of both α1β1 integrin (VLA-1)

and IL-7R enhance the ability of CD4+ T Cells to induce

the formation of osteoclasts from human monocytes via

synergic increase in RANKL production

Hypothesized

Mechanism

• Inhibit the recruitment of lymphocytes into the

synovium

Potential

considerations

• The anti-a4 integrin TYSABRI (Biogen Idec), and the

anti-aVb3 integrin Vitaxin (MedImmune) were both

discontinued in Phase II

• BTT-1023 showed encouraging efficacy and safety in

early clinical studies in RA. In April 2012, Biotie and

Seikagaku agreed to terminate their License

Agreement for BTT-1023

• The safety, tolerability, pharmacokinetics, and

pharmacodynamics of a single dose of SAN-300 is

being investigated in about 60 subjects, including

healthy controls and RA patients in a Phase I study

Pipeline

Phase I • BTT-1023 (Biotie Therapies)

• SAN-300 (Santarus)

69

Sources: Sources: Simmonds RE and Foxwell BM.. NF-kB and its relevance to arthritis and inflammation. Rheumatology 2008;47:584–590

NF-κB is involved in many aspects of RA pathology, including inflammation, development of T

helper 1 responses, activation, abnormal apoptosis and proliferation of RA fibroblast-like

synovial cells, and differentiation and activation of bone resorbing activity of osteoclasts.

Physiology • The transcription factor nuclear factor kB (NF-kB)

regulates many aspects of cellular activity in response

to stress and injury, especially the inflammatory

response via induction of IL-1, TNF-a, and the

adhesion molecules E-selectin, VCAM-1, and ICAM-1

• NF-kB consists out of homo- and hetero-dimers of

different subunits: p50, p52, p65, RelB, and c-Rel

• NF-kB dimers are sequestered in the cytosol of

unstimulated cells via non-covalent interaction with

the inhibitor protein IkB; upon phosphorylation, IkB is

degraded, and NF-kB enters the nucleus and binds to

DNA to induce gene expression. - In the synovial cells of patients with RA, NF-kB activation

results in the transactivation of multiple genes that

contribute to the inflammatory phenotype, including TNF-

α from macrophages, matrix metalloproteinases from

synovial fibroblasts, and chemokines that recruit immune

cells to the inflamed pannus

Hypothesized

Mechanism

• Inhibition of NFkB and p38 MAP kinase pathways,

leading to the inhibition of multiple cytokines

Potential

considerations

• A Phase I trial has been completed to evaluate the

safety, tolerance, pharmacokinetics, and activity of

Triolex (HE3286) in RA patients taking MTX ‐ Triolex was found to be safe and well tolerated, and no

drug-drug interactions were observed

‐ Triolex is also being investigated in Phase II for use in type

2 diabetes, in Phase I for use in ulcerative colitis, and in

preclinical stage for use in cystic fibrosis and Parkinson’s

disease

• A Phase I safety and pharmacokinetic study of VGX-

1027 in healthy subjects has been completed

Pipeline

Phase I • Triolex (Harbor Bioscience) • VGX-1027 (Inovio Pharmaceuticals)

70

Sources: van Eden W. XToll, a recombinant chaperonin 10 as an anti-inflammatory immunomodulator. Curr Opin Investig Drugs 2008;9:523-533;

O’Neill LA. Primer: Toll-like receptor signaling pathways--what do rheumatologists need to know? Nat Clin Pract Rheumatol 2008;4:319-327

One asset targeting the Toll-like receptor (TLR) pathway remains in Phase II; XToll is a

recombinant chaperonin 10; IMO-3100, a TLR7/TLR9 inhibitor, is no longer in trials for RA.

Physiology • Toll-like receptors (TLRs) play a key role in innate

immunity; they are pattern recognition receptors

that recognize structurally conserved microbial

molecules; TLR7 and 9 are expressed on monocytes,

macrophages, plasmatoid DCs, and B Cells; TLRs are

potent activators of proinflammatory cytokines, such

as TNFa and IL-6, and of metalloproteinases - In RA patients, immune complexes containing host-

derived nucleic acids have been shown to induce

inflammatory responses mediated through TLR7 and 9;

the expressions of TLR2, 3, 4, and 7 are increased in the

rheumatoid synovium; synovial fibrobalsts of RA patients

constitutively express TLR1-6

Hypothesized

Mechanism

• Inhibition of TLR signaling

Potential

Considerations

• IMO-3100 (Idera) is no longer being pursued in RA. A

Phase II trial in psoriasis was initiated in April 2012

• XToll is a recombinant chaperonin 10 (heat-shock

protein 10), a mitonchondrial protein that inhibits

TLRs; XToll was investigated for safety and efficacy

in 155 patients with moderate to severe RA despite

MTX treatment in a Phase IIa trial; XToll was found to

be safe and well-tolerated; improvement in ACR20 in

RA patients failed to reach statistical significance;

however, a statistically significant effect was

observed in several secondary efficacy parameters

Pipeline

Phase II • XToll (CBio Ltd.)

71

Sources: Company press releases; 3rd party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; Centerwatch

Several additional assets have generated Phase III or Phase II data; Regeneron/Sanofi’s

Sarilumab, which is in phase III trials, achieved 72% ACR20 at week 12.

Mechanism of Action Phase Efficacy Data Safety Data

Sarilumab

(Regeneron/

Sanofi)

• Anti-IL-6Ra

monoclonal

antibody

III • Sarilumab in combination with MTX

demonstrated efficacy: ACR20

response at Wk 12 was significantly

greater with 150 mg QW sarilumab

(72.0%) than with placebo (46.2%)

• The most common treatment

emergent AEs reported by patients in

the treatment arms were infections

(non-serious) 12-26%, neutropenia 0-

20%, and ALT increase 0-6%

Ozoralizumab

(Pfizer/Ablynx)

• Anti-TNF-a

nanobody

II • 80 mg every 4 weeks statistically

significantly improved ACR20

responses over placebo at Week 16

• Improvements of clinical scores,

DAS28, ACR50, ACR70 and EULAR

response at Week 16

• No dose limiting toxicities were

observed, and the AEs and SAEs that

occurred did not show a clinically

significant increase on increased

dosing

Apilimod

(Synta Pharma)

• IL-12/IL-23

transcription

inhibitor

II • No significant difference was found

between apilimod and placebo

• Headache and nausea were reported

with apilimod 180 mg BID for 8

weeks

LX2931

(Lexicon

Pharma)

• Sphingosine 1-

phosphate (S1P)

lyase inhibitor

II • The 150 mg dose did not show a

statistically significant benefit vs.

placebo on ACR20 response

• However, a pooled analysis of the

placebo plus low-dose cohorts (70

mg and 110 mg) vs. the 150 mg

cohort showed a statistically

significant benefit on ACR20

response

• LX2931 exhibited a favorable safety

profile at all three doses tested

72

Table of Contents

Slide Number



• 3 – 6

• 7 – 9






10 • 11 - 12

• 13 - 14

• 15

• 16 – 27

• 28



• JAK Inhibitors

• Syk Inhibitors




29 • 30 - 32

• 33 – 38

• 39 – 45

• 46 - 48

• 49 - 50

• 51 - 52

• 53 – 71





72 • 73 – 78

• 79

• 80 – 81

• 82 – 90



91 • 92 – 93

• 94 – 96

73

How large is

the global

market and what

growth

is forecast?

• Global ’11 brand revenue for RA was ~$14.7B, steadily increasing throughout the last 3 years

• The market will continue its growth by ~4.5% to ~$18.3B between ’12 and ’15 as currently approved

biologics will continue to dominate rheumatoid arthritis treatment in the next 5 years - US: ‘11 brand revenue increased by ~12% to ~$6.3B, and is forecast to continue this trend to ~$6.8B in ’12, and

increase ~4.7% annually to ~$7.8B through ’15, driven by steady anti-TNFα growth and adoption of newer biologics

in 2nd line treatment based on head-to-head studies versus Humira and newer sub-cutaneous formulations • In Q4 ’11, Orencia showed strong 11% growth driven by its recently approved sub-cutaneous formulation

- EU: ’11 brand revenues were ~$5.0B which is forecast to grow ~4.6% annually between ’12 and ’15, with pipeline

drugs expected to capture limited market share; anti-TNFα bio-similars are anticipated

- JP: Japan’s ’11 brand revenue was ~$1.0B with pipeline drugs expected to accelerate growth through ’15

- RW: ‘11 brand revenue increased by ~33% to ~$2.4B reflecting biologic penetration over the past three years,

however total revenue growth is expected to slow and start to reverse by ’15 • Remicade and Enbrel are expected to lose market share to bio-similars, which are already available in some geographies

What are launch

forecasts?

• Wall Street consensus estimates forecast new product launches will expand the ’15 global market by

~$1.1B, driven largely by anticipated launches: ‐ 2012: Tofacitinib (PFE)

‐ 2013: Iguratimod (Eisai), Secukinumab (NVS)

‐ 2014: Fostamatinib (AZN/Rigel), Sarilumab (SNY), Tabalumab (LLY), Ixekizumab (LLY)

• Analyst forecasts are tempered by the: (1) Crowded competitive landscape, (2) High likelihood that

regulators will constrain launches to 3rd line, (3) Unclear future treatment paradigm, (4) Payor resistance

What trends

are driving the

US market?

• In Q4 ’11 US retail revenue increased ~18% compared to Q4 ’10, driven by a ~7.5% increase in days of

therapy, a ~4.3% increase in price per day, and a 6.4% increase in product mix; Rx volume gains are driven

by capture of Orencia’s sub-cutaneous formulation data at retail pharmacies - Mix: In the US, the prescription market for RA stayed relatively constant in the first 3 quarters in ’11; Humira,

Enbrel and Remicade accounted for ~70% market share; Orencia gained 5 market share, 5 percentage points, after

the approval of its sub-cutaneous formulation

- Promotion: In the three month period ending December ’11, healthcare professional (HCP) spend grew ~10% as

Humira increased its spend by 36% from the previous period; direct to consumer (DTC) spend has been dominated

by Enbrel and Humira, which account for 50%-85% share of DTC voice since April; Simponi and Cimzia, the 4th and

5th anti-TNFα’s to market, have steadily decreased promotional spend throughout 2011 indicating the challenge to

competing in this crowded market; Actemra, which has a restricted 3rd line label, is also reducing marketing spend

Executive Summary: Commercial Landscape

74

Sources: SDI (IMS) PDDA 2010

Methodologically to estimate Rx and revenues specific to rheumatoid arthritis, we pro-rate each drug’s total revenue and prescription volume, based on it percent use in rheumatoid arthritis versus other indications, as reported by physicians; we the use US mix as a global proxy.

54%

47%

44%

96%

64%

51%

6%

100%

0% 20% 40% 60% 80% 100%

Enbrel

Humira

Remicade

Orencia

Simponi

Cimzia

Rituxan

Actemra

Physician reported prescription mix by indication 2010 US

Rheumatoid

Arthritis

Other

Indications

Indication

75

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations,

analyst day transcripts); 3rd party equity research reports; Bio-Pharma Insight

Global ’11 brand revenue for RA was ~$14.7B, steadily increasing throughout the last 3 years; The market is forecast to grow by ~4.5% to ~$18.3B between ’12 and ’15 as current biologics will continue to dominate rheumatoid arthritis treatment in the next 5 years.

’11 Sales ($B) ’10–’11A ’11-’12F ’12–’15F

CAGR

Global &

Pipeline $14.7 18.7% 9.5% 4.5%

US $6.3 11.6% 8.5% 4.7%

EU $5.0 17.3% 17.4% 1.8%

JP $1.0 31.5% 16.2% 26.3%

RW $2.4 39.0% 17.4% 1.8%

Recent and Anticipated New Product Launches - Global

• Roche’s Actemra (01/10)

• Eisai/Abbott’s Humira (07/11, JP)

• PFE’s Tofacitinib (’12)

• Eisai’s Iguratimod (’13 JP) ‐Simcere’s Iremod, approved China, 08/11)

• NVS‘s Secukinumab (’13)

• AZN/Rigel’s Fostamatinib (’14)

• SNY’s Sarilumab (’14)

• LLY’s Tabalumab (’14)

• LLY’s Ixekizumab (’14)

• LLY’s Baricitinib (’15)

Recent and Anticipated Line Extensions

• BMY’s Orencia (08/11, sub-cutaneous)

Recent and Anticipated Loss of Exclusivity

• US: Kineret (12/13), Enbrel (02/14), Rituxan (09/16), and

Humira (12/16)

• EU: Rituxan (08/13), Remicade (08/14), Enbrel EU (10/15)

RA’s Global Brand Revenue ($B)

Actual: Solid bars Consensus Wall Street Forecast: Hashed bars

$9.2

$12.4

$14.7 $16.1

$17.2 $18.0 $18.3

$0.0

$10.0

$20.0

09A 10A 11A 12F 13F 14F 15F

EU

US

JP

RW

Updated: 04/15/12

Pipeline

Notes: Branded sales excludes generic revenues; Pipeline includes: PFE’ s Tofacitinib (’12), Eisai’s Iguratimod (’13), NVS’ s Secukinumab (’13),

AZN/Rigel’ s Fostamatinib (’14), SNY’s Sarilumab (’14), LLY’s Tabalumab (’14), Ixekizumab (’14), Baricitinib (’15)

76

RA’s United States Yearly Brand Revenue ($B) 2011 RA’s United States Quarterly Brand Revenue ($B)

’11 Revenue

($B)

’10–’11A

’11-’12F

’12–’15F

CAGR

United States $6.3 11.6% 8.5% 4.7%

Humira $1.6 19.3% 8.7% 5.7%

Enbrel $1.9 4.7% 0.1% -3.6%

Remicade $1.4 5.7% -1.4% -15.7%

Orencia $0.6 12.4% 23.3% 10.6%

Actemra $0.2 71.4% 37.0% 14.0%

Simponi $0.2 21.8% 17.0% 12.8%

Cimzia $0.2 36.1% 75.7% 21.2%

Rituxan $0.3 2.3% 3.7% 3.0%



Q4 Revenue

($B)

Q3A–Q2A

Q3A–Q4A

United States $1.69 2.3% 4.7%

Humira $0.50 8.4% 20.5%

Enbrel $0.48 -3.5% 2.0%

Remicade $0.34 4.8% -11.4%

Orencia $0.16 1.3% 11.0%

Actemra $0.06 5.9% 1.4%

Simponi $0.04 -3.3% 5.1%

Cimzia $0.05 -2.5% 14.3%

Rituxan $0.06 1.3% 0.2%

United States brand revenue increased by ~12% to ~$6.3B in ’11, and is forecast to continue this

trend’12, and increase ~4.7% annually to ~$7.8B through ’15, driven by steady anti-TNFα growth

and new drug launches; in Q4 ’11, Orencia grew by 11% based on its sub-cutaneous approval.

Actual: Solid bars Wall Street Consensus Forecast: Hashed bars Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

$5.1 $5.6

$6.3 $6.8

$7.2 $7.5 $7.8

$0.0

$5.0

$10.0

09A 10A 11A 12F 13F 14F 15F

Thousa

nds

Updated: 04/15/12

$1.4

$1.6 $1.6 $1.7

$0.0

$1.0

$2.0

Q1A Q2A Q3A Q4A

Updated: 04/15/12

US

Pipeline



77

European Union ’11 brand revenues were ~$5.0B and are forecast to grow ~4.6% annually

between ’12 and ’15 with bio-similar competition offsetting launches; Japan’s ’11 brand

revenue was ~$1.0B with pipeline drugs expected to accelerate growth through ’15.

RA’s Japan Brand Revenue ($B)

RA’s European Union Brand Revenue ($B) ’11 Revenue

($B)

’10–’11A

’11-’12F

’12–’15F

CAGR

European

Union $5.0 17.3% 6.2% 4.2%

Humira $1.8 19.3% 8.7% 5.7%

Enbrel $1.3 6.0% -1.6% 4.1%

Remicade $1.3 5.7% -1.4% -15.7%

Orencia $0.2 62.4% 2.3% 10.3%

Actemra $0.2 186.3% 37.0% 14.0%

Simponi $0.1 237.7% 67.4% 29.7%

Cimzia $0.1 161.3% 59.8% 26.0%

Rituxan $0.1 13.2% 9.7% 1.9% Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

Updated: 04/15/12

Updated: 04/15/12

EU

Pipeline

’11 Revenue

($B)

’10–’11A

’11-’12F

’12–’15F

CAGR

Japan $1.0 31.5% 16.2% 26.3%

Humira $0.1 88.7% 16.4% 28.6%

Enbrel $0.3 19.9% 5.8% 3.3%

Remicade $0.4 23.4% 6.1% 3.3%

Orencia $0.1 62.4% 2.3% 10.3%

Actemra $0.2 37.5% 21.4% 19.1%

Simponi $0.0 67.9%

Cimzia $0.0 79.4%

Rituxan $0.0 9.7% 47.4% 1.6%



JP

Pipeline

$2.9

$4.2 $5.0

$5.3 $5.6 $5.9 $6.0

$0.0

$4.0

$8.0

09A 10A 11A 12F 13F 14F 15F

Thousa

nds

$0.5 $0.8

$1.0 $1.2

$1.5

$1.8

$2.4

$0.0

$1.5

$3.0

09A 10A 11A 12F 13F 14F 15F

Thousa

nds



78

Rest of world brand revenue increased by ~33% to ~$2.4B in ’11 with increasing biologic

penetration; However total revenue growth is expected to slow and start to reverse by ’15;

Remicade and Enbrel are expected to lose market share to bio-similars.



RA’s Rest of World Brand Revenue ($B) ’11 Revenue

($B)

’10–’11A

’11-’12F

’12–’15F

CAGR

Rest of World $2.4 39.0% 17.4% 1.8%

Humira $0.4 41.4% 44.5% 16.0%

Enbrel $0.8 21.6% -1.1% -20.9%

Remicade $0.8 34.7% 4.7% -9.5%

Orencia $0.0 62.4% 2.3% 10.3%

Actemra $0.1 174.8% 91.2% -6.6%

Simponi $0.2 237.7% 60.2% 27.3%

Cimzia $0.0 400.0% 432.2% 41.1%

Rituxan $0.1 20.6% 17.9% -0.5% Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

Updated: 04/15/12

RW

Pipeline

$0.7

$1.8

$2.4

$2.9 $3.1 $3.1 $3.0

$0.0

$2.0

$4.0

09A 10A 11A 12F 13F 14F 15F

Thousa

nds



79

$0.1 $0.2

$0.5

$1.1

$0.0

$0.6

$1.2

09A 10A 11A 12F 13F 14F 15F

Baricitinib

Tofacitinib

Secukinumab

Sarilumab

Ixekizumab

Iguratimod

Fostamatinib

Tabalumab

Notes: These forecasts are not representative of Lumleian’s viewpoint; Ad-hoc Lumleian develops its own forecasts for clients

based on its proprietary analytics and research

Global AZN’s Fostamatinib

Equity Research Forecasts ($B)

Global Pipeline Assets Wall Street Consensus Forecast ($B)

Sources: Consensus estimates based on publicly available equity research forecasts that have been updated in the past 12

months (since 02/15/11); Consensus estimate is the ‘straight line’ average with each bank’s forecast weighted equally

Wall Street consensus estimates forecast new product launches will increase the ’15 global market

by ~$1.1B, driven largely by anticipated launches for PFE’s Tofacitinib (’12), Eisai’s Iguratimod

(’13), NVS’ s Secukinumab (’13), AZN/Rigel’ s Fostamatinib (’14), SNY’s Sarilumab (’14), LLY’s

Tabalumab (’14), Ixekizumab (’14) and Baricitinib (’15).

Global LLY’s Ixekizumab


$0.00

$0.10

$0.20

12F 13F 14F 15F

Thousa

nds

$0.00

$0.11

$0.22

12F 13F 14F 15F

Thousa

nds

Updated: 04/15/12

15F Consensus: $0.15B 15F Consensus: $0.98B

Wall Street Consensus Forecast: Hashed bars

Global PFE’s Tofacitinib


$0.00

$0.40

$0.80

12F 13F 14F 15F

Thousa

nds

15F Consensus: $0.46B

(Adjusted for RA only)

80

0%

15%

30%

Sources: SDI (IMS) retail sales and prescription data

Notes: Revenues include both branded and generic products; YTD growth compares 2011 vs. 2010; QTD growth compares the 3months 10/11-12/11

vs. the 3 months 7/11-9/11; MTD compares the month 12/11 vs. the month 12/10

In Q4 ’11, US RA retail revenue increased ~18% compared to Q4 ’10, driven by a ~7.5% increase

in days of therapy, a ~4.3% increase in price per day, and a 6.4% increase in product mix; Rx

volume gains are driven by capture of Orencia’s sub-cutaneous formulation data at retail

pharmacies.

Decomposition of Q4’11 US RA’s Retail Revenue Growth (over Q4 ’10)

Updated: 04/15/12

Dec-11 vs. Dec-10 46.7% 2.5% 0.7% 49.8%

2011 vs. 2010 10.0% 5.7% 4.3% 20.1%

Days of

Therapy

Price per day

(Independent of Mix)

Product

Mix

Retail

Revenue

+7.5%

+4.3%

+6.4% +18.3%

81

0%

50%

100%

In the US, the prescription market for RA has been relatively constant for the first 3 quarters of

’11; Humira, Enbrel and Remicade accounted for ~70% market share; However, Orencia has steadily

gained share from 13% in Q3 to 18% in Q4 with the approval of it sub-cutaneous formulation.

Share

Share Change

(% points) Growth

Dec '11 1 mon 3 mon 12 mon QTD YTD

Total TRx 5.2% 3.4%

Humira 20.4% -0.2 -1.4 -1.9 -2.3% -1.1%

Enbrel 26.4% -0.7 -2.1 -4.4 -8.3% -7.2%

Remicade 20.6% 1.0 -1.3 -0.3 5.5% -2.2%

Orencia 18.1% -0.3 3.7 5.3 36.7% 22.7%

Actemra 1.3% 0.1 0.5 0.8 94.4% 75.3%

Simponi 4.4% -0.1 -0.3 -0.5 -3.9% 16.1%

Cimzia 4.5% 0.0 0.0 0.0 9.9% 25.1%

Rituxan 3.9% 0.2 1.0 1.1 53.8% 77.1%

Kineret 0.5% 0.0 -0.1 -0.1 -15.7% -5.9%

US RA’s Prescription Share (TRx)

Updated: 04/15/12

Humira

Enbrel

Remicade

Orencia

Cimzia

Simponi

Rituxan

Sources: SDI (IMS) Oncology Tracker data

Notes: Patient share includes both branded and generic products; Share Change compares the share for 12/11 vs. 1 month, 3

months, and 12 months ago; YTD growth compares the patient share for 2011 vs. the patient share for 2010; QTD growth

82

In the three month period ending December ’11, healthcare professional (HCP) spend grew ~14% as

Humira increased its spend by 36% from the previous period; direct to consumer (DTC) spend has

been dominated by Enbrel and Humira, which account for 50%-85% share of DTC voice since April.

$0

$30

$60

J F M A M J J A S O N D

$0

$10

$20


Millions

DTC

HCP

$40.5M

(12/11)

$17.5M

(12/11)

$32.6M

(12/11)

2011 Total Promotional Spend ($M)

2011 Healthcare Professional Spend ($M) 2011 Direct to Consumer Spend ($M)

Updated: 04/15/12

Updated: 03/15/12 Updated: 03/15/12

Share of

Wallet

Growth

Rate

(Dec-11) 3MR

HCP 37.5% 14.3%

DTC 62.5% 8.1%

Share of

Voice

Growth

Rate

HCP (Dec-11) 3MR

Humira 35.3% 36.2%

Enbrel 18.8% -0.7%

Remicade 14.0% 35.9%

Orencia 7.5% 37.8%

Actemra 4.0% 17.5%

Simponi 1.8% -41.2%

Cimzia 10.2% -35.8%

Rituxan 2.8% -3.1%

NPS(RA) 5.5% 188.4%

Share of

Voice

Growth

Rate

DTC

(Dec-

11) 3MR

Humira 18.7% -37.6%

Enbrel 63.7% 70.4%

Orencia 11.0% 89.6%

Actemra 0.1% -36.2%

Simponi 0.0% 197.7%

Cimzia 1.5% -37.0%

NPS(RA) 4.9% -13.0%

$0

$20

$40


Millions

Sources: SDI (IMS) Promotion Audits, Kantar Media Research 2010 - 2011

Note: Healthcare Professional (HCP) spend includes marketing to physicians, nurse practitioners, physician assistants through marketing & event

promotions, journals, and online promotions; Direct to Consumer (DTC) includes marketing channels in television, radio, newspapers,

magazines, outdoor advertisements, and internet; 3 month rolling (3MR) compares spend for the 3 months 8/11-10/11 vs. the 3 months 5/11-

7/11; The promotional spend for a certain drug covers all indications.

83

0

15

30



Share of

voice

HCP 14.5% 20.7% 21.3% 19.9% 21.0% 15.7% 13.6% 24.2% 26.4% 18.7% 18.2% 18.8%

DTC 26.8% 30.0% 30.1% 44.7% 37.5% 29.3% 23.7% 39.6% 34.2% 25.6% 63.9% 63.7%

Notes: Updated: 04/15/12; 3 month rolling (3MR) compares spend for the 3 months 8/11-10/11 vs. the 3 months 5/11-7/11; The promotional

spend for a certain drug covers all indications.

Sources: SDI Promotion Audits, Kantar Media Research

From the second half of ‘11, Humira’s promotional spend leaned towards DTC;

Humira messaging focuses on preventing joint damage.

HCP

$10.1M

Growth

Rate

(Dec-11) 3MR

HCP $5.4M 36.2%

DTC $4.7M -37.6%

DTC

5/11, 6/11, 10/11, 11/11 & 12/11 -

Help manage many threats.

Rheumatoid arthritis. Psoriatic

arthritis. Ankylosing spondylitis. One

Humira. HUMIRA

11/11 - Help stop joint damage before

it stops you. For many patients with

moderate to severe RA, Humira has

been proven to help relieve pain and

stop further joint damage. Receive

free RA Health Organizer and

Educational Series. www.humira.com

7/11 - Humira has been proven to help

prevent further joint damage while

reducing pain, stiffness, and swelling

in many patients with moderate to

severe RA. Send attached card in

today for a free RA educational series.

www.humira.com

84

0

10

20

30


Total Promotional Spend ($M)

Share of

voice

HCP 14.5% 20.7% 21.3% 19.9% 21.0% 15.7% 13.6% 24.2% 26.4% 18.7% 18.2% 18.8%

DTC 26.8% 30.0% 30.1% 44.7% 37.5% 29.3% 23.7% 39.6% 34.2% 25.6% 63.9% 63.7%


Enbrel has been widely co-promoted with use for psoriatic arthritis in 2011;

Total promotional spend doubled that of Humira, for November and

December of 2011, with a DTC campaign emphasizing earlier treatment.

DTC

$19M

Growth

Rate

(Dec-11) 3MR

HCP $2.9M -0.7%

DTC $16.1M 70.4%

DTC

Notes: Updated: 04/15/12; 3 month rolling (3MR) compares spend for the 3 months 8/11-10/11 vs. the 3 months 5/11-7/11; The promotional

spend for a certain drug covers all indications.

10/11 - Do you have psoriasis and

joint pain? You may have psoriatic

arthritis. Enbrel is indicated for

reducing signs and symptoms in

adults 18 years or older with

chronic moderate to severe plaque

psoriasis and is taken by injection.

www.enbrel.com

5/11 - If you have psoriatic

arthritis or moderate to

severe rheumatoid arthritis

"Don't let joint pain keep

you from the things that

matter the most." At six

months, Enbrel was shown

to be effective in about

50% of psoriatic arthritis

patients. www.enbrel.com

HCP

10/11 - In patients with

moderate to severe

rheumatoid arthritis (RA).

You may be thinking

"Wait," but their joints may

be saying "Now". ENBREL

10/11 - In appropriate

patients with psoriatic

arthritis or moderate to severe

rheumatoid arthritis, consider

Enbrel "Now". ENBREL

85

0

2

4



Share of

voice

HCP 12.0% 6.2% 17.6% 14.4% 8.7% 20.4% 8.9% 8.4% 13.3% 13.6% 8.5% 14.0%

DTC 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

Remicade promotional spend focuses exclusively on HCP; messaging encourages use

with methotrexate to delay disease advancement versus symptom relief.

HCP

$2.1M

Growth

Rate

(Dec-11) 3MR

HCP $2.1M 35.9%

7/11 - How do you control

an aggressive disease? For

moderately to severely

active rheumatoid arthritis

an aggressive disease

demands aggressive

control. Remicade can help

hold back the progression

of RA. REMICADE

Sources: SDI Promotion Audits, Kantar Media Research;

Notes: Updated: 04/15/12; 3 month rolling (3MR) compares spend for the 3 months 8/11-10/11 vs. the 3 months 5/11-7/11; The

promotional spend for a certain drug covers all indications.

86

0

2

4

6



Share of

voice

HCP 1.6% 4.9% 3.9% 2.7% 6.9% 6.4% 5.3% 4.5% 6.6% 7.0% 5.2% 7.5%

DTC 11.6% 19.9% 11.1% 13.4% 11.4% 5.8% 3.2% 0.3% 15.3% 9.7% 12.9% 11.0%

Promotional spend for Orencia is heavily concentrated in DTC, given its more

convenient formulation, with an emphasis on aiding daily activities; HPC

promotional spend touted Orencia as a unique biologic solution for 1s line RA.

DTC

$3.9M Growth

Rate

(Dec-11) 3MR

HCP $1.1M 37.8%

DTC $2.8M 89.6%

DTC

HCP

9/11 & 2/12- We're

about to flatten what

you may think is a big

obstacle to prescribing

Orencia. Orencia is the

first and only RA

biologic to offer both IV

and SC formulations.

ORENCIA

7/11 - We're about

to shatter how you

may think about

prescribing Orencia

as a first biologic.

ORENCIA

4/11 - Do you have

trouble with everyday

activities? If your

current treatment isn't

helping enough, it may

be time for a change.

Orencia reduces signs

and symptoms in adults

with moderate to

severe RA. Complete

card for Orencia

information.

www.orencia.com

9/11 - I wanted to button my

shirt. I wanted to open a jar.

I wanted to pick up the

paper. Is RA getting in the

way of how you start your

day? Orencia helps reduce

signs and symptoms of

moderate to severe RA.

www.orencia.com 9/11 - Will today be an "I

Want" day or an "I Can" day?

10/11- Is RA getting in

the way of how you start

the day? I wanted...to

open a jar, to get out of

bed, to button my shirt,

to pick up the paper.

Change your "I want" to

"Oh, yes I can!"

www.orencia.com




87

0

5



Share of

voice

HCP 7.2% 7.5% 6.3% 4.9% 5.6% 8.0% 6.1% 9.1% 10.2% 5.4% 4.9% 10.6%

DTC 0.1% 6.3% 0.0% 9.5% 0.0% 4.2% 3.2% 0.1% 0.1% 0.1% 0.1% 0.1%

Actemra tapered off 2011 DTC spend in June; HPC spend focused on anti-TNFα

inadequate patients, reflecting its narrow launch label.

$0.6M

Growth

Rate

(Dec-11) 3MR

HCP $0.6M 17.5% HCP

4/11 - Fill out the attached card to

get helpful information. The

Actemra Patient Support Program.

Getting support could help you with

your fight against rheumatoid

arthritis. Want to learn more about

RA and Actemra, complete and

return card. www.actemra.com

6/11 -

Important

safety

information for

physicians

about risks in

patients

receiving

Actemra.

ACTEMRA

4/11 - Offer rapid

improvement and

increasing

response. Help

TNF-IR patients

like Arlene and

Megan with

Actemra. ACTEMRA

12/11 - Important

safety information

for neurologists

about demyelinating

disorders in co-

managing

rheumatoid arthritis

patients receiving

Actemra. ACTEMRA

6/11 -

Important

safety

information for

oncologists

about

malignancy risk

with Actemra.

ACTEMRA




88

0

5

10



Share of

voice

HCP 11.7% 12.3% 11.6% 12.2% 13.5% 8.6% 17.5% 12.4% 7.6% 3.7% 7.7% 10.2%

DTC 21.9% 16.1% 19.0% 10.4% 12.0% 13.5% 5.3% 9.6% 8.8% 8.9% 2.8% 1.5%

From the second half of ‘11, Cimzia’s promotional spend has concentrated on DTC

advertising messaging rapid onset and its convenient sub-cutaneous formulation;

Cimzia has steadily decreased promotional spending throughout the year.

DTC

$1.9M

Growth

Rate

(Dec-11) 3MR

HCP $1.6M -35.8%

DTC $0.38M -37.0% HCP

3/11 & 6/11 & 7/11 - For treatment

of adults with moderate to severe

Rheumatoid Arthritis. Cimzia. RA

relief that can help you get better

grip on life. Reduces RA pain,

stiffness and fatigue in as little 1-2

weeks. Prefilled syringe for comfort.

www.cimzia.com




89

0

5



Share of

voice

HCP 6.9% 6.7% 3.1% 4.1% 2.1% 5.0% 4.0% 3.0% 11.3% 2.8% 4.8% 5.1%

DTC 3.5% 8.2% 9.4% 3.2% 10.5% 5.3% 9.7% 4.6% 0.0% 1.7% 0.0% 4.0%

Similarly Simponi promotional spend has also decreased throughout the year,

reflecting the challenge of competing in a market with five approved anti-TNFα’s.

DTC

$0.3M

Growth

Rate

(Dec-11) 3MR

HCP $0.3M -41.2%

HCP

3/11 - Simponi: A

once-monthly,

subcutaneous

(SC) anti-TNFα

agent.

Dependable

dosing with the

Smartject

Autoinjector.

SIMPONI

10/11- Why make starting a biologic a bigger step

than it has to be? SIMPONI

5/11- A full month of efficacy. For your patients with

moderately to severely active RA. Choose Simponi as their

first biologic. SIMPONI




90

0

1

2

3

4


2011 Total Promotional Spend ($M) UCB PHARMA HCPPFIZER HCP ABBOTT PHARMA DTCABBOTT PHARMA HCP UNSPECIFIED COMP HCPBRISTOL-MYERS SQUIBB DTC BRISTOL-MYERS SQUIBB HCP

Share of

voice

HCP 4.2% 4.2% 9.2% 6.3% 4.2% 2.0% 5.7% 3.8% 1.4% 4.7% 6.5% 3.7%

DTC 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

NPS (Non-Product-Specific) promotional spend for RA peaked in October along with most other

drug-specific promotional campaigns; NPS HPC promotional spend was dominated by messaging

from Pfizer around the JAK pathways, preceding Tofacitinib’s anticipated launch in Q4.

BMS

10/11 -"Thirsty? Are you

going to try and open me

yourself? Or are you going

to ask someone for help?"

Is your RA still

challenging you?

www.realraliving.com

BMS

10/11 - Are you settling or

living? Mail this card to get

your free realRAliving

information kit.

www.realraliving.com

Abbott

7/11 - A little information can help make a big

decision. Return this card for your free

educational series. To help us better help you,

tell us more about yourself and your RA. Fill

out the form and receive information about RA

and a treatment option.

Pfizer

5/11, 6/11 -In rheumatoid

arthritis, there may be a

different path to take in

approaching cytokine

signaling. Explore an

intracellular approach. JAK

pathways in action.

Pfizer

9/11 - In rheumatoid

arthritis, JAK pathways

transmit signals that

drive inflammation.

Pfizer

7/11 – Explore a

different path to

cytokine signaling in

rheumatoid arthritis.


Notes: Updated: 04/15/12

91

Table of Contents

Slide Number



• 3 – 6

• 7 – 9






10 • 11 - 12

• 13 - 14

• 15

• 16 – 27

• 28



• JAK Inhibitors

• Syk Inhibitors




29 • 30 - 32

• 33 – 38

• 39 – 45

• 46 - 48

• 49 - 50

• 51 - 52

• 53 – 71





72 • 73 – 78

• 79

• 80 – 81

• 82 – 90



91 • 92 – 93

• 94 – 96

92

Table of Acronyms (1 of 2)

ACE Angiotensin-converting enzyme

ACPA Anti-citrullinated protein antibody

ACR American College of Rheumatology

AE Adverse event

ALT Alanine aminotransferase

B Billions

BAFF B Cell-activating factor

BID Bis in die (twice daily)

bDMARD Biologic DMARD

CAMKII

Ca2+/calmodulin-dependent protein

kinase

CDAI Clinical disease activity index

COPD Chronic Obstructive Pulmonary Disease

COX Cyclooxygenase

CRP C-reactive protein

CTLA4 Cytotoxic T lymphocyte antigen 4

CTX

C-terminal telopeptide of type I

collagen

DAS Disease activity score

DHODH Dihydroorotate dehydrogenase

DMARD Disease-modifying antirheumatoid drug

DRESS

Drug reaction with eosinophilia and

systemic symptoms

ECG Electrocardiogram

ES Erosion score

ESR Erythrocyte sedimentation rate

EULAR European League Against Rheumatism

FACIT

Functional assessment of chronic illness

therapy

GI Gastrointestinal

GM-CSF

Granulocyte-macrophage colony-

stimulating factor

GSK GlaxoSmithKline

HAQ-DI

Health assessment questionnaire

disability index

HDL High density lipoprotein

HLA Human leukocyte antigen

IFN Interferon

Ig Immunoglobulin

IL Interleukin

ITAM

Immunoreceptor tyrosine-based

activation-motif

IV Intravenously

JAK Janus kinase

LDL Low density lipoprotein

LOCF Last observation carried forward

MAPK Mitogen-activated protein kinase

M-CSF Macrophage colony-stimulating factor

mg Milligram

miRNA microRNA

MMP Matrix metalloproteinase

MoA Mode of action

MRI Magnetic resonance imaging

mTSS Modified total sharp scores

MTX Methotrexate

NFkB Nuclear factor kappa B

NIAMS

National Institute of Arthritis and

Musculoskeletal and Skin Disease

NSAID Nonsteroidal antiinflammatory drug

OAM Once a month

OPG Osteoprotegerin

PAS Patient activity index

PCP Primary care physician

PD Pharmacodynamics

PDE4 Phosphodiesterase-4

PINP Procollagen type I N propeptide

PI3K Phosphoinositide 3-kinase

PK Pharmacokinetics

PML

Progressive multiple focal

leukoencephalopathy

PPAR

Peroxisome proliferator-activated

receptor

93

Table of Acronyms (2 of 2)

QD Quaque die (once daily)

QM Once a month

q8w Every eight weeks

QOD Every other day

QOW Every other week

QW Once weekly

RA Rheumatoid arthritis

RANK

Receptor activator of nuclear factor

kappa-B

RANKL

Receptor activator of nuclear factor

kappa-B ligand

RAPID Routine assessment patient index data

RF Rheumatoid factor

RN Registered nurse

SAE Serious adverse event

sub-c Subcutaneously

SCF Stem cell factor

SFDA Quarter To Date

SF-36 Once weekly

SF-36 Short form 36

SJC Swollen joint count

SQ Subcutaneously

STAT

Signal transducer and activator of

transcription

Syk Spleen tyrosine kinase

TB Tuberculosis

Th T helper

TJC Tender joint count

TLR Toll-like receptor

TNF Tumor necrosis factor

TNF-IR Inadequate responder to TNF Inhibitors

VAP-1 Vascular adhesion protein-1

VAS Visual analog scale

VLA-1 Very late activation antigen-1

94

• Frank Deane, Ph.D. is a Director of Decision Science and Founder of Lumleian. Frank has over ten years experience

working with life science companies and concurrently holds an appointment in the department of strategy at the

Carroll School of Management, Boston College, where he teaches ‘Strategic Issues in Pharma and Bio-Tech,’ to MBA

students. Prior to founding Lumleian, Frank was a director with Leerink Swann and a case team leader with Bain,

where he gained substantial operational experience growing and operating a diverse set of businesses. Frank

entered consulting after spending three years in the bio-pharmaceutical industry with Eli Lilly, supporting portfolio

optimization and business unit strategic planning. He began his career, as a quantitative risk analyst working at

BlackRock. Frank earned a Ph.D. in econometrics from the Krannert School of Management at Purdue University,

where his dissertation focused on applying game theory and statistical modeling to optimize pharmaceutical sales

and marketing resources. Frank has a bachelor of arts in economics from Princeton University.

As a leadership team, we designed Lumleian’s business model based on our collective

experience in: academic R&D, bio-pharmaceutical industry, equity research and strategy

consulting …

• Mark Hochstetler, MBA is a Director of Decision Science at Lumleian. Mark has over ten years experience working

with life science companies. Prior to joining Lumleian, Mark served as the CFO at OPK Biotech, which focuses on

developing oxygen therapeutics for the treatment of anemia, ischemia, and trauma. Before segueing to industry,

Mark spent 5 years as a strategy consultant and equity research analyst at Leerink Swann, where he covered:

Array, Arqule, Ariad, Celgene, Chelsea, Cougar, Cubist, Genentech, GTx, Hana, Idenix, InterMune, Kosan,

Millennium, MGI Pharma, Onyx, Poniard and Vertex. Mark earned an MBA from Duke University’s Fuqua School of

Business with a concentration in health sector management. Mark has a bachelor of arts in political science from

Stanford University.

• Sarah Haigh Molina, Ph.D. is a Manager of Decision Science at Lumleian, where she leads the Academia and Non-

profit practice. Sarah has over ten years experience working and researching in the life sciences. Prior to joining

Lumleian, Sarah was an Assistant Professor of Medicine at Boston University School of Medicine where she served

as the Director of High-throughput Screening. Before returning to academia, Sarah was US Operations Manager at

Molecular Cytomics. Sarah earned a Ph.D. in biology from York University, an MBA from Boston University with a

concentration in entrepreneurship, and a bachelors of science in biochemistry from Dundee University.

95

… Having lived the client experience, we know quality is paramount, and pioneered our

approach with quality and process efficiency as dual mantras.

• Jean Kung, M.Eng, MBA as Manager of Process Efficiency and Quality Control oversees day-to-day operations and

finances at Lumleian and has over five years experience working in the life sciences. Jean designed the process

by which Lumleian efficiently and effectively creates and quarterly updates its disease state primers and serves as

the final point of quality control. Prior to joining Lumleian, Jean served as a contract project manager to various

life science clients. Before entrepreneurship, Jean was a clinical research associate at Health Policy Associates

and a researcher at the Harris Orthopedic Biomaterials and Biomechanics Laboratory, Massachusetts General

Hospital. Jean earned a masters of science in biological engineering from Cornell University and an MBA in the

Health Sector Management Program from Boston University with a concentration in operations and technology

management. Jean has a bachelor of science and masters of engineering in biological engineering, also from

Cornell University.

• Morgen Caroll, MBA as Manager of the Customer Experience at Lumleian, aspires to provide Lumleian's clients with

superior care and service based on their particular needs. Morgen brings over five years life science experience

and has a background in Marketing, Sales, and Public Relations. Prior to joining Lumleian, Morgen worked at

GlaxoSmithKline, with responsibility for the company’s flagship cardiology and endocrinology products. At

GlaxoSmithKline, Morgen was a primary care and specialty care sales representative while serving as a liaison

between product management teams and field sales. As a representative, Morgen consistently ranked in the top

10% of GSK’s sales force, despite working in an inner city territory with significant access challenges. Prior to

entering the life sciences Morgen worked on the sales and marketing staff at Philadelphia Magazine and Food &

Wine Magazine. Morgen earned an MBA from the Villanova School of Business with a concentration in marketing,

and a bachelor of arts in English from Gettysburg College.

• Qingwei Sun, M.Eng., MS as a Decision Science Analyst oversees secondary data collection, synthesis and analysis

and designed analytical methodologies fundamental to Lumleian’s knowledge management platform. KM

database. Using meta-analysis method, he aggregates the clinical and commercial data required to generate

Lumleian’s disease state primers. His work has wide application in product development, portfolio management,

and investment strategy for both large pharmaceutical companies and emerging bio-techs. Qingwei, who is fluent

in Chinese and Japanese, leads our work with Asian clients. Qingwei joined Lumleian after obtaining a master of

science degree from Harvard School of Public Health. He earned both bachelor and master of engineering degrees

from Kyoto University, Japan, concentrating in materials science.

96

We recruit decision scientists explicitly for their expertise and relevant experience across

the gamut of major therapeutic areas and disease states.

• Whitney Amyot, Ph.D. as Decision Scientist focusing on infectious disease leverages her expertise in

scientific investigation and infectious disease to support primary and secondary research for strategic

decision making with biopharmaceutical clients and investors. She has more than ten years of experience in

scientific research, including positions at Atlanta’s Veteran Affairs hospital and in the pharmacology

department at Emory University School of Medicine. In her current role Whitney provides a broad knowledge

base to ensure Lumleian is up to date on current discovery and clinical trends. Whitney earned a Ph.D. in

Molecular Microbiology from Tufts University Sackler Graduate School of Biomedical Sciences where her

dissertation focused translocation in the becterium Legionella pneumophila. Whitney has a Bachelor of

Science degree in Biology from Emory University.

• Alice S. Kaanta, Ph.D. as Decision Scientist focusing on oncology is responsible for leading a team of decision

scientists in reviewing the scientific, clinical and regulatory landscape in numerous oncology indications.

Alice has over ten years of experience in scientific research, in both academia and industry, where her

primary focus has been on cancer research. Alice earned her Ph.D. in Biological and Biomedical Sciences

from Harvard University. At Harvard, Alice worked in the Brugge Lab studying the regulation of pro-

apoptotic Bcl-2 family member Bim in breast cancer progression and in the Neel lab where she identified and

characterized a novel multi-potent mammary progenitor with pregnancy-specific activity. Alice earned dual

bachelor of science degrees in Biology and Physics from the Massachusetts Institute of Technology.

• Olivier Morteau, Ph.D. is a Decision Scientist at Lumleian, where he focuses on the scientific, clinical, and

market developments of therapeutics for autoimmune and inflammatory diseases. Olivier has conducted

research in the field of inflammation and autoimmunity for over 10 years, as a postdoctoral scientist at the

University of North Carolina at Chapel Hill and at Children’s Hospital in Boston, and as a junior faculty at

Children’s Hospital, at the Cummings School of Veterinary Medicine at Tufts University, and at the University

of Oxford (UK). More recently, Olivier was a Senior Immunologist at ImmunoCore Ltd, and a Senior

Communications Scientist at Vertex Pharmaceuticals. Olivier earned a Ph.D. in Pharmacology from Paul

Sabatier University, in Toulouse (France).