Pipeline Insight: Disease Modification In Rheumatoid Arthritis - Pipeline Uptake Inhibited By Anti-TNFs

Published by: Datamonitor

Published: Oct. 5, 2005 - 199 Pages

Table of Contents

About the CNS, Arthritis and Pain pharmaceutical analysis team

Scope of the analysis

Datamonitor insight into the RA market

Summary

Definition of the disease

Epidemiology of RA

US and northern Europe show a higher prevalence of RA across the seven major markets

Average RA clinical trial participant is over 50 and female

Decrease in RA severity due to better treatment but epidemiology research continues

Key epidemiology studies in RA in the US, EU and Japan

2005 studies are coming from France and Canada but key Japanese studies need updating

US

Europe

Japan

Statistical caveats

Prevalence versus incidence

Diagnosed versus undiagnosed prevalence

Different methods of gathering prevalence data

Data ranges

Unmet need in RA is still headed by efficacy

Clinical unmet needs

Efficacy

Side effects

Administration and patient compliance

Cytokine assays a key challenge for treatment development

Environmental unmet needs

Cost

The current treatment approach puts biologic therapy after different combinations of traditional DMARD treatments

Current market definition includes the most common biologic and traditional DMARDs

The Japanese market

The market value is calculated using IMS diagnosis value

Classification of pipeline products

Cytokines

Interleukins

TNF inhibitors

Cell adhesion molecule inhibitors

MAP kinase

Immunomodulators

Other chemokines

Clinical trial design

Clinical trial endpoints in RA

American College of Rheumatology (ACR) measures are the most common endpoints

Disease Activity Scale

Tender Joint Count and Swollen Joint Count

Quality of Life Questionnaires

HAQ

Medical Outcome Short Form 36 (SF-36) Health Survey

Blood testing

Erythrocyte sedimentation rate (ESR)

C-reactive proteins (CRP)

Disease progression

RA pipeline overview

Pre-registration and Phase III

Phase II

Key companies involved in the RA pipeline

Roche dominates the late-stage pipeline

Sanofi-Aventis is a key player in traditional DMARDs but has not broken into the biologic arena

Strategies for success

Improved dosing and administration methods will drive sales

Patient preference or marketing strategies?

Flexibility in dosing will be key

Is a humanized Mab better than a chimeric one?

Therapeutic antibody types

The antibody misconception

Mabs vs. therapeutic proteins vs. small molecules

Biologic combinations should continue to be tested, but not in the near future

Overview for traditional DMARDs

Pipeline summary

Methotrexate is key comparator but Arava shows most innovation and highest sales in the traditional DMARD class

Comparison of key compounds in the traditional DMARD class

Prograf (tacrolimus)

Drug overview

Clinical trial data

Tacrolimus will compete with cyclosporine and methotrexate but only possibility of modified release give it any advantage

RA is just one more indication for Astellas's already top-selling drug

Prograf competes in terms of cost and its oral administration, but side effects and comparative efficacy to biologics are major drawbacks

Forecasts to 2014

US

EU

Japan

T-614 (iguratimod)

Drug overview

Clinical trial data

A broad action for T-614 raises side-effect concerns

Launch in Japan is more likely than in the US or EU

ACR50 scores lacking in the latest data making clinical efficacy difficult to compare

Forecasts to 2014

US

EU

Japan

Other traditional DMARDs

Teriflunomide

Rosaglitazone

Overview for biologic therapies

Pipeline summary

Current biologic comparator therapy is Enbrel

Comparison of key compounds in biologic DMARD class

Actemra (tocilizumab/MRA)

Drug overview

Clinical trial data

IL-6 inhibition has potential in many immune disorders

Chugai's new "Strategic Marketing Units" add considerable competitive strength to Actemra

Actemra's IV dosing may prove more popular in Japan, which will be this product's key market

Forecasts to 2014

US

EU

Japan

Rituxan/MabThera (rituximab)

Drug overview

Clinical trial data

Rituximab's considerable use in the cancer market dispels any fears over side effects

The Rituxan/MabThera brand has a strong marketing infrastructure behind it

A minimal dosing frequency offers a considerable advantage for rituximab

Forecasts to 2014

US

EU

Japan

Orencia (abatacept, CTLA4-Ig)

Drug overview

Clinical trial data

Orencia's novel mechanism shows great promise in TNF-failures

BMS may lack experience in the RA market, but its proposed pharmacovigilance program is well received by the FDA

Orencia competes well in most clinical aspects

Forecasts to 2014

US

EU

Japan

Cimzia (CDP 870)

Drug overview

Clinical trial data

Crohn's disease is the primary indication for Cimzia

A lack of recent data in RA may be losing physician faith in Cimzia, but ACR 2005 meeting data may save it

Cost advantage needs to follow through for Cimzia to succeed

Forecasts to 2014

US

EU

Japan

AMG-714 (HuMax Il-15)

Drug overview

Clinical trial data

AMG-714 shows promise in many indications, including increase in BMD for osteoporosis

Amgen's experience will be an advantage, but AMG-714 may reach the market too late

AMG-714 offers yet another TNF-failure alternative

Forecasts to 2014

US

EU

LymphoStat-B (belimumab)

Drug overview

Clinical trial data

BLyS shows promise in Lupus, which is expected to be the next major indication for biologic therapies

HGS should seek a partner to bring this product to the RA market

Initial ACR20 values not promising, but mechanism is sound

Forecasts to 2014

Other drugs in DMARD class

RGN-303 (IL-1 Trap)

SCIO-469

MLN 1202

VX-702

CNTO-148

AZD-9056

AT-001 (dnaJp1)

AMG-162

Eculizumab (Mab C5)

INCB-3284

AD

Recently discontinued late-stage development compounds

CDP-484

ABT-874

ISIS-104838

Doramapimod (BIRB-796)

AGIX 4207

Key Phase I and preclinical compounds in RA

Phase I

Preclinical

CD20 directed therapy

The candidates so far?

HuMax-CD20

TRU

PR070769

Will they succeed?

BLyS inhibitor BR3-FC

Less concern exists about long-term safety of BLyS antagonists

Preliminary data from a similar pipeline product, LymphoStat-B, appear sub-par

Methodology

Datamonitor forecast methodology

Assumptions

Company and product assessments

Company factors and score definitions

Product factors and score definitions

Report methodology

Definitions

Standard units

Japanese market data

Derivation of sales forecasts and pricing trends

Regional launch dates for new products

Generic erosion and pricing assumptions

Contributing experts

Bibliography

Websites

US

Japan

France

Germany

Italy

Spain

UK

5 EU

Global

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

About the CNS, Arthritis and Pain analysis team

Disclaimer

List of Tables

Table 1: Global RA forecast, US$m, 2004-2014

Table 2: RA population by country, 2005

Table 3: Point prevalence of RA, by age and sex, per 100 patients in Norfolk UK study, 2002

Table 4: RA prevalence, by gender and country

Table 5: Key American RA epidemiology studies

Table 6: Key European RA epidemiology studies

Table 7: Japan age-adjusted point prevalence of RA in nine consecutive surveys of the Kamitonda population, %, 1965-96

Table 8: Annual costs for biologic and traditional DMARDs, UK, 2000

Table 9: NICE incremental cost effectiveness ratio per QALY

Table 10: Key interleukin targeted products in R&D pipeline, 2005

Table 11: TNF products in the pipeline, 2005

Table 12: Approved biologic TNF inhibitors

Table 13: p38 MAP kinase targets in the RA pipeline

Table 14: Immunosuppressant in the RA pipeline

Table 15: Breakdown of other chemokine-targeted inhibitors in the pipeline, 2005

Table 16: Key trial data presented in prescribing information and used for approval of Enbrel and Remicade

Table 17: DMARD pipeline breakdown, 2005

Table 18: Pre-registration and Phase III DMARDs in the pipeline, 2005

Table 19: Phase II DMARD pipeline, 2005

Table 20: Products undergoing human clinical trials in RA in collaboration with Roche

Table 21: Advantages and disadvantages of IV and sc administration methods

Table 22: Key traditional DMARDs on the market

Table 23: Overview of late Phase traditional DMARDs

Table 24: Results of trial to find optimal dosing of tacrolimus in refractory RA, %, 2004

Table 25: Tacrolimus Phase II trial results

Table 26: Prograf Phase III trial results

Table 27: Global franchise and clinical trial phase summary for Prograf, 2005

Table 28: Tacrolimus RA forecast by country, $000's, 2005-14

Table 29: Iguratimod RA forecast, $000's, 2005-2014

Table 30: Overview of late phase biologic DMARDs

Table 31: Enbrel: key facts

Table 32: MRA RA forecast by country, $000's, 2005-2014

Table 33: Primary and secondary endpoints in rituximab's Phase IIb DANCER trial, 2005

Table 34: Clinical response over two years following a single treatment course of rituximab

Table 35: Rituximab RA forecast by country, $000's, 2005-2014

Table 36: Change from baseline in structural damage and progression, AIM trial

Table 37: Infections seen in each treatment arm, %

Table 38: Etanercept plus anakinra serious infection rates, %

Table 39: Comparative one and two year trial results, % of patients achieving ACR20, 50 and

Table 40: Abatacept RA forecast by country, $000's, 2005-2014

Table 41: CDP 870 Phase IIb trial results, 2001

Table 42: CDP 870 RA forecast by country, $000's, 2005-2014

Table 43: AMG-714 Phase II results

Table 44: AMG 714 RA forecast by country, $000's, 2005-2014

Table 45: LymphoStat-B Phase II RA trial results, 2005

Table 46: IL-1 Trap Phase II trial results, 2003

Table 47: Recently discontinued projects, 2005

Table 48: Phase I and preclinical targets, 2005

Table 49: Phase I DMARD pipeline, 2005

Table 50: Preclinical pipeline DMARDs, 2005

Table 51: CD20 directed therapies in the pipeline

Table 52: ICD10 codes used to define an RA diagnosis

Table 53: Company factors

Table 54: Product factors

Table 55: US RA forecast, US$, m, 2004-2014

Table 56: Japan RA forecast, US$m, 2004-2014

Table 57: France RA forecast, US$m, 2004-2014

Table 58: German RA forecasts, US$m, 2004-2014

Table 59: Italy RA forecast, US$m, 2004-2014

Table 60: Spain RA forecast, US$m, 2004-2014

Table 61: UK RA forecast, US$m, 2004-2014

Table 62: Five major EU countries RA forecast, US$m, 2004-2014

Table 63: Global RA forecast, US$m, 2004-2014

List of Figures

Figure 1: The future RA market

Figure 2: Normal and rheumatoid joint comparison

Figure 3: Main cause of disability of civilian non-institutionalized people age 18 and over, %, 1999

Figure 4: Likely sites of action of the major novel drugs on the RA market

Figure 5: RA prevalence, by gender and country

Figure 6: Unmet needs in RA cited by physicians in Datamonitor primary research, 2003

Figure 7: Treatment algorithm for RA

Figure 8: Historical sales for IL-1 inhibitor Kineret, Q3 2001-Q4 2004

Figure 9: Overview of Interleukin targets in the pipeline

Figure 10: Mechanism of action of tacrolimus (FK506) and cyclosporine (CsA)

Figure 11: Swollen and tender joint count assessment

Figure 12: DMARD pipeline breakdown by mechanism or structure, Phase I to Pre-registration, 2005

Figure 13: Roche portfolio breakdown

Figure 14: Biologic vs. traditional DMARD sales for RA in the US, 2004

Figure 15: Breakdown of late-stage projects by administration method, 2005

Figure 16: Improved self-administration syringe

Figure 17: Enbrel retail vs. hospital sales, for all indications, Q2 2003 to Q1 2005

Figure 18: Patient preference for administration methods

Figure 19: Definitions of antibody sections

Figure 20: Illustration of Mab types

Figure 21: Volume and value comparison of traditional DMARDs for RA, 2001-04

Figure 22: Traditional DMARDs company and product profiles

Figure 23: Prograf comparative clinical profile

Figure 24: T-614 comparative clinical profile

Figure 25: Biologic DMARDs company and product comparison

Figure 26: MRA ACR responses at 12 and 16 weeks

Figure 27: MRA comparative clinical profile

Figure 28: Primary Phase IIb DANCER results for rituximab, 2005

Figure 29: Prospective MabThera, and B-cell depiction, for rituximab in RA

Figure 30: Rituximab comparative clinical profile

Figure 31: AIM and ATTAIN trial results

Figure 32: Abatacept comparative clinical profile

Figure 33: Cimzia comparative clinical profile

Figure 34: Comparison of German biologic uptake in RA, $m, 2001-04

Figure 35: AMG-714 comparative clinical profile

Figure 36: LymphoStat-B comparative clinical profile

Abstract

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