Pipeline Insight: Osteoarthritis - The Wait for a DMOAD Continues

Published by: Datamonitor

Published: Nov. 15, 2006

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

About the CNS, Arthritis and Pain pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

Scope of the analysis

Datamonitor insight into the osteoarthritis market

Summary

Key metrics

Datamonitor pipeline assessment summary

CHAPTER 2 PATIENT POTENTIAL

Definition of osteoarthritis

Segmentation of osteoarthritis

Primary (idiopathic) osteoarthritis

Secondary osteoarthritis

Epidemiology of osteoarthritis

Country calculations

OA affects 11% of the adult US population

OA will be a growing problem as the elderly European population increases

OA of the knee affects 70% of the Japanese OA population

Unmet need in OA

Disease modification is the key unmet need in OA

OA drugs require a reduced side effect profile

Quality of life and patient education should be addressed for all treatments

OA awareness and perception in society requires improvement

Emerging imaging and biomarker research will impact both on diagnosis and trial endpoints

CHAPTER 3 R&D APPROACH

Classification of marketed and pipeline OA drugs

Non-steroidal anti-inflammatory drugs (NSAID)

Disease modifiers (DM)

DMOADs

Growth factors and hormones

Cell therapy and gene therapy

Analgesics

Corticosteroids (CS)

Hyaluronic acids (HA)

Nutriceuticals

Clinical trial design in osteoarthritis

Comparator Drugs

The choice of comparator drug is vital to ensure OA trial reliability

The FDA requires the use of naproxen as the comparator drug in long-term safety studies in OA

Clinical trial endpoints in OA

Pain scale endpoints

Western Ontario and McMaster Osteoarthritis (WOMAC) Index remains the most widely used clinical trial endpoint

Australian/Canadian (AUSCAN) Index is used specifically in clinical trials of hand OA

Lequesne's Algofunctional Indices

OARSI/OMERACT Response Criteria aim to improve responder criteria in clinical trials but needs better validation

Disease modification endpoints

Radiography remains the most widely used endpoint in DMOAD trials but accuracy is questionable

Magnetic Resonance Imaging is a powerful but costly tool for monitoring disease progression in articular joints

Biomarkers are still under investigation and require further validation

Other endpoints

Anti-Platelet Trialists' Collaboration (APTC) is a useful endpoint to assess the CV risk of COX-2s

CHAPTER 4 OSTEOARTHRITIS PIPELINE ANALYSIS

Pipeline overview

Pre-registration

Phase III

Phase II

Key companies involved in the osteoarthritis pipeline

Pfizer dominates the OA market with Celebrex, but will it be first to market with a DMOAD?

Celebrex is the market leading COX-2 inhibitor and has achieved blockbuster status

Pfizer has two DMOAD candidates in Phase II development

Pfizer buys Rinat Neuroscience to extend neuroscience research and in doing so acquires a product candidate for OA

NicOx expects naproxcinod to compete with COX-2 inhibitors

NicOx has developed clear strategies for success

Overview of strategies for success

CHAPTER 5 NSAID LATE-STAGE DRUG ANALYSIS & FORECASTS

Overview for NSAIDs

Pipeline summary

Definition of current NSAID comparator therapy

Lumiracoxib

Drug overview

Clinical trial data

Study 1

Study 2

Study 3

Patient potential

Prexige will be an attractive treatment option for OA, and has been shown to be as safe as ibuprofen and naproxen

Marketing factors

Novartis is in a good position to market Prexige with strong safety data and significant market experience

Satisfaction of unmet needs

The FDA has concluded that Prexige carries only a moderate CV risk, similar to Pfizer's Celebrex

Forecasts to 2015

Etoricoxib

Drug overview

Clinical trial data

Study 1

Study 2

Study 3

Patient potential

Merck is enrolling unprecedented numbers of OA patients on the MEDAL trial to investigate the CV safety of Arcoxia

Arcoxia has a limited patient potential, however, there is a possibility that a niche market for Arcoxia exists in patients who found relief from Vioxx

Marketing factors

It would be inadvisable for Merck to market Arcoxia in a similar fashion as seen previously with Vioxx

Satisfaction of unmet needs

Arcoxia carries a high cardiac risk and the EMEA recommends that Arcoxia be contra-indicated in patients with hypertension

Forecasts to 2015

Naproxcinod (AZD3582)

Drug overview

Clinical trial data

Study 1

Study 2

Study 3

Patient potential

Naproxcinod will gain from the anxieties that surround the COX-2s

Marketing factors

NicOx needs to secure a marketing partner for naproxcinod

Satisfaction of unmet needs

Naproxcinod has an improved safety profile over other NSAIDs and COX-2s

Naproxcinod may have a niche market in OA patients with hypertension and increased CV risk

Forecasts to 2015

Licofelone

Drug overview

Clinical trial data

Study 1

Study 2

Patient potential

Licofelone has similar efficacy to NSAIDs and COX-2s but its long-term safety still needs to be assessed

Marketing factors

EuroAlliance need to secure a new global marketing agreement to ensure the success of licofelone

Satisfaction of unmet needs

Hepatic tolerability could help differentiate Licofelone from Celebrex

Forecasts to 2015

IDEA-033

Drug overview

Clinical trial data

Study 1

Study 2

Patient potential

Topical IDEA-033 could be a safe and effective alternative to oral NSAIDs and COX-2s

Marketing factors

Idea Therapeutics lacks experience of the OA market and requires a marketing partner

Satisfaction of unmet needs

IDEA-033 has a reduced potential for side effects because of low systemic concentrations of ketoprofen

Forecasts to 2015

GW-406381

Drug overview

Clinical trial data

Study 1

Patient potential

As measured by WOMAC subscore, GW-406381 is more effective than Celebrex at improving pain in OA

Marketing factors

GW-406381 has a similar effect on blood pressure as Celebrex

Satisfaction of unmet needs

The commercial attractiveness of GW-406381 will be significantly reduced because it will have fourth to market status

Forecasts to 2015

LAS-34475

Drug overview

Clinical trial data

Study 1

Patient potential

The patient potential for LAS-34475 will not be as great as the potential seen with previous COX-2 inhibitors

Marketing factors

LAS-34475 will benefit from Almirall's previous experience of the OA market

Satisfaction of unmet needs

LAS-34475 requires a long-term safety study

Fifth to market status will damage LAS-34475's commercial attractiveness

Forecasts to 2015

Other late stage NSAIDs

Efipladib

Phospholipase inhibitors are not specific and would be more interesting in truly inflammatory arthritis

PN 100

Combination therapies, such as PN 100, ensure patient compliance

SFPP

Mitsubishi Pharmaceuticals pulls out of SFPP development

Late-stage development compounds recently discontinued

Tilmacoxib

AZD-9056

CHAPTER 6 DISEASE MODIFIER LATE-STAGE DRUG ANALYSIS

Overview for disease modifiers

Definition of current comparator therapy

ChondroCelect

Overview

ChondroCelect is a cell therapy for the treatment of cartilage damage in OA

ChondroCelect began the TiGenix Phase III clinical trial (TIGACT-01) in 2005

Salmon Calcitonin

Drug overview

Salmon calcitonin could prevent the enhanced turnover of bone that is associated with OA progression but osteoporosis appears to be the primary indication

Salmon calcitonin has a good safety profile and is not carcinogenic

Clinical trial data

Doxycycline

Drug overview

Clinical trial data

Other disease modifiers

Anakinra

Anakinra improves WOMAC pain subscore but the improvement is not statistically significant

Adalimumab

Pilot studies at Universities are underway for Humira in OA

SD-6010

Pfizer sees iNOS as a potential therapeutic target

CP-544439

Pfizer's CP-544439 specifically targets MMP-13

AZD-8955

CPA-926

Late-stage development compounds recently discontinued

Pralnacasan

AMG-108

S-3536

ONO-4817

ICE Inhibitors

AD-729

CHAPTER 7 ANALGESICS LATE-STAGE DRUG ANALYSIS & FORECASTS

Overview for analgesics

Pipeline summary

Current comparator therapy: Acetaminophen

Zucapsaicin

Drug overview

Clinical trial data

Patient potential

Zucapsaicin will be limited to OA patients who do not tolerate or whose pain is not controlled by NSAIDs or COX-2s

Marketing factors

Winston Laboratories does not have experience in the OA market and requires a partner for zucapsaicin

Satisfaction of unmet needs

The future long-term safety trial for zucapsaicin will help clarify a reduced side effect profile

Forecasts to 2015

Other analgesic drugs

AT-1022

AT-1022 is a hydromorphone patch that has been specifically designed to provide sustained levels of analgesia

RN-624

RN-624 is a first in class biologic therapy for the treatment of the pain associated with OA

Clinical trial data

Bicifadine

With sustained release bicifadine, OA patients will experience less frequent daily dosing and an increased tolerability of the drug

Clinical trial data

MK-0686

Merck has not disclosed the mode of action of MK-0686

Icatibant

Icatibant is a selective bradykinin B2 receptor antagonist

CHAPTER 8 CORTICOSTEROID LATE-STAGE DRUG ANALYSIS & FORECASTS

Overview for corticosteroids

Definition of current comparator therapy

CRx-102

Drug overview

Clinical trial data

Study 1

Patient potential

CRx-102 will have a greater patient potential than the gold standard corticosteroid prednisolone

Marketing factors

CombinatoRx has collaborations and agreements with pharmaceutical companies for some of its product candidates but requires a partner for CRx-102

Satisfaction of unmet needs

CRx-102 is a well tolerated drug, which has a reduced side effect profile

Forecasts to 2015

CHAPTER 9 INNOVATIVE EARLY-STAGE PROJECTS

Overview for innovative early-stage projects

Phase I

Preclinical

MMP inhibitors

MMP-1 and MMP-13 are key targets for future OA therapies

Most early-stage DMOADs are directed against MMPs but side effects are an issue

Tumor necrosis factor and Interleukin-1

TNF-alpha and IL-1 antagonists offer promise but problems such as short half life remain an issue

Cathepsin K inhibitors

Cathepsin K inhibitors are being developed by GSK and Medivir

Bone modulators

Preventing the loss of bone in OA could slow or stop disease progression

c-fms inhibitors

GSK is looking to treat OA by inhibiting inflammatory cells

Botox

Intra-articular Botox injections might provide pain relief in OA but unwanted effects on surrounding muscle might become evident

NFKappaB modulators and IKK beta inhibitors

Therapies targeting gene transcription raise concerns over potential side effects

Key research impacts on osteoarthritis

APPENDIX A

Methodology

Datamonitor forecast methodology

ICD10 code definition of OA indication

Product forecasts

Definition of a standard unit

Contributing experts

Bibliography

Websites

Datamonitor reports

Report methodology

APPENDIX B

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: Estimated adult OA populations in the seven major markets, by age group, 2006 (000s)

Table 2: OA sufferers who present with the disease in specific parts of the body (%): US, Japan and 5EU markets, 2003

Table 3: US OA patient population by age group and gender, 2006 (000s)

Table 4: Breakdown of arthritis population from NHIS survey and estimated OA percentages, 2003

Table 5: Adult OA population in five major EU countries, by age and gender, 2006 (000s)

Table 6: Combined sample of northern England studies, radiographic knee OA by age and gender

Table 7: Estimated symptomatic knee OA prevalence: UK adults

Table 8: Spanish EPISER study showing breakdown of hand and knee OA by age group, 2001

Table 9: Adult OA population (000s) in Japan, by age and gender, 2006

Table 10: GAIT study response rates by treatment group and pain level, 2005, %

Table 11: Baseline Lequesne and WOMAC, with 6-month ITT changes and % of OARSI-A responders in the GUIDE study

Table 12: Biomarkers in OA

Table 13: Pipeline drugs in pre-registration development for OA, 2006

Table 14: Pipeline drugs in Phase III development for OA, 2006

Table 15: Pipeline drugs in Phase II development for OA, 2006

Table 16: Number of key OA therapies by class and phase of development, 2006

Table 17: Pipeline OA therapies by mode of delivery, 2006

Table 18: NicOx R&D pipeline, 2006

Table 19: Key NSAIDs in late-stage R&D pipeline for OA, 2006

Table 20: Aleve's key facts, 2006

Table 21: Lumiracoxib TARGET study: summarized GI safety results

Table 22: Lumiracoxib TARGET study: summarized CV safety results,

Table 23: Lumiracoxib vs celecoxib: WOMAC total score.

Table 24: Lumiracoxib vs celecoxib: VAS total score.

Table 25: Factors having an impact on Prexige's sales revenue across the seven major markets, 2006-15

Table 26: Cost per standard unit for COX-2s in the UK

Table 27: Factors having an impact on Arcoxia's revenue 2006-15

Table 28: Difference between groups in the change in WOMAC pain subscale score (mm) from baseline to the mean of weeks 4 and 6.

Table 29: Factors having an impact on naproxcinod's revenue from launch-2015

Table 30: Change from baseline in liver enzyme levels at week 12 for licofelone and celecoxib

Table 31: Factors having an impact on licofelone's revenue from launch-2015

Table 32: Factors impacting IDEA-033's revenue from launch-2015

Table 33: GW-406381 vs celecoxib: Effect on systolic blood pressure

Table 34: Factors having an impact on GW-406381's revenue from launch-2015

Table 35: LAS-34475: OARSI criteria results, EULAR 2003

Table 36: Factors having an impact on LAS-34475's revenue from launch-2015

Table 37: Discontinued R&D projects in NSAIDs, 2003-06

Table 38: Key disease modifiers in late-stage R&D pipeline for OA, 2006

Table 39: Results of a Phase II efficacy trial for oral salmon calcitonin

Table 40: Results of doxycycline vs placebo on JSN

Table 41: Discontinued R&D projects in DMOADs, 2003-06

Table 42: Key analgesics in late-stage R&D pipeline for OA, 2006

Table 43: Factors having an impact on zucapsaicin's revenue from launch-2015

Table 44: RN-624: Results of Phase I study

Table 45: Key products in late-stage R&D pipeline for corticosteroids, 2006

Table 46: CRx-102: Phase II clinical trial results, 2006

Table 47: Factors having an impact on CRx-102's revenue from launch-2015

Table 48: Phase I and preclinical molecular targets for disease modifying therapies, 2006

Table 49: Pipeline drugs in Phase I development for OA, 2006

Table 50: Pipeline drugs in preclinical development for OA, 2006

Table 51: Datamonitor's definition of OA market by ICD10 code

Table 52: Datamonitor's forecast OA revenues of pipeline drugs across the seven major markets ($m)

Table 53: Calculation of the $/SU of Celebrex and Arcoxia for Japan based on average historic sales in Pacific Rim from 2002 - 2005

List of Figures

Figure 1: The OA market, 2006-2015

Figure 2: Comparative sales revenue for key OA pipeline products in the seven major markets, US$, m, 2006-2015

Figure 3: Drug OA drug assessment summary

Figure 4: Adult (15+) OA population in the seven major markets, 2006

Figure 5: Adult OA population, five major EU countries, by age group, 2006

Figure 6: Key unmet needs in OA, 2006

Figure 7: Number of key OA therapies by class and phase of development, 2006

Figure 8: Pfizer's therapeutic focus, 2005

Figure 9: Total vs OA-specific historical sales of Celebrex in the US

Figure 10: Total historic sales and OA-specific sales of Bayer's Aleve in the US, 2002 - 2005

Figure 11: Datamonitor's competitive positioning analysis of Prexige for OA, 2006

Figure 12: Comparison of IC50s of NSAIDs and COX-2 inhibitor

Figure 13: Datamonitor's forecast of OA sales for Prexige across the seven major markets (US$m), 2006-2015

Figure 14: Datamonitor's competitive positioning analysis of Arcoxia for OA, 2006

Figure 15: Datamonitor's forecast of OA sales for Arcoxia across the seven major markets (US$m), 2006-2015

Figure 16: Datamonitor's competitive positioning analysis of naproxcinod for OA, 2006

Figure 17: Datamonitor's forecast of OA sales for naproxcinod across the seven major markets (US$m), 2006-2015

Figure 18: Datamonitor's competitive positioning analysis of licofelone for OA, 2006

Figure 19: Datamonitor's forecast of OA sales for licofelone across the seven major markets (US$m), 2006-2015

Figure 20: Datamonitor's competitive positioning analysis of IDEA-033 for OA, 2006

Figure 21: Datamonitor's forecast of OA sales for IDEA-033 across the seven major markets (US$m), 2006-2015

Figure 22: GW-406381: Phase II study design

Figure 23: GW-406381: Improvement in WOMAC subscore

Figure 24: Datamonitor's competitive positioning analysis of GW-406381 for OA, 2006

Figure 25: Datamonitor's forecast of OA sales for GW-406381 across the seven major markets (US$m), 2006-2015

Figure 26: Datamonitor's competitive positioning analysis of LAS-34475 for OA, 2006

Figure 27: Datamonitor's forecast of OA sales for LAS-34475 across the seven major markets (US$m), 2006-2015

Figure 28: Datamonitor's competitive positioning analysis of zucapsaicin for OA, 2006

Figure 29: Datamonitor's forecast of OA sales for zucapsaicin across the seven major markets (US$m), 2006-2015

Figure 30: CRx-102: Primary endpoint results for Phase II study

Figure 31: Datamonitor's competitive positioning analysis of CRx-102 for OA, 2006

Figure 32: Datamonitor's forecast of OA sales for CRx-102 across the seven major markets (US$m), 2006-2015

Abstract

Osteoarthritis (OA) is characterized by the progressive destruction of articular joints and is a major cause of pain in Western populations. Osteoarthritis is the most common form of arthritis and severely impacts the physical function and day-to-day quality of life of an individual. It also impacts heavily on the economy and it is believed to cost the US alone an estimated $60 billion per year.

• Detailed pipeline analysis of the key osteoarthritis products in development, plus indication-specific drug sales forecasts to 2015
• Competitive drug analysis of the late-phase osteoarthritis pipeline, based on clinical and commercial attractiveness
• Overview of patient potential and unmet needs in osteoarthritis across the US, 5EU and Japanese markets
• Identification of licensing opportunities based on company portfolios and market needs

The key unmet need in osteoarthritis is disease modification. The early-phase pipeline is dominated by disease-modifying OA drugs (DMOADs), clearly indicating the future direction of the market. With the first DMOAD to market likely to reach blockbuster status, companies should strengthen their R&D potential by focusing efforts on DMOAD research.

The issue of cardiovascular safety remains at the forefront of the COX-2 and traditional NSAID classes. As evidenced by Prexige (lumiracoxib) and Arcoxia (etoricoxib), appropriately designed, large-scale safety studies will be crucial if any COX-2s are to be approved by the FDA and EMEA. Prexige and Arcoxia remain in pre-registration in the US.

Over the next ten years a number of COX-2 inhibitors as well as NSAIDs and corticosteroids, some with novel mechanisms of action and reportedly improved side effect profiles, will enter the market. Success will depend on effective but restrained marketing, product differentiation and strategic out-licensing arrangements.

• Explore the potential of COX-2s such as Novartis' Prexige and Merck's Arcoxia in the osteoarthritis indication
• Quantify the future size of and market potential for novel treatments in the osteoarthritis indication
• Identify who the key players in the osteoarthritis market will be as well as understanding gaps in the market for potential products

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