Pipeline Insight: Hematological Malignancies - Targeted Treatments and Immunotherapy Infuse New Blood

Published by: Datamonitor

Published: Apr. 20, 2005 - 219 Pages

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

About the Oncology pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

Datamonitor insight into the hematological malignancy market

R&D pipeline dynamics

Cytotoxic drugs - first-line indication for MGI Pharma/Supergen's Dacogen confers leading player designation

Immunotherapy - Chiron's low-dose Proleukin provides rebranding opportunity

Molecular-targeted treatment - J&J's Zarnestra forges the way

Millennium's paradigm-changing Velcade to have significant impact beyond myeloma

Regulatory challenges - reduced rates of accelerated approval may affect hematological malignancy drug development

Pharmacoeconomic constraints will increasingly influence up take of new agents

MTT era will necessitate an evolution in clinical trial design

CHAPTER 2 HEMATOLOGICAL MALIGNANCIES: PIPELINE OVERVIEW

Hematological malignancies are an intense focus of R&D activity with a total of 86 compounds in clinical development

Non-Hodgkin's lymphoma remains the tumor type with the greatest developmental activity

Molecular-targeted therapy (MTT) dominates the hematological malignancy pipeline

Signal transduction inhibitors dominate the molecular-targeted treatment class

Glivec: the exception rather than the rule - targeting a single molecular aberration is unlikely to be a model for success

Resistance to signal transduction inhibitors an emerging problem

Immunotherapy accounts for 29% of the pipeline and most R&D activity is focused on nonspecific immunoadjuvants

Cytotoxics still focus of development

PHASE III DEVELOPMENT IS LED BY COMPANIES WITH AN ESTABLISHED ONCOLOGY FRANCHISE

High remission rates in certain hematological malignancies confer high barriers

Key metrics

Datamonitor pipeline assessment summary

CHAPTER 3 PATIENT POTENTIAL: A DYNAMIC AND LUCRATIVE MARKET

A diverse range of disease subtypes

Genetic basis of cancer evolution

Tumorigenesis is the result of cooperative accumulated mutations

Existing pharmacotherapy approaches provide limited treatment benefit

Cytotoxic drugs lack specificity

Optimizing current treatment strategies is paramount

The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy

Dynamic cancer market offers significant commercial opportunity

Ongoing sales growth drives the market

Intensive R&D produces a rich developmental pipeline

Growing patient population and significant unmet needs propel innovation in the cancer market

Cancer epidemiology - an expanding patient base

Significant areas of unmet need persist

Clinical and strategic threats to the commercialization of cancer drugs

Progressively rising R&D costs threaten industry productivity

High attrition rates can be mitigated by improved strategic decision-making

Lengthening drug approval process a consequence of increased regulatory demands

Pharmacoeconomic pressures drive payers to implement restrictive pricing and reimbursement policies

Increased therapeutic and generic competition results in reduced periods of market exclusivity

Segmentation of market will require changes in clinical trial methodology

CHAPTER 4 R&D APPROACH

Classification of pipeline products

Cytotoxics drugs

Molecular-targeted therapies (MTTs)

Few pipeline MTTs meet the criteria suggested by some investigators in defining this drug class

Development of targeted therapies relies on identification of biologic drivers of oncogenesis

Signal transduction inhibitors

Angiogenesis inhibitors

Apoptosis inducers

Cell cycle inhibitors

Immunotherapy-based treatments

Miscellaneous agents

Evolution in oncology clinical trial design

Patient selection is increasingly significant in the era of targeted treatment

Clinical trials must have sufficient follow-up to establish true clinical benefit

Diversity of targeted treatments will require an evolution in clinical trial design

Most oncology clinical trials designate multiple endpoints

Survival

Quality of life

Tumor response rates

Toxicity

Time to tumor progression

Modification of accelerated approval process may impact significantly on approval times for hematologic oncology drugs

CHAPTER 5 CYTOTOXICS - FIRST-LINE INDICATION FOR MGI PHARMA/SUPERGEN'S DACOGEN CONFERS LEADING PLAYER DESIGNATION

Bendamustine (SDX-105), Salmedix

Bendamustine demonstrates promising single-agent activity in refractory and relapsed indolent NHL

Synergy of bendamustine and rituximab without excessive toxicity

Bendamustine/mitoxantrone/rituximab (BMR) combination, active in refractory and relapsed indolent lymphoma

Activity in broad spectrum of the hematological malignancies affords expanded commercial opportunity

Bendamustine's established safety profile will facilitate regulatory approval

Nelarabine, GlaxoSmithKline

Nelarabine demonstrates activity in aggressive, treatment-resistant pediatric patients with T-ALL

Nelarabine fails to exhibit the same efficacy in adults

Nelarabine hindered by limited patient population

Decitabine, MGI Pharma/Supergen

Decitabine demonstrates significant improvements in time to AML or death compared to best supportive care in patients with MDS

Decitabine as a potential treatment for Glivec-resistant/refractory CML

Enhanced understanding of molecular biology generates renewed interest in DNA demethylators

Pixantrone, Cell Therapeutics

Pixantrone demonstrates promising single agent activity

Successful results from a randomized Phase III trial of CPOP versus CHOP will drive uptake

Pixantrone would benefit from co-licensing agreement with Roche

Pixantrone, high commercial potential if problems associated with genericization can be overcome

Cloretazine (VNP-40101M), Vion Pharmaceuticals

Leukemia and MDS are the focus of ongoing development

Development of fast-tracked Cloretazine recently progressed to Phase III trials

Phase II trials displayed encouraging results among patients with limited treatment options

Significant opportunity for Vion Pharmaceuticals

Cytotoxic sales forecasts to 2014

Datamonitor drug assessment summary

CHAPTER 6 IMMUNOTHERAPY - CHIRON'S LOW-DOSE PROLEUKIN PROVIDES REBRANDING OPPORTUNITY

Ceplene (histamine dihydrochloride, subcutaneous), Maxim Pharmaceuticals

Ceplene improves leukemia-free survival but not overall survival in adult AML patients in first remission

FDA requests additional Phase III trial despite primary endpoints being met

Maxim will need to form a strategic alliance to ensure Ceplene's commercialization

Proleukin (aldesleukin), Chiron

Phase II trials demonstrate that Proleukin augments rituximab activity in NHL

Low-dose approach is the key to success

Chiron's long-standing association with IL-2 will facilitate Proleukin uptake following approval of expanded indication

Revlimid (lenalidomide), Celgene

Revlimid achieves significant improvements in time to progression in previously treated multiple myeloma patients

Phase II trial demonstrates 85% response rate in newly diagnosed multiple myeloma patients

Celgene anticipate initiating a Phase III trial examining Revlimid in MDS

Phase II trials demonstrate Revlimid therapy facilitates transfusion independence in MDS patients

Revlimid is most active in early-stage MDS

Celgene's developmental strategy promises significant commercial potential

Radioimmunotherapy (RIT) - extending the spectrum of indications beyond indolent NHL

Dual mechanism of action enhances activity the radioimmunoconjugates (RICs)

RICs are associated with a logistically complex administration schedule

Radioisotope differences favor Biogen Idec's Zevalin

Horizontal product expansion key to optimizing commercial value

Opinion leaders remain divided about RICs' potential utility in DLBCL

RICs have demonstrated promising single-agent activity in MCL

Bexxar versus Zevalin: who will be the major player?

Immunotherapy sales forecasts to 2014

Datamonitor drug assessment summary

CHAPTER 7 MOLECULAR-TARGETED TREATMENT - J&J'S ZARNESTRA FORGES THE WAY

Temsirolimus (CCI-779), Wyeth Research

Temsirolimus demonstrates significant antitumor activity in relapsed mantle cell lymphoma (MCL) in Phase II trial

Phase III trials of temsirolimus may need to evaluate lower doses.

Phase II trial suggests temsirolimus may have activity in ALL.

Novelty of target and competition from Millennium's Velcade will challenge commercial potential

Wyeth has the experience to launch novel oncology products successfully

Tipifarnib (R-115777; Zarnesta), Janssen Pharmaceutica BV and Johnson & Johnson

Tipifarnib demonstrates activity in poor risk, previously untreated elderly AML

Molecular markers predict tipifarnib response in AML

Phase II trials suggest activity in MDS with limited toxicity

Tipifarnib most advanced farnesyl transferase inhibitor (FTI) in clinical development.

J&J's global marketing and distribution presence will facilitate tipifarnib uptake

Focus on gene expression profiling may lead to fragmentation of market

First-to-market designation doesn't guarantee commercial success

Arsenic trioxide (Trisenox), CTI

Arsenic trioxide demonstrates activity in drug-resistant multiple myeloma

Arsenic trioxide demonstrates synergy with ascorbic acid and dexamethasone.

CTI-sponsored Phase III development for myeloma unlikely

Arsenic trioxide is active in both high- and low-risk MDS

Competitive landscape means that arsenic trioxide is unlikely to make a significant impact in the MDS market

Arsenic trioxide will benefit from patent extension

Arsenic trioxide will most likely be used in combination with other therapies

Innovative early-stage MTTs

BMS-354825, Bristol-Myers Squibb

BMS-354825 overcomes Glivec resistance in chronic phase CML patients

BMS-354825 already faces potential competition from Novartis's AMN107

Sorafenib (BAY 43-9006), Onyx and Bayer

Multi-targeted approach makes sorafenib an attractive proposition

Phase I trials demonstrate limited anti-leukemic activity

Combinatorial treatment approaches are likely to be the key to success

Flt-3 inhibition offers a lucrative new target

Cephalon's Lestaurtinib demonstrates activity in preliminary Phase II AML trials

Lestaurtinib represents the first generation of a of a new class of agents

Cephalon's limited commercial experience will require augmenting

Avastin, Genentech/Roche

Combining Avastin with R-CHOP does not significantly increase toxicity

Avastin's first-to-market status provides Genentech/Roche with valuable head start

Genentech/Roche's established oncology franchise will help drive sales in what will be a competitive antiangiogenic market

Suberanilohydroxyamic acid (SAHA), Merck & Co.

Histone deacetylation plays a pivotal role in transcriptional regulation

Phase I study demonstrates differences in DLTs between IV and oral formulations

Phase II trial demonstrates promising activity in cutaneous T-cell lymphoma (CTCL)

Commercial opportunity offered by CTCL indication is weak

MTT sales forecasts to 2014

Datamonitor drug assessment summary

CHAPTER 8 ALTERNATE INNOVATIVE PROJECTS - MILLENIUM'S PARADIGM-CHANGING VELCADE TO HAVE SIGNIFICANT IMPACT BEYOND MYELOMA

Velcade (bortezomib), Millennium Pharmaceuticals

Potential clinical utility of Velcade in indolent NHL

Velcade demonstrates particularly promising activity in MCL

Millennium will need to define how this novel technology should be integrated into conventional NHL treatment paradigms

Parentin, Ligand Pharmaceuticals

Development of Ligand Pharmaceuticals' Parentin capsules (alitretinoin) for the treatment of hematological malignancies appears to have stalled

Promising early-stage results in APL but despite initiation of a Phase III trial no results have been forthcoming

Suboptimal treatment tolerability limits development for MDS

APPENDIX A

Report methodology

Datamonitor forecast methodology

Datamonitor drug assessment summary

List of tables

List of figures

List of abbreviations

APPENDIX B

Opinion leader interview transcripts

Contributing experts

Opinion leader 1

Opinion leader 2

Opinion leader 3

Opinion leader 4

APPENDIX C

Bibliography

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

About the Oncology analysis team

Disclaimer

List of Tables

Table 1: Drugs in development for the treatment of hematological malignancies, 2005

Table 2: Developmental pipeline of drugs targeting hematological malignancies by phase and class, 2005

Table 3: Forecast incidence of hematological malignancies in the seven major pharmaceutical markets, 2004-14

Table 4: Late-phase pipeline malignant hematology sales forecasts ($m), 2005-14

Table 5: Datamonitor drug assessment summary

Table 6: Common mutations involved in tumor development

Table 7: Forecast incidence of hematological malignancies in the seven major pharmaceutical markets, 2004-14

Table 8: FDA approval information for drugs used to treat hematologic malignancies

Table 9: Pipeline cytotoxic drugs for hematological malignancies, 2005

Table 10: Single-agent bendamustine demonstrates acceptable hematological toxicity and moderate non-hematological toxicity

Table 11: Nelarabine is active in aggressive, refractory childhood T-ALL

Table 12: Nelarabine in adult CTCL and PTCL demonstrated low efficacy

Table 13: Nelarabine trial in adult CTCL and PTCL was halted due to unacceptable toxicity

Table 14: Comparison between Vidaza and Dacogen

Table 15: Replacing doxorubicin with pixantrone in CHOP regime has tolerable toxicity profile

Table 16: Ongoing clinical trials exploring Cloretazine in hematological malignancies

Table 17: Cytotoxic drugs sales forecast assumptions

Table 18: Cytotoxic drugs sales forecasts, 2005-14

Table 19: Research, clinical and commercial attractiveness summary for pipeline cytotoxic drugs

Table 20: Immunotherapy drugs in development for hematological malignancies

Table 21: Proleukin augments rituximab activity in rituximab-resistant NHL, Phase II trial results

Table 22: Phase II trial results of Revlimid in patients with refractory multiple myeloma

Table 23: Ongoing clinical trials exploring Revlimid in hematological malignancy

Table 24: Comparison of radioisotopes in Bexxar and Zevalin

Table 25: Ongoing studies evaluating RICs

Table 26: Immunotherapy sales forecasts assumptions

Table 27: Immunotherapy drugs sales forecasts, 2005-14

Table 28: Research, clinical and commercial attractiveness summary for pipeline immunotherapy drugs

Table 29: MTTS drugs in development for hematological malignancies

Table 30: Phase II trial results of temsirolimus in refractory mantle cell lymphoma

Table 31: Ongoing Phase II and Phase I trials for temsirolimus

Table 32: Phase I/II/III trials of tipifarnib in hematological malignancies

Table 33: Toxicities associated with tipifarnib in high-risk MDS patients

Table 34: Phase II drug regime of multiple myeloma patients receiving arsenic trioxide, ascorbic acid and dexamethasone

Table 35: Phase I/II/III/IV trials of arsenic trioxide in hematological malignancies

Table 36: Phase II trials of Avastin in AML and NHL

Table 37: MTT sales forecasts assumptions

Table 38: MTT sales forecasts, 2004-15

Table 39: Research, clinical and commercial attractiveness summary for pipeline MTT drugs

Table 40: Alternative innovative drugs in clinical development for the treatment of hematological malignancies

Table 41: Phase II study of Velcade in NHL: Owen et al., 2003

Table 42: Phase II study of Velcade in NHL: Goy et al., 2003

Table 43: Ongoing and planned trials of Velcade in hematological malignancies

Table 44: Datamonitor drug assessment parameters

Table 45: Abbreviations used in PI: Hematological Malignancies

List of Figures

Figure 1: Number of compounds in clinical development for hematological malignancies, 2005

Figure 2: Number of compounds in clinical development by drug class, 2005

Figure 3: Molecular-targeted treatment dominates the hematological malignancy pipeline

Figure 4: Signal transduction inhibitors dominate the MTT class

Figure 5: Non-specific immunoadjuvants dominate immunotherapy class

Figure 6: Topoisomerase inhibitors dominate the cytotoxic pipeline

Figure 7: Phase III development is dominated by companies with an existing oncology franchise

Figure 8: Phase II development reflects a more heterogeneous mix of company profiles

Figure 9: Cytotoxics for hematological malignancies sales forecasts, 2005-14

Figure 10: Molecular-targeted agents for hematological malignancies sales forecasts, 2005-14

Figure 11: Immunotherapy agents for hematological malignancies sales forecasts, 2005-14

Figure 12: Datamonitor drug assessment summary for pipeline cytotoxics in development for malignant hematology

Figure 13: Drug assessment summary for the late-phase immunotherapy drugs

Figure 14: Datamonitor's drug assessment summary for the late-phase pipeline MTT drugs

Figure 15: Future focus the challenges

Figure 16: Forecasted global oncology sales, 2002-09

Figure 17: Oncology pipeline, 2003

Figure 18: Forecast incidence of hematological malignancies across the seven major markets, 2004-14

Figure 19: Increasing combined incidence of leukemia, lymphoma and myeloma with increasing age, 2004

Figure 20: Incidence increases, while the rate of cure and death reduces disease prevalence

Figure 21: Disparity in relative point prevalence compared to incidence for leukemia and lymphoma, 2004

Figure 22: Unmet needs in cancer, 2005

Figure 23: Kaplan-Meier estimates of disease-free survival with bendamustine and rituximab in indolent and mantle cell lymphoma

Figure 24: Bendamustine versus chlorambucil in treatment-naïve B-CLL patients, Phase III trial design

Figure 25: Over half of treatment-resistant pediatric patients with T-ALL exhibited a response to nelarabine

Figure 26: Phase III trial of decitabine in MDS patients demonstrates significant

Figure 27: Cytotoxic drugs sales forecasts, 2005-14

Figure 28: Drug assessment summary for the late-phase pipeline cytotoxic drugs.

Figure 29: Phase III PEaRL trial design

Figure 30: Immunotherapy drugs sales forecasts, 2005-14

Figure 31: Drug assessment summary for the late-phase immunotherapy drugs

Figure 32: MTT sales forecasts, 2004-15

Figure 33: Datamonitor's drug assessment summary for the late-phase pipeline MTT drugs

Figure 34: Example of Datamonitor drug assessment scorecard

Figure 35: Example of Datamonitor drug assessment graph

Abstract

• Overview of hematological malignancy market including patient segmentation, unmet needs and how novel therapies will alter existing treatment patterns
• Profiles of key agents in late stage development including cytotoxics, immunotherapies and targeted treatments
• Analysis of trial data, marketing factors and sales forecasts for key technologies in late-stage clinical development
• Clinical, regulatory and pharmacoeconomic challenges and strategies for commercialization

• Understand unmet needs in the hematological malignancy market based on opinion leader comments regarding both currently marketed and pipeline products
• Gain a greater understanding how future economic and regulatory constraints may affect approval for hematological malignancy drugs
• Assess the global sales forecasts of late-stage pipeline drugs for hematological malignancies and examine their clinical and commercial potential

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