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Frontier Pharma: Innovative Licensing Opportunities in Non-Hodgkin Lymphoma

Frontier Pharma: Innovative Licensing Opportunities in Non-Hodgkin Lymphoma

Summary


Non-Hodgkin Lymphoma (NHL) can be seen as a collection of up to 60 smaller subtypes of malignant lymphoid disease, defined by distinct morphological, cytogenetic and immunophenotypic characteristics that can be broadly classified as either indolent or aggressive disease. The slow growing nature of the former means that first-line treatment for diagnosed patients can be delayed, an option not commonly recommended for aggressive disease. Across both indolent and aggressive disease, first-line chemotherapy in combination with the blockbuster drug rituxumab can induce high rates of response, and prolonged durations of remission. Despite this, indolent disease is typically incurable, with the most aggressive lymphoma subtype - diffuse large B-cell lymphoma having 5-year survival rates of ~50%. Re-treatment with chemotherapy can induce second and subsequent remissions, but most NHL patients develop chemotherapy resistant disease, for whom there are limited treatment options. Overall, in terms of numbers small molecule chemotherapeutic agents dominate the current market, with a clear need for novel targeted therapies to prolong durations of remission, and provide options for patients with chemo resistant, heavily pretreated disease.

The current developmental pipeline addresses these gaps in the market, dominated by cancer immunotherapies and inhibitors of cancer-associated signal transduction. Pathways of significant interest include B-cell receptor signaling, the PI3K/Akt/mTOR pathway, and Wnt/ß-catenin signaling, as well as oncogenes such as BCL-6 and BCL-2. Characteristic cell surface molecules that represent targets for cancer immunotherapies include CD19, LMP-1/2 and CD20, with several pipeline drugs already approved for CD20. First-in-class drug development in NHL corresponds strongly to these known somatic mutations and affected pathways. Clinical results of drugs against profiled targets in this report show many are being investigated in relapsed disease.

Scope

There are 666 marketed products for NHL, 95% of which are small molecules -

  • What are the dominant mechanisms of action across marketed products?
The treatment of lymphoma is dominated by the use of combination cyclophosphamide based chemotherapy in combination with rituximab -
  • What are these chemotherapy regimens?
  • How did they perform in key clinical trials?
The variation in molecule type has shifted away from small molecules, whose dominance has decreased to 46% across the pipeline -
  • What are the dynamics of the remaining 54% of the pipeline?
  • How does this reflect the need for novel targeted therapies?
There is a significant shift away from cytotoxic agents, with the current pipeline dominated by cancer immunotherapies and signal transduction inhibitors -
  • What is the scientific rationale behind these mechanisms of action?
  • How successful have approved targeted therapies been?
Profiled first-in-class therapies include: PIK3CA, EZH2, CD40 and MDM2 -
  • What is the scientific rationale behind these targets?
  • What preclinical and clinical results are available for drugs against these targets?
  • What is the overall opinion on these targets for drug development across NHL?
Reasons to buy

This report will allow you to -
  • Understand the current clinical and commercial landscape. This includes a comprehensive study of disease pathogenesis, diagnosis, prognosis and the available treatment options available at each stage of diagnosis.
  • Visualize the composition of the NHL market in terms of dominant molecule types and targets, highlighting what the current unmet needs are and how they can be addressed. This knowledge allows a competitive understanding of gaps in the current market.
  • Analyze the NHL pipeline, and stratify by stage of development, molecule type and molecular target. There are promising signs in focussed on the development of targeted therapies for this disease.
  • Visualize the clinical safety and efficacy of drugs against first-in-class targets via a detailed heat map, outlining the results across major clinical trial endpoints.
  • Identify commercial opportunities in the NHL deals landscape by analyzing trends in licensing and co-development deals, and those first-in-class drugs which are yet to be involved in a strategic alliance.


Non-Hodgkin Lymphoma Treatment Pipeline Shows Below Average Innovation, says GBI Research

The product pipeline for Non-Hodgkin Lymphoma (NHL) exhibits a lower degree of innovation than both the industry and oncology average, with just 28% of all pipeline products, or 33% of the pipeline for which there is a disclosed molecular target, categorized as first-in-class. This is in comparison to industry, breast cancer and lung cancer innovation rates of 43%, 57% and 59%, respectively, says business intelligence provider GBI Research.

The company’s latest report* states that while NHL, collectively, is the sixth to tenth most common cancer dependent on territory, each individual subtype is classified as an orphan disease. With significant differences in each subtype’s genetic profile and current treatment, there is reduced scope for the development of a targeted therapy with cross-subtype activity.

This does not present NHL drug development as an attractive investment in comparison to other indications in oncology, particularly as survival durations across many NHL subtypes are relatively strong, and likely the reason for low first-in-class innovation levels.

However, Katie Noon, Senior Analyst for GBI Research says that innovation is present to varying degrees across the majority of molecular target families and development stages for NHL therapeutics, rather than localized to a particular subset of therapies.

Noon says: “There is a considerable range of clinical potential across treatments with first-in-class status, particularly those restricted to the early-stage NHL pipeline. Some targets, such as spleen tyrosine kinase, boast plenty of supporting scientific and clinical evidence, while others have shown mixed results in Preclinical studies and lack clarity on their role in disease pathophysiology.”

GBI Research’s report also notes that despite the difficulty of several targeted NHL therapies in achieving improved efficacy rates, the development of such treatments remains of key interest across NHL.

Noon continues: “It is hoped that one of these many targeted therapy pipeline products will replicate the success observed with rituximab, which significantly altered the NHL treatment landscape following its approval.

“Clear gaps in the treatment algorithm include maintenance therapies to prolong initial or subsequent durations of remission, and improved therapies for relapsed patients, particularly those with a second or subsequent relapse,” the analyst concludes.

*Frontier Pharma: Innovative Licensing Opportunities in Non-Hodgkin Lymphoma

This report provides analysis of the Non-Hodgkin Lymphoma (NHL) treatment pipeline, stratified by stage of development, molecule type and molecular target. It includes information on the current clinical and commercial landscape, and the composition of the NHL therapeutics market in terms of dominant molecule types and targets, as well as highlighting current unmet needs.

This report was built using data and information sourced from proprietary databases, primary and secondary research, and in-house analysis conducted by GBI Research’s team of industry experts.

1 Table of Contents
1.1 List of Tables
1.2 List of Figures
2 Executive Summary
2.1 Development of Targeted Therapies Remains a Focus across NHL Drug Development
2.2 NHL Shows a Moderate Level of First-in-Class Innovation
2.3 High Number of First-in-Class Pipeline Drugs with No Associated Deal
3 The Case for Innovation in NHL Development
3.1 Growing Opportunities for Biological Products
3.2 Diversification of Molecular Targets
3.3 Innovative First-in-Class Product Developments Remain Attractive
3.4 Regulatory and Reimbursement Policy Shifts Favor First-in-Class Product Innovation
3.5 Sustained Innovation
3.6 Report Guidance
4 Clinical Landscape
4.1 Disease Overview
4.2 Epidemiology and Risk Factors
4.3 Symptoms
4.4 Diagnosis
4.4.1 Biopsy
4.4.2 Flow-Cytometry and Immunophenotyping
4.5 Normal B-Cell Development and NHL Classification
4.6 Pathophysiology
4.6.1 BCL2
4.6.2 BCL6
4.6.3 Wnt/β-catenin Pathway
4.6.4 BCR Pathway
4.6.5 PI3K/Akt/mTOR Pathway
4.7 Patient Prognosis
5 Overview of Marketed Products and Treatment Algorithm for NHL
5.1 Marketed Products by Molecule Type and Mechanism of Action
5.2 Treatment Algorithm
5.2.1 Clinical Trial Response Criteria in NHL
5.2.2 Indolent NHL – Follicular Lymphoma
5.2.3 Aggressive NHL
5.3 Unmet Needs
6 Assessment of Pipeline Product Innovation
6.1 Non-Hodgkin Lymphoma Pipeline by Phase and Molecule Type
6.2 Non-Hodgkin Lymphoma Pipeline by Mechanism of Action
6.3 First-in-Class Pipeline Programs Targeting Novel Molecular Targets
7 Signaling Network, Disease Causation and Innovation Alignment
7.1 The Complexity of Signaling Networks in Oncology
7.2 Signaling Pathways, Disease-Causing Mutations and First-in-Class Molecular Target Integration
7.3 First-in-Class Target Matrix Assessment
8 First-in-Class Target Evaluation
8.1 Pipeline Programs Targeting Spleen Tyrosine Kinase
8.2 Pipeline Programs Targeting PIK3CA and PIK3CB
8.3 Pipeline Programs Targeting PDPK1
8.4 Pipeline Programs Targeting EZH2
8.5 Pipeline Programs Targeting MDM2
8.6 Pipeline Programs Targeting PTPRC
8.7 Pipeline Programs Targeting CD40
8.8 Pipeline Programs Targeting IRAK4
8.9 Pipeline Programs Targeting CD22
8.10 Pipeline Programs Targeting BCL6
9 Deals and Strategic Consolidations
9.1 Industry-Wide First-in-Class Deals
9.2 Licensing Deals
9.2.1 Licensing Deals by Molecule Type
9.3 Co-development Deals
9.3.1 Molecule Type and Mechanism of Action
9.4 First-in-Class Programs not Involved in Licensing of Co-development Deals
10 Appendix
10.1 Abbreviations
10.2 Bibliography
10.3 Methodology
10.4 Secondary Research
10.5 Contact Us
10.6 Disclaimer
1.1 List of Tables
Table 1: WHO Classification of Lymphoid Neoplasms, 2008
Table 2: Key Lymphoma Subtypes, Associated Morphological Features, and Cytogenetic and Immunohistochemical Profiles
Table 3: Approximate One- and Five-Year Survival Rates of Major NHL Subtypes
Table 4: International Working Formulation (IWF) Classification System
Table 5: Ann Arbor Staging of Lymphoma and Associated Criteria
Table 6: ECOG Performance Status Grade and Criteria
Table 7: Follicular Lymphoma International Prognostic Index and International Prognostic Index, Prognostic Risk Criteria for Follicular Lymphomas and All Other Lymphomas Respectively
Table 8: Combination Therapies Used in the Treatment of FL, DLBCL and MCL, Part 1
Table 9: Combination Therapies Used in the Treatment of FL, DLBCL and MCL, Part 2
Table 10: Non-Hodgkin Lymphoma Therapeutics, Clinical Trial Endpoints and Response Criteria
Table 11: Clinical Results, R-CHOP21 versus R-CHOP14, 2004
Table 12: Effects of Selected Prognostic Factors on the Survival of Patients Treated with R-ICE and R-DHAP for Relapsed DLBCL
1.2 List of Figures
Figure 1: Innovation Trends in Product Approvals, 1987–2013
Figure 2: Sales Performance of First-in-Class and Non-First-in-Class Product Post Marketing Approval
Figure 3: Non-Hodgkin Lymphoma, Marketed Products
Figure 4: Treatment Algorithm, Follicular Lymphoma
Figure 5: Treatment Algorithm, Diffuse Large B-Cell Lymphoma
Figure 6: Clinical Trials of Intensive Chemotherapy for Newly Diagnosed Mantle Cell Lymphoma in Eligible Patients
Figure 7: Treatment Algorithm, Mantle Cell Lymphoma
Figure 8: Pipeline Overview by Stage and Molecule Type
Figure 9: Comparative Analysis of Mechanisms of Action between Pipeline and Marketed Products
Figure 10: Developmental Pipeline by Mechanism of Action
Figure 11: Molecular Target Category Comparison, Pipeline First-in-Class and Established Molecular Targets
Figure 12: Non-Hodgkin Lymphoma, Pipeline Drugs Acting Against First-in-Class Targets, Part 1
Figure 13: Non-Hodgkin Lymphoma, Pipeline Drugs acting Against First-in-Class Targets, Part 2
Figure 14: Non-Hodgkin Lymphoma, Pipeline Drugs Acting Against First-in-Class Targets, Part 3
Figure 15: Non-Hodgkin Lymphoma, Pipeline Drugs acting Against First-in-Class Targets, Part 4
Figure 16: Non-Hodgkin Lymphoma, Pipeline Drugs acting Against First-in-Class Targets, Part 5
Figure 17: Signaling Networks of Functional Families in Non-Hodgkin Lymphoma
Figure 18: Location of Key First-in-Class Targets within the Signaling Matrix
Figure 19: Target Matrix Assessment (Part 1)
Figure 20: Target Matrix Assessment (Part 2)
Figure 21: Clinical Trial Results, Drugs Targeting Spleen Tyrosine Kinase
Figure 22: Pipeline Programs Targeting Spleen Tyrosine Kinase
Figure 23: Clinical Trial Results, Drugs Targeting PIK3CA/PIK3CB
Figure 24: Pipeline Programs Targeting PIK3CA/PIK3CB
Figure 25: Pipeline Programs Targeting PDPK1
Figure 26: Clinical Trial Results, Drugs Targeting EZH2
Figure 27: Pipeline Programs Targeting EZH2
Figure 28: Clinical Trial Results, Drugs Targeting MDM2
Figure 29: Pipeline Programs Targeting MDM2
Figure 30: Clinical Trial Results, Drugs Targeting PTPRC
Figure 31: Pipeline Programs Targeting PTPRC
Figure 32: Clinical Trial Results, Drugs Targeting CD40
Figure 33: Clinical Trial Results, Drugs Targeting IRAK4
Figure 34: Pipeline Programs Targeting IRAK4
Figure 35: Clinical Trial Results, Drugs Targeting CD22
Figure 36: Pipeline Programs Targeting CD22
Figure 37: Clinical Trial Results, Drugs Targeting BCL6
Figure 38: Pipeline Programs Targeting BCL6
Figure 39: Industry-Wide Deals by Stage of Development, 2006–2014
Figure 40: Industry Licensing Deal Values by Stage of Development, 2006–2014
Figure 41: Licensing Deals, Geographic Distribution, 2006–2014
Figure 42: Licensing Deals by Year and Value ($), 2006–2014
Figure 43: Licensing Deals Analysis by Value, Stage of Development and Molecule Type, 2006–2014
Figure 44: Non-Hodgkin Lymphoma, Completed Licensing Deals, 2006–2014
Figure 45: Co-development Deals, Geographic Distribution, 2006–2014
Figure 46: Co-development Deal Value Analysis, 2006–2014
Figure 47: Co-development Deals Analysis by Value, Stage of Development and Molecule Type, 2006–2014
Figure 48: Non-Hodgkin Lymphoma Market, Completed Co-development Deals, 2006–2014
Figure 49: Non-Hodgkin Market, First-in-Class Programs with no Recorded Prior Deal Involvement, 2006–2014 101"

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