Multi-Targeted Therapies
New Wave of Combination Therapies in Late Stage Development for Lung
Cancer Offer Promise
GBI Research Report Guidance
GBI Research Report Guidance
· Section two gives a general introduction to multi-targeted therapies, the rationale behind them and
the range of therapies available.
· Section three provides a summarizing overview of the design of multi-target drugs.
· Section four provides an overview of the design of combination therapies and the regulatory
environment surrounding them.
· The last section includes an analysis of combination therapies in the developmental pipeline for
oncology. Analysis provides an overview of the distribution of combination therapies across major
oncology indications and the most common types of drug combination found in each. Promising
compounds found in each indication are also discussed.
© GBI Research. This is a licensed product and is not to be photocopied GBIHC229MR / Published JUL 2012
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Executive Summary
The FDA has released draft Executive Summary
guidance and A Multi-Target Approach is Needed to Combat Complex Diseases like Cancer
recommendations on how to
develop these combinations Cancers are dependent on many altered molecular pathways and networks which pose challenges to the
of drugs. efficacy of single-agent therapies and can enable biological systems to effectively compensate for the
therapies’ action. Even without these buffering effects, most single-target drugs cannot fully rectify a
complex and multifactorial disease condition such as cancer. Even when a monotherapy is able to produce
an objective response, this is relatively short-lived, due to mutations in drug targets leading to resistance.
For this reason, multi-targeted drugs and combination therapies could be better suited to providing long-
term treatment in patients.
In Silico Approaches to Multi-Target Drug Discovery
Due to technological advances, there are now much more biological and chemical data available on ligands
and targets. Computational methods have been widely explored to deal with the wealth of bioactivity
information available and facilitate lead discovery. In silico methods are being used to identify and design
multi-target compounds. Despite the promising potential of these methods, there are also limitations to
these methods, such as access to drug data.
Regulatory Concerns for Novel Drug Combinations
A major concern regarding the co-development of novel drugs is that the process will provide less
information about the safety and effectiveness of these agents than if each were developed and tested
individually. The FDA has released draft guidance and recommendations on how to develop these
combinations of drugs. They propose that drugs should only be developed in combination when there is a
compelling biological rationale for the use of the combination, or where the drugs cannot be developed
individually, for example if this would lead to drug resistance. Combinations also need to be shown in
preliminary clinical studies to provide greater-than-additive activity or a more durable response compared
to using the agents alone.
Pipeline Analysis Reveals that Lung Cancer has the Most Drug Combinations in Phase III
Combination Therapies in Oncology, Phase III Pipeline by Indication, 2012
Lung Cancer
16%
Breast Cancer
13%
Other
56%
Colorectal Cancer
8%
Lymphoma
7%
Source: GBI Research’s proprietary pipeline products database [accessed on: March 20, 2012]
Combination therapies are common across all oncology indications. Lung cancer holds the greatest share of
the pipeline, accounting for 16% of the oncology drug combinations in Phase III. As lung cancer is such a
prevalent indication, it would be expected to have a large number of combinations in the pipeline. Multiple
myeloma, a much less prevalent cancer indication, was not expected to hold such a large share of the
pipeline.
© GBI Research. This is a licensed product and is not to be photocopied GBIHC229MR / Published JUL 2012
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Table of Contents
1 Table of Contents
1 Table of Contents ........................................................................................................................................ 4
1.1 List of Tables .................................................................................................................................... 5
1.2 List of Figures................................................................................................................................... 5
2 Multi-Targeted Therapies - Overview ......................................................................................................... 6
2.1 Introduction..................................................................................................................................... 6
2.1.1 Biological Networks ................................................................................................................. 6
2.1.2 History of Multi-component Drugs .......................................................................................... 8
2.1.3 Types of Multi-Targeted Therapy ............................................................................................ 8
2.1.4 Many Small Molecule Drugs are Promiscuous ........................................................................ 9
2.1.5 Off-target Effects and Drug Repositioning .............................................................................. 9
2.2 Promiscuous Drugs versus Combination Therapies....................................................................... 10
3 Designing Multi-Target Drugs ................................................................................................................... 11
3.1 Lead Generation Approaches ........................................................................................................ 11
3.1.1 Knowledge-based Approaches .............................................................................................. 11
3.1.2 Screening ............................................................................................................................... 12
3.1.3 Fragment-based Approach .................................................................................................... 12
3.1.4 In Silico Screening Methods ................................................................................................... 12
3.1.5 Conclusions ............................................................................................................................ 13
3.1.6 Challenges of Lead Optimization ........................................................................................... 14
3.2 Multi-Target Protein Kinase Inhibitors .......................................................................................... 14
3.2.1 Early Marketed Kinase Inhibitors .......................................................................................... 14
3.2.2 Newer Designed Multi-kinase Inhibitors ............................................................................... 15
3.2.3 Oncogene Addiction .............................................................................................................. 15
3.2.4 Overcoming Resistance ......................................................................................................... 15
4 Designing Combination Therapies ............................................................................................................ 16
4.1 Which Products to Combine? ........................................................................................................ 16
4.1.1 Cell-based Phenotypic Assays ................................................................................................ 16
4.1.2 Synthetic Lethality ................................................................................................................. 16
4.2 Designing Dual Novel Drug Combinations ..................................................................................... 17
4.3 Challenges for Development and Design of Combination Drugs ................................................... 18
4.3.1 Combined Toxicity ................................................................................................................. 18
4.3.2 FDA Guidelines for Development of Drugs for Use in Combination ....................................... 18
4.3.3 Clinical Trial Design ............................................................................................................... 20
4.3.4 Developing Drugs in Collaboration ........................................................................................ 21
5 Pipeline Analysis of Late Stage Oncology Combination Therapies ............................................................ 22
5.1 Phase III Oncology Pipeline by Number of Drugs in Combination ................................................. 22
5.2 Phase III Oncology Pipeline by Indication ...................................................................................... 23
5.2.1 Overall ................................................................................................................................... 24
5.2.2 Lung Cancer ........................................................................................................................... 26
5.2.3 Breast Cancer ........................................................................................................................ 29
5.2.4 Colorectal Cancer .................................................................................................................. 31
5.2.5 Lymphoma............................................................................................................................. 33
5.2.6 Multiple Myeloma ................................................................................................................. 35
5.2.7 Ovarian Cancer ...................................................................................................................... 37
5.2.8 Prostate Cancer ..................................................................................................................... 39
5.2.9 Leukemia ............................................................................................................................... 41
5.2.10 Head and Neck Cancer .......................................................................................................... 43
5.2.11 Squamous Cell Carcinoma ..................................................................................................... 45
5.2.12 Other Oncology Indications ................................................................................................... 47
6 Appendix ................................................................................................................................................... 53
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Table of Contents
6.1 Abbreviations ................................................................................................................................ 53
6.2 Sources .......................................................................................................................................... 53
6.3 Research Methodology ................................................................................................................. 54
6.3.1 Secondary Research .............................................................................................................. 54
6.3.2 Primary Research .................................................................................................................. 54
6.3.3 Expert Panel Validation ......................................................................................................... 55
6.4 Contact Us ..................................................................................................................................... 55
6.5 Disclaimer ...................................................................................................................................... 55
1.1 List of Tables
Table 1: Clinical Trial Design Considerations for Three Typical Scenarios Combining Drug A and Drug B . 20
Table 2: Combination Therapies in Oncology, Phase III Pipeline by Number of Drugs in Combination. 2012
...................................................................................................................................................... 23
Table 3: Combination Therapies in Oncology, Phase III Pipeline by Indication, 2012 ................................ 24
Table 4: Phase III Pipeline Combinations in Lung Cancer ........................................................................... 27
Table 5: Phase III Pipeline Combinations in Breast Cancer ........................................................................ 30
Table 6: Phase III Pipeline Combinations in Colorectal Cancer .................................................................. 32
Table 7: Phase III Pipeline Combinations in Lymphoma ............................................................................. 34
Table 8: Phase III Pipeline Combinations in Multiple Myeloma ................................................................. 36
Table 9: Phase III Pipeline Combinations in Ovarian Cancer ...................................................................... 38
Table 10: Phase III Pipeline Combinations in Prostate Cancer ..................................................................... 40
Table 11: Phase III Pipeline Combinations in Leukemia ............................................................................... 42
Table 12: Phase III Pipeline Combinations in Head and Neck Cancer........................................................... 44
Table 13: Phase III Pipeline Combinations in Squamous Cell Carcinoma ..................................................... 46
Table 14: Phase III Pipeline Combinations in Remaining Oncology Indications ........................................... 49
1.2 List of Figures
Figure 1: Three Different Approaches to Multi-Target Therapy .................................................................... 8
Figure 2: Determining if Co-development is an Appropriate Development Option .................................... 19
Figure 3: Combination Therapies in Oncology, Phase III Pipeline by Number of Drugs in Combination, 2012
...................................................................................................................................................... 22
Figure 4: Combination Therapies in Oncology, Phase III Pipeline by Indication, 2012 ................................ 24
Figure 5: Multi-Targeted Therapies, Drug Category and Color Used for Analysis ....................................... 25
Figure 6: Multi-Targeted Therapies, Phase III Pipeline Combinations in Lung Cancer, 2012 ...................... 26
Figure 7: Multi-Targeted Therapies, Phase III Pipeline Combinations in Breast Cancer, 2012 .................... 29
Figure 8: Multi-Targeted Therapies, Phase III Pipeline Combinations in Colorectal Cancer, 2012 .............. 31
Figure 9: Multi-Targeted Therapies, Phase III Pipeline Combinations in Lymphoma, 2012 ........................ 33
Figure 10: Multi-Targeted Therapies, Phase III Pipeline Combinations in Multiple Myeloma, 2012............. 35
Figure 11: Multi-Targeted Therapies, Phase III Pipeline Combinations in Ovarian Cancer, 2012.................. 37
Figure 12: Multi-Targeted Therapies, Phase III Pipeline Combinations in Prostate Cancer, 2012................. 39
Figure 13: Multi-Targeted Therapies, Phase III Pipeline Combinations in Leukemia, 2012 ........................... 41
Figure 14: Multi-Targeted Therapies, Phase III Pipeline Combinations in Head and Neck Cancer, 2012 ...... 43
Figure 15: Multi-Targeted Therapies, Phase III Pipeline Combinations in Squamous Cell Carcinoma, 2012. 45
Figure 16: Color Map Showing Phase III Pipeline Combinations in Remaining Oncology Indications, 2012 . 47
Figure 17 : Color Map Showing Phase III Pipeline Combinations in Remaining Oncology Indications, 2012
(cont) ............................................................................................................................................ 48
© GBI Research. This is a licensed product and is not to be photocopied GBIHC229MR / Published JUL 2012
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Multi-Targeted Therapies – Overview
2 Multi-Targeted Therapies - Overview
2.1 Introduction
Traditional drug discovery and development has focused on the identification of molecular bottlenecks that
enable the development of single specific ligands, which have led to disease-modifying therapeutics in the
past. However, this approach has led to the discovery of successful drugs but only works primarily when
disease-modifying targets are addressed. It is assumed that by designing ligands that are very selective, the
drugs will be safer and more effective. However, over the past few years, a significant number of
compounds have failed in late-stage clinical trials due to insufficient clinical efficacy or severe side effects.
The number of drugs gaining US FDA approval is also in decline, even though spending on pharmaceutical
R&D is rising. This decline in pharmaceutical R&D productivity suggests that new approaches to drug
discovery and development are needed.
Cancers are dependent on many altered molecular pathways and networks, so single-agent therapies may
not produce any long-lasting benefits for patients. Even in the event of a monotherapy producing an
objective response, this is relatively short-lived due to mutations in drug targets or changes in pathways as
the disease progresses, leading to drug resistance. Multi-targeted drugs or drug combinations are
preferable long-term treatment options. Combination therapies are already the standard treatment options
for diseases such as tuberculosis and HIV/AIDS. For example, Highly Active Anti-Retroviral Therapy (HAART)
changed HIV infection from a virtually untreatable disease to a more manageable chronic illness.
Advocates of the use of network pharmacology for developing drugs say that drugs developed this way will
have greater efficacy and fewer side effects as well as being cheaper and quicker to develop. Presently,
there are still huge gaps in biological knowledge of these networks, which need to be filled for this method
to be effective. Many drug developers are still in support of using the single-target reductionist approach to
drug discovery due to success in the past, despite the recent high drug attrition rates.
2.1.1 Biological Networks
Complex diseases such as
cancer are dependent on Complex diseases such as cancer are dependent on multiple factors, which make it difficult to produce
multiple factors, which make successful therapies. To create effective therapies there is a need to understand the mechanisms underlying
it difficult to produce disease processes. Cancer is controlled by complex signaling networks, not just linear signaling pathways as
successful therapies once was thought, and so understanding network properties is important for identifying possible
therapeutic targets.
2.1.1.1 Many Diseases are Caused by Multiple Factors
The single-target approach has been successful for treating diseases with a clearly defined mechanism. A
major factor in drug attrition rates may be due to the fact many diseases are caused by many different
factors, or more complex mechanisms, rather than bei