Multitargeted Therapies:Promiscuous Drugs and Combination Therapies

Allan Haberman, PhD

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Multitargeted Therapies:Promiscuous Drugs and Combination Therapies

by Allan Haberman, Ph.D.

Published in June 2011 by Cambridge Healthtech Institute

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Multitargeted Therapies:Promiscuous Drugs and Combination Therapies

by Allan Haberman, Ph.D.

About the AuthorAllan B. Haberman, PhD, is Principal of Haberman Associates, a consulting firm specializing in science and technology strategy for pharmaceutical, biotechnology, and other life science companies. He is also a Principal and Founder of the Biopharmaceutical Consortium (www.biopharmconsortium.com), an expert team formed to assist life science companies, research groups, and emerging enterprises to identify and exploit promising breakthrough technologies. Dr. Haberman is also the author of numerous publications on the pharmaceutical and biotechnology industries, their technologies and products, and the major therapeutic areas for drug discovery and development. Formerly the Associate Director of the Biotechnology Engineering Center at Tufts University, he received his PhD in biochemistry and molecular biology from Harvard University.

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Executive Summary Multitargeted Therapies: Promiscuous Drugs and Combination Therapies

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M odern drug discovery, especially since the publication of the human genome in 2001, has been centered on the concept of drug targets, which are biomolecules that, actually or potentially, interact with a drug or

drug candidate to produce a clinically relevant effect. Target-based drug discovery is generally based on a reductionist model, in which a molecular target has a causative role in a disease process, and modulating that target should ameliorate or cure the disease. This paradigm has resulted in the quest to identify and validate targets. Once researchers have a validated target, they work to discover or design drugs which modulate that target. Under the target-based drug discovery paradigm, drugs that modulate validated targets, and which have good ADME, pharmacokinetic, and pharmacodynamic properties and safety and toxicity profiles, should be useful in treating subsets of patients in whom the target is critical in their disease.

The target-based drug discovery and development paradigm has resulted in the successful development of numerous small-molecule drugs and biologics. However, over the past decade, the productivity of pharmaceutical R&D has been falling, despite increasing R&D budgets and the use of advanced technologies. Analyses designed to identify the reasons for this decline in productivity have identified several major factors that result in the high rates of clinical attrition seen today.

A major factor behind the high rate of clinical attrition in drug development is that researchers have been addressing complex diseases, such as cancer, cardiovascular disease, type 2 diabetes, Alzheimer’s disease, and Parkinson’s disease. A major challenge in addressing complex diseases is that they are caused by multiple genetic and environmental factors. These diseases thus have multiple “causes.” In addition, a complex disease may really be more than one disease, each with its own set of causative factors. Thus the reductionist model that one drug modulating one target results in effective treatment of a disease may not hold. In this case, drug therapies need to address multiple targets.

Researchers have long known that certain diseases have multiple causes that involve multiple targets, and they have developed suites of drugs to treat these diseases. Such drugs may be used in combination to treat individual patients. For example, physicians may treat patients with combinations of drugs to treat such complex diseases as type 2 diabetes, hypertension, HIV/AIDS, and cancer.

In addition, researchers have found that many successful, marketed small-molecule drugs that were developed before the era of genomics and high-throughput screening are promiscuous drugs, i.e., they are single drugs that address multiple targets. This finding provides a rationale for developing new promiscuous drugs. The multitargeted nature of these drugs may account both for their efficacy and their side effect profile.

Executive Summary

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Executive Summary Multitargeted Therapies: Promiscuous Drugs and Combination Therapies

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This is an issue with all multitargeted drugs—both these older drugs and newer agents that are designed to be multitargeted. One newer class of drugs that includes many multitargeted agents is that of the protein kinase inhibitors, such as imatinib, sunitinib, sorafenib, and dasatinib.

Researchers involved in the systematic construction of single-gene knockouts in various models have also observed that in many cases, knockout of a single gene has little or no effect on phenotype. In the case of deletions of “druggable” genes in the mouse genome, only about 10% of deletions appear to have phenotypes that can be used for target validation. Biologists generally attribute this phenomenon to the redundancy of pathways and networks.

In the emerging discipline of network pharmacology, researchers combine network biology with chemogenomics. For example, they may map drug-target networks (i.e., networks of targets that are modulated by promiscuous drugs) onto biological networks (e.g., networks of protein-protein interactions of disease-related proteins). Studies of this type have shown that marketed drugs commonly act on multiple targets, and that targets of a particular drug are often involved with multiple diseases. Network pharmacology thus shows that polypharmacy is very common among approved small-molecule drugs. Researchers can also use it in designing novel promiscuous small-molecule drugs.

This report covers both major approaches to development of multitargeted therapies: the discovery and design of single drugs that address multiple targets, and the rational design of novel combination therapies. Both of these strategies are especially aimed at addressing complex diseases that have multiple causes and/or that involve causation by interacting or redundant pathways. Chapter 1 serves as an introduction to the report.

Chapter 2 discusses the emerging area of network pharmacology, which demonstrates that most approved small-molecule drugs are

promiscuous. It can also be used to: develop computational tools to predict the biological activity of compounds; find new targets, often in different therapeutic areas, for known approved drugs as well as for drugs that failed in clinical trials for efficacy but not for safety (drug repositioning); and design new multitargeted drugs. Chapter 2 includes a case study on designing targeted polypharmacology inhibitors to control nitric oxide (NO) levels, for use as antitumor therapeutics.

Chapter 3 is a discussion of multitargeted protein and lipid kinase inhibitors. The field of kinase inhibitors is a highly successful area of drug discovery, which is being pursued by numerous pharmaceutical and biotechnology companies. Most kinase inhibitors are promiscuous agents, since they target the ATP-binding sites of kinases, and these binding sites have extensive homology with each other. In many cases, the efficacy of a kinase inhibitor against a particular type of cancer depends on its addressing multiple targets. Moreover, the multitargeted nature of a kinase inhibitor may enable its use in treating more than one type of cancer, as in the classic case of imatinib (Novartis’ Gleevec/Glivec), which can be used to treat chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). However, kinase inhibitors may also exhibit off-target adverse effects.

Chapter 3 includes a discussion of the development of second-generation agents to overcome resistance to imatinib. Discovery and design of these second-generation agents depends on interactions between the inhibitors and the active and inactive form of their kinase targets, which affect the degree of promiscuity of the inhibitors. Chapter 3 also discusses chemical proteomics methods designed to assess the degree of promiscuity of kinase inhibitors and to develop specifically multitargeted kinase inhibitors. The chapter also discusses the design of the exquisitely specific kinase inhibitor Roche/Daiichi Sankyo/Plexxikon’s PLX4032 (vemurafenib), which targets the BRAF (V600E)

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Executive Summary Multitargeted Therapies: Promiscuous Drugs and Combination Therapies

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mutation, which is the driver mutation for some 60% of cases of metastatic melanoma. PLX4032 has shown dramatic results in clinical trials in metastatic melanoma. However, all patients eventually develop PLX4032 resistance and relapse.

The focus of Chapters 4, 5, and 6 is on developing novel combination therapies designed to address multiple targets. Chapter 4 discusses the use of synthetic lethality to design combination therapies for cancer. In classic synthetic lethality, mutation in either of two genes individually has no effect, while simultaneous mutation in both genes is lethal. KuDOS/AstraZeneca’s late-stage drug olaparib, which is specific for BRCA1- or BRCA2-negative breast, ovarian, and prostate cancer, utilizes a synthetic lethal mechanism and provides proof of concept for the use of synthetic lethality strategies in cancer drug discovery and development.

Chapter 4 discusses the use of synthetic lethal screening with RNA interference (RNAi) to identify chemosensitizing targets for paclitaxel, in lung cancer and in breast cancer, and to identify sensitizing targets for gemcitabine therapy in pancreatic cancer. The chapter also discusses an RNAi-based synthetic lethal screening approach to developing therapies for p53-negative cancers. p53 is a key tumor suppressor factor in the majority of human cancers. In these cases, researchers identified new potential targets for synthetic lethality-based treatments.

Chapter 5 focuses on using pathway biology to design rational combination therapies for cancer. The chapter contains three case studies: 1) designing combination therapies to simultaneously block the mitogen-activated protein kinase (MAPK) pathway and the PI3K pathway in KRAS (Kirsten rat sarcoma viral oncogene homolog)-mutant cancers; 2) designing combination therapies to overcome acquired resistance to PLX4032 in metastatic melanoma; and 3) designing therapies to overcome epidermal growth factor receptor (EGFR) kinase inhibitor resistance in lung cancer.

All three case studies involve studying intracellular signaling pathways (especially the MAPK and PI3K pathways) and how they are affected in cancers that are resistant to certain drugs, and then using these studies to design patient-specific combination therapies to overcome this resistance. However, 50% of cases of EGFR inhibitor resistance are due to secondary mutations in the target of the inhibitors itself, so effective therapy involves development of second-generation EGFR inhibitors rather than inhibitors designed on the basis of pathway biology.

Combination therapies developed using the methods discussed in Chapter 5 are “personalized medicines,” and require the development and use of companion diagnostic products to determine which patients might benefit from specific combination therapies.

Chapter 6 focuses on Zalicus’ combination high-throughput screening technology. Zalicus was formed in 2009 by the merger of the developer of the technology, CombinatoRx, with Neuromed, whose R&D programs had nothing to do with development of combination therapies. Zalicus has refocused itself on two product areas: pain and immuno-inflammatory conditions. These are derived from Neuromed and CombinatoRx, respectively. The use of CombinatoRx/Zalicus’ combination high-throughput screening (cHTS) technology has resulted in the development of Zalicus’ Synavive (dipyridamole/prednisolone) for rheumatoid arthritis, which is in Phase II clinical trials, as well as Prednisporin (prednisolone/cyclosporine A) (FOV1101), a topical ocular drug candidate for treatment of persistent allergic conjunctivitis. Prednisporin is being developed by Fovea Pharmaceuticals.

Zalicus has a collaboration with Novartis, which is focused on the discovery of novel anticancer drug combinations, based on cHTS technology. Zalicus also recently has been collaborating with PGxHealth, a division of Clinical Data, Inc., on development of combination therapies for such B-cell malignancies as multiple myeloma (MM) and

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Executive Summary Multitargeted Therapies: Promiscuous Drugs and Combination Therapies

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diffuse large B-cell lymphoma (DLBCL). (Forest Laboratories acquired Clinical Data in April 2011.) These studies have resulted in the design and identification of novel preclinical-stage combination therapies for these diseases.

Network pharmacology studies indicate that multitargeted, or “promiscuous,” drugs may often work better than precisely targeted drugs, especially in complex diseases. This may be one reason for the high rate of attrition due to efficacy failures of drugs in the clinic, since most small-molecule drugs taken into clinical trials in recent years have been designed according to the “one drug-one target-one disease” model. Nevertheless, currently development of small-molecule multitargeted drugs is a minority activity in pharmaceutical companies (except for kinase inhibitors). This is mainly due to the early-stage nature of design tools for rational design of multitargeted small-molecule drugs. However, innovative research groups (in pharmaceutical and biotechnology companies as well as in academia) may be able to develop tools that will enable them to discover successful multitargeted small-molecule drugs well in advance of the routine use of network pharmacology. Moreover, academic research groups and biotech companies active in designing multitargeted small-molecule drugs may be able to forge partnerships with Big Pharmas in this area.

However, the design of multidrug combination therapies to address multiple targets in a disease is a very active area of R&D, especially in oncology. The development of these combination therapies is one of the most exciting areas of cancer research today. We expect at least several of these therapies to advance in clinical trials over the next several years and to enter medical practice.

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