Beads-on-a- The 30nm Fibre Active Chromosome The Metaphase Chromosome. Less active genes During interphase During cell division
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1 Overview of Epigenetics Figure 2.2. The Increasing Structural Complexity of Genetic Information from the Double-Helical Structure of DNA, through Nucleosome and Chromatin Structures, to the Chromosome DNA The Beads-on-a- Nucleosome String The 30nm Fibre Active Chromosome The Metaphase Chromosome Isolated Patches Genes under active transcription Less active genes During interphase During cell division Add core histones Add histone H1 Add further scaffold proteins Add further scaffold proteins Source: Histones are small, alkaline proteins that are associated with the DNA. The major types of histones are referred to as H1, H2A, H2B, H3, and H4, although additional types of histones exist. Portions of DNA wrap around the histones to form nucleosomes, which resemble a string of beads, as shown in Figure 2.2. Nucleosomes are the basic structural unit of chromatin, which is the complex between DNA and proteins in eukaryotic cells. As demonstrated in Figure 2.2, the extent of condensation of chromatin varies with different stages of the cell lifecycle. In nondividing (interphase) cells, most of the chromatin is euchromatin, which is relaxed chromatin that is not tightly condensed. However, some of the chromatin is heterochromatin, which is highly condensed. Genes in the heterochromatin cannot be transcribed. The N-terminal domain of histones can be modified by various enzymes. These modifications can include acetylation, methylation, ubiquitylation, or phosphorylation, and modifications of the histones may either activate or repress transcription of the genes. Figure 2.3 shows the nucleosome, with the N-terminal region of the histone, and the many different types of post-translational modifications that can occur. Figure 2.3. Schematic of the Nucleosome Showing Types of Post-Translational Modifications That Can Occur and the Enzymes Responsible for Them Acetyltransferases Deacetylases Ac Kinases P Ligases Ub Histone Me Me PKMTs Demethylases PRMTs Ac, acetylation; P, phosphorylation; Ub, ubiquitylation; Me, methylation; PKMT, protein lysine methyltransferase; PRMT, protein arginine methyltransferase Source: Insight Pharma Reports Nucleosome 8 Reproduction prohibited
2 Diagnostic Companies in Epigenetics Table 3.1. Companies Developing and/or Offering Epigenetic-Based Diagnostic Tests Company Product/Technology Status Comments Real-time PCR assay that detects the presence of methylated Septin9 in plasma For colorectal cancer screening Abbott Molecular Abbott RealTime ms9 Colorectal Cancer assay Available in Europe and Asia/Pacific 9/07: Epigenomics announced a nonexclusive strategic collaboration and license agreement with Abbott for development of an in vitro diagnostic test for early detection of colorectal cancer based on the Septin9 biomarker. 10/05: Rubicon Genomics announced a multiyear Research and Option Agreement with Abbott Molecular to develop and commercialize Rubicon s MethylPlex methylation detection technology for diagnosis and prognosis of cancer. Abbott Molecular Cancer tests based on Rubicon s MethylPlex methylation detection technology In development 1/09: Rubicon Genomics announced an agreement granting Abbott a nonexclusive license to Rubicon s MethylPlex technology for in vitro molecular diagnostics to detect the presence or risk of prostate, bladder, and colon cancer for screening and non-screening indications. Abbott also obtained a non-exclusive license for non-screening applications with other diseases and options to colon cancer markers developed in collaboration with Rubicon. Continued 20 Reproduction prohibited
3 Epigenetic Drugs On The Market And In Development Both FDA-approved DNA methyltransferase inhibitors are indicated for treatment of myelodysplastic syndrome (MDS). The numbers of people with MDS are not large (see Chapter 4). Thus, the clinical trials required for their approval were not large in terms of numbers of patients. Also, before approval of these agents, there were no approved treatment options for MDS and so the clinical trials were designed to compare the DNA methylation inhibitor plus best supportive care versus best supportive care alone. While the response rates with Vidaza or Dacogen were not high, there were no responses to best supportive care. Thus, treatment with a DNA methylation inhibitor was shown to be clearly better than no treatment (at least for those patients who responded to the therapy). However, these agents can cause a number of different adverse reactions. Selected data (response rates and most common adverse effects) from the clinical studies are discussed below. Additional data from these clinical studies can be found in the prescribing information for each drug. While these indirect DNA methylation inhibitors represent an important improvement in the care of patients with MDS, there is a clear need for better therapies. Researchers have been interested in the development of novel DNA methyltransferase inhibitors that can directly inhibit the enzyme (without prior incorporation into the cell s DNA), but identifying compounds that could be successfully commercialized as therapies has proven to be challenging. At this time, no direct inhibitors of DNA methyltransferase appear to be in clinical development. While one company (SuperGen) is developing a novel DNA methyltransferase inhibitor, that new agent (SGT-110) is a prodrug of decitabine, one of the two DNA methyltransferase inhibitors that is already FDA-approved. Table 5.1. Companies Marketing and Developing DNA Methylation Inhibitors Company Product/Technology Status Comments Celgene Vidaza (azacitidine) On the market DNA hypomethylation agent. It is incorporated into DNA and then inhibits DNA methylation. FDA-approved for treatment of myelodysplastic syndrome. Also approved in Europe. Eisai Dacogen (decitabine) On the market (United States) DNA hypomethylation agent. It is incorporated into DNA and then inhibits DNA methylation. FDA-approved for treatment of myelodysplastic syndrome. Continued 50 Reproduction prohibited
4 Epigenetic Drugs On The Market And In Development sales milestones, could exceed $350 million. In addition, Spectrum Pharmaceuticals will pay TopoTarget royalties if belinostat is successfully commercialized and sold by Spectrum Pharmaceuticals in the regions covered by the agreement. Spectrum Pharmaceuticals was granted the right to market belinostat in North America and India, and was granted a right of first offer for China. Belinostat is currently being evaluated in a registration clinical trial in patients with peripheral T-cell lymphoma (PTCL). This trial is being conducted under a Special Protocol Assessment (SPA), and belinostat has been granted both Orphan Drug and Fast Track designation by the FDA. In addition, belinostat is in a randomized Phase II study in combination with carboplatin and paclitaxel for treatment of patients with cancer of unknown origin (CUP). As part of the agreement between TopoTarget and Spectrum Pharmaceuticals, Spectrum Pharmaceuticals agreed to fund 100% of the costs for the PTCL study, and TopoTarget is funding 100% of the costs of the ongoing CUP clinical trial. In the future, clinical trial costs will be shared 70/30, with Spectrum Pharmaceuticals paying 70%. Belinostat is currently being evaluated in additional earlier-stage trials in other cancers, which are being sponsored by Spectrum Pharmaceuticals. Spectrum Pharmaceuticals also has an ongoing collaboration with the National Cancer Institute (NCI), which is conducting a number of clinical studies to evaluate belinostat. The February 2010 announcement of the agreement between TopoTarget and Spectrum Pharmaceuticals also reported that belinostat was being evaluated in 20 clinical trials in hematological and solid tumors, both in monotherapy and combination therapy regimens. Additional information about TopoTarget and the HDAC inhibitor belinostat can be found in the interview with Henri Lichenstein, PhD, TopoTarget s chief development officer (see Chapter 7). In this interview, he reports that one of belinostat s differentiating characteristics is its safety profile; they have not seen the hematological and cardiac toxicity that have been seen with other HDAC inhibitors. In addition, in May 2010, TopoTarget and Spectrum Pharmaceuticals both announced that abstracts on belinostat would be presented at the upcoming American Society of Clinical Oncology (ASCO) meeting. This includes an abstract on the ongoing trial of belinostat in patients with PTCL. As of January 4, 2010, 19 patients had been included in this clinical trial Emerging Therapies Directed Against Other Epigenetic Targets As discussed in the previous section, much of the current drug discovery and development activity in the field of epigenetics is focused on the class of drugs known as HDAC inhibitors. While companies in this field are working to differentiate their HDAC inhibitors from other emerging HDAC inhibitors, this is already a crowded area. Given this high level of competition, combined with the fact that many different enzymes are involved in epigenetics and thus are potential targets, some companies are already starting to develop potential therapies that have other (non-hdac) mechanisms of action. Examples are discussed below and in Table Reproduction prohibited
5 Epigenetic Drug & Diagnostic Pipelines: DNA Methylation, HDAC Inhibitors, and Emerging New Targets Table 6.1. Reported 2009 Sales of Approved Epigenetic Drugs Company Drug Sales/Comments DNA Methylation Inhibitors Celgene Vidaza (azacitidine) $387 million $150 million in the United States Eisai Dacogen (decitabine) 15 billion yen (total Eisai Dacogen sales) Johnson & Johnson Dacogen (decitabine) Dacogen s sales not reported HDAC Inhibitors Celgene Istodax (romidepsin) None (FDA-approved in late 2009; market launch in 2010) Merck Zolinza (vorinostat) Zolinza s sales not reported Source: Publicly reported figures Interest in the epigenetic market is being fueled by the large potential markets for these therapies. Potential patient populations for emerging new epigenetic therapies are discussed in Chapter 4. While these indications and the emerging therapies targeting these indications are promising, most of the epigenetic product candidates are in relatively early development. Of the agents included in Chapter 5 that are not yet on the market, only two have reached Phase III or registration clinical trials. Novartis panobinostat (LBH589) is in Phase III in patients with relapsed multiple myeloma, and a Phase III trial in Hodgkin s lymphoma is planned. In addition, TopoTarget s belinostat is in a registration clinical trial in patients with peripheral T-cell lymphoma (PTCL), which is another indication with a very small market. Belinostat is also being evaluated in a randomized Phase II study in combination with carboplatin and paclitaxel for treatment of patients with cancer of unknown origin (CUP). Thus, it is likely be several years before the combined market for epigenetic-based therapies is large Major Challenges/Hurdles and Strategic Issues for Diagnostic Companies in Epigenetics Research activity has exploded in the field of epigenetics, as demonstrated by the number of publications (see Figure 1.1 in Chapter 1). These ongoing research activities have resulted in significant advances in our knowledge of epigenetics. The first diagnostic tests have been CE-marked and are available in Europe, and initial tests are being offered as laboratory-developed tests by reference laboratories in the United States. Four epigenetic drugs have been approved by the FDA, including two agents that inhibit DNA methylation and two HDAC inhibitors. Reproduction prohibited 81
6 Business Considerations in Epigenetics Agreements in the Epigenetic Therapy Market; Companies Entering and Exiting the Market The epigenetic-based therapy market has evolved in recent years. Over 40 companies appear to be actively developing and/or commercializing epigenetic-based therapies. (See Chapter 5 and Tables ) Therapeutic companies in this field range from relatively new, venture capital-funded startups to large, multinational pharmaceutical companies, and include companies throughout this range (in terms of size and age of the companies). This has been a dynamic market with many corporate agreements (see Table 6.2). Some major pharmaceutical companies that were developing an epigenetic drug appear to have exited this market (Table 6.3). However, it is possible that one or more of these companies may decide to reenter the epigenetic therapy field. For example, in May 2009, AstraZeneca licensed its HDAC inhibitor AZD9468 to Celleron Therapeutics, which now calls this compound CDX101. As part of this agreement, AstraZeneca was granted the option to discuss reacquisition of commercialization rights in the future. Table 6.2. Selected Epigenetic Therapeutic Agreements Epigenetic Company Partner Company, or Company Out-Licensing Technology and Exiting Date (Or Date Announced) Subject of Agreement 4SC Nycomed July 2008 Announcement that 4SC had completed the transaction to acquire eight oncology programs from Nycomed. These programs included the HDAC inhibitors resminostat (4SC-201) and 4SC-202, plus two other HDAC inhibitor programs. [Nycomed is also included in Table 6.3.] Aphios VivaCell Biotechnology España March 2009 Announcement of collaborative research and development agreement between Aphios and VivaCell Biotechnology España to develop a combination therapy for treatment of HIV latency. This combination therapy consists of bryostatins (PKC modulators) and HDAC inhibitors. CellCentric Takeda Pharmaceutical February 2010 CellCentric announced that it had out-licensed one of its cancer programs to Takeda Pharmaceutical. This is an exclusive agreement that could potentially be worth more than $200 million to CellCentric over its course. Celleron Therapeutics AstraZeneca May 2009 Announcement that Celleron licensed the HDAC inhibitor AZD9468 from AstraZeneca. Celleron now calls it CDX101. AstraZeneca was granted the option to discuss reacquisition of commercialization rights in the future. [Astra- Zeneca is also included in Table 6.3.] Continued 92 Reproduction prohibited
7 Chapter 7 Expert Interviews 7.1. Walter C. Ogier President and Chief Executive Officer Acetylon Pharmaceuticals Insight Pharma Reports (IPR): Please provide a brief history of Acetylon Pharmaceuticals. Walter C. Ogier: While Acetylon is a relatively new company, founded in late 2008, we are the outgrowth of work that goes back six or more years within the confines of Harvard University and the Dana-Farber Cancer Institute. Harvard was the first to discover the existence of histone deacetylases (HDACs) and also identified the first half dozen or so of the human HDACs. There are now a total of 18 known HDACs, seven of which comprise the sirtuin family. Sirtris, which was taking these forward as drug opportunities, was acquired by GlaxoSmithKline in Sirtuins are NAD-dependent enzymes. They have a biological function that is distinct from the other 11 human HDACs that I will be talking about, which employ zinc atoms in their catalytic active site. But, strictly speaking, the sirtuins are part of the overall HDAC family. There have been some recent publications that cast doubt on the potential clinical utility of these enzymes and enzyme activators, but for several years Sirtris was a high-flyer (GlaxoSmithKline paid $720 million for the company). The research that has, at least in part, cast doubt on the potential utility of this subset of HDAC enzymes as drug targets was published by Pfizer. The sirtuins have generally been billed as potential drugs for treatment of diseases of aging and metabolic dysregulation, including type 2 diabetes and other disease indications which do not overlap substantially with the potential clinical utility of the 11 zinc-containing HDACs as drug targets. The portion of the HDAC family that Acetylon is interested in comprises the other 11 human HDACs. The first selective HDAC inhibitor was created by Stuart Schreiber and colleagues at Harvard University and was made widely available in academic circles. It was a compound called tubacin which selectively inhibits Reproduction prohibited 97
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