Salinomycin

On November 3, 2011, Cambridge MA biotech firm Verastem announced that it was filing a prospectus for an initial public offering (IPO). At that time, the company was 15 months old.

Verastem is led by Christoph Westphal, MD, PhD, a founder and the former CEO of Sirtris and a veteran entrepreneur and venture capitalist. The IPO has been underwritten by UBS, Leerink Swann, Lazard Capital Markets, Oppenheimer & Co., and Rodman & Renshaw.

On January 27, 2012, Fierce Biotech reported that Verastem had announced the previous night that its IPO raised $55 million from the sale of 5.5 million shares at $10 apiece. This price fell exactly in the middle of its expected $9 to $11 price range, and the company had even increased the offering by a million shares over what had originally been planned.

On the same day, Verastem’s stock opened at $11 a share on the NASDAQ, up from its initial public offering price of $10.

Verastem not only has Christoph Westphal as its Chairman and CEO, but is also based on science from eminent MIT researchers Robert Weinberg, Ph.D. and Eric Lander, Ph.D., and has several other well-respected academic researchers (including Nobelist Phillip Sharp, Ph.D.) plus biotech industry drug discoverers Julian Adams, Ph.D. (MIllennium’s Velcade) and Roger Tung, Ph.D. (Vertex’ Lexiva and Agenerase) on its Scientific Advisory Board. The company has had considerable fundraising success prior to its IPO, including raising $32 million in venture capital  in July 2011.

However, Verastem has not one lone drug in human clinical trials, its most advanced compounds are in the preclinical stage, and the company does not plan to file an IND until 2013! Thus Verastem has successfully gone public, in an era in which even most private biotech companies with drugs in late-stage clinical trials are finding it very difficult to do so, despite its lack of any clinical-stage drugs.

As noted in the Fierce Biotech article, Dr. Westphal as well as other venture capital funders of Verastem agreed to buy up to $16.3 million of the IPO. This in part explains the success of the IPO. As also noted by Fierce Biotech, with over 19 million common shares outstanding, the offering valued Verastem at $192 million.

We discussed Verastem in our August 2, 2011 Biopharmonsortium Blog article entitled “Development of personalized therapies for deadly women’s cancers”. Verastem focuses on discovery and development of drugs to target cancer stem cells. Its technology is based on a strategy for screening for compounds that specifically target cancer stem cells, developed by Drs. Weinberg, Lander, Piyush Gupta (MIT and Broad Institute) and their colleagues.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial, as discussed in our article. Whether cancer stem cells are involved in the pathobiology of solid tumors (or a particular type of solid tumor) or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT). In the Cell paper, the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin (now being marketed as a generic veterinary antibiotic) as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As we discussed in our article, triple-negative (TN) breast cancer cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. It is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy typically results in early relapse and metastasis. However, TN breast cancer includes two experimentally defined subtypes that have gene expression signatures related to the EMT. One or both of these subtypes might therefore be expected to be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem is focusing on TN breast cancer as its first therapeutic target.

Verastem’s VS-507, a proprietary formulation of salinomycin, is being developed to treat TN breast cancer. The company is also screening for additional compounds, including New Chemical Entities (NCE) that can achieve stronger intellectual property protection than a salinomycin formulation. Verastem had not chosen a lead compound as of the middle of 2011. The company is now reported to be doing preclinical studies on three of its compounds, and also plans to create diagnostic tests to identify patients that could benefit from its treatments. (As we discussed in our article, biomarker-based tests will be critical in making such therapies work.)

As one can discern from our blog article, we are intrigued by Verastem’s approach to cancer treatment, and especially its approach to TN breast cancer. The science behind Verastem’s drug discovery strategy, developed by 2011 ASCO award-winning oncogene and cancer stem-cell pioneer Bob Weinberg, is very compelling. We would love to see Verastem’s therapeutic strategy succeed.

However, as virtually all pharmaceutical and biotechnology R&D researchers well know, it is difficult to translate even the most compelling science developed by the most brilliant researchers into the clinic. Even therapeutic strategies with an excellent scientific rationale that have achieved proof of principle in the best animal models can result in clinical failure, especially with the first compound tested in proof-of-concept studies in human patients. The cancer stem cell hypothesis remains controversial. Moreover, diseases such as TN breast cancer are complicated, they may have mechanisms of resistance to a new experiential therapy that no one knows about, and our understanding of disease biology is limited.

Thus at least until Verastem’s therapies achieve proof of concept in human studies, purchase of Verastem stock is risky indeed. Moreover, there are other risks involved other than technical and clinical risk–especially competition for developing cancer stem cell-based therapies by other biotech/pharma companies. Venture capitalists (and certain knowledgeable individual investors and funds) are in the business of taking on high-risk investments for the sake of potential large rewards, but ordinary retail investors in the public markets are not. Therefore, it seems too early for Verastem to go public, even if it has founders and investors with enough clout to make an IPO successful.

Expert analysts in the IPO field, as stated in the Fierce Biotech article, are puzzled by the rationale for Verastem going public at this time. The financial news and services website “TheStreet.com” agrees. Our own sense of puzzlement is symbolized by the interobang (‽) in the title of this article.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

RNase/RNase inhibitor protein-protein interaction. Dcrjsr http://bit.ly/zRrlaz

We mentioned Forma Therapeutics in two previous articles on this blog. In one article, we focused on Forma’s R&D efforts in discovering small-molecule inhibitors of protein-protein interactions (PPIs).  The other article included a discussion on Forma’s efforts in cancer metabolism.

This month–January 2012–when the new year had barely started–Forma signed two new Big Pharma alliances, covering both of these areas.

On January 5, Forma announced that it had entered into an R&D collaboration with Boehringer Ingelheim, focusing on discovery and development of small molecule drugs to address oncology-relevant PPIs. Under the terms of the agreement, Forma will receive a total of $65 million in up-front payments and research funding, and could be eligible for up to $750 million in pre-commercial milestone payments for development programs resulting from the collaboration.

As with the Genentech deal in cancer metabolism that we discussed in an earlier article, the new Boehringer Ingelheim agreement provides Forma and its shareholders several opportunities to realize early return through assets developed under the collaboration. However, details of how this might occur were not disclosed. According to a January 6, 2012 article in BioWorld Today, flexibility and liquidity (without the need for a IPO or an acquisition) are importance goal of Forma’s business development activity in general. Nevertheless, Forma CEO Steven Tregay does not rule out a future acquisition, and says that large pharmaceutical companies are interested in such a deal.

On January 10, 2012, Forma announced an exclusive alliance with Janssen Biotech (a Johnson & Johnson company), in which the companies will collaborate on the discovery, development and commercialization of novel small molecule drug candidates that target mechanisms of tumor metabolism.

Under the terms of the agreement, Forma will discover and develop drugs against a panel of tumor metabolism targets. Forma may receive up to $700 million in project and milestone funding. In addition, FORMA may receive royalties on revenues from products commercialized as a result of the collaboration. Moreover, if certain milestones are achieved during the initial phase of the collaboration, FORMA will have the opportunity to co-develop and maintain North American commercial rights to one program selected by Janssen. The two companies may also expand the collaboration to include other targets, including those in areas beyond tumor metabolism.

Once again, Dr. Tregay sees the opportunity to maintain North American rights to a product resulting from the collaboration as in line with the company’s strategy to create long-term shareholder value within Forma.

In December 2011, Forma moved its operations from Cambridge MA to Watertown MA, in the process gaining double the amount of space it had before. This will allow for the company’s growth in new internal and partnered R&D projects, and for the growth in staff that this will entail.

As we discussed in earlier articles on this blog, PPIs have been considered “undruggable” targets. However, given that researchers have been able to discover and in at least one case develop small-molecule agents to address this class of targets, it is best to think of this area as a premature technology. As discussed in our July 27, 2011 article, Forma believes that it has developed a set of enabling technologies to move the PPI field up the technology curve, similar to what happened to the monoclonal antibody field in the 1990s. Apparently, several partner organizations–not only Boehringer Ingelheim, but also Novartis and the Leukemia & Lymphoma Society–agreed with Forma enough to invest in partnerships in this area.

Forma is not the only Boston-area biotech to have a major program in discovery of drugs that modulate PPIs. Ensemble Therapeutics (Cambridge, MA), has internal programs and partnerships in discovery of small-molecule compounds that target PPIs, and Aileron Therapeutics (Cambridge, MA), which we discussed in our November 27th 2009 and our August 24th 2010 blog articles, is developing peptide compounds designed to target PPIs in internal and partnered programs.

As for cancer metabolism, Forma is once again not the only Boston-area biotech to have major programs in drug discovery in this area. We have discussed Agios Pharmaceuticals, which specializes in that area, in our December 31, 2009, April 23, 2010, and November 30, 2011  Biopharmconsortium Blog articles.

In our December 22, 2010 blog article, we discussed the field of intermediary metabolism, asking “Will intermediary metabolism be a hot field of biology again?” In the 1920s through the 1950s, intermediary metabolism was a hot field of biology, but the field was eclipsed by molecular biology starting with the Watson and Crick paper in 1953. However, largely as the result of research that combines intermediary metabolism and molecular biology, metabolism is coming to the forefront of biomedicine again. In the area of cancer metabolism, researchers such as signal-transduction pioneer (and Agios scientific founder) Lewis Cantley have been combining the two fields in order to understand cancer disease pathways, with implications for drug discovery and development.

All of the companies mentioned in this article are research-stage companies, with no drug candidates yet beyond the preclinical stage. The strategies of these companies, and the compounds that have resulted from them, thus must be validated in clinical studies. Nevertheless, we are encouraged by these companies’ success so far, and the interest show in them and their science and technology platforms by large pharmaceutical companies. The success of these companies also provides an object lesson–premature technologies and neglected fields may at least in some cases provide opportunities for drug developers.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Happy New Year! http://bit.ly/tKUKIR

We commend for your New Year’s reading the review article entitled “Cancer immunotherapy comes of age” in the 22 December 2011 issue of Nature. It was written by Drs. Ira Mellman (Genentech),  George Coukos (University of Pennsylvania School of Medicine), and Glenn Dranoff (Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Center/Brigham and Women’s Hospital and Harvard Medical School, Boston, MA).

As you may recall, Genentech’s Dr. Mellman was mentioned in our November 25, 2011 blog article on Dr. Ralph Steinman. Dr. Mellman was a former member of Dr. Steinman’s lab, and he was one of the researchers who helped plan the strategy for the immunotherapy-based treatment of Dr. Steinman’s own pancreatic cancer.

The review by Dr. Mellman and his colleagues is truly comprehensive. It covers research and events in drug development in cancer immunotherapy that we also discussed in the following 2011 blog articles:

• March 30, 2011: FDA approves ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy) for treatment of metastatic melanoma.

• April 27, 2011: Adoptive immunotherapy for metastatic melanoma? 

• November 25, 2011: Ralph Steinman, dendritic cell vaccines, and clinical trials.

• December 26, 2011: The 2011 Nobel Prize in Physiology or Medicine–Innate and Adaptive Immunity.

The Nature review ties all these subjects and events together, and gives additional in-depth information on each of them. For example, in discussing adoptive immunotherapy for cancer with tumor infiltrating lymphocytes (TILs), the review presents new studies on the use of T-cell engineering and bispecific antibodies. Such methods may enable researchers and clinicians to get beyond the need for resectable tumors harboring reactive T cells, or even allow them to stimulate TILs in situ, thus avoiding the need to isolate and culture autologous T cells altogether.

Both the new Nature review and the discussions on our blog show that 2011 was a big year for cancer immunotherapy. The past year was proceeded by the 2010 approval of the first ever cancer vaccine, sipuleucel-T (Dendreon’s Provenge) for prostate cancer. 2011 saw the approval of ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy), and the awarding of a Nobel Prize for discoveries with profound implications for the development of cancer immunotherapies.

The importance for cancer immunotherapy of the discoveries represented by this Nobel Prize was vividly illustrated by the survival of Ralph Steinman an almost incredible four-and-a-half years after his being diagnosed with pancreatic cancer, while receiving a series of immunotherapy treatments along with conventional chemotherapy. (Although there is no way to know whether any of the treatments was responsible for Dr. Steinman’s unexpectedly long survival, participating researchers agree that this one-patient experimental treatment moved the cancer immunotherapy field forward.)

The Nature review concludes that despite the long history of cancer immunotherapy, these are early days for research and clinical practice in the field. (This is typical for a premature technology! Nevertheless, the review concludes, cancer immunotherapy has come of age.

The review goes on to suggest that cancer immuntherapies might be used in combination with the new targeted therapies, such as vemurafenib (Plexxikon/Roche’s Zelboraf; PLX4032) and crizotinib (Pfizer’s Xalkori), which were approved in 2011. These targeted agents can give “significant and sometimes spectacular responses in several indications.” However, even the most dramatic responses are usually followed by drug resistance and relapse. If targeted therapies can be given with the appropriate immunotherapies, it might be possible to achieve long-term, durable responses.

This is the last article on the Biopharmconsortium Blog for 2011. We at Haberman Associates wish you all a very Happy New Year, and look forward to interacting with you in 2012.
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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Blood cells

Our November 25, 2011 article on this blog focused on Ralph Steinman, one of the three winners of The Nobel Prize in Physiology or Medicine for 2011. That article focused on dendritic cell-based vaccines for cancer, and the application of this area of science and technology to treating Dr. Steinman’s own pancreatic cancer. Dr. Steinman died on September 30, 2011 after a four-and-a-half year battle with his disease, and was awarded the Nobel Prize three days later. He is the only person to ever have been awarded a Nobel Prize posthumously.

Now comes a Nobel Prize Essay, in the December 9, 2011 issue of Cell, entitled “Bridging Innate and Adaptive Immunity”, written by William E. Paul (Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH”). It is immediately followed by an obituary for Ralph Steinman, written by Antonio Lanzavecchia and Federica Sallusto (Institute for Research in Biomedicine, Bellinzona, Switzerland).

The Nobel Prize in Physiology or Medicine for 2011 was divided, one half awarded jointly to Drs. Bruce A. Beutler (Scripps Research Institute, LA Jolla, CA and University of Texas Southwestern Medical Center, Dallas, TX) and Jules A. Hoffmann [National Center of Scientific Research (CNRS), Strasbourg, France] “for their discoveries concerning the activation of innate immunity” and the other half to Dr. Ralph M. Steinman (Rockefeller University, New York, NY) “for his discovery of the dendritic cell and its role in adaptive immunity”. So the focus of this year’s Nobel Prize in Physiology or Medicine is on the two arms of the immune response–innate and adaptive immunity, and the relationship between the two.

Innate and adaptive immunity in the early to mid-20th century

Dr. Paul’s essay is a historical exposition of how researchers came to understand the basis of the innate and the adaptive immune responses, and how they work together as a coherent system. Adaptive immunity focuses on the ability of a vertebrate organism to “learn” to respond to a specific new antigen, and to “recall” and respond to an antigen that it had been exposed to in the past. Innate immunity focuses on the ability of nearly all multicellular life forms, including plants, to respond rapidly to protect themselves against pathogens, using the inflammatory system.

The essay begins with the first ever Nobel Prize given for a discovery in immunology, in 1908. This was shared by two pioneers in the field–Paul Ehrlich and Ilya (or Élie) Metchnikoff. Ehrlich pioneered the study of what is now called adaptive immunity. His work in immunology focused on the ability of humans and animals to develop specific antibodies to toxins such as tetanus toxin and diphtheria toxin. Metchnikoff pioneered the study of what is now called innate immunity. His work resulted in the discovery of phagocytosis, the process by which certain white blood cells can ingest and destroy harmful microbes.

As outlined in Dr. Paul’s article, most of the attention of immunologists between the awarding of the 1908 Nobel Prize and the modern era was on adaptive immunity, focused on the clonal selection theory of immunity and on discoveries in the the cellular (e.g., T cells) and humoral (e.g., antibodies) arms of adaptive immunity. A key practical application of the study of adaptive immunity–from Ehrlich’s day to the present–has been the development of vaccines.

Adjuvants and Charles Janeway’s pattern recognition hypothesis

However, mid-20th century immunology had a “dirty little secret”. Immunization with a pure antigen produces either a very weak immune response, or immune tolerance. In order to obtain a strong immune response, it is necessary to co-inject an adjuvant along with the antigen. The creation of adjuvants–which is involved not only in experimental immunology, but in such practical applications as vaccines–has been something of a black art. Adjuvants used in vaccines include  oil emulsions (which are thought to serve as depots for an antigen) and aluminum hydroxide (which is thought to act as an irritant). The most famous adjuvant in experimental immunology is complete Freund’s adjuvant, a strong adjuvant that consists of killed Mycobacteria tuberculosis bacteria in a water-in-oil emulsion. (Complete Freund’s adjuvant is too toxic for use in humans.)

In 1989, the late Dr. Charles Janeway (Yale University, New Haven, CT) proposed a hypothesis to explain the need for adjuvants; this hypothesis was very fruitful in stimulating further research on the immune response. Dr. Janeway hypothesized that the immune system required both an antigen/receptor interaction (as in classic adaptive immunity) and a recognition of pathogen-associated molecular patterns (PAMPs). PAMPs would be recognized by “pattern-recognition receptors” (PRRs), which would be broadly expressed by immune and inflammatory cells. Recognition of PAMPs by cells carrying PRRs would result in an innate immune response, which would be interpreted by cells of the adaptive immune system, the lymphocytes, as “permission” to mount an adaptive response when they recognized a specific antigen. In vaccination, the function of an adjuvant would be to provide the needed PAMPs.

Drs. Hoffman and Beutler and innate immunity

Beginning in 1996, Jules Hoffmann and his colleagues elucidated the innate immune response pathway in the fruit fly Drosophila, which enables the fly to produce the antifungal peptide drosomycin, and thus to become resistant to fungal infection. This pathway is initiated by the cell surface receptor Toll, and is homologous to the interleukin 1 (IL-1)/NF-κB signaling pathway, which is a key pathway in vertebrate immune and inflammatory responses.

Dr. Janeway and his colleagues then followed up on this study, in order to identify the corresponding microbial sensors in humans. They first scanned a molecular biology database, and identified a transcript that encoded a human homologue of Drosophila Toll, which they named a “Toll-like receptor” (TLR). Since Dr. Janeway and his colleagues did not know the ligand for their TLR, they constructed a chimeric molecule in which the extracellular domain of CD4 was linked to the cytoplasmic domain of the TLR. They expressed this chimera in a human monocyte cell line. When the chimera was crosslinked with an anti-CD4 antibody, NF-κB was activated, resulting in the production of the proinflammatory cytokines IL-1, IL-6, and IL-8. This showed that humans had at least one Toll homolog (Dr. Janeway’s TLR turned out to be TLR4) and that it controlled a signaling pathway similar to those controlled by Drosophila Toll or human IL-1. The ligands for human TLRs remained unknown, as did whether TLRs were the microbial sensors/PRRs postulated by Dr. Janeway had postulated.

It was Bruce Beutler who first determined the nature of TLR recognition specificity. In the 1990s, he worked to identify the genetic defect that rendered some mice unresponsive to lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, which acts as an endotoxin in humans and other mammals. He used two closely related mouse strains, one of which was responsive to LPS (the “wild type” strain), and the other that was unresponsive (the “mutant” strain). Upon stimulation with LPS, macrophages from the wild type mouse produced tumor necrosis factor alpha (TNFα), while macrophages from mutant mice did not. Dr. Beutler used positional cloning to determine the gene that was mutant in the LPS unresponsive mice. In 1998, he and his colleagues reported that that gene was Tlr4, which codes for the very same TLR identified by Dr. Janeway and his colleagues a year earlier. Dr. Beutler’s study indicated that LPS was a direct or indirect ligand for TLR4. It also showed that one type of molecule that would fulfill the criteria for a “PAMP”, namely LPS, working via TLR4 as a “PRR”, could activate the NF-κB-IL-1 pathway.

Since the initial identification of TLR4 by Dr. Beutler and his colleagues, other researchers have identified numerous other TLRs, which are activated by a variety of bacterial and viral molecules. These include such types of molecules as single- and double-stranded RNAs, CpG oligodeoxynucleotides, bacterial flagellin, lipopeptides, and zymosan, all of which fit with Dr. Janeway’s PAMP hypothesis. Different TLRs occupy different subcelluar locations–some are on the cell surface, others in intracellular vesicles. In addition to TLRs, other types of molecules may also act as PRRs.

Dr. Steinman, dendritic cells, and the unification of innate and adaptive immunity

Now we come to the work of Ralph Steinman and his colleagues on the role of dendritic cells in adaptive immune responses, and their relationship to innate immunity.

Antibodies (whether free antibodies or antibodies on the surface of B cells) can recognize molecules on the surface of pathogens. T cell receptors, however, recognize small antigenic peptides carried by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). This recognition, together with the activity of other signaling molecules on APCs, results in the activation of the T cell.

The requirement for an APC in T-cell activation was first recognized in the late 1960s and early 1970s. At that time, immunologists generally believed that macrophages and perhaps B cells were the major APCs. In 1973, Ralph Steinman and Zanvil Cohn identified mouse dendritic cells, which are rare cells in the spleen and lymph nodes that have a stellate morphology. In 1978, Dr. Steinman and his colleagues published evidence that dendritic cells had potent immunostimulatory activity, and were over 100 times as effective in immunostimulation as macrophages and B or T cells.

Researchers were initially skeptical about Dr. Steinman’s studies, largely based on the widely held view that the far more numerous macrophages were the major APCs. However, a series of studies by Dr. Steinman and his colleagues showed that dendritic cells are the key APCs for nearly all aspects of T cell activation, and that the potency of dendritic cells as APCs far exceeds that of macrophages and B cells.  Indeed, modern techniques that led to the deletion of dendritic cells result in a profound inability to mount adaptive immune responses.

Dendritic cells are found in perhaps every type of tissue, where they exist in an immature state. For example, the population of immature dendritic cells in the skin are known as Langerhans cells–these cells are illustrated in the figure at the top of our November 25, 2011 article. Immature dendritic cells in tissues act as sentinels of microbial infection, and function to capture antigens (e.g., antigens from pathogenic microbes, or from cells infected by viruses or bacteria). They also express TLRs.

When tissue dendritic cells are stimulated via their TLRs (e.g., by TLR4 binding to bacterial LPS), the dendritic cells change to a mature phenotype, which is specialized in antigen presentation. These mature dendritic cells migrate from the tissue into the draining lymph node. The stimulated dendritic cells in the lymphoid system upregulate class II MHC molecules and other cell surface molecules involved in antigen presentation, and they also produce cytokines involved in T cell activation. The dendritic cells thus activate T cells, and the antigens presented on their surface, as well as the pattern of cytokines they produce, determine the specificity and the type of activated T cells that will result from their actions.

Thus, the work of Dr. Steinman and his colleagues serves to integrate studies of innate and adaptive immunity, and to elucidate how these two branches of the immune system work together to enable humans and other vertebrates to mount immune responses against pathogens and other insults such as tumors.

Despite the major advances in the relationship between innate and adaptive immunity that have been made in recent years, their are still many unknowns. For example, there are minority types of T cells such as natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are conventionally thought to be involved in bridging innate and adaptive immunity. However, their functions are not well understood. Moreover, there are also numerous subsets of dendritic cells, and the functions of these subsets is also not well understood. These cell types, and other unknowns in the relationship between innate and adaptive immunity might, for example, be involved in the pathogenesis of steroid-resistant asthma, the most serious type of asthma.

Implications for drug discovery and development

Our previous article on Ralph Steinman and dendritic cells emphasized the development of dendritic cell vaccines, especially those for cancer. However the broad area of the relationship between innate and adaptive immunity has been and is expected to be a major factor in discovery and development of many types of drugs, vaccines, and immunotherapies.

• Numerous cytokine-based therapies (e.g., interferons, interleukins, and TNF-related therapeutics) have already been developed and marketed. Dr. Beutler himself was the co-discoverer of TNFα in 1985,  and now there are several types of TNF inhibitors on the market.

• In the vaccine area, Dr. Steniman’s work may allow researchers to design more effective adjuvants, a key need in the design of novel anti-viral and anti-cancer vaccines.

• Several companies are developing TLR modulators as drugs or vaccine adjuvants. These include TLR agonists and antagonists. For example, Pfizer is developing the oligonucleotide TLR9 agonist vaccine adjuvant CpG7909 (in Phase 3 trials with GlaxoSmithKline’s MAGE-A3 melanoma vaccine), and another oligonucleotide TLR9 agonist product agatolimod, in combination with trastuzumab (Genentech/Roche’s Herceptin) in treatment of breast cancer (Phase 2). [Pfizer’s TLR agonists were originally developed by Coley Pharmaceuticals (Cambridge, MA), which Pfizer acquired in 2008.] TLR antagonists in development include Eisai’s eritoran tetrasodium, a TLR4 antagonist in Phase 3 trials for the treatment of sepsis and septic shock.

• Research on the role of various immune cell populations that are thought to link innate and adaptive immunity (e.g. Th17 cells, NKT cells, and γδ T cells) in steroid-resistant asthma may lead to the design of new medicines to treat this serious condition.

There are likely to be numerous other drug discovery and development applications of research on the relationship between innate and adaptive immunity that will emerge as work in this very complex area continues.
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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Agios Nikolaos, Crete http://bit.ly/uNaFMW

On November 17, 2011, Agios Pharmaceuticals (Cambridge, MA), arguably the leader in cancer metabolism R&D, secured $78 million in an oversubscribed Series C financing.

The company intends to use the proceeds of this financing to advance its preclinical cancer metabolism therapeutics into the clinic, and to expand its R&D efforts into inborn errors of metabolism (IEMs). IEMs comprise a large class of inherited disorders of metabolism, most of which are defects in single genes that code for metabolic enzymes. These conditions have a high level of unmet medical need.

Investors participating in this round included Agios’ existing strategic partner Celgene, existing investors ARCH Venture Partners, Flagship Ventures and Third Rock Ventures, and several new, undisclosed investors, including three leading large public investment funds. In conjunction with the new financing, Perry Karsen, COO of Celgene, joined Agios’ Board of Directors.

Despite being only a preclinical-stage biotech company, and despite the tough early-stage biotech venture capital market, Agios has done very well in fundraising.  In April 2010, as discussed in a Biopharmconsortium Blog article, Agios secured a $130 million upfront payment in a strategic collaboration with Celgene. In October 2011, Celgene extended its collaboration with Agios from three to four years, including making an additional $20 million payment to Agios. According to a November 11, 2011 Fierce Biotech article, Agios has secured a total of over a quarter of a billion dollars in financing, beginning with its $33 million Series A round in July 2008.

Also according to Fierce Biotech, by bringing in public investors in its new financing round, Agios has taken a financing route that has enabled other biotechs to go public. For example, Ironwood Pharmaceuticals took this route. Agios’ CEO, David Schenkein, told Fierce Biotech that his management intends to build an independent company for the long term, including securing an investor base that could support a public offering.

The Biopharmconsortium Blog has been following Agios since December 2009. See our December 31, 2009 and April 23, 2010 articles. Also see our December 22, 2010 article on the reemergence of intermediary metabolism as an important field of biology, which highlighted the role of Agios in developing applications of this field to oncology therapeutics.

Recent research at Agios

More recently, Agios researchers and academic collaborators led by Agios Scientific Advisory Board member David Sabatini M.D., Ph.D (Whitehead Institute and Massachusetts Institute of Technology, Cambridge MA) published a study in the 18 August 2011 issue of Nature. In this study, the researchers demonstrated that 70% of estrogen receptor (ER)-negative human breast cancers exhibit amplification and elevated expression of the gene for phosphoglycerate dehydrogenase (PHGDH). PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased flux through this pathway. This in turn results in increased levels of α-ketoglutarate, which is a tricarboxylic acid (TCA) cycle intermediate. (The TCA cycle, the central pathway in intermediary metabolism, was illustrated in the figure at the top of our December 22, 2010 blog post).

Suppression of PHGDH [via RNA interference (RNAi)] in breast cancer cell lines with elevated PHGDH expression, but not in those without, causes a strong reduction in cell proliferation, a reduction in serine synthesis, and a reduction in levels of α-ketoglutarate. This result indicates that most ER-negative breast cancers are dependent on deregulation of the serine synthesis pathway, and that targeting this pathway may provide a novel therapeutic strategy for this subset of breast cancers.

In the September 2011 issue of Nature Genetics, Agios founder Lewis C. Cantley, Ph.D., and Agios advisor Matthew Vander Heiden, M.D., Ph.D., (Beth Israel Deaconess Medical Center/Harvard Medical School and MIT, respectively) published a report that provides further evidence that amplification of PHGDH and deregulated activity of the serine pathway are linked to the growth and survival of certain cancers, especially melanoma and subtypes of breast cancer. This study was carried out using a novel research method called metabolic flux analysis, which is an important component of Agios’s technology platform in cancer metabolism.

These studies provide additional validation for the field of cancer metabolism as a source of novel therapeutic strategies.

Pharmaceutical industry interest in cancer metabolism

Agios is not the only company that is active in the field of cancer metabolism. For example, Forma Therapeutics (Cambridge, MA) is also conducting R&D in this field. According to an article in XConomy Boston, Forma entered into a collaboration with Genentech in cancer metabolism on June 27, 2011. Under the agreement, Genentech will receive exclusive rights to acquire one of Forma’s early preclinical-stage cancer metabolism drugs. In return, Forma will receive an upfront payment, research support, R&D milestone payments, and development funding for that drug. If Genentech decides to acquire the drug after it has met its development goals, Forma will forgo any royalty payments. Instead, Genentech will make an asset buyout payment, which will be distributed to Forma’s investors. In addition, Forma will receive milestone payments on sales of the drug.

Thus Forma’s investors will receive a return on their investments, without the need for an acquisition or an initial public offering. Forma will thus remain an independent company, free to develop its other pipeline drugs, including any other of the approximately 8-10 cancer metabolism drugs that it has already discovered.

This deal, which is made possible by the industry’s keen interest in cancer metabolism-based therapeutics, suggests that Forma, like Agios, intends to remain an independent company over the long haul. Forma has raised over $50 million in venture capital so far, and has revenue-producing alliances with Novartis, Cubist, and the Leukemia & Lymphoma Society as well as Genentech.

Conclusions

Agios is leveraging the strong biotech/pharma industry interest in cancer metabolism, and its own leadership in the field, to build and to finance its R&D programs, and also its corporate development. However, as always, all will depend on the performance of the company’s compounds in the clinic. Dr. Schenkein is providing no information on the timeline for entry of Agios’ drugs into clinical trials. However, he says that the funding secured by Agios will provide the means to get its lead drugs through proof-of-concept studies in humans.

Interestingly, Agios Pharmaceuticals’ founders and management have a particular fondness for the Greek language. At the apex of Agios’ values is arete (ἀρετή), an ancient Greek word that connotes virtue, excellence, and courage and strength in the face of adversity. CEO Schenkein also adds another meaning, “living up to ones potential”.

“Agios” itself is a Greek word (Άγιος), which means “holy” or “Saint”. This is why I chose the figure at the top of this article. It is a photo of the town of Agios Nikolaos (Άγιος Νικόλαος), Crete, which is named for Saint Nicholas.
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