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.

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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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.

Citric acid cycle

The 3 December issue of Science featured a Special Section on metabolism, headed by an introductory article entitled “Metabolism is Not Boring”.

Way back in the 1920s through the 1950s, intermediary metabolism was a hot field of biology. This culminated in the awarding of the Nobel Prize in Physiology or Medicine in 1953 to Hans Krebs “for his discovery of the citric acid cycle” and Fritz Lipmann “for his discovery of co-enzyme A and its importance for intermediary metabolism”.

As most of you know, that same year, 1953, Watson and Crick published the structure of DNA, which won them the Nobel Prize in Physiology or Medicine in 1962. This began the great era of molecular biology. As the result of the overwhelming success of molecular biology, the study of intermediary metabolism receded into the background. Answering most questions in leading-edge biology required little or no attention to intermediary metabolism. However, as discussed in the review article by Steven L. McKnight included in the Special Section, metabolism is coming to the forefront of biomedicine again. Research problems that require both consideration of molecular biology and of metabolism now appear as interesting and important challenges.

Considerations of intermediary metabolism have always been important in the study of what are known as metabolic diseases, especially type 2 diabetes and obesity and such related conditions as dyslipidemia. However, as detailed both in the McKnight article and in an article by Arnold J. Levine and Anna M. Puzio-Kuter, the study of intermediary metabolism has now also become important in cancer, with the discovery that alterations in metabolic enzymes can result in the production of “oncometabolites” that support the growth of cancer cells.

In an article on this blog dated December 31, 2009, we discussed research in cancer metabolism that is behind the technology platform of Agios Pharmaceuticals (Cambridge, MA). In that article, we highlighted the discovery that mutations in a metabolic enzyme, cytosolic isocitrate dehydrogenase (IDH1) are a causative factor in a major subset of human brain cancers. The wild-type form of IDH1 catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, the mutant forms of IDH1 catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG appears to be an oncometabolite that is involved in the progression of low-grade gliomas to lethal secondary glioblastomas. Agios researchers and their academic collaborators later implicated mutations in isocitrate dehydrogenase enzymes and the production of the oncometabolite 2HG in the pathogenesis of acute myelogenous leukemia (AML).

Also discussed in our article was the Warburg effect, in which cancer cells carry out aerobic glycolysis (conversion of glucose to lactate, with the production of 2 molecules of ATP even in the presence of oxygen). In contrast, most normal mammalian cells metabolize glucose to CO2 and water via glycolysis coupled to the mitochondrial citric acid cycle, generating 36 molecules of ATP. Agios scientific founder and signal-transduction pioneer Lewis Cantley showed that there is a connection between growth factor-mediated signal transduction and aerobic glycolysis in cancer cells. In particular, Dr. Cantley and his colleagues found that pyruvate kinase M2 (PKM2) is a link between signal transduction and aerobic glycolysis. PKM2 binds to tyrosine-phosphorylated signaling proteins, which results in the diversion of glycolytic metabolites from energy production via mitochondrial oxidative phosphorylation to anabolic processes required for rapid proliferation of cancer cells.

The McKnight and Levine and Puzio-Kuter papers also discuss the Warburg effect in cancer cells, and the role of mutations in several metabolic enzymes that contribute to malignant phenotypes. The McKnight article notes that in addition to dominant mutations in isocitrate dehydrogenates, rare recessive mutations in fumarate hydratase and succinate dehydrogenase are also associated with cancer. Mutations in the genes for these enzymes, coupled with loss of the wild-type allele, result in elevated intracellular levels of fumarate and succinate, respectively. These appear to act as oncometabolites that can induce activation of the hypoxia response pathway, which triggers the induction of aerobic glycolysis (the Warburg effect) and angiogenesis.

The Levine and Puzio-Kuter paper also discusses the role of oncogenes and tumor suppressor genes and their signaling pathways in regulating metabolism and in particular in inducing the Warburg effect. For example, p53 regulation suppresses the Warburg effect and promotes mitochondrial oxidative metabolism. Thus the loss of p53 function seen in most human cancers tends to promote aerobic glycolysis. Other signaling pathways that have been implicated in cancer-associated changes in metabolism include the Akt and mTOR pathways, which are frequently altered by mutations in key genes (e.g., mutations in PTEN and amplifications of such growth factor receptors as Her2 and EGFR) in cancer.  Deregulation of these pathways activates the hypoxia response pathway, thus triggering the Warburg effect.

Levine and Puzio-Kuter suggest that research aimed at a deeper understanding of how cancer-associated signaling pathways regulate biochemical metabolic pathways and trigger the Warburg effect, and the role of the Warburg effect in the pathogenesis of cancer, may lead to novel drug discovery strategies in oncology.

The Special Section on metabolism also includes an article on autophagy, a process by which cells break down cellular components in order to eliminate damaged biomolecules and organelles or to provide substrates for metabolism in case of starvation. Although autophagy promotes the health of cells and can prevent degenerative diseases, it can also enable cancer cells to survive in nutrient poor tumors.

There is also a review by Jay Keasling on metabolic engineering to produce such substances as natural product drugs, chemicals, and biofuels. Metabolic engineering is a branch of synthetic biology that engineers metabolic pathways to produce such substances, hence the inclusion of this review in the Special Section on metabolism. We have several articles on synthetic biology on this blog, most of which focus on metabolic engineering and its role in drug manufacture and drug discovery.

All in all, the 3 December Special Section on metabolism is worth reading by basic researchers, and by drug discovery and development researchers in biotechnology and pharmaceutical companies. It may broaden your perspectives, and lead to new ideas for R&D or partnering, especially in oncology drug discovery.
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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.