Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: November 2011

Cancer metabolism specialist Agios Pharmaceuticals continues its spectacular fundraising success


Agios Nikolaos, Crete

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.


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.

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.

Ralph Steinman, dendritic cell vaccines, and clinical trials


Dendritic cells in skin

Ralph M. Steinman, MD of the Rockefeller University (New York, NY) the discoverer of the dendritic cell and its central role in the immune system, died on September 30, 2011 at age 68 after a four-and-a-half year battle with pancreatic adenocarcinoma. On October 3, 2011, he was awarded half of the The Nobel Prize in Physiology or Medicine for 2011 “for his discovery of the dendritic cell and its role in adaptive immunity”. (The other half of the Prize was shared between Bruce A. Beutler and Jules A. Hoffmann “for their discoveries concerning the activation of innate immunity”.)

Previously, in 2007, Dr. Steinman had been awarded an Albert Lasker Basic Medical Research Award for the discovery of dendritic cells.

Dendritic cells are the principal antigen-presenting cells (APCs) in the immune system. They process antigenic material (for example, from invading bacteria and viruses, and from cancer cells), and present antigens on their surfaces to other types of immune cells, especially T cells. This results in antigen-specific activation of the T cells. Dendritic cells thus serve as the principal link between the innate and the adaptive immune system.

Nobel Prizes are not awarded posthumously, but the Nobel Committee was not aware that Dr. Steinman had died when they made the award. So the award still stands. Dr. Steinman thus has the distinction of being the only person to be awarded a Nobel Prize posthumously. The Nobel Foundation said, after reviewing the case, “The decision to award the Nobel Prize to Ralph Steinman was made in good faith, based on the assumption that the Nobel Laureate was alive.”

Nature published a “News in Focus” article on Dr. Steinman in its 13 October 2011 issue, written by Lauren Gravitz, a freelance writer and editor based in Los Angeles, California. The article details the attempt by Dr. Steinman and his colleagues to use dendritic cell-based immunotherapy to treat Dr. Steinman’s own cancer.

Ms. Gravitz met Dr. Steinman during her two-year tenure as a science writer in the Rockefeller University communications department.  While she was there, Dr. Steinman educated her on the complex field of dendritic cell biology. It was also during her time at Rockefeller that Dr. Steinman was diagnosed with advanced pancreatic cancer (in March 2007). Starting at the time of his diagnosis, Dr. Steinman and his colleagues began developing and using their experiential immunotherapies against that cancer. Thus Ms. Gravitz has been following this story from the beginning, and the October 2011 Nature article is the result.

An approved and marketed dendritic cell-based immunotherapy

Only one dendritic cell-based immunotherapy, Dendreon’s Sipuleucel-T (APC8015, Provenge) for treatment of advanced prostate cancer, has been approved by the FDA. The FDA approved it on April 29, 2010, and it is considered the first approved and marketed cancer vaccine. Sipuleucel-T was the first therapeutic cellular immunotherapy for cancer to demonstrate efficacy in Phase 3 clinical trials; this led to the FDA approval. However, Sipuleucel-T only extended mean survival by four months as compared to placebo in Phase 3 clinical trials. And the treatment is expensive, costing a total of $93,000 for the full treatment of three infusions.

Since Sipuleucel-T must be prepared specifically for each patient, using the patients own dendritic cells, a discussion of this product is relevant to the case of Dr. Steinman’s experimental treatment, which also involved autologous dendritic cells.

To prepare Sipuleucel-T, a patient’s autologous dendritic cells are purified from his or her blood. The cells are then sent to a Dendreon site, where they are incubated with a fusion protein, consisting of two moieties–the antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells, and a granulocyte-macrophage colony stimulating factor (GM-CSF) moiety, which is an immune cell activator. The resulting product, APC8015 or Sipuleucel-T, is returned to the infusion center and infused into the patient. The goal is to stimulate an immune response to tumor cells carrying the PAP antigen.

Although Sipuleucel-T is the the first therapeutic cellular immunotherapy for cancer to demonstrate efficacy in Phase 3 clinical trials in terms of overall survival, neither it, nor other cancer vaccines in clinical trials, gives complete responses. In our April 27, 2011 blog post, we discussed another therapeutic cellular immunotherapy for cancer, known as adoptive immunotherapy, which does give some complete responses in metastatic melanoma. However, this therapy is experimental and difficult to standardize, and has thus attracted no commercial interest. It is not approved by the FDA, and will not be covered by third-party payers. Thus the emphasis on dendritic cell vaccines.

Using dendritic cells to stimulate immune responses to Dr. Steinman’s pancreatic cancer

There are no approved cancer vaccines for pancreatic adenocarcinoma, which has a poor prognosis (survival measured in weeks or a few months in advanced cases). The disease is generally treated with the cytotoxic drug gemcitabine (Lilly’s Gemzar). However, this treatment appears to be mainly palliative in patients with advanced pancreatic cancer, giving an improved quality of life and a 5-week improvement in median survival. Most patients soon develop resistance to treatment with this agent. Thus, when Dr. Steinman (with the help of his colleagues) attempted to treat his own pancreatic cancer, he was venturing into the unknown.

According to Ms. Gravitz’ article, Dr. Steinman had a meeting with two immunotherapy researchers who had formerly been members of his lab–Michel Nussenzweig of Rockefeller and Ira Mellman of Genentech, shortly after he had been diagnosed with pancreatic cancer. The three planned a strategy to design potential therapies for Dr. Steinman’s cancer.  Dr. Nussenzweig would implant some of the tumor as xenografts in mice so that there would be enough material to work with. Dr. Mellman would start a cell line, so that drugs could be screened for activity in killing the cells. Other colleagues would look for mutations in tumor cell DNA that could be used to design drug treatments, and another would isolate surface peptides from the tumor cells so that they could be used as the basis of a vaccine. Meanwhile, Dr. Steinman would undergo conventional chemotherapy with gemcitabine  in combination with whatever experimental therapies that might be deemed to have potential to treat the cancer.

Dr. Steinman tried eight experimental therapies, one at a time. For each of these treatment, he and his colleagues submitted a single-patient, compassionate-use protocol to the FDA, and received approval from the agency. Among these treatments were three cancer vaccines. One of them was a form of BioSante’s GVAX (now Aduro’s GVAX, as of the February 2013 acquisition) . The product GVAX Pancreas for pancreatic cancer (which is now in clinical trials) is based on human pancreatic cell lines that have been engineered to secrete GM-CSF, and have then been lethally irradiated. In the case of Dr. Steinman’s treatment, cells from his own tumor were used instead of cell lines.

The other two cancer vaccines were dendritic cell-based immunotherapies, and used dendritic cells isolated from Dr. Steinman’s own blood. The first of these immunotherapies was developed by Argos Therapeutics (Durham, NC), of which Dr. Steinman was a cofounder. It involved transfecting Dr. Steinman’s dendritic cells with RNA derived from his own tumor. The resulting dendritic cells expressed tumor antigens on their surfaces, and were injected back into Dr. Steinman’s blood to potentiate the production of tumor antigen-specific T cells. The second immunotherapy, developed by researchers at the Baylor Institute for Immunology Research (Dallas, TX) involved loading Dr. Steinman’s dendritic cells with peptide antigens from the surface of his tumor. These were also injected back into Dr. Steinman’s blood, in order to potentiate a tumor-specific immune response.

Dr. Steinman also wanted to try combination therapies with ipilimumab. Dr. Steinman tried ipilimumab as a monotherapy, but never got the permissions needed to try the combination therapy. Ipilimumab is an immunomodulator that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) (a cell surface protein that transmits an inhibitory signal to T cells) to potentate an antitumor T-cell response. The FDA refused permission for the combination therapy despite his belief, and that of other leading immunologists, that the cancer vaccines were likely to work better in combination with ipilimumab. Ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy) was approved by the FDA in March 2011, and clinical trials of combination therapies of ipilimumab and dendritic-cell vaccines are in early stages.

The course of Dr. Steinman’s disease

Patients with advanced pancreatic adenocarcinoma typically have a poor prognosis. The median survival for locally advanced and for metastatic pancreatic cancer (advanced pancreatic cancer represents over 80% of individuals diagnosed with the disease) is about 10 and 6 months respectively. For all stages of pancreatic cancer combined, the 1- and 5-year relative survival rates are 25% and 6%, respectively.

However, Dr. Steinman survived for four-and-a-half years!

Did any of the treatments that Dr. Steinman received extend his life? No one can know, since with a one-patient experimental treatment there are neither controls nor statistical data as in properly controlled clinical trials.

Dr. Steinman appeared to be much more responsive to gemcitabine than is usually the case. And he had a measurable antitumor immune response, since approximately 8% of his cytotoxic T cells targeted his cancer. Was this due to his natural immunity, or due to the dendritic cell immunotherapies and/or other treatments that he received? Did Dr. Steniman’s antitumor immune response make his cancer more susceptible to gemcitabine than is usually the case? There is no way to know.

The implications of Dr. Steinman’s one-patient experimental treatment

According to Lauren Gravitz’ article, despite these unanswerable questions, Dr. Steinman’s treatment helped move the cancer vaccine field forward. For example, it showed that the leaders in the cancer vaccine field can work together as a team to design and carry out therapies. It also showed that conventional chemotherapy can be given in combination with cancer vaccines. And it also bolstered Dr. Steinman’s passionate belief that it is vitally important to move beyond in vitro studies and animal models into human studies of dendritic cell vaccines, especially given the limitations of animal models.

With respect to animal models and dendritic cell vaccines:

  • Dendritic cell immunotherapies designed for use in humans cannot be directly tested in standard animal models. For example, species specificity issues made direct testing of Sipuleucel-T in rodents impossible. Therefore, in preclinical studies researchers constructed “rodent equivalents” of Sipuleucel-T. These consisted of rodent APCs loaded with fusion proteins composed of either rat PAP (rPAP) fused to rat GM-CSF (rPAP•rGM-CSF) or human PAP (hPAP) fused to murine GM-CSF (hPAP•mGM-CSF), and these surrogate versions of Sipuleucel-T were tested in rodents.
  • Autologous dendritic cell immunotherapies have proven to be “remarkably safe” in human studies. Therefore, it may not be necessary to test for safety in animal models.
  • Dendritic cell biology is complicated. For example, researchers are still attempting to identify human dendritic cell subsets that correspond to known mouse dendritic cell subsets, especially subsets that appear to be the most promising for vaccine design. Therefore, the results of studies carried out in mice may not be directly applicable to humans. Moreover, the use of rhesus macaques for translational studies of vaccines based on dendritic cell biology is expensive.

Should autologous dendritic cell immunotherapies/vaccines for cancer be tested directly in humans, without the use of animal models for preclinical studies? In the case of the treatment of Dr. Steinman, the FDA allowed this to happen. Authorities in the field and regulatory agencies need to continue to discuss this issue.

Meanwhile, as stated at the end of Ms. Gravitz’ article, Anna Karolina Palucka of Baylor, a researcher who had been involved in Dr. Steinman’s treatment, says that she and her colleagues at Baylor are developing an immunotherapy program against pancreatic cancer based on the data from Dr. Steinman’s one-person trial. And Baylor will honor Dr. Steinman by opening a Ralph Steinman Center for Cancer Vaccines. This will be one of many tributes to a pathbreaking physician/scientist.

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.