Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: April 2010

Agios Pharmaceuticals partners with Celgene

On December 31, 2009, we posted an article on this blog about Agios Pharmaceuticals (Cambridge, MA). Agios is a private research-stage biotech company that is developing a pipeline of oncology drugs based on targeting metabolic pathways in cancer cells. In our article, we focused on Agios’ research on mutations in the metabolic enzyme cytosolic isocitrate dehydrogenase (IDH1) as a causative factor in gliomas and glioblastomas. We also mentioned Agios’ research on pyruvate kinase M2 (PKM2) and aerobic glycolysis in cancer.

On April 15, 2010, it was announced that Agios and Celgene Corporation (Summit, NJ), a public biotechnology company with marketed products, had formed a strategic collaboration in the area of cancer metabolism.

Celgene markets Thalomid (thalidomide), which is approved by the FDA for treatment of multiple myeloma (MM). Thalidomide was notorious for causing birth defects in the late 1950s and early 1960s. However, beginning in the late 1990s, this drug has undergone a rehabilitation, provided that proper precautions are maintained to prevent its use in pregnant women and women who may become pregnant. Celgene has also been developing a class of thalidomide-derivative immunomodulatory drugs (IMiDs), which are designed to have greater efficacy against cancer and lesser toxicity than thalidomide. Of these drugs, Revlimid (lenalidomide) is approved by the FDA for treatment of MM and myelodysplastic syndromes (MDS) (life-threatening diseases of the bone marrow in which abnormally functioning immature hematopoietic cells are made; MDS can progress to acute myeloid leukemia in a substantial percentage of patients.) Celgene is researching additional indications for lenalidomide, and is also developing other IMiDs for various indications in cancer and inflammatory and neurodegenerative diseases.

Celgene’s Vidaza (azacitidine), a nucleoside metabolic inhibitor, is also indicated for the treatment of MDS. Celgene acquired Vidaza via its 2007 acquisition of Pharmion (Boulder, CO), which had developed the drug. Vidaza is an inhibitor of DNA methyltransferases (DNMT), which are enzymes that methylate DNA at specific sites and are important in epigenetic regulation. It was the first approved drug that works via an epigenetic mechanism. (Epigenetics is the study of heritable changes in gene function that do not involve changes in the nucleotide sequence of DNA. Major epigenetic processes include DNA methylation, modification of histones in chromatin, and RNA interference.)

Since Vidaza’s approval in 2004, two histone deacetylase (HDAC) inhibitors, which also modulate epigenetic regulation, have been approved. In late 2009, Celgene acquired the HDAC inhibitor romidepsin (Istodax) [approved in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL)], via its acquisition of Gloucester Pharmaceuticals (Cambridge MA).

Celgene is also developing several other anti-inflammatory drugs and kinase inhibitors.

The goal of the Agios/Celgene collaboration is to discover, develop, and commercialize novel oncology therapeutics based on Agios’ innovative cancer metabolism platform. Celgene sees the potential for early drug development opportunities in Agios’ IDH1 and PKM2 programs, as well as future opportunities based on new targets expected from Agios research programs. Celgene also sees opportunities to harness Agios’ R&D to expand its own pipeline in cancer and other diseases.

Under the terms of the agreement, Agios will receive a $130 million upfront payment, including equity. In return, Celgene will receives an initial period during which it will have the exclusive option to develop any drugs resulting from the Agios cancer metabolism platform. Celgene may also extend this exclusivity period through additional funding. Agios will lead discovery and early development for all cancer metabolism programs. During the period of exclusivity, Celgene will have an exclusive option to license any clinical candidates at the end of Phase I, and will lead and fund global development and commercialization of licensed programs. On each program, Agios may receive up to $120 million in milestones as well as royalties, and may also participate in the development and commercialization of certain products in the United States.

The Celgene collaboration continues Agios’ record of success in fundraising, and in gaining the recognition of the scientific and corporate communities. Despite the generally unfavorable financial environment for young biotech companies, Agios has raised, through alliances and investments, over $163 million in less than two years. This is despite the fact that the company has not one drug in the clinic. Agios expects to have a lead compound in the clinic some time in 2010, however. As is always the case, the validation of Agios’ innovative biology-driven platform awaits the results of human clinical trials and the attainment of regulatory approval.

Some notes on acute promyelocytic leukemia (APL)

In our last blog post (April 15, 2010), we discussed genetically engineered mouse cancer models, with emphasis on the work of Dr. Pier Paolo Pandolfi (Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center, Boston MA) and his colleagues. Part of that discussion was on Dr. Pandolfi’s earlier work on the construction of genetically engineered models of acute promyelocytic leukemia (APL), and the use of these models in designing therapies for that disease. As the result of these studies and the work of others, the major form of APL (in which leukemic cells express the fusion protein PML-RARα) is now treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3). What once was an invariably fatal disease now has about a 90% survival rate.

For those of you who are interested in the mechanisms by which ATRA and As2O3 work in treatment of APL: the 9 April 2010 issue of Science has a Perspective and a research report that focus on the mechanistic basis for the action of As2O3. For the mechanistic basis of the action of ATRA in APL, you may read a November 2008 research report published in Nature Medicine.

As soon as I posted the blog article on Dr. Pandolfi’s work, I received my 9 April issue of Science with the articles on As2O3 in APL. So I am passing this information on to readers of this blog.

Developing improved mouse models of cancer for drug discovery and development

The April 1, 2010 issue of The Scientist has an article, entitled “Building a better mouse”, on efforts of researchers to develop improved mouse models of cancer.

Current mouse models of cancer, mainly xenograft models in which human cancer cell lines are transplanted into immune deficient mice, are notoriously unpredictive of efficacy when oncology drug candidates are tested in them. This is a major factor in the high failure rate of oncology drugs in clinical trials. It is estimated that oncology drugs that enter human clinical trials have a 95 percent attrition rate, as compared to the 89 percent attrition rate for all clinical candidates. (Poorly predictive animal models are a major factor in the failure of clinical candidates in all therapeutic areas, but cancer models are particularly unpredictive.)

The Scientist article focuses on the ongoing “co-clinical mouse/human trials” now being led by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center). Dr. Pandolfi and his colleagues have constructed genetically engineered transgenic mouse strains that have genetic changes that mimic those found in human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In the co-clinical mouse/human trials, researchers simultaneous treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models.

The human clinical trials being “shadowed” by simultaneous studies in mice include Phase III trials of several targeted therapies for lung and prostate cancer. Xenograft models in which tumor tissue from the patients have been transplanted into immunosuppressed mice are being tested in parallel with the genetically engineered mouse models. This two-year project represents the most rigorous test to date of how well genetically engineered mouse models of cancer can predict clinical outcomes.

Dr. Pandolfi started in the mouse cancer model field with his studies of acute promyelocytic leukemia (APL). Unlike humans, mice do not naturally develop APL. Chromosomal translocations, in which the gene for the retinoic acid receptor alpha (RARα) (located on chromosome 17) becomes fused to one of several partner genes (known as “X genes”) on different chromosomes, are involved in the causation of APL. In over 98% of cases of APL, RARα is fused to the promyelocytic leukemia (PML) gene, located on chromosome 15. In a relatively small percentage of cases, RARα is fused to other X genes. An example of one of these other genes is the promyelocytic leukemia zinc finger (PLZF) gene, located on chromosome 11.

In studies in the late 1990s, Dr. Pandolfi and his colleagues constructed transgenic mice that expressed either PML-RARα or PLZF-RARα transgenes, in a promyelocytic-specific manner. (Expression of these transgenes in every cell of a mouse embryo results in embryonic lethality, and their expression in all early hematopoietic progenitors results in impaired myelopoiesis but no leukemia; these transgenic mice are thus not informative with respect to APL. The researchers were able to model PML only by expressing the transgenes specifically and exclusively in promyelocytes.)

The promyelocytic-specific PML-RARα-transgenic mice exhibit abnormal hematopoiesis over their first year of life, and between 12-14 months of age 10% of them develop APL.The promyelocytic-specific PLZF-RARα transgenic mice also exhibit a long latency period, and a subset of these mice eventually develops a leukemia that has features of human chronic myelogenous leukemia (CML).

Importantly, the above transgenic mouse models were useful in designing therapies for human patients. The leukemias in both the PML-RARα-transgenic mice and in patients with the PML-RARα translocation were responsive to treatment with all-trans retinoic acid (ATRA) (Genentech’s Vesanoid, generics). However, both the PLZF-RARα transgenic mice and patients with APL bearing the PLZF-RARα translocation were not responsive to ATRA. APL patients who initially responded to ATRA developed resistance to the drug, as did the PML-RARα transgenic mice. Using the PML-RARα transgenic mice, the researchers found that a combination of ATRA with arsenic trioxide (As2O3) (Cephalon’s Trisenox) cured the mice of leukemia. This later proved to also be true for human patients with APL bearing the PML-RARα translocation. Thus a cancer that once was uniformly fatal now has an approximately 90% survival rate.

Leukemic mice with the PLZF-RARα transgene were not responsive to As2O3. However, later studies have indicated that histone deacetylase inhibitors such as phenylbutyrate, in combination with ATRA, may be effective in treating these transgenic mice. These drug combinations may therefore be effective in APL patients with the PLZF-RARα translocation.

The success of Dr. Pandolfi’s genetically engineered mouse model in designing an effective therapy for the major type of APL illustrates the potential power of improved mouse models for cancer. Of course, this is a special case, since researchers were able to use the model to design an effective therapy using already-approved drugs. In most cases, researchers use the models to develop novel therapeutic strategies for a particular cancer, which involves discovery and development of new drugs or design of clinical trials using experimental drugs that have yet to be approved. The “co-clinical mouse/human trials” being run by Dr. Pandolfi and his colleagues may result in additional validation of the power of genetically engineered mouse models of cancer, and may thus encourage their adoption by companies developing new oncology drugs.

Our recently published book-length report, Animal Models for Therapeutic Strategies, includes a case study on a genetically engineered model of pancreatic cancer. Pancreatic cancer is one of the most lethal of cancers. Although models bearing transplanted human pancreatic tumors (i.e., xenograft models) are sensitive to numerous chemotherapeutic agents, human pancreatic cancers are insensitive to the same agents. Using a genetically engineered mouse model of pancreatic cancer, researchers hypothesized that the reason for the insensitivity of human pancreatic cancer (and of tumors in the mouse model) is impaired drug delivery. Researchers have been using the mouse model to develop novel therapeutic strategies to enhance drug delivery and thus to achieve improved treatment of this disease.

Our 2009 book-length report, Approaches to Reducing Phase II Attrition, includes a case study on adoption of genetically engineered cancer models by industry. Most animal models designed to enable researchers to develop novel therapeutic strategies for complex human diseases are developed by academic researchers. This includes genetically engineered cancer mouse models. However, most drugs are developed by industry, not academia. Industrial researchers are hampered in their ability to develop successful new oncology drugs by the poorly predictive xenograft models. Genetically engineered mouse models of cancer may help biotechnology and pharmaceutical company researchers to be more productive in oncology drug development, provided the corporate researchers can adopt these animal models for use in their discovery research and preclinical studies. However, for several reasons, industry has not widely adopted these models.

Our report discusses the barriers to adoption of these models, large pharmaceutical companies that are beginning to adopt the models, and the biotechnology company Aveo Pharmaceuticals, whose technology platform is based on in-licensing genetically engineered mouse cancer models from its principals’ academic laboratories and developing new models in-house. Aveo uses its models in its own internal drug discovery and development, and also collaborates with several large pharmaceutical companies. Aveo thus serves as a means of technology transfer from academia to industry, including both to its own internal programs and to its partners. The article in The Scientist also discusses Aveo’s research on genetically engineered mouse cancer models, and their use in the company’s internal drug development programs.