Friday, June 11, 2010

We've moved!

Haberman Associates' Biopharmconsortium Blog has moved to our own site. You can now find it at

Please go to the new site, which has many new posts on it. We invite you to keep reading our blog, to subscribe to it, and to make useful comments to our blog posts if you so desire.

Saturday, June 5, 2010

We're moving!

Haberman Associates' Biopharmconsortium Blog is in the final stages of moving to our own site. You can now find it at

Our new site is now also powered by WordPress. We hope that you like the new format, and the WordPress features. We are new to WordPress, so will be making further improvements as we learn more about the system.

We hope that you will also make use of the other resources on our website,

As you may have noticed, many blogs that start out as Blogspot blogs (hosted by Google's Blogger) eventually change to WordPress, and migrate to the blogger's own site. Now our blog has migrated as well.

We shall keep this old blog online for awhile to help our visitors and subscribers to make the transition to the new site. However, all new posts will appear only on the new blog.

We hope that you will continue to visit the Biopharmconsortium Blog at its new home, and to subscribe to our posts. We also welcome your constructive comments as always.

Thursday, May 13, 2010

A frog jumps into the animal model lineup

The cover of the 30 April 2010 issue of Science bears a photo of a tadpole of the western clawed frog Xenopus tropicalis. In that issue is a report on the draft sequence of the genome of this organism, and a short companion news feature. The report on the genome emphasizes X. tropicalis’ role as an emerging animal model in developmental and evolutionary biology and in comparative genomics.

X. tropicalis is also an emerging animal model in biomedical research, potentially including development of disease models for drug discovery. We emphasize that potential role in Chapter 5 (“Xenopus tropicalis: an emerging model system”) of our book-length report, Animal Models for Therapeutic Strategies, published by Cambridge Healthtech Institute in March 2010.

The Nature news feature, authored by Elizabeth Pennisi, also cites the potential role of this frog in biomedical research. X. tropicalis has about 1700 genes that are related to human genes that have been linked to disease. Some of these diseases are type 2 diabetes, acute myeloid leukemia, congenital muscular dystrophy, alcoholism, and sudden infant death syndrome. In our book chapter, we discuss efforts to develop an X. tropicalis model of congenital spinal muscular atrophy (SMA). We also discuss studies aimed at using the frog as an animal model of human congenital heart disease, and for developing novel therapies for these conditions.

The related frog Xenopus laevis (known as the African clawed frog) is an old animal model that has long been used in developmental and cell biology research. However, X. laevis (pictured above) is genetically intractable, since its genome is allotetraploid, having been formed by fusion of diploid genomes from two different species. This makes genetic and genomic studies with this frog difficult. In contrast, X. tropicalis is diploid. X tropicalis also has a much shorter generation time than X. laevis, and is much smaller, thus requiring less space and making breeding and experimentation much more feasible than with X. laevis.

Some of the same researchers that have been participating in the X. tropicalis genome sequencing project have been developing genetic tools such as transgenics, genetic screening, and gene knockdown using antisense morpholinos. With the determination of the genome sequence, X. tropicalis may join the zebrafish as a lower vertebrate animal model in developing novel therapeutic strategies for human diseases.

Elsewhere on the animal model genome front, researchers recently published a draft sequence of the genome of Hydra magnipapillata. Hydra, a freshwater cnidarian or polyp, has long been a staple of high school and university biology lab courses, so is a favorite of many biologists. The University of California at Irvine, whose researchers participated in the Hydra genome project along with many others (e.g., leading genomics researcher J. Craig Venter), has long been a center of Hydra research, beginning in the late 1960s.

Hydra is used as an animal model in the study of regeneration, body patterning, and stem cell biology. The determination of the genome sequence of Hydra will facilitate these studies, as well as studies of comparative genomics and evolutionary biology.

Hydra may also be of interest for biomedical research. As discussed in the genome report, Hydra possesses four homologues of the Myc oncogene, which is involved in human cancers and also regulates pluripotency and self-renewal of mammalian stem cells. Myc is also central to the pluripotentency of Hydra stem cells. The researchers also found genes in the Hydra genome that are linked with Huntington's disease and with the beta-amyloid pathway of Alzheimer's disease.

Tuesday, May 11, 2010

More on anti-aging research: Continuing controversy, opportunity, and good news

1. Continuing Controversy

In our blog post on 10 February 2010, we discussed the controversy over Sirtris/GlaxoSmithKline’s reseveratrol formulation, and its second-generation sirtuin-1 (SIRT1) activators. Researchers at Amgen and Pfizer found that the apparent in vitro activation of SIRT1 by these compounds was an artifact of the experimental method used by Sirtris researchers. The Amgen group found that the fluorescent SIRT1 peptide substrate used in the Sirtris assay is a substrate for SIRT1, but in the absence of the covalently linked fluorophore, the peptide is not a SIRT1 substrate. Although resveratrol appears to be an activator of SIRT1 if the artificial fluorophore-conjugated substrate is used, resveratrol does not activate SIRT1 in vitro as determined by assays using two other non-fluorescently-labeled substrates.

Last month, I attended two meetings at which this controversy was discussed. One was the Bio-IT World Conference & Expo in Boston. At that conference, Christoph Westphal (then CEO of Sirtris) gave a keynote address. In that presentation, Mr. Wesphal stuck with the story that Sirtis’ compounds and its assays are valid. The day after his presentation, Mr. Westphal resigned as Sirtris’ CEO, and now is the head of GSK’s SR One venture fund. He and other Sirtris and Vertex founders also started the Longwood Founders Fund in February of this year.

At the other meeting (which was Harvard-related), one of the most respected leaders of the longevity-related pathway field (whose name I am withholding) stated that the whole resveratrol/sirtuin-activator story is nonsense. He did, however, concur with our views on anti-aging pathways as expressed in our November 8, 2009 article on this blog. We do not go as far as calling the resveratrol story nonsense, but remain unconvinced of the mechanistic basis for resveratrol action pending further evidence.

Meanwhile, Derek Lowe’s “In the Pipeline” blog has a discussion of Mr. Wesphal’s talk at the Bio-IT conference.

In its 25 March 2010 issue, Nature also has a News Feature centered upon the controversy. This article (written by Cambridge MA-based Nature reporter Heidi Ledford) basically says that the controversy remains unsettled, but that several laboratories are working to resolve the assay issue. These include corporate researchers at Sirtris, Leonard Guarente of MIT (another leader in the longevity-related pathway field, who is co-chair of Sirtris’ scientific advisory board), and Anthony Sauve of Weill Cornell Medical School (also a member of Sirtris’ scientific advisory board).

2. Opportunity

There was a review of longevity-related pathways in the 16 April 2010 issue of Science. It covers all the bases of anti-aging research in yeast, worms, flies, and mammals, with an emphasis on the TOR and insulin-like growth factor-1 (IGF-1) pathways. Sirtuins and resveratrol rate a minimal mention in the review.

Cynthia Kenyon, another leader in the longevity pathway field, published a review on the genetics of aging in a special Nature Insight section on aging in the 25 March 2010 issue. In this review, Dr. Kenyon discussed the panoply of aging-related pathways in worms, flies, and mice, especially the insulin/IGF-1 and TOR pathways, as well as several other biomolecules and biological processes. Dr. Kenyon discusses sirtuins, but notes the unknowns in aging-related mechanisms involving sirtuins, especially in mammals. She also notes the difficulties in interpreting results with resveratrol. In addition to the issue with the assays involving the fluorescent substrate, she notes that although (in studies conducted by Sirtris researchers and their academic colleagues) resveratrol has been found to extend the lifespan of mice fed a high-fat diet, it did not extend the lifespan of mice fed a normal diet. Dr. Kenyon also cited the results of studies with resveratrol in yeast, worms, and flies that are not consistent with the hypothesis that resveratrol extends lifespan by acting as a sirtuin activator.

The bottom line of the discussion in the two reviews in Science and Nature is that lifespan is controlled by sets of complex, interacting pathways. Sirtuins represent only one control point in these pathways, which might not be the most important one. Thus no one company “owns” the anti-aging field in terms of drug discovery and development, and there is a lot of opportunity out there. Even Mr. Westphal stated as much in his Bio-IT World presentation.

Interestingly, Dr Kenyon notes that different closely related animals can have large differences in lifespan. For example, rats live for three years, but squirrels for 25. She speculates that differences in longevity might be easily evolvable, and mechanisms by which lifespan changes during evolution (perhaps involving mutations in regulatory genes or that affect rates of respiration) might constitute novel intervention points.

3. Good News

Now for some good news about aging. In an article in the 25 March 2010 Nature Insight section by James W Vaupel (Max Planck Institute for Demographic Research, Rostock, Germany, University of Southern Denmark, Odense, and Duke University), the author presents evidence that human senescence (i.e., deterioration with age)—at least in advanced countries—has been postponed by a decade. This process, first noted in 1994, is continuing. The factors that are making this possible are prosperity (which promotes good health) and medicine (including medical and surgical interventions to prevent or treat disability, and public health efforts). These two factors enable people to reach old age in better health, as well as promoting better health in older people.

This ongoing postponement of senescence and mortality provides a foundation for ongoing anti-aging research and eventual treatments based on that research. (One must remember, however, that regulatory agencies as well as the practical considerations of drug development will not permit researchers and companies to utilize mortality as an endpoint in clinical trials. Companies must therefore develop putative “anti-aging drugs” for specific diseases associated with aging, such as diabetes, cancer, various cardiovascular indications, and dementia.) The postponement of senescence also has profound implications for how one lives one’s life, as well as for social policy and the practice of medicine.

Friday, April 23, 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.

Monday, April 19, 2010

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.

Thursday, April 15, 2010

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.

Thursday, March 18, 2010

Some notes on this blog

We started the Biopharmconsortium Blog in July of 2009, so it is relatively new. Since that time, we have posted 21 articles (not including this one), 7 of which were posted in 2010.

The blog has gradually been picking up a following, and it recently made a "Top 50 Biotech Blogs" list. Thanks to Medicareer for honoring our blog in that way. (Haberman Associates has no business or financial relationship with Medicareer, nor do I even know the people there.)

The 21 articles now posted on the blog may at first glance seem to be on random subjects—commentary on recent news and/or recent published scientific reports or business articles, and a few announcements and commentaries on Haberman Associates publications or events. However, there is a strong theme of R&D strategy—especially productive R&D strategies—running through the whole blog.

When we first began the blog, the masthead at the top read “Your place for discussion of scientific and business issues in the biotechnology, pharmaceutical, diagnostics, and research products industry". Earlier this month, we changed the masthead to read “Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.” The new heading better reflects what the blog has become since we started it, and also reflects the fact that it is a business blog. Nevertheless, our blog is also a service to the life science community, including companies, academic institutions, and disease organizations and patient advocates. We continue to welcome your comments and discussions of our articles.

Friday, March 12, 2010

“Animal Models for Therapeutic Strategies” published by Cambridge Healthtech Institute

On March 5, 2010, Cambridge Healthtech Institute (CHI) announced the publication of our new book-length report, Animal Models for Therapeutic Strategies. This new Insight Pharma Report discusses the use of animal models to develop new paradigms for drug discovery and development in important human diseases. The report also discusses strategies for developing more predictive animal models of drug efficacy. Poorly predictive animal models are a major reason for Phase II and Phase III pipeline drug attrition. Thus this new report complements our May 2009 Insight Pharma Report, Approaches to Reducing Phase II Attrition.

We have an article, published in Genetic Engineering News in 2004, on the use of animal models in developing novel therapeutic strategies for the treatment of Alzheimer’s disease (AD), available free on our website. This article, based on our 2004 animal models report that is now out of print, gives examples of the use of animal models (the mouse, C. elegans, Drosophila, and the zebrafish) in developing therapeutic strategies. These animal model studies were key to the eventual development of nearly all the pipeline drugs now in the clinic for AD, as well as the development of alternative hypotheses to the dominant amyloid hypothesis (and therapeutic strategies based on them).

The 2010 report includes discussions of using animal models to develop therapeutic strategies for such diseases as Parkinson’s disease, polycystic kidney disease (PKD), autism, and various types of cancer. It also includes discussion of development of emerging animal models, from fish to frogs to mammals.

In the “emerging mammalian model systems” chapter, we include a discussion of the “reemergence” of the laboratory rat, an old animal model that had been eclipsed by the mouse in the era of knockout mice and genomics. Many of you have no doubt seen the ads from SAGE Labs (Sigma Advanced Genetic Engineering) in scientific and trade journals, announcing that “knockout rats are finally here”. Some of you may also have seen the Nature news article Return of the rat. We cover the technologies behind the reemergence of the rat, and the companies and research groups that are driving this development, in our report. As we also discuss in the report, some of the new technologies used in developing rat models are also being applied to other mammalian species.

The report also covers the issue of why it is so difficult to model the complex diseases that are the major focus of current drug discovery and development efforts in the pharmaceutical/biotechnology industry, and strategies that researchers are using to develop more predictive animal models, especially more predictive mammalian models.

For more information on the report, or to order it, see the CHI Insight Pharma Reports website.

Wednesday, March 10, 2010

Plexxikon’s discovery of PLX4032, a selective targeted therapeutic for metastatic melanoma

In our March 2, 2010 blog post, we focused on a Phase I clinical trial of Plexxikon/Roche’s PLX4032, in which clinical researchers led by Keith T. Flaherty achieved a dramatic breakthrough in treatment of metastatic melanoma. Now we shall discuss the discovery of the drug itself, PLX4032.

In 2002, a research consortium based at the Wellcome Trust Sanger Institute in the U.K. found B-Raf somatic missense mutations in 66% of malignant melanomas (as well as in a subset of other cancers). V600E (valine substituted by glutamic acid at position 600) accounted for 80% of these mutant forms of B-Raf. The V600E mutation causes destabilization of the inactive conformation of B-Raf kinase, shifting the equilibrium toward the catalytically active conformation.

B-Raf is a serine/threonine protein kinase that is a component of an intracellular pathway that mediates signals from growth factors. B-Raf is regulated by binding to Ras. In turn, B-Raf activates MEK (mitogen-activated protein kinase kinase), which activates ERK (extracellular signal-regulated kinase). Activated ERK goes on to upregulate transcriptional pathways that promote cellular proliferation and survival.

Growth factors → →Ras→ B-Raf→ MEK→ ERK→ →upregulation of cell proliferation and survival

Growth factor signaling via Ras also controls other signaling pathways that upregulate cell proliferation, notably the PI3K-Akt (phosphatidylinositol-3-OH kinase-Akt) pathway.

The Sanger researchers found evidence that cells carrying B-Raf(V600E) no longer require Ras function for proliferation. This would mean that melanoma cells carrying this mutation could proliferate independently of growth factor signaling, resulting in the runaway proliferation characteristic of the malignant phenotype.

These results suggested that B-Raf(V600E) would be a good target for novel kinase inhibitors to treat malignant melanoma. The first such kinase inhibitors to be developed, although they had inhibitory activities at low nanomolar concentrations against B-Raf (both wild-type and mutant), were not successful in the clinic, due to their inhibition of multiple nonspecific targets and/or their poor bioavailability. Plexxikon researchers therefore set out to discover inhibitors that are highly selective for B-Raf(V600E). The result was the discovery of PLX4032.

The discovery of PLX4720 (a tool compound or chemical probe related to PLX4032) by Plexxikon researchers and their academic colleagues, and its preclinical validation, is described in a 2008 publication, Tsai et al. Plexxikon used its proprietary “scaffold-based drug design” technology platform to discover PLX4720. Scaffold-based drug design involves synthesizing sets of low-molecular weight “scaffold-like’” compounds. These compounds interact (typically at low affinity) with many members of a protein family by targeting their conserved regions.

In the B-Raf study, the researchers identified protein kinase scaffolds by screening a select library of 20,000 150-350-dalton compounds for inhibition of a set of three structurally characterized protein kinases at a concentration of 200 micromolar (μM). Of this library, 238 compounds were selected on the basis of their inhibition of the kinases by at least 30% at the 200 μM concentration. Each of the compounds was cocrystallized with one if the three kinases, Pim-1. Using this method, the researchers found that 7-azaindole bound to the ATP-binding site of Pim-1 kinase. They further modified this compound by adding side chains on the 3 position of 7-azaindole, resulting in a “scaffold candidate” with increased affinity for the ATP binding site of PIm-1 and other kinases. The researchers further modified this scaffold, based on structural data from other kinases. Ultimately, they cocrystallized their modified compounds with wild-type B-Raf and B-Raf(V600E), and optimized the structure of their compounds to give a compound, PLX4720, with selectivity for B-Raf(V600E) and against wild-type B-Raf and other kinases. This process (including the relevant chemical and protein structures) is illustrated in Figure 1 of Tsai et al.

In biochemical assays, the researchers found that PLX4720 inhibited B-Raf(V600E) at low nanomolar concentrations, and was 10-fold more selective for B-Raf(V600E) than for wild-type B-Raf, and was even more selective for B-Raf(V600E) than for other kinases.

Surprisingly, in cellular assays, PLX4720 is over 100-fold (not 10-fold) more selective in inhibiting proliferation of tumor cell lines that bear B-Raf(V600E) as compared to those that bear wild-type B-Raf. Moreover, as first found by researchers at Pfizer and their academic collaborators, a specific inhibitor of MEK (Pfizer’s CI-1040) is also similarly selective for tumor cell lines bearing B-Raf(V600E). This suggests that the B-Raf-MEK-ERK pathway is critical for the proliferation of B-Raf(V600E) cells, but not for cells bearing wild-type B-Raf. [For example, tumor cells that bear wild-type B-Raf might use the PI3K-Akt pathway to upregulate pathways that control cell proliferation independent of ERK signaling, while tumor cells that bear B-Raf(V600E) cannot.]

The B-Raf-MEK-ERK pathway dependence of B-Raf(V600E) cells may in part be related to feedback inhibition of B-Raf (and other isoforms of Raf). Activated ERK can phosporylate wild-type Raf isoforms at specific inhibitory sites. This results in downregulation of signaling via the Raf-MEK-ERK pathway. However, in cells bearing B-Raf(V600E), this feedback inhibition is disabled, resulting in uncontrolled signaling.

The Plexxikon researchers (Tsai et al.) tested PLX4720 against tumor xenograft models. Oral administration of PLX4720 blocked tumor growth, and in 4 out of 9 cases caused tumor regressions, in mice with tumor xenografts bearing B-Raf(V600E). Treatment with PLX4720 was well tolerated, and showed no adverse effects. Growth of tumor xenografts bearing wild-type B-Raf was not affected by PLX4720. In mice with tumors bearing B-Raf(V600E), PLX4720 blocked B-Raf-MEK-ERK pathway signaling, as demonstrated by immunohistochemical assays.

The exquisite specificity of PLX4720/PLX4032 for B-Raf(V600E) as compared to wild-type B-Raf was made possible by Plexxikon’s structure-guided “scaffold-based drug design” technology. Other structure-guided drug design technologies, such as fragment-based lead design, as is carried out in several companies, might be used to design comparably specific drugs.

The discovery of PLX4720/PLX4032 is an example of the use of new-generation chemistry technologies (or the revival of the old, and now disused natural products chemistry approach), coupled with biology-driven drug discovery strategies, to discover promising new drugs. We have discussed this strategy in several articles on this blog. (For example, see here and here).

Despite the promising results seen in Phase I clinical trials of PLX4032, it must be emphasized that the establishment of the efficacy and safety of this compound awaits the completion of the ongoing Phase III trials. Moreover, despite the dramatic regressions and increased survival seen in the Phase I trials, all the patients apparently eventually suffered relapses. Dr. Flaherty, as discussed in our earlier blog post, sees the need for combination therapies to effectively combat metastatic melanoma. In early 2009, Dr. Flaherty and his colleague Keiran S Smalley published a mini-review on potential strategies for developing such combination therapies.

Tuesday, March 2, 2010

Bringing targeted therapy of metastatic melanoma into the clinic--the crucial role of translational researchers

During the week of February 22, 2010, the New York Times (NYT) ran a three-part series on a Phase I trial in 2008/2009 of a targeted therapy for metastatic melanoma, a disease that is almost always fatal within a year. The trial was led by Keith T. Flaherty, M.D. (then at the University of Pennsylvania in Philadelphia, and now at the Dana-Farber Cancer Center in Boston). The drug was PLX4032, developed by Plexxikon, which is co-developing the compound with Roche. PLX4032 is a kinase inhibitor, which specifically targets the V600E mutant of the B-Raf oncoprotein. This is the most common somatic mutation found in human melanomas. Researchers believe that B-Raf(V600E) is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation. PLX4032 entered Phase III clinical trials in 2009.

The NYT series, authored by Amy Harmon, focused on the stories of several patients, and on the dogged efforts of Dr. Flaherty to help his patients and to prove the value of targeted therapy. Although the targeted kinase inhibitor imatinib (Novartis’ Gleevec/Glivec) produces complete responses in the majority of treated patients in the chronic phase of CML (chronic myelogenous leukemia) and long-lasting remissions in many of these patients, many researchers believe that this is a special case, and they cite evidence that targeted therapy, especially in solid tumors, almost never produces durable responses. But Dr. Flaherty pressed on with his quest to prove the value of targeted therapy, despite this skepticism.

A key point in the story was when the original formulation of PLX4032, at the highest dose that patients could absorb, produced neither adverse effects nor clinical responses. Because of his belief in targeted therapy, and in this particular drug, Dr. Flaherty convinced Roche to reformulate the drug to enable patients to absorb a higher dose. With the higher doses of the drug made possible by the new formulation, the researchers saw dramatic clinical responses in the great majority of patients whose tumors contained B-Raf(V600E). Responses lasted an average of nearly 9 months, a dramatic breakthrough in treatment of metastatic melanoma.

As the series ended, Dr. Flaherty was working with his colleagues and the pharmaceutical industry to find ways to enable the testing of combination therapies of targeted drugs (including PLX4032) that might result in long-lasting remissions in patients with metastatic melanoma. Meanwhile, Plexxikon and Roche have taken PLX4032 into Phase II clinical trials and now into Phase III.

The NYT series is essentially a human-interest story. I commend it to all researchers, executives, and consultants in the industry whose work does not involve contact with patients, since creating products that can help patients is what our work is all about.

Dr. Flaherty reminds me, and others who have commented on this story, of Brian J. Druker, M.D. at the Oregon Health Sciences University in Portland. It was Dr. Druker’s efforts, centered on helping patients and proving the value of targeted therapy, that was the driving force behind the development of imatinib (Novartis’ Gleevec/Glivec). Without this effort (conducted in collaboration with biochemist Nicholas B. Lydon, then at Novartis), the whole field of kinase inhibitors for targeted therapy of cancer would not have emerged. Dr. Flaherty, as well as several other oncologists, is continuing this worthy tradition.

As pointed out to me by a leading Boston-area academic researcher in a cancer-related area, the NYT series did not give credit to the academic researchers who identified the role of B-Raf in cancer, and especially the role of B-Raf(V600E) in human melanoma. (For that matter, it did not credit the Plexxicon researchers who discovered PLX4032.) She said that the series sounded as if only one person, Dr. Flaherty, was responsible for the development of PLX4032. Moreover, the development of imatinib was made possible by decades of academic research on the target of the drug, Bcr-Abl, a fusion protein formed as the result of a chromosomal translocation. Drs. Druker and Lydon thus were not solely responsible for the development of imatinib either.

The academic researcher has a point. However, some industry commentators take a contrary point of view, downplaying the role of academic researchers in the drug discovery/development process and giving most of the credit to industry.

For years, we have taken the point of view that biology-driven drug discovery and development (arguably the most successful drug discovery/development strategy in the post-genomic era) requires the contributions of both academia and industry, and that more effective collaboration between academia and industry would result in more effective drug discovery and development. (See also my 2005 letter to the editor of BusinessWeek.)

It is basic research, usually in academic laboratories, that has resulted in the very best validated targets. Basic research on a particular target typically takes years or even decades (as in the case of Bcr-Abl). Many of the breakthrough drugs that have emerged in the past 10-15 years (as well as numerous promising pipeline drugs now in clinical testing) were made possible by this research. In contrast, large-scale “target validation” testing in industry more often than not results in targets whose role in normal physiology and in disease is poorly understood. This is an important cause of clinical attrition in drug development.

Nevertheless, it is industry, not academia, which uses this basic research to create drugs. In particular, it is industry that bears the enormous economic risk of drug development, especially of late-stage clinical trials.

Translational researchers, who are involved in taking the results of academic research and/or of discovery research in industry, and translating them into therapies that benefit patients, are—or should be—a key component of the drug discovery-development process. Drs. Druker and Flaherty are two outstanding examples.

However, at least some sectors of academia (and of governmental policy-makers and the media) are suspicious of the type of closer industry-academic collaboration that is needed to produce more effective translation of basic and drug-discovery research into the clinic. An editorial in the 25 February issue of Nature notes that there has been criticism of the recent hiring of William Chin, Lilly’s senior VP for discovery and clinical research, to be the executive dean for research at Harvard Medical School. The critics charge that strong research collaborations between academia and industry will inevitably result in conflicts of interest. The Nature editorial supports institutional policies that require disclosure of links between academic researchers and industry, but deplores the views of influential critics who believe that any collaboration between academic researchers and industry “corrupts” the academic research enterprise.

In addition to Nature, some leading academic researchers say that it is time for industry and the academic medical community to fight back against the critics, rather than appeasing them with ever more restrictive conflict-of-interest policies. These researchers note that the main purpose of medical research is not to publish scientific papers, but to translate this knowledge into therapies that benefit patients. This requires effective collaboration between academia and industry. We agree.

Friday, February 19, 2010

Across-the-board R&D cuts will not solve the pharmaceutical industry’s productivity crisis

The big topic in pharmaceutical news lately has been layoffs, including layoffs due to major cuts in R&D. For example, the popular pharmaceutical industry blog “In the Pipeline” has had one story after another, in late 2009 and early 2010, about R&D cutbacks, including many comments from people affected by the reductions in staff. Such companies as Pfizer, GlaxoSmithKline (GSK), AstraZeneca, Sanofi-Aventis, and most recently Merck have been affected.

Layoffs, and cuts in R&D, were expected in companies that underwent big mergers in 2009, especially Pfizer/Wyeth and Merck/Schering-Plough. Much of the value of large-scale mergers to shareholders is realized by cost savings due to restructurings (especially elimination of redundancies between the two merging companies) and reductions in staff.

The more fundamental reason that motivates large pharmaceutical companies to enter into big mergers and/or to undertake restructurings that include reductions in R&D programs and in staff is the need to deal with the combination of major challenges facing the industry, which some experts have called a “perfect storm”. The most important of these challenges are low R&D productivity, increasing R&D costs, and expirations of patents of blockbuster drugs.

From the point of view of a financial analyst, the move to cut internal pharmaceutical R&D is a matter of “sheer economics”. Putting more and more money into R&D without any increase in numbers of high-valued new drugs, especially in the face of patent expiries, is a losing proposition. Why not then cut internal R&D, and concentrate on in-licensing pipeline drugs from biotech companies? In-licensed drugs, and drugs developed by smaller pharmaceutical and biotech companies, have shown a higher rate of success in development (measured in terms of percentage of drugs entering clinical trials that reach the market) than drugs developed internally by large pharmaceutical companies.

The problem with this line of reasoning is that we’ve been here before. Big Pharma went through a previous wave of large-scale mergers and restructurings in the late 1990s and early 2000s. These megamergers and restructurings enabled the surviving companies to realize significant cost savings from staff reductions, and in some cases enabled them to acquire blockbuster drugs (notably Pfizer’s acquisitions of Lipitor [atorvastatin] and Celebrex [celecoxib]). However, these gains were temporary, since the industry faced an even worse set of threats in the 2008-2010 period than it faced in 1997-2003. And the disruptions in R&D staffs and programs caused by these moves contributed to a reduction of the capacity of merged or restructured companies to carry out productive R&D.

Moreover, the move toward a strategy of depending more on in-licensing of pipeline drugs from smaller companies (or acquiring the companies outright) comes at a very bad time. The financial crisis of 2008-2009 resulted in a virtual drying up of venture capital investment in private biotech companies (especially start-ups), and in the inability of development stage private and public biotech companies to raise funds in the capital markets. In the resulting cash crunch, many biotech companies ceased work on all but their most advanced pipeline drugs, and laid off large numbers of their researchers.

For example, here in the Boston area, Dyax, then a development-stage public company, adopted cash-conserving measures in 2009. It stopped early-stage research on internal (as opposed to partnered) drug candidates, and laid off 36% of its staff. It also sold its shares at low prices in the public markets to raise what cash it could. On December 1, 2009, the FDA approved Dyax’ lead drug, the plasma kallikrein inhibitor ecallantide (Kalbitor) for the treatment of hereditary edema, a rare genetic disorder. The FDA approval process had not been easy (for example, Dyax received a “complete response” letter from the FDA last year). Other development stage biotech companies have not been as fortunate, and venture capital for start-up companies (such as spin-offs of university laboratories) has been very hard to come by.

Unless large pharmaceutical companies are prepared to serve as venture capitalists on a much larger scale than they are currently doing, and to invest in earlier-stage, riskier companies and drug candidates, they may be competing for fewer and fewer good in-licensing opportunities. This will result in bidding up the prices for what opportunities exist, and a dearth of drug candidates for pharmaceutical companies to develop. The venture capital market for early-stage biotechs appears to be easing somewhat, and a few companies (some of which have been discussed in this blog) have managed to obtain funding. However, much uncertainty remains.

Moreover, large pharmaceutical companies will need to have internal researchers (or consultants) who are competent to evaluate in-licensing candidates, and internal researchers who can collaborate with their smaller licensing partners. One critical area for such collaboration is translational medicine, in order to predict the outcomes of treatment with in-licensed drug candidates and to increase the probability of clinical success.

The real issue is that the pharmaceutical industry cannot use mergers, restructurings, across-the-board R&D cuts, and layoffs to solve its productivity crisis, except in the short term. It has to work on the actual problem—how to increase the productivity of R&D.

We recently authored two publications that analyzed the nature of the R&D productivity problem, and which outlined solutions. These are an article, “Overcoming Phase II Attrition Problem”, published in Genetic Engineering News (GEN) and available free on our website, and a book-length report, Approaches to Reducing Phase II Attrition, available from Cambridge Healthtech Institute (CHI). In summary, we proposed a two-part strategy to increase rate of success in drug development:
  • Identify those targets and drugs that have the best chance of success in the discovery phase, mainly via focusing on biology-driven drug discovery (i.e., strategies based on understanding of disease mechanisms).
  • Employ early stage proof-of-concept (POC) clinical trials to weed out drugs and targets that do not achieve POC.
With respect to this strategy, it is interesting that two large pharmaceutical companies, the Swiss pharmaceutical giants Novartis and Roche, are not emphasizing layoffs and R&D cuts. Both have biology-driven R&D strategies.

In a recent Reuters article entitled “Killing research no certain cure for Big Pharma”, Novartis’ chairman and former CEO Daniel Vasella is quoted as saying, "You can improve margin up to self-dissolution. You save and you save and you cut costs and cut costs -- and then you have no sales anymore and then you have a collapse."

We have discussed Novartis’ R&D strategy in several articles on this blog, notably our July 20, 2009 article “Biology-driven drug discovery: a ‘disruptive innovation’?”

Roche came by its biology-driven R&D strategy via its 2009 acquisition of Genentech. As we also noted in our July 20 blog post, Roche has been integrating itself with Genentech to become essentially a large biotech company.

In striking contrast to his colleagues in most Big Pharma companies, Roche’s CEO Severin Schwan is optimistic about the future of drug discovery and development in the pharmaceutical industry. He believes that the industry is “poised for a quantum leap into a golden age”, because of continuing discoveries in disease pathways that will enable researchers to design targeted drugs to address unmet medical needs. Roche has no plans to diversify into generics, over-the-counter drugs, or vaccines, as other Big Pharmas have been doing in order to mitigate the lack of high-valued new products coming from their R&D operations.

In addition to overall reductions in R&D and shifting toward greater reliance on in-licensing of drugs, some Big Pharma companies have been taking other, more selective measures in their attempts to cut R&D costs and improve R&D performance. One approach has been to get out of therapeutic areas that are no longer productive for a particular company, and to focus on more promising areas. For example, GSK is eliminating its R&D in depression, anxiety, and pain, and focusing its neuroscience efforts on neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. It is also building a new R&D unit that will focus on rare diseases. These seem to be sensible moves.

With respect to rare diseases, in addition to adopting the “Genzyme strategy” (which seems to be GSK’s main goal), some rare diseases share pathways with more common diseases. As discussed in our July 20 blog post, Novartis has been developing drugs that address these common pathways, beginning with the rare disease and then expanding to the more common diseases.

Another strategic move by several Big Pharma companies is to shift away from small-molecule drugs toward a greater emphasis on biologics. Biologics have shown a higher rate of success in development than small-molecule drugs. However, kinase inhibitors also have shown a higher success rate than other oncology agents that have entered clinical trials in the last 15 years. As with biologics, kinase inhibitors have been developed via biology-driven drug discovery, resulting in much stronger clinical hypotheses for the mechanisms of action of these drugs. Might not shifting toward biology-driven R&D strategies, rather than just shifting toward biologics, enable companies to improve their R&D productivity, both for small-molecule and large-molecule drugs?

Shifting toward biology-driven R&D strategies should also enable companies to reduce R&D costs, by reducing reliance on the costly and unproductive technology-driven “industrialized drug discovery” approach. However, unlike across-the-board R&D cuts, this more selective approach should result in improved R&D productivity.

Wednesday, February 10, 2010

Update on anti-aging biology, sirtuins, and Sirtris/GlaxoSmithKline

On November 8, 2009, we posted an article entitled “Anti-aging biology: new basic research, drug development, and organizational strategy" on this blog. This article focused on new findings in anti-aging biology, their applications to drug discovery and development, and on how this field has affected the organizational strategy of GlaxoSmithKline (GSK).

GSK acquired Sirtris for $720 million in 2008. Later that year, GSK appointed Christoph Westphal, the CEO and co-founder of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD). The CEEDD works to develop external alliances with biotech companies, with the goal of acquiring promising new drug candidates for GSK’s pipeline. Michelle Dipp, who was the vice president of business development at Sirtris at the time of GSK’s appointment of Dr. Wesphal, became Vice President and the head of the US CEEDD at GSK. Thus GSK has been using its relationship with Sirtris to restructure its organizational strategy, attempting to become more “biotech-like” in order to improve its R&D performance.

Now we learn that several research groups and companies have been questioning whether resveratrol (a natural product derived from red wine which has been the basis of Sirtris’ sirtuin-activator platform), as well as Sirtris’ second-generation compounds, may not modulate the sirtuin SIRT1 at all. Thanks to Derek Lowe’s “In the Pipeline” blog for the information. This issue was also covered in a second post on the same blog. It was also covered by articles in the 15 January 2010 issue of New Scientist and in the January 26, 2010 issue of Forbes. Nature also covered this story in an online news article.

In a report published in December 2009, researchers at Amgen found evidence that the apparent in vitro activation of SIRT1 was an artifact of the experimental method used by Sirtris researchers. The Amgen group found that the fluorescent SIRT1 peptide substrate used in the Sirtris assay is a substrate for SIRT1, but in the absence of the covalently linked fluorophore, the peptide is not a SIRT1 substrate. Although resveratrol appears to be an activator of SIRT1 if the artificial fluorophore-conjugted substrate is used, resveratrol does not activate SIRT1 in vitro as determined by assays using two other non-fluorescently-labeled substrates.

More recently, researchers at Pfizer published a study of SIRT1 activation by resveratrol and three of Sirtris’ second-generation sirtuin activators (which the Pfizer researchers synthesized themselves, using published protocols). These researchers also found that although these compounds activated SIRT1 when a fluorophore-bearing peptide substrate was used, they were not SIRT1 activators in in vitro assays using native peptide or protein substrates. The Pfizer researchers also found that the Sirtris compounds interact directly with the fluorophore-conjugated peptide, but not with native peptide substrates.

Moreover, the Pfizer researchers were not able to replicate Sirtris’ in vivo studies of its compounds. Specifically, when the Pfizer researchers tested SRT1720 in a mouse model of obese diabetes, a 30 mg/kg dose of the compound failed to improve blood glucose levels, and the treated mice showed increased food intake and weight gain. A 100 mg/kg dose of SRT1720 was toxic, and resulted in the death of 3 out of 8 mice tested.

The Pfizer researchers also found that the Sirtris compounds interacted with an even greater number of cellular targets (including an assortment of receptors, enzymes, transporters, and ion channels) than resveratrol. For example, SRT1720 showed over 50% inhibition of 38 out of 100 targets tested, while resveratrol only inhibited 7 targets. Only one target, norepinephrine transporter, was inhibited by greater than 50% by all three Sirtris compounds and by resveratrol. Thus the Sirtris compounds have a different target selectivity profile than resveratrol, and all of these compounds exhibit promiscuous targeting.

Sirtris and GSK dispute the findings of the Amgen and Pfizer researchers. One issue raised by Sirtris is that the Sirtris compounds synthesized by Pfizer may have contained impurities, resulting in the toxicity and lack of specificity of the compounds in vivo. Researchers associated with Sirtris and GSK also contend that although the Sirtris compounds only work with fluorophore-conjugated peptides in vitro, they appear to increase the activity of SIRT1 in cells. However, other researchers assert that since resveratrol interacts with many targets in cells, the results of the cellular assays are difficult to interpret. In the Forbes article, GSK’s CEO Andrew Witty is quoted as calling the dispute over the activity of the Sirtris compounds “a bit of a storm in a teacup”. He says that the compounds that Pfizer tested in mice are not the same ones that Sirtris and GSK are currently testing in clinical trials for treatment of diabetes and cancer. (Sirtris’ compounds in clinical trials, discussed in the next paragraph, are in fact different from the ones tested by the Pfizer researchers.)

Currently, Sirtris is testing its proprietary formulation of resveratrol, SRT501, in a Phase IIa clinical trial in cancer. The company reports that SRT501 lowered blood glucose and improved insulin sensitivity in patients with type 2 diabetes in a Phase IIa trial. Sirtris is also testing a second-generation SIRT1 activator, SRT2104, in Phase IIa trials in patients with metabolic, inflammatory and cardiovascular diseases. SRT2104 was found to be safe and well tolerated in Phase I trials in healthy volunteers. Sirtris is also testing another second-generation SIRT1 activator, SRT2379, In Phase I trials. SRT2379 is structurally distinct from resveratrol and from SRT2104.

As we discussed in our original blog post, Elixir Pharmaceuticals is also developing various sirtuin inhibitors and activators for metabolic and neurodegenerative diseases and for cancer. One of Elixir’s products, the SIRT1 inhibitor EX-527, was in-licensed by Siena Biotech (Siena, Italy) in 2009, and was entered into Phase I clinical trials in January 2010. Siena Biotech is developing this compound for treatment of Huntington’s disease.

Despite the dispute over whether Sirtris’ compounds are real SIRT1 activators, the numerous studies on the biology of sirtuins are still valid. Companies with assays that use native peptide substrates and are amenable to high-throughput screening could use these assays to discover novel sirtuin activators. For example, Amgen published a report in 2008 describing such assays. The ability of companies such as Amgen and Pfizer to commercialize such novel sirtuin activators would depend on whether they could overcome the intellectual property position of Sirtris (and Elixir). Since Amgen and Pfizer are working in this area, this indicates that they believe that they can do so.

The efficacy of high doses of resveratrol in improving metabolic parameters of mice fed a high-calorie diet is also not invalidated by the Amgen and Pfizer studies. However these studies cast doubt on the mechanisms by which resveratrol exerts these effects. The apparent efficacy of SRT501 in improving metabolic parameters in patients with type 2 diabetes in a Sirtris Phase IIa trial is consistent with the mouse studies.

Finally, as we discussed in our November 8, 2009 blog post, longevity is controlled by numerous interacting pathways, which may provide at least several targets for drug discovery. Researchers are hard at work to gain additional understanding of these pathways, and some companies are working to discover and develop compounds that modulate these targets. For example, several companies are developing AMPK activators, as discussed in our original blog post. And numerous research groups are reportedly attempting to find drugs that act similarly to rapamycin in increasing lifespan in mice (the main focus of our November blog post), without rapamycin’s immunosuppressive effects.

Thursday, January 28, 2010

Update on liraglutide (Novo Nordisk’s Victoza)—approved by the FDA for treatment of type 2 diabetes

On October 25, 2009, we posted an article on this blog that focused on liraglutide (Novo Nordisk’s Victoza) as a potential treatment for obesity. As we stated in the article, at that time liraglutide had recently been approved in Europe for treatment of type 2 diabetes. The drug was also awaiting FDA approval for that indication.

On January 26, 2010, after a 21-month review, the FDA approved liraglutide for treatment of type 2 diabetes. This followed the approval of the drug in Japan a week earlier.

The approval process for liraglutide in the United States had not been straightforward. In April 2009, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 6-6 (with one abstention) on approval versus disapproval of liraglutide, because of the finding of thyroid C-cell tumors in studies of the drug in rodents. There is no evidence, however, that liraglutide has ever caused thyroid tumors (or other types of cancer) in humans.

As a result, the drug’s label carries a black box warning of the risk for thyroid cancer, and requires a risk-mitigation strategy. However, as we discussed in our article, liraglutide has an advantage over most antidiabetic drugs in that it induces weight loss. It also has a low risk of triggering hypoglycemia, which is a problem with several antidiabetic drugs.

As we also discussed in our article, liraglutide belongs to a class of agents known as incretin mimetics. The first incretin mimetic to reach the market was exenatide (Amylin/Lilly’s Byetta). Exenatide, which is approved for type 2 diabetes, also induces weight loss. Physicians therefore sometimes prescribe exenatide off-label for treatment of obesity. However, exenatide has a relatively short half-life, and must be self-injected twice a day. In contrast, liraglutide has a longer half-life than exenatide, and is self-injected only once a day. Amylin and Lilly are developing a longer-acting, once-weekly formulation of exenatide (known as Exenatide Once Weekly) for treatment of type 2 diabetes. The new formulation is being developed in collaboration with Alkermes, which developed the long-acting drug-delivery technology. Amylin, Lilly, and Alkermes are awaiting FDA approval of the NDA for Exenatide Once Weekly.

Exenatide’s label carries no warning with respect to thyroid cancer. However, it does carry a warning concerning the risk of drug-associated pancreatitis. Moreover, the FDA Advisory Committee raised concerns that the risk of thyroid C-cell tumors may be a class effect of incretin mimetics. The FDA has mandated that Amylin conduct postmarketing studies to deal with this concern; depending on the results of the studies, a warning of a risk for thyroid cancer may (or may not) appear on the labels of Byetta and Exenatide Once Weekly.

Despite these safety concerns, the stocks of not only Novo Nordisk, but also Amylin and Alkermes, rose on the news that the FDA had approved Victoza. Stock analysts predicted that the approval of Victoza implied that the FDA was likely to approve Exenatide Once Weekly later in 2010.

Our October 2009 blog post discussed exenatide and liraglutide in the context of the obesity drug market, and specifically drugs that treat both type 2 diabetes and obesity. Neither exenatide not liraglutide is approved for treatment of obesity in any jurisdiction, however. As we discussed in our original article, Novo Nordisk has been developing liraglutide for obesity, but Amylin is developing other, earlier-stage drugs for that indication despite the weight loss benefits seen with exenatide. Novo Nordisk had been waiting for FDA approval of liraglutide for treatment of type 2 diabetes before proceeding with further development of the drug for obesity. Now that the company has obtained that approval, we expect that development of liraglutide for obesity will be restarted.

Tuesday, January 26, 2010

ApoE4 and Alzheimer’s disease: stratified medicine and development of new therapeutic strategies

In the December 15, 2009 issue of Neurology, a research report by Stephen Salloway and his colleagues at the Butler Hospital and Brown University (Providence, RI) and an editorial by Dan Kaufer and Sam Gandy (University of North Carolina at Chapel Hill) focus on a Phase II multicenter placebo-controlled clinical trial of Elan/Wyeth’s bapineuzumab (AAB-001) in patients with mild to moderate Alzheimer's disease (AD). (Wyeth is now part of Pfizer.) (A subscription is required to read the full text of both of these articles.) Bapineuzumab is a monoclonal antibody (MAb) drug that is specific for amyloid-β (Aβ) peptide. The dominant paradigm among AD researchers and drug developers is that the disease is caused by aberrant metabolism of Aβ, resulting in accumulation of neurotoxic Aβ plaques. This paradigm is known as the “amyloid hypothesis”.

The overall result of the study by Salloway et al. was that there was no difference in cognitive function between patients in the drug-treated and the placebo groups. However, the study did not have sufficient statistical power to exclude the possibility that there was such a difference. About 10% of patients treated with the agent also experienced vasogenic edema (VE), which was reversible. (Cerebral VE is the infiltration of intravascular fluid and proteins into brain tissue, as the result of breakdown of the blood-brain barrier.)

Retrospective analysis of the data suggested that bapineuzumab-treated patients who were not carriers of the apolipoprotein E epsilon4 allele (ApoE4) showed improved cognitive function as compared to placebo treatment, and that they had a lower incidence of VE than ApoE4 carriers. The ApoE4 polymorphism is the only known, well-characterized genetic risk factor associated with the development of late-onset AD. Of the three common isoforms of ApoE, ApoE3 is the most common, followed by ApoE4 and ApoE2, respectively. Unlike ApoE4, the ApoE2 allele appears to protect against development of AD. Some researchers estimate that allelic variations in ApoE may account for over 95% of AD cases.

In the study by Salloway et al., nearly two-thirds of the AD patients carried one or more ApoE4 alleles; thus only the remaining one-third of patients appeared to show positive effects of bapineuzumab treatment according to the retrospective analysis. However, the idea that the drug is efficacious in ApoE4 noncarriers is only a hypothesis, which will require prospective clinical trials to confirm. Elan and Pfizer are now conducting large Phase III clinical trials of bapineuzumab, which have prospectively segregated enrollment into ApoE4 carrier and noncarrier groups.

The hypothesized association of ApoE4 noncarrier status of AD patients with bapineuzumab efficacy and safety has been used as a case study in workshops on stratified medicine sponsored by the FDA, MIT, and industry partners in 2009 and 2010. You can read about the October 2009 workshop here and here. The most recent workshop was held at MIT on January 19, 2010. In these workshops, two case studies were discussed: the use of diagnostic tests for the HER2 receptor in identifying breast cancer patients who are likely to benefit from treatment with trastuzumab (Genentech/Roche’s Herceptin), and the bapineuzumab/ApoE4 case. The HER2/ trastuzumab relationship is well known and well characterized, and is considered to be a paradigm of stratified medicine. This contrasts with the bapineuzumab/ApoE4 association, which remains a hypothesis pending the results of the Phase III prospective clinical studies.

A growing minority of researchers is skeptical that the amyloid hypothesis is sufficient to account for AD pathogenesis in all stages of the disease or in various disease subpopulations, and they are investigating other pathways that may contribute to the disease, either in combination with the amyloid pathway or as alternative mechanisms. We have discussed alternative hypotheses for AD pathogenesis in a 2004 article published in Genetic Engineering News (available on our website), and in book-length reports published by Cambridge Healthtech Institute in 2006 and in 2009.

The search for alternative hypotheses takes on added urgency because of the clinical failure of several AD drugs that had been designed based on the amyloid hypothesis. These include Neurochem’s (now Bellus Health) Alzhemed (3-amino-1-propanesulfonic acid) and Myriad Pharmaceuticals’ Flurizan (tarenflurbil), both of which failed in Phase III clinical trials. Based on the overall results of the Phase II trial of bapineuzumab, most researchers and industry commentators would add bapineuzumab to the list, unless the stratified Phase III trial shows that the drug is significantly efficacious and safe for ApoE4 noncarriers.

Since ApoE4 carrier status is such a prominent risk factor for developing late-onset AD, might ApoE4 itself be a target for drug discovery in AD? Drs. Kaufer and Gandy suggest that such an approach might be fruitful, whatever the outcome of the Phase III trial of bapineuzumab. Several academic laboratories have been investigating mechanisms by which ApoE4 may be involved in the pathobiology of AD. You may read two recent papers on this subject here and here. ApoE4 may contribute to AD pathogenesis via multiple mechanisms, including by causing synaptic deficits and mitochondrial dysfunction in neurons, and by inducing endoplasmic reticulum stress leading to astrocyte dysfunction.

Given the prominence of ApoE4 expression as a risk factor for AD, the study of the mechanistic basis of ApoE4’s role in AD pathobiology needs greater attention. Hopefully, this research will lead to the development of novel therapeutic strategies for AD.