Two recent research reports may point the way to developing more effective, personalized therapies for two deadly women’s cancers for which their are currently few treatment options–triple-negative breast cancer and ovarian cancer. The approach followed in both reports is to use gene expression analysis to stratify each of the two diseases into subtypes. Researchers can then use gene expression and order aspects of the biology of each subtype to design subtype-specific targeted therapies, whether single drugs or drug combinations. If the drugs (whether approved or experimental) already exist, they can be tested in clinical trials, stratified by subtype. If no appropriate drugs exist, researchers can discover the drugs based on subtype-appropriate drug targets.

Triple-negative (TN) breast cancer refers to breast cancers that are negative for expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. [HER2 is the target of trastuzumab (Roche/Genentech’s Herceptin) and lapatinib (GlaxoSmithKline’s Tykerb/Tyverb)]. Lacking all three receptors, it cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. TN breast cancer is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy regimens typically results in early relapse and metastasis.

TN breast cancers constitute approximately 25 percent of breast cancers. They are diagnosed most often in younger women, those who have recently given birth, women with BRCA1 mutations, and African-American and Hispanic women.

There is a Triple Negative Breast Cancer Foundation, which was founded in 2006 in honor of a mother in her mid-thirties who died of the disease.

Ovarian cancer, the ninth most common cancer in women, caused nearly 14,000 deaths in the U.S. in 2010. In its earliest stages, its symptoms are usually very subtle and mimic other, less serious diseases. As a result, it is usually detected at later stages in which treatment is more difficult and gives poorer outcomes. The 2001 five-year survival rate was 47%, up from 38% in the mid-1970s. This compared to an overall survival rate for cancer of 68% in 2001, up from 50% in the mid-1970s.

Treatment usually involves surgery and chemotherapy, and sometimes radiotherapy. Surgery (preferably by a gynecological oncologist) may be sufficient for earlier-stage tumors that are well-differentiated and confined to the ovary. In this early-stage disease (which represents about 19% of women presenting with ovarian cancer), the five-year survival rate is 92.7%. However, about 75% of women presenting with ovarian cancer already have stage III or stage IV disease, in which the cancer has spread beyond the ovaries. Then the prognosis is much poorer, and the vast majority of patients will have a recurrence.

The triple-negative breast cancer study

The TN breast cancer study was carried out by researchers at the Vanderbilt-Ingram Cancer Center (Vanderbilt University, Nashville, TN), and published in the 1 July 2011 issue of the Journal of Clinical Investigation. In this study, the researchers analyzed gene expression profiles from 21 publicly available breast cancer data sets, and identified  587 cases of TN breast cancer (by non-expression of mRNAs that encode ER, PR, and HER2). Using cluster analysis, they identified six TN breast cancer subtypes:

  • two basal-like subtypes (BL1 and BL2),
  • an immunomodulatory (IM) subtype (i.e., expressing genes involved in immune cell processes)
  • a mesenchymal (M) subtype
  • a mesenchymal stem–like (MSL) subtype
  • a luminal androgen receptor (LAR) subtype.

Using gene expression analysis, the researchers identified TN breast cancer model cell lines that were representative of each of these subtypes. On the basis of their analysis, the researchers predicted “driver” signaling pathways, and targeted them pharmacologically as a proof-of-principle that analysis of gene expression signatures of cancer subtypes can inform selection of therapies.

BL1 and BL2 subtypes had higher expression of genes involved in the cell cycle and response to DNA damage, and model cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched for expression of genes involved in the epithelial-mesenchymal transition (EMT), and growth factor-related pathways in model cell lines responded to the PI3K/mTOR inhibitor BEZ235 (Novartis, now in Phase 1 and 2 for solid tumors) and to the ABL/SRC inhibitor dasatinib [Bristol-Myers Squibb’s Sprycel, currently approved for treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), and under investigation for treatment of solid tumors). The LAR subtype was characterized by androgen receptor (AR) signaling, and included patients with decreased progression-free survival. LAR model cell lines were uniquely sensitive to the AR antagonist bicalutamide (AstraZeneca’s Casodex/Cosudex, currently approved for the treatment of prostate cancer and hirsutism, and under investigation for treatment of androgen receptor-positive, ER negative, PR negative breast cancer).

The researchers plan to use the TN breast cancer subtype-specific model cell lines for further molecular characterization, to identify new components of the “driver” signaling pathways for each subtype. These pathways can be targeted in further drug discovery efforts. The subtype-specific cell lines can also be used in preclinical studies with targeted agents, and in identification of subtype-specific biomarkers that can potentially be used in stratifying TN breast cancer patients so that they might be treated with the best agents for their disease.

The ovarian cancer study

The ovarian cancer study was carried out by the Cancer Genome Atlas Research Network [a consortium of academic researchers jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI)], and published in the 30 June 2011 issue of Nature. In this study, the researchers analyzed mRNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas, as well as the DNA sequences of exons from coding genes in 316 of these tumors. Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85 percent of all ovarian cancer deaths.

The researchers found that nearly all of the high-grade serous ovarian cancers (HGS-OvCa) studied had mutations in the TP53 gene, which encodes the p53 tumor suppressor protein. On the basis of their gene expression (mRNA) signatures, the researchers divided the population of HGS-OvCa into four subtypes:

  • an immunoreactive subtype (i.e., expressing genes involved in immune cell processes)
  • a differentiated subtype (high expression of markers of differentiated female reproductive tract epithelia)
  • a proliferative subtype (high expression of markers of cell proliferation)
  • a mesenchymal subtype (high expression of HOX genes and of markers of mesenchymal-derived cells)

The researchers also determined subtypes on the basis of microRNA expression and promoter methylation. microRNA subtype 1 overlapped the mRNA proliferative subtype and miRNA subtype 2 overlapped the mRNA mesenchymal subtype. Patients with miRNA subtype 1 tumors survived significantly longer that those with tumors of other microRNA subtypes.

Although the researchers found no significant difference in survival between the four transcriptional subtypes, they did identify a 193-gene expression signature that was predictive of overall survival. 108 genes were correlated with poor survival and 85 were correlated with good survival.

The researchers identified cancer-associated pathways in the HGS-OvCA population; this is equivalent to the prediction of “driver” signaling pathways in the TN breast cancer study. They found that 20% of the HGS-OvCA samples had germline or somatic mutations in BRCA1 or BRCA2, and that 11% lost BRCA1 expression through DNA hypermethylation. As we discussed in an earlier article on this blog, BRCA1- or BRCA2-negative tumor cells cannot repair their DNA via homologous recombination. They are dependent on an alternative pathway of DNA repair, which involves the enzyme poly(ADP) ribose polymerase (PARP). These tumors are thus sensitive to a class of drugs known as PARP inhibitors, such as KuDOS/AstraZenaca’s olaparib. There are now six PARP inhibitors, including olaparib, in clinical development.

The researchers found genetic alterations in several other genes involved in homologous recombination. Altogether, defects in homologous recombination may be present in approximately half of HGS-OvCa cases, and these tumors may be sensitive to PARP inhibitors. This provides a rationale for clinical trials of PARP inhibitors in women with ovarian cancers with defects in homologous recombination-related genes.

Olaparib and other PARP inhibitors are in clinical trials in women with advanced with BRCA-1 or -2 mutations and with other defects in homologous recombination. As discussed in the 2011 ASCO meeting, early Phase 2 results indicate that olaparib gives dramatic improvements in progression-free survival in these women. (See this article.) In these studies, in addition to tumors with genetic defects in homologous recombination, olaparib or another PARP inhibitor, Abbott’s ABT-888, appears to give improved progression-free survival in women who have previously been treated with chemotherapy drugs that result in DNA damage. This suggests that oncologists may be able to use a “one-two punch”, consisting of a DNA-damaging drug [such as the alkylating agent temozolomide [Merck’s Temodar]) followed by a PARP inhibitor, to treat advanced ovarian cancer.

In addition to BRCA-1 and BRCA-2 mutations and other genetic alterations that result in defects in homologous recombination, the HGS-OvCa population exhibited genetic changes that would result in deregulation of several other cancer related pathways. These pathways included the RB1 (67% of cases), RAS/PI3K (45% of cases), and NOTCH (22% of cases) pathways, as well as the FOXM1 transcription factor network (87% of cases). All of these pathways represent opportunities for target identification and drug discovery. FOXM1 (Forkhead box protein M1) was named the Molecule of the Year for 2010 by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research (ISMCBBPR) because of “its growing potential as a target for cancer therapies.” FOXM1 overexpression results in destabilization of the cell cycle, which can lead to a malignant phenotype.

The researchers also identified 22 genes that were frequently amplified or overexpressed in HGS-OvCA tumors (other than genes that are involved in homologous recombination). Inhibitors (including approved and experimental compounds) already exist for the products of these genes, and researchers might assess these compounds in HGS-OvCa cases in which target genes are amplified.

Can Verastem develop new therapeutics for triple negative breast cancer?

The private biotechnology company Verastem (Cambridge, MA) focuses on discovery and development of drugs to target cancer stem cells. The company was founded in 2010, and is based on a strategy for screening for compounds that specifically target cancer stem cells. This strategy, published in the journal Cell in 2009, was developed by Drs. Robert Weinberg (MIT Whtehead Institute), Eric Lander (Broad Institute of MIT and Harvard University), and Piyush Gupta (MIT and Broad Institute) and their colleagues. Drs. Weinberg, Lander, and Gupta are on the Scientific Advisory Board of Verastem.

On July 14, 2011, Verstem announced that it had raised $32 million in a Series B financing. Verastem had previously raised $16 million from a group led by former Christoph Westphal’s Longwood Founders Fund. Dr. Westphal (formerly of Sirtris) is now Chairman of Verastem.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial. The cancer stem cell hypothesis asserts that a small subpopulations of cells in a leukemia or solid tumor have characteristics that resemble normal adult stem cells, such as self renewal, the ability to give rise to all the cell types found in the leukemia or cancer, and stem cell markers. The hypothesis further asserts that most cancer treatments fail to knock out cancer stem cells, which can repopulate a tumor cell population, resulting in treatment relapses. Cancer stem cell researchers therefore propose developing cancer stem-cell specific therapeutics that can be used to eliminate these cells, which can block these relapses.

Whether cancer stem cells are involved in the pathobiology of solid tumors or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT), and in the Cell paper the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As discussed earlier in this article, TN breast cancer includes two subtypes that have gene expression signatures related to the EMT: the mesenchymal (M) subtype and the mesenchymal stem–like (MSL) subtype. One or both of these subtypes might be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem recognizes this, and is thus focusing on TN breast cancer as its first therapeutic target. The Vanderbilt TN breast cancer study suggests that trials of any “cancer stem cell-specific” therapeutics for TN breast cancer should be guided by subtype-specific biomarkers.

Hope for treatment of TN breast cancer and advanced ovarian cancer

Researchers and oncologists have made great strides in increasing the percentage of breast cancers that are treatable or even curable in recent years. For example, prior to the FDA approval of trastuzumab in 1998, HER2 positive breast cancer carried a grim prognosis. But the advent of trastuzumab (and later, lapatinib) has had a major impact on treatment of this once uniformly deadly type of breast cancer.

We hope that the new, personalized medicine-based approach to TN breast cancer and advanced serous ovarian adenocarcinoma will also result in successful new therapeutic strategies for these deadly women’s cancers.


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.

Piwi-siRNA base pairing. Source: Narayanese

In our November 23, 2010 blog post, we discussed Roche’s November 2010 R&D cuts, especially its decision to discontinue R&D in RNAi therapeutics. This had followed closely on the October 2010 publication of our report RNAi Therapeutics: Second-Generation Candidates Build Momentum (Insight Pharma Reports, Cambridge Healthtech Institute). Our report included a discussion of Big Pharma efforts in therapeutic RNAi R&D, specifically including Roche.

Now a second Big Pharma with a significant internal therapeutic RNAI R&D project area covered in our report, Pfizer, announced on February 1, 2011, that it was exiting therapeutic RNAi R&D. This was a small part of a global R&D restructuring plan aimed at saving the company $1.5 billion. The new R&D cuts at Pfizer will eliminate an estimated 3500 jobs worldwide, and will close Pfizer’s large R&D facility in Sandwich, U.K. (eliminating 2400 jobs) and eliminate 1100 jobs at its large R&D facility in Groton, Connecticut.

In addition to exiting RNAi therapeutics research, Pfizer is also discontinuing most of its regenerative medicine research. Both research groups are located at the company’s Memorial Drive laboratory in Cambridge, MA, which will be closed, resulting in approximately 100 layoffs.

Other areas to be discontinued include allergy and respiratory medicine and internal medicine (located in Sandwich), and antibacterials (located in Groton). Pfizer will focus its R&D efforts in neuroscience, cardiovascular, metabolic and endocrine diseases, inflammation and immunology, oncology, and vaccines. The company will create new units in pain and sensory disorders, biosimilars, and Asia R&D. Pfizer’s regenerative medicine group in Cambridge, UK (which had been focusing on development of preclinical embryonic stem (ES) cell-based ophthalmology therapies, in collaboration with the University of London) will be folded into the new pain and sensory disorder research unit.

Although Pfizer will be closing the Memorial Drive laboratory in Cambridge, MA, it intends to expand its R&D efforts in Cambridge/Boston, creating an estimated 450 new jobs. Cardiovascular and neuroscience units will be moved from Groton to a new facility (yet to be acquired or built) in Cambridge/Boston. Pfizer will also maintain its manufacturing and research facility in Andover, MA, which specializes in biologics. Pfizer plans for its R&D units in Cambridge/Boston to interact more intensively with the local biomedical research and entrepreneurial community.

Pfizer’s Sandwich laboratories have long served as the company’s center for small-molecule drug discovery. Researchers at Sandwich discovered such drugs as the erectile dysfunction treatment Viagra, the blood pressure medicine Norvasc, and the antifungal Diflucan.

According to company spokespeople, it is possible that Pfizer might partner, out-license, or spin off some of its discontinued research programs. And some venture capitalists also expect to see new biotech companies emerge, at least from the Sandwich site.

This latest Pfizer R&D restructuring is on top of the 15% of its 128,000 employees Pfizer laid off over the past two years after its acquisition of Wyeth. In late 2009, the company said it was closing six of its 20 research sites as it reduced its R&D operations by 35%. A major factor in the latest round of layoffs and facility closings is the impending loss of patent protection (in Novemer 2011) for Pfizer’s largest-selling drug, the cholesterol-lowering agent Lipitor (atorvastatin). This is coupled with Pfizer’s R&D productivity deficit, and resulting inability to bring enough large-selling drugs to market to maintain its growth.

According to Pfizer’s new CEO, Ian C. Read, “The most fundamental question that Pfizer has to fix is our innovative core. This [restructuring] is the start of fixing that in a way that will give us consistent productivity in our innovation.” Read further says that the company’s goal is to stop putting resources into high-risk areas that provide a low return on investment or where Pfizer lacks the expertise to compete.

Pfizer’s exit from RNAi and regenerative medicine: the issue of technological prematurity

The RNAi therapeutics research and biotech company community, is as expected focused on Pfizer’s discontinuation of its efforts in this area. Even the New York Times has echoed this emphasis, with an article that is marred by several erroneous statements. [For example, in humans the RNAi pathway, although one of its functions is defense against viruses (as stated in the article), is mainly involved in a fundamental process of cellular regulation, principally via microRNAs.] Pfizer’s exit from the RNAi therapy field comes on the heels of the discontinuation of therapeutic RNAi research at Roche, and of Novartis’ termination of its 5-year partnership with Alnylam. According to  Dirk Haussecker’s RNAi Therapeutics blog, Big Pharmas have decided to exit internal development of RNAi technologies and drugs, and to wait to partner with or acquire RNAi specialty companies as their RNAi therapeutics programs yield meaningful clinical results. (Even Pfizer already has two external RNAi collaborations, with Quark and Tacere.) Dr. Haussecker himself plans to blog less, and only resume blogging as clinical results come in.

Despite this focus on Pfizer’s RNAi discontinuation by RNAi researchers and some journalists, Pfizer’s exit from RNAi therapeutics R&D is a small part of the company’s restructuring. It should therefore be put into the context of the strategic intent of the company’s restructuring as a whole. From our point of view, it is significant that Pfizer is discontinuing not only RNAi therapeutics R&D, but also regenerative medicine R&D.

The very first article on this blog, dated July 13, 2009, is entitled “RNAi, embryonic stem cells, and technological prematurity”. Both RNAi therapeutics and ES cell research (the latter of which includes induced pluripotent stem cells as well as ES cells per se, and which is the basis for Pfizer’s regenerative medicine R&D) are technologically premature, or at the very least very early-stage technologies. (Regenerative medicine based on adult stem cells is also technologically premature.) As the New York Times article–among others–points out, monoclonal antibody (MAb) therapeutics took 20 years from the time of the discovery of MAbs to achieve market success, and RNAi therapeutics might have a similar timeline. So might regenerative medicine based on stem cell technology.

However, a premature technology is not simply a technology that takes a long time to be translated into successful products. It is a technology that requires development of enabling technologies to overcome hurdles to development, and to move the technology up the development curve. MAb therapeutics represented a classic case of a premature technology. We discussed the history of the MAb therapeutics field in our September 28, 2009 blog article. Successful enabling technologies for MAb therapeutics began to be developed in the early 1980s, by biotechnology companies and by academic laboratories. Some of these companies eventually became leaders in the MAb field.

Arguably the most successful MAb development company, Genentech, developed enabling technologies in collaboration with academic researchers beginning in the early 1980s. But Genentech’s first MAb products, the highly successful antitumor agents Rituxan (codeveloped with Idec) and Herceptin, did not reach the market until 1997 and 1998, respectively. Roche purchased a majority stake in Genentech in 1990, when Genentech needed an infusion of capital to complete clinical development of its MAb products. In 2009, Roche moved to fully acquire Genentech, which now operates as a wholly-owned subsidiary. Most of the other leaders in the MAb therapeutics field were acquired by Big Pharmas or Big Biotechs in the late 1990s, after the MAb field became successful.

The take-home lessons for RNAi therapeutics and stem cell-based regenerative medicine R&D are that enabling technologies are necessary to move these fields up the technology development curve as well. In the case of RNAi therapeutics, specialty biotech companies in that area have been busy working on such enabling technologies, in two principal areas–design of the oligonucleotide molecules themselves, and delivery technologies. With respect to oligonucleotide design, certain types of chemical modifications enabled researchers to develop siRNAs (small interfering RNAs) that do not trigger an innate immune response. The immunogenicity of early siRNA drug candidates was a significant hurdle to the development of siRNA therapeutics. The New York Times article sounds as if the problem of immunogenicity of siRNAs has not been overcome, which is not true.

Ironically, the article quotes Arthur Krieg, the head of the RNAi group at Pfizer, in support of this contention. But although Dr. Krieg did the studies quoted in the article that showed the extent of the problem of immunogenicity in early siRNA candidates, he himself is one of the researchers who developed means to overcome this problem. Dr. Kreig came to Pfizer via the company’s 2008 acquisition of Coley Pharmaceuticals, where he was the head of R&D. Coley was focused on developing RNA-based immunotherapeutics, so Dr. Kreig is a leader in the field of RNA-mediated immunogenicity. As a result of the Coley acquisition, Pfizer has been developing oligonucleotide vaccine adjuvants, which are now in Phase III trials and have been licensed to GlaxoSmithKline.

Even when enabling technologies that ultimately prove to be successful have been developed, it typically takes many years before this produces promising clinical results, let alone approved drugs. The example of Genentech, which developed its patented MAb enabling technology platform in the early 1980s, but produced no marketed drugs based on that technology platform until the late 1990s, is illustrative of this point. (Of course, the long timeline to produce any marketed drug, from initial drug discovery to approval, is a large part of the reason for this time gap.) Therefore, any company that undertakes to develop products based on an exciting, but premature, technology must be both highly creative and very patient–and have patient capital behind it. An infusion of capital as such a company moves into the clinical phase–as with Roche’s 1990 equity investment in Genentech, helps as well.

The reward for companies that develop products based on a premature technology is that such a company may become a leader in an important new area of technology, with a large market. However, the risk of undertaking such a course of action is high.

As we discussed in our 2010 RNAi therapeutics report, Big Pharma was interested in getting into RNAi therapeutics, despite the field’s risks, in part because of its past experience with MAbs and other biologics. Because Big Pharma companies had failed to get into the now highly successful biologics field early, acquiring a major stake in that field had been expensive. Seeing the promise of RNAi therapeutics, Big Pharmas were therefore eager to get into RNAi therapeutics early, in the hope of capturing a commanding position in the field once drugs reached the market.

However, with any RNAi drugs still far in the future, and with their increasing short-term pressures, Big Pharmas have been losing the needed patience to continue with a technologically premature field like RNAi therapeutics. Therefore. their interest has been cooling. As (according to the New York Times article) Klaus Stein, head of therapeutic modalities for Roche, said, “I have no doubt that at a certain point in time RNAi will make it to the market….[but] when we looked into this, we came to the conclusion that we have opportunities that have higher priorities.”

Meanwhile, R&D and dealmaking continues in the small RNAi and microRNA specialty companies. For example, on February 3, 2010, it was announced that RNAi specialty firm Marina Biotech (Bothell, WA) entered into an agreement with Swiss biotech development group Debiopharm to develop and commercialize Marina’s preclinical RNAi-based therapy for bladder cancer. The deal is worth up to $25 million to Marina, based on predefined R&D milestones and royalties on the sales of products resulting from the agreement. Also in February 2010, Marina raised $5.1 million in a new public offering, and plans to use the proceeds to fund development of a drug candidate for familial adenomatous polyposis (FAP).

Preclinical and clinical studies are also continuing at such leading RNAi or microRNA therapeutics companies as Alnylam, Tekmira, Quark, RXi, Silence, Calando, Dicerna, Regulus, Santaris, and miRagen. If and when the products of these companies reach late-stage trials or commercialization, Big Pharmas may have to partner for or acquire these products or companies on a similar basis as for biologics in the last decade. A  key question is whether the RNAi/microRNA therapeutic sector can raise enough capital to fund its R&D, now that several Big Pharmas’ exit from the field appears to have dampened investors’ interest.

Pfizer’s restructuring strategy as a whole

As for Pfizer’s restructuring as a whole, we discussed the Big Pharma strategy of attempting to deal with loss of revenues from aging blockbusters and the lack of R&D productivity via megamergers, restructuring, and outsourcing in our February 19, 2010 blog post. Earlier megamergers, such as Pfizer’s acquisitions of Warner-Lambert in 2000 and of Pharmacia in 2002, followed by restructurings, enabled Pfizer to acquire blockbuster products (including Lipitor) and to realize significant cost savings from staff reductions. However, the continuing lack of productivity in R&D and the looming patent expiration of Lipitor and other large-selling drugs, motivated Pfizer management to enter into yet another megamerger, with Wyeth in 2009.

However, the Wyeth acquisition has not altered Pfizer’s fundamental issues. R&D productivity remains low, and Pfizer is the Big Pharma company that is most affected by upcoming patient expirations. Patent expirations are expected to expose approximately two-thirds of Pfizer’s total sales to generic competition over the next three years. This is mainly due to Pfizer’s dependence on revenues from Lipitor.

Meanwhile, Pfizer is maintaining its stock price not only by R&D retrenchment, but by spending $5 billion to buy back its own stock. The combination of cutting R&D and stock buy-backs is popular with investors. As of February 4, Pfizer’s stock was up 5.2% since the February 1 announcement of the R&D cuts and stock buy-back. In contrast, Merck’s new CEO Ken Frazier said on February 3 that that company would not make the cuts necessary to meet its long-term earnings forecasts. Instead, it would focus on investing in pharmaceutical R&D to drive future growth. Merck’s stock dropped 2.7% that day. However, Pfizer’s stock buy-back and R&D cuts only provide temporary relief, since they do not alter the fundamentals.

Meanwhile, the “other Merck”, Merck KGaA (Darmstadt, Germany), is expanding its R&D. This includes expansion of the company’s facility in Billerica, MA, where it will hire about 100 new researchers, doubling its staff. The Billerica R&D team will focus on discovery and development of new agents for cancer, neurodegenerative diseases and infertility.

As for Pfizer’s exiting the therapeutic areas of allergy, respiratory medicine, and internal medicine, it makes sense for a company to terminate programs that have not been productive. However, which areas to cut will vary by company. For example, in our February 19, 2010 blog post, we mentioned that GlaxoSmithKline (GSK) had eliminated its R&D in depression, anxiety, and pain. In contrast, Pfizer is building a new unit in pain and sensory disorders.

The main issue, however, as Pfizer’s CEO Ian Read said, is for Pfizer to fix its “innovative core”. The restructuring may help by freeing resources that had been devoted to low productivity therapeutic areas, and to high-risk/low-return areas. However, the cutbacks will not fix Pfizer’s low R&D productivity in any fundamental way.

As with other Big Pharma companies, Pfizer needs to fundamentally rethink its R&D strategy, and move towards the types of “smarter R&D” and partnering discussed in our December 3, 2010 blog article, and in the one-page article by GSK CEO Andrew Witty referenced in that article. This does not mean copying other companies’ “smart R&D” strategies, even Novartis’ or Roche/Genentech’s strategies that have been the most successful. It means developing a new R&D and partnering strategy specific for Pfizer, based on the fundamentals of what has worked in R&D in the past ten years or so, and building on Pfizer’s R&D assets. (Given the fast-changing nature of biomedical science and technology, as well as of the pharmaceutical and health care business landscape, even companies like Novartis and Roche/Genentech need to keep honing their R&D and partnering strategies.)

As we stated in our December 3 2010 article, this revamping of R&D strategy may well enable Pfizer to achieve additional cost savings. However, such selective R&D budget cuts would not impair the ability of the company to successfully discover and develop new, medically-significant drugs as across-the-board cuts tend to do.

Pfizer’s decision to concentrate its R&D facilities in research hubs such as Greater Boston, and to mandate that its researchers interact more intensively with academic and biotechnology researchers and entrepreneurs located in these hubs, can facilitate moving towards a “smarter R&D” and partnering strategy. We in the Boston area welcome Pfizer researchers and executives who will be moving here, and hope that we can work with Pfizer to help facilitate its R&D success.


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.

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.

There have been a lot of new papers on stem cells in leading journals recently. Stem cells made the covers of the 26 June issue of Science and the 2 July issue of Nature, and both issues contained special sections on stem cells.

Note especially the review by Shinya Yamanaka of progress in the field of induced pluripotent stem cells (iPS), a field that was first developed by his laboratory.

In that article, Dr. Yamanaka discusses hurdles to efficient iPS cell generation, ways by which these hurdles may be overcome, and the great potential of the field once this is accomplished. This is an example of the need to develop enabling technologies to move a technologically immature field up the development curve, as discussed in our earlier post.

Both the Science and Nature issues also discuss regeneration in such animals as planarians, fish, and salamanders. This is a favorite subject of many biologists. The Science article considers the implications of molecular and cellular studies of regeneration in these organisms for wound repair in humans.

The July/August issue of Technology Review also has an article on stem cells, which emphasizes iPS technology.

The article also discusses companies that are attempting to commercialize the infant field of iPS technology, especially California start-up iZumi Bio, which since publication of the article has merged with Pierian to form iPierian. iPierian is focusing on using iPS cells for drug discovery, by creating disease models based on iPS cells derived from patients with such diseases as Parkinson’s disease, spinal muscular atrophy and amyotrophic lateral sclerosis.

RNAi, embryonic stem cells, and technological prematurity

During the Bush administration, the US scientific community, numerous biotech companies, “disease organizations”, many politicians, and families affected by diseases such as juvenile diabetes, spinal cord injuries, and neurodegenerative diseases, deplored the administration’s restrictions on use of Federal funds for human embryonic stem (hES) cell research. Many predicted that countries with fewer restrictions, such as the UK, would far outdistance the United States in stem cell research, and in its applications to regenerative medicine.

In March of this year, the new Obama administrations lifted many restrictions on hES cell research. However, it is clear that the US did not significantly fall behind countries that did not have the Bush-era restrictions in place during the past eight years. Why not? It is because hES cell research constitutes a scientifically premature technology.

A field of biomedical science is said to be scientifically or technologically premature when despite the great science and exciting potential of the field, any practicable therapeutic applications are in the distant future, due to difficult hurdles in applying the technology. Thus researchers in countries not hampered by the former US restrictions were unable to capitalize on their “head start” as was feared.

On January 22, I gave a presentation at the Center for Business Intelligence (CBI) conference “Executing on the Promise of RNAi” in Cambridge MA. My presentation, “The Therapeutic RNAi Market – Lessons from the Evolution of the Biologics Market”, compared the field of monoclonal antibody (MAb) drugs to that of RNAi drugs. Despite the high level of investment in therapeutic RNAi, the formation of numerous biotech companies specializing in RNAi drug development, and the strong interest of Big Pharma in the field, there is still not one therapeutic RNAi product on the market. Researchers also see significant hurdles to the development of RNAi drugs, especially those involving systemic drug delivery. As a result, many experts believe that therapeutic RNAi is scientifically premature.

MAbs currently represent the most successful class of biologics. However, the therapeutic MAb field went through a long period of scientific prematurity, from 1975 through the mid-1990s. Several enabling technologies, developed from the mid-1980s to the mid-1990s, were necessary for the explosion of successful MAb drugs, from the mid-1990s to today. Similarly, many companies and academic laboratories are hard at work developing enabling technologies to catalyze the development of the therapeutic RNAi field. Among researchers active in developing these enabling technologies were several speakers at the CBI conference, from such companies as Alnylam, RXi, Dicerna, Calando, miRagen, Santaris, and Quark.

With respect to hES cells, researchers (including American researchers) have been hard at work on developing enabling technologies to move that field up the technology development curve. Notably, within the last three years, researchers in Japan, the US, Canada, and other countries have developed the new field of induced pluripotent stem (iPS) cells. This field is based on a set of technologies in which adult cells are reprogrammed, via insertion of four (or fewer) specific genes, into pluripotent cells that resemble embryonic stem cells. This approach not only gets around many of the ethical objections to the use of embryo-derived hES cells, but also potentially puts stem cells into the hands of many more researchers, who do not have ready access to human embryos. Moreover, iPS technology has the potential to enable researchers to construct patient-matched stem cells for cellular therapies, thus eliminating the prospect of immune rejection of transferred cells.

The iPS cell field was reviewed in a News Feature in the 23 April 2009 issue of Nature. As discussed in this review, researchers have been concentrating on developing the technology, for example reprogramming cells by using non-integrating or excisable vectors, or even with no inserted genes at all (e.g., combinations of small-molecule drugs and proteins). One researcher, Rudolf Jaenisch of MIT and the Whitehead Institute, said in the article that research in the iPS field has so far been all about technology. At some point in the near future, Jaenisch believes that the field will shift to considering scientific questions such as mechanisms of reprogramming and of cellular differentiation and dedifferentiation.

A few potential hES cell-based therapies are making their way to the clinic. In January, Geron announced that the FDA had cleared the company’s Investigational New Drug application (IND) for human clinical trials of an hES cell-based therapy for spinal cord repair. Pfizer, in collaboration with researchers at University College, London, is working to develop a hES cell-based therapy for age-related macular degeneration (AMD), a leading cause of blindness. This will involve treatment of patients with retinal pigment epithelial cells derived from hES cells. The researchers anticipate beginning clinical trials within two years. Especially in the case of the hES-based spinal cord therapy, many researchers see major pitfalls, which may result in clinical failure. This situation is typical for initial applications of an early-stage or premature technology.

Early-stage or premature technologies often still have great value in the research laboratory, including enabling research breakthroughs that can lead to new therapies. For example, MAb technology, even in its earliest days, enabled researchers to discover receptors that are key to the activity of cells of the immune system and of tumor cells. This resulted in enormous breakthroughs in immunology and in cancer biology, with eventual applications to the development of successful anti-inflammatory, anti-HIV/AIDS, and anti-tumor drugs. RNAi technology has become a mainstay of target validation and pathway studies in drug discovery. Similarly, researchers expect that hES cell technology—and especially iPS cell technology—will provide breakthrough tools for drug discovery researchers. This may well happen far in advance of the development of hES/iPS-based cellular therapies.