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20 February 2010

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

By |2018-09-12T21:41:36+00:00February 20, 2010|Strategy and Consulting|

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.

11 February 2010

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

By |2018-09-13T22:37:25+00:00February 11, 2010|Anti-Aging, Drug Development, Drug Discovery, Metabolic diseases|

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.

29 January 2010

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

By |2010-01-29T00:00:00+00:00January 29, 2010|Drug Development, Metabolic diseases|

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.

27 January 2010

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

By |2019-04-16T21:57:47+00:00January 27, 2010|Biomarkers, Drug Development, Drug Discovery, Neurodegenerative Diseases, Personalized Medicine, Translational Medicine|

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. 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.

1 January 2010

Cancer metabolism as a target for drug discovery: Agios Pharmaceuticals

By |2010-01-01T00:00:00+00:00January 1, 2010|Biomarkers, Cancer, Drug Discovery, Strategy and Consulting|

In the December 10 2009 issue of Nature, researchers at Agios Pharmaceuticals (Cambridge, MA) and their academic collaborators published an article implicating mutations in a metabolic enzyme, cytosolic isocitrate dehydrogenase (IDH1) as a causative factor in a major subset of human brain cancers.

The mutated forms of IDH1 are found in around 80% of human grade II-III gliomas and secondary glioblastomas. The mutations occur in arginine 132, which is usually mutated to histidine. (In other less common mutations, arginine 132 is mutated to serine, cysteine, glycine, or leucine.) Typically, only one allele of IDH1 is mutated. These mutations appear to occur early in the process of tumorigenesis, and often appear to be the first mutation that occurs. The mutant forms of IDH1 are also found in a subset of acute myelogenous leukemia (AML).

The wild-type form of IDH1 catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, the researchers found that the mutant forms of IDH1 no longer catalyzes this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). This is the result of changes in the active site of the enzyme, as demonstrated by structural studies carried out by the researchers. Tumors that harbor the mutant form of IDH1 have elevated levels of 2HG. The researchers therefore hypothesize that these elevated levels of 2HG are a causative factor in tumorigenesis and/or tumor progression in human gliomas.

This hypothesis is supported by the effects of the familial metabolic disorder 2-hydroxyglutaric aciduria. This disease is caused by a deficiency of 2-hydroxyglutarate dehydrogenase, an enzyme that converts 2HG to α-ketoglutarate. Patients with this metabolic disease have elevated levels of 2HG in bodily fluids and in the brain, and an increased risk of developing brain tumors.

The mechanism by which 2HG might contribute to tumorigenesis is unknown. The authors advance several hypotheses, including increasing reactive oxygen species (ROS) levels, serving as an NMDA (N- methyl-D-aspartate) receptor agonist, and competitive inhibition of enzymes that use glutamate and/or α-ketoglutarate resulting in the induction of hypoxia-inducible factor-1α, a transcription factor that facilitates tumor growth under conditions of hypoxia.

According to the authors, these results suggest that in patients with low-grade gliomas containing mutant forms of IDH1, therapeutic inhibition of 2HG production may slow or halt progression of these tumors to lethal secondary glioblastomas. 2HG levels may also be used as a prognostic test for IDH1 mutations, since patients with these mutations tend to live longer than patients with gliomas that have other mutations.

The company that led this research, Agios Pharmaceuticals, is developing a pipeline of oncology drugs based on targeting metabolic pathways in cancer cells. Interestingly, Agios means “holy” in Greek.

Way back in 1924, Otto Warburg demonstrated a difference between cancer cells and normal adult cells in glucose metabolism. In the presence of oxygen, most normal adult cells metabolize glucose to pyruvate via the process of glycolysis, generating two molecules of ATP (the energy currency of the cell) per glucose molecule. In the mitochondria, they then utilize oxygen to catabolize pyruvate to CO2 and water, in the process generating 36 molecules of ATP per glucose molecule. Cancer cells, however, predominantly carry out aerobic glycolysis, in which they carry out glycolytic conversion of glucose to pyruvate, followed by reduction of pyruvate to lactate. Despite the presence of oxygen, cancer cells generate the bulk of their ATP from glycolysis, not mitochondrial oxidative phosphorylation, in the process consuming large amounts of glucose. The reliance of cancer cells on aerobic glycolysis for their metabolism is known as the “Warburg effect”.

Agios’ platform is based in part on the work of signal-transduction pioneer Lewis Cantley (Beth Israel Deaconess Cancer center/Harvard Medical School, Boston MA). It is Dr. Cantley’s work on the connection between growth factor-mediated signal transduction and aerobic glycolysis that is the basis for Agios’ platform. In particular, Dr. Cantley and his colleagues found that pyruvate kinase M2 (PKM2) is a link between signal transduction and aerobic glycolysis. PKM2 binds to tyrosine-phosphorylated signaling proteins, which results in the diversion of glycolytic metabolites from energy production via mitochondria oxidative phosphorylation to anabolic processes required for rapid proliferation of cancer cells.

Agios closed a $33 million Series A financing in July 2008, co-led by Third Rock Ventures, Flagship Ventures and ARCH Venture Partners. In June 2009, Fierce Biotech named Agios to the 2009 FierceBiotech “Fierce 15” list. On December 21, 2009, Agios received funding from the nonprofit organization Accelerate Brain Cancer Cure (ABC2), to supplement Agios’s research on the development of IDH1-based therapeutics and diagnostics. Agios expects to have a lead compound in the clinic some time in 2010.

The Agios website calls cancer metabolism “one of the most exciting new areas of cancer research”. But the study of cancer metabolism, and especially the Warburg effect, is not new—the Warburg effect is a classic observation going back 85 years. Moreover, biotechnologists working in such areas as production of recombinant proteins in CHO cells have been familiar with aerobic glycolysis, which is carried out by most mammalian cell lines in culture, for decades. Nevertheless, cancer metabolism has been well out of the mainstream of cancer drug discovery. It was Dr. Cantley’s work, which links the classic Warburg effect to the mainstream area of signal transduction and protein kinases, which has made Agios’ platform possible.

Similarly, it was Julian Adams’ work on the biology of the proteasome in the 1990s, through a series of biotechnology company mergers that eventually led him to Millennium Pharmaceuticals (now Millennium: The Takeda Oncology Company), which resulted in Millennium’s proteasome inhibitor Velcade (bortezomib). Velcade, the only proteasome inhibitor on the market, is now approved by the FDA for the treatment of multiple myeloma and mantle cell lymphoma. Prior to Dr. Adams’ work, proteasome biology and protein degradation were out of the mainstream of cancer drug discovery. Now Joseph Bolen, the chief scientific officer of Millennium, sees “protein homeostasis” as one of the most exciting areas of cancer research.

Finally, although the development of protein kinase inhibitors to target signaling pathways in cancer is now well within the mainstream of oncology drug discovery, prior to the discovery and development of imatinib (Novartis’ Gleevec/Glivec) (approved by the FDA in 2001), specific targeting of protein kinases was though to be unlikely, since all of these enzymes have a high degree of similarly in their ATP binding sites. Thus the field of protein kinase inhibitors did not enter the mainstream until the late 1990s-early 2000s.

The take-home lesson is that drug developers may find fertile areas for innovation in seemingly obscure or out-of-the mainstream areas of biology (or of chemistry, as we have discussed in previous blog posts). Some of these areas may be technologically premature, and not quite ready for exploitation by drug developers. However, as demonstrated by our blog post on monoclonal antibodies, even some technologically premature areas may yield to innovators who are willing and able to develop enabling technologies to move these areas up the development curve.

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