“That’s all, folks!” http://bit.ly/gSgL6b
As we said in our December 8, 2010 blog post, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that the FDA approve Orexigen’s Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.
This followed the earlier rejections in 2010 by the Advisory Committee and the FDA of two other preregistration antiobesity drugs–Vivus’ Qnexa and Arena Therapeutics’ lorcaserin (Lorqess). Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. Concern about long-term safety was the major consideration in the rejection of Qnexa and lorcaserin, and safety issues (increased risk of cardiovascular events) were the reason for the withdrawal of sibutramine. Thus the Advisory Committee’s recommendation for approval of Contrave was surprising, to us as well as to many others.
Despite the Advisory Committee’s vote to recommend approval of Contrave, it did have safety concerns. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as sibutramine.
As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.
Yesterday–January 31, 2011–was the Prescription Drug User Fee Act (PDUFA) deadline for the FDA to act on the approval of Contrave. This morning, Orexigen and its partner for Contrave commercialization, Takeda, announced that the FDA had issued a Complete Response Letter regarding the New Drug Application for Contrave.
The FDA’s Complete Response Letter stated, “before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.” Essentially, the FDA required Orexigen and Takeda to conduct the cardiovascular safety trial of Contrave prior to marketing approval, not post-marketing as recommended by the Advisory Committee. The safety trial required by the FDA will be neither fast nor inexpensive.
As a result of the FDA ruling, what we called “the pall of gloom” descended once again on the antiobesity drug field. Forbes’ Matthew Herper, for example, declared the antiobesity drug field “effectively dead”. Herper further said, “The clear lesson is that weight-loss medicines simply do not have enough of a benefit to justify any risk – and that this makes getting them approved just about impossible.”
If you click on the “metabolic diseases” category on the right-hand panel of this blog, you will see that we have quite a number of blog articles on obesity, usually in the more holistic context of metabolic diseases–obesity, type 2 diabetes, and metabolic syndrome (which is a major risk factor for cardiovascular disease). In these articles, you will see that we are not negative about antiobesity drug development. However, we are–and have been for some time–quite negative about developing appetite suppressant drugs that address common neurotransmitter receptors in the CNS. Such agents might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy.
If you read our articles, you will see that there are several companies that have strategies to develop antiobesity agents that are not appetite suppressants, and that are being–or can be–developed for diabetes and/or metabolic syndrome in addition to obesity. A common strategy is to develop diabetes/obesity drugs first for diabetes, resulting in easier FDA approval. Such drugs may later also be developed for obesity, after they prove to be safe and to induce weight loss in diabetes trials. For example, Novo Nordisk is following this strategy with the development of liraglutide (Victoza), which is already approved for treatment of type 2 diabetes.
Other established companies are pursuing different strategies, such as Amylin/Takeda’s development of pramlintide/metreleptin for obesity. This is really a metabolic syndrome-based approach to obesity. Indeed, Amylin (whose assets have passed on to AstraZeneca as of early 2014) had been developing metreleptin as a single agent for treatment of diabetes and high triglycerides in patients with lipodystrophy.
Then there are several young companies covered in this blog that are developing antiobesity treatments via innovative biology-driven strategies. Two of these companies, Energesis and Acceleron, are developing antiobesity therapies that target brown fat. Such an approach is really a metabolic syndrome-based one, and might also be applied to various diabetes and/or cardiovascular indications for easier regulatory approval.
Meanwhile, a News and Analysis article in the January 2011 issue of Nature Reviews Drug Discovery lists several agents not covered in our blog. One agent, tesamorelin (Theratechnologies/Merck KGaA’s Egrifta) was approved by the FDA in November 2010 as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy. Tesamorelin is a synthetic analogue of growth hormone–releasing factor — a hypothalamic peptide that acts on the pituitary to stimulate production and release of human growth hormone. This drug is now in a Phase 2 clinical study for treatment of human growth hormone deficiency associated with abdominal obesity. This represents a potential personalized medicine approach for treatment of a specific population of obese patients. Such an approach may be looked at more favorably by regulatory agencies than a “diet pill” for the general obese population.
As we also discussed in another article, John C. Lechleiter, Ph.D., the chairman, president and CEO of Lilly, outlined the need for “public policies that enable and reward medical innovation”, especially in the metabolic syndrome/diabetes/obesity therapeutic area. This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the PDUFA, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for negotiation between industry and the FDA to achieve these ends.
We hope that industry and the FDA can work toward a more favorable environment for the approval of safe and efficacious antiobesity drugs. And Dr. John Jenkins, director of the FDA office of new drugs, said that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.” Nevertheless, we do not see the FDA approving a minimally-efficacious CNS-acting appetite suppressor for the general obese population any time in the foreseeable future.
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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.
PLX4032
On January 19, 2011, Plexxikon and Roche announced the results of an interim analysis of a large multicenter Phase 3 clinical study (the BRIM3 trial) of the targeted anticancer drug PLX4032 (which Roche has designated as RG7204). PLX4032 is a kinase inhibitor that is exquisitely specific for B-Raf carrying the V600E mutation [B-Raf(V600E)]. This is the most common somatic mutation found in human melanomas (accounting for approximately 50% of cases of this disease), and is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation.
According to the Plexxikon and Roche press releases, the Phase 3 trial met its prespecified criteria for co-primary endpoints of overall survival and progression-free survival, as compared to a control arm, in which patients were treated with the current standard of care, dacarbazine. The safety profile was consistent with previous clinical studies of the drug.
Based on the results of the interim analysis, patients in the dacarbazine arm of the study will have the option to crossover to receive PLX4032. Moreover, the Expanded Access Program will be opened to previously untreated melanoma patients whose tumors carry the B-Raf(V600E) mutation. As the companies announced in November 2010, as the result of widespread demand from patients, oncologists, and patient advocates, they had been in discussion with global regulatory authorities regarding an Expanded Access Program for PLX4032. In late December 2010, the Expanded Access Program for PLX4032 was initiated. A cofounder of one of the patient advocate organizations pushing for expanded access to PLX4032 prior to its FDA approval, the Abigail Alliance, commented on this issue on our blog in November 2010.
The big news in Plexxikon and Roche’s report on the BRIM3 trial is that treatment with PLX4032 gave enhanced overall survival as companied with dacarbazine in previously untreated metastatic melanoma patients carrying the B-Raf(V600E) mutation. Although previous studies showed tumor shrinkage and enhanced progression-free survival (by approximately seven months) in the majority of PLX4032-treated patients as compared to dacarbazine, this is the first report that PLX4032 give enhanced overall survival. However, the companies did not report the extend of the enhanced overall survival. They plan to present comprehensive data from the BRIM3 trial at a major scientific meeting later this year. We expect that in due course the researchers that have been conducting the trial will publish the results in a peer-reviewed medical journal, as in the case of the published Phase 1 trial.
On November 8, 2010, Plexxikon and Roche reported preliminary results of a parallel open-label Phase 2 trial (designated BRIM2) of PLX4032 in previously treated metastatic melanoma patients whose tumors carried the B-Raf(V600E) mutation. Researchers who had been conducting that trial presented the data at the Seventh Annual International Melanoma Research Congress of the Society for Melanoma Research (SMR) in Sydney, Australia. Consistent with earlier Phase 1 trials, the BRIM2 trial showed that of the 132 patients enrolled, 3 patients had complete responses, and 66 had partial responses (i.e., tumor shrinkage of over 30 percent). The overall response rate was 52 percent, with a median duration of response of 6.8 months. At the time the results were reported, it was too early to gauge overall survival.
The Biopharmconsortium Blog has been following the PLX4032 story since March 2010. We have published several articles on the drug and on related scientific, clinical trial strategy, and business issues:
The last two articles discuss the novel personalized medicine (or “stratified medicine”) hypothesis-testing clinical trial strategy, which is especially applicable to highly targeted oncology drugs (such as PLX4032) for which the relevant biomarkers are available.
The dramatic results of the Phase 1 trials of PLX4032 (now confirmed by Phase 2 and Phase 3 trials) led some oncologists, as well as patient advocates, to question the ethics of conducting standard controlled Phase 3 trials in which some patients were placed in a dacarbazine arm. This question might apply to other drugs for cancer and other very serious diseases for which personalized medicine hypothesis-testing clinical trials indicate superior performance as compared to the standard of care. Such cases would at least call for establishment of Expanded Access Programs for such drugs, on a case-by-case basis.
The clinical trial community, as well as regulatory agencies such as the FDA and the European Medicines Agency, also need to continue to monitor and study the progress of the personalized medicine hypothesis-testing clinical trial strategy. This may led to modifications in clinical trial standards for approval if they deem they are warranted. We can also expect that patient advocates (including M.D. and non-physician advocates), as well as other stakeholders (e.g., third party payers) would be participating in that process.
In parallel with the development of PLX4032, Plexxikon and Roche Molecular Diagnostics are developing a DNA-based companion diagnostic to identify patients whose tumors carry B-Raf(V600E). The companies plan to launch PLX4032 together with the companion diagnostic, so that oncologists can readily identify patients who would benefit from treatment with the drug.
Despite the dramatic results with PLX4032, so far all patients treated with the drug eventually suffer relapses, and die of their disease. This presumably occurs because a fraction of tuner cells develop resistance to PLX4032. Oncologists, especially those who have been involved in the clinical trials of the drug, therefore advocate using PLX4032 as the basis for potentially still more effective treatments, especially combination therapies.
With respect to combination therapies, on January 6, 2011, Plexxikon announced that it had signed an agreement with Genentech (a member of the Roche group) to co-promote PLX4032 (RG7204) in the United States. Plexxikon will also codevelop PLX4032 with Genentech in addition to Roche. Plexxikon and Genentech are planning, beginning in the first quarter of 2011, to begin a Phase 1b clinical trial of a combination therapy of PLX4032 and Exelixis/Genentech’s oral, small-molecule MEK inhibitor RG7420/GDC-0973. MEK is downstream from B-Raf in the signaling pathway by which B-Raf(V600E) acts to produce the malignant phenotype. Researchers studying mechanisms by which PLX4032 resistance occurs have found evidence that suggests that combination therapy with PLX4032 and a MEK inhibitor may overcome resistance that occurs via some mechanisms. More generally, studies of mechanisms of PLX4032 resistance may provide means of developing specific combination therapies for different mechanisms of resistance, and of stratifying patients to determine which particular personalized combination therapy will best treat their disease.
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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.
Source: Mnolf http://bit.ly/gEg5yo
In our November 11, 2010 blog post, we discussed the September 2010 acquisition of Seattle biotech firm ZymoGenetics by Bristol-Myers Squibb (BMS). Also in November 2010, Nature Biotechnology published an article about this acquisition, in which I was quoted.
As our blog post states, most commentators believe that BMS’ main motivation for acquiring ZymoGenetics was to gain full ownership of ZymoGenetics’ pegylated interferon-lambda (Peg-IFN-λ) program for treatment of hepatitis C (HepC). The two companies had been been collaborating to develop Peg-IFN-λ since January 2009. However, ZymoGenetics was much more than a one-product company. Its other pipeline drugs included interleukin-21 (denenicokin) for treatment of metastatic melanoma, which is now in Phase 2b development. And over the years, ZymoGenetics has proven to be an important drug discovery engine, from the days in which it was a division of Novo Nordisk, and continuing on into 2010.
Now–as of the first week of January 2011–we learn that former ZymoGenetics CEO Douglas E. Williams Ph.D. has been named as Executive Vice President, R&D., at Biogen Idec (Weston, MA).
Dr. Williams has over 20 years of biotech R&D and senior leadership experience. He was the chief technology officer at Seattle biotech firm Immunex, and played a significant role in the discovery and development of the blockbuster tumor necrosis factor (TNF) inhibitor etanercept (Enbrel). After Amgen’s 2002 acquisition of Immunex, Dr. Williams resigned from Amgen later in 2002, and moved on to Seattle Genetics in 2003 as chief scientific officer (CSO). In 2004, he joined ZymoGenetics as chief scientific officer (CSO). On January 1, 2009, he became ZymoGenetics’ CEO.
During his tenure as CSO and then CEO of ZymoGenetics, the company achieved considerable success in the development of its pipeline products, especially Peg-IFN-λ and interleukin-21. And the company entered into its $1.1 billion agreement with BMS to codevelop Peg-IFN-λ. However, during Dr. Williams’ tenure as CEO, ZymoGenetics had some financial rough spots, mainly caused by the lack of commercial success of the company’s first self-marketed product, recombinant thrombin (Recothrom). This was compounded by failed clinical trials of the company’s immunomodulatory drug atacicept, which is now being developed by Merck Serono. After a series of downsizing moves, ZymoGenetics agreed to be acquired by BMS in October 2010. In November 2010, Dr. Williams left ZymoGenetics and became a “free agent”, followed by his joining Biogen Idec in January 2011.
Biogen Idec, which was founded as Biogen in 1978 and merged to form Biogen Idec in 2003, is one of the world’s major biotech companies, and has long been a major fixture of the Boston-Cambridge biotech scene. The company had 2009 revenue of $4.38 billion. However, Biogen Idec had some ups and downs of its own in recent years. It has been targeted for reorganization, breakup, or sale by activist investor Carl Icahn, who currently owns 5.4% of the company’s shares, and who controls three seats on Biogen Idec’s board as the result of series of proxy fights.
During 2010, long-time CEO (and Icahn target) James Mullen retired from the company, and was succeeded by former Exelixis (South San Francisco, CA) CEO George Scangos, Ph.D. In January 2011, at the same time as Dr. Williams joined Biogen Idec, the company announced that Steven H Holtzman (who was formerly the CEO of Cambridge MA biotech Infinity Pharmaceuticals) would be executive vice president of corporate development.
Biogen Idec derives most of its revenues from three drugs–multiple sclerosis (MS) treatments Avonex (interferon beta-1a) and Tysabri (natalizumab), and Rituxan (rituximab), a treatment for non-Hodgkin’s lymphoma. Tysabri is also approved for treatment of Crohn’s disease and is co-marketed with Élan, and Rituxan is also approved for rheumatoid arthritis and is co-marketed with Roche/Genentech.
Among these products, Avonex (which was introduced in 1996, and is Biogen Idec’s largest selling drug) and Rituxan are maturing. In particular, Avonex faces increased competition from newer products. Growth in sales and revenues from these two products is slowing.
Tysabri is intended to be Biogen Idec’s growth driver. However, Tysabri has had major issues. Soon after its launch in 2004, Biogen Idec withdrew Tysabri from the market, after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML), when co-administered with Avonex. PML is caused by the JC virus, which is normally controlled by he immune system, but which can rarely cause disease in patients under immunosuppresive therapies such as the Tisabri/Avonex combination. After a safety review and no further deaths, the drug was returned to the US market in 2006 under a special prescription program, in part as the result of pleas by MS patients. However, since then additional cases of PML–including fatalities–have occurred.
In December 2010, Biogen Idec and Elan submitted a supplemental Biologics License Application (sBLA) to the FDA and a Type II Variation to the European Medicines Agency (EMA), proposing updated product labeling to include anti-JC virus antibody status. The companies propose using this test to help stratify the risk of developing PML in patients treated with Tysabri. Biogen Idec expects that a commercial anti-JC virus antibody test will be available later in 2011. It is expected that this test will help to lower the risk of Tysabri-associated PML, which is low to begin with.
In addition, Tysabri faces potential strong competition from the first approved oral treatment for MS, fingolimod (Novartis’ Gilenya), which the FDA approved in September 2010. The day that Gilenya was approved, Biogen Idec issued a press release acknowledging the desire of MS patients for an oral treatment, and noting that it also has an oral MS treatment in Phase 3 trials, BG-12.
Biogen Idec estimated that as of the end of 2010, approximately 56,600 MS patients were using Tysabri worldwide. That represented an increase of 1,700 patients in the fourth quarter and 8,200 patients over the course of 2010.
In November 2010, Dr. Scangos announced a reorganization of Biogen Idec. As of that date, the company would focus on neurology, and leverage its strengths in biologics research and development (R&D) and manufacturing to pursue select, high-impact biologic therapies and to be a leading collaborator in the biotechnology industry. (Biogen Idec’s efforts in biologics might, for example, include entering the biosimilars market.) Biogen Idec also terminated its efforts in cardiovascular medicine, and is seeking to spin out or outlicense its oncology programs.
The restructuring also involved consolidating its sites, and reducing its work force by 13%, or 650 full-time positions. As a result of the restructuring, the company expected to save approximately $300 million annually. Dr. Scangos said that the restructuring would enable Biogen Idec to gain focus and to become more nimble.
The company intends to become a global leader in neurological diseases. This will involve not only maximizing the potential of its two marketed MS drugs, but also bringing forward its MS pipeline products. Biogen Idec will also pursue programs in amyotrophic lateral sclerosis (ALS)/Lou Gehrig’s disease and Parkinson’s disease.
Biogen Idec’s late-stage products in neurology are shown in the table. (Please click on the table to read it clearly.) The company intends to launch five new products by 2015.
Source: Haberman Associates
Although Biogen Idec now has several late-stage products moving toward commercialization, the company’s R&D productivity has lagged in recent years. The company has not launched a new drug since Tysabri was approved in 2004. Dr. Williams says that he is planning a review of he company’s R&D organization and its pipeline. He intends especially to focus on Biogen Idec’s early- and mid-stage programs. Dr. Williams intends to boost these programs both via internal R&D and via licensing and acquisition to bring in externally developed compounds.
Overall, Dr. Williams hopes to return Biogen Idec to the culture of a biotech start-up. “We don’t have the luxury of sitting back. We have to push hard like we are a scrappy, hungry, cash-starved biotech,” he says. Dr. Williams’ statement is in accord with that of Dr. Scangos, who speaking at the J.P. Morgan 29th Annual Healthcare Conference in January 2011, said that Biogen Idec had the choice of being either a small pharma or a big biotech. The company has chosen to be a big biotech.
We wish Dr. Williams–working together with George Scangos and Steven Holtzman–well as they work to return Biogen Idec to productive and innovative R&D.
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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.
2010
Breakthroughs of the Year
As it does every year, Science published its “Breakthrough of the Year” for 2010 in the 17 December issue of the journal.
For its “Breakthrough of the Year”, Science chose a non-life science innovation, the first quantum machine. Interestingly, the same issue of Science included a Perspective on biophysicist Britton Chance, who died last November at the age of 97. Among his many accomplishments, Dr. Chance discovered that biological electron transfer operates via quantum tunneling, a mechanism central to photosynthesis, respiration, and many oxidoreductase enzymes. Mitochondria, chloroplasts, and oxidoreductase enzymes thus constitute biological quantum machines of a sort.
Interestingly, Dr. Chance continued to work on metabolism all of his long working life, including in the era of molecular biology when interest in that field waned. By doing so, he made many important contributions, including the mechanism for the generation of the reactive oxygen species (ROS) superoxide and peroxide during normal mitochondrial respiration, and the use of near-infrared (NIR) light for noninvasive diagnostics.
Although Science chose a non-life science advancement as its “Breakthrough of the Year”, the journal’s runners-up for “Breakthrough of the Year” were replete with life science items. The first runner-up was the synthetic Mycoplasma mycoides genome constructed by the J. Craig Venter Institute, which they used to create “the first synthetic cell”. As we discussed in a series of two articles on this blog (see here and here) although the creation of the synthetic genome and the “synthetic cell” represented a technical tour de force, it did not represent a true breakthrough. Many leading scientists, including leaders in the field of synthetic biology, agreed with us. However, at least several bioethicists and philosophers hailed this work as a milestone, calling it “the end of vitalism”. (As we noted in another blog post, however, not all bioethicists agree.)
Moreover, policy-makers were sufficiently alarmed by the “synthetic cell” that (as noted in the Science “Breakthrough of the Year” runners-up article) the Presidential Commission for the Study of Bioethical Issues held hearings on policy implications of this research. Nevertheless, the report of this commission (issued in December 2010) concluded that the Venter research “does not amount to creating life as either a scientific or a moral matter” and that synthetic biology remains “in the early stages,” with any dangers well into the future. The commission recommended continuing White House oversight, but a relatively mild set of regulatory measures.
As we said in our second article on the “synthetic cell”, we are much more impressed by the metabolic engineering studies of Jay Keasling, and by George Church’s automated method for optimizing metabolic engineering pathways, which we had discussed in an earlier blog post. The Science “Breakthrough of the Year” runners-up article mentioned Dr. Church’s automated system, among other synthetic biology advances made in 2009 and 2010.
Meanwhile, in a review of metabolic engineering published in the 3 December 2010 issue of Science, Dr. Keasling says that although minimal bacterial hosts such as Dr. Venter’s “synthetic” mycoplasma may be of scientific interest, they are not suitable to use in metabolic engineering studies whose goal is scale-up for industrial production of medicines, chemicals, or biofuels. This agrees with our statement that such applications require “workhorse” organisms that can take the extensive genetic manipulation needed to engineer new metabolic pathways, and which are capable of scale-up.
We therefore believe that the “synthetic cell” is not the life science breakthrough of the year, despite its placement at the top of Science‘s “Breakthrough of the Year” runners-up article.
Our nominee for the life science breakthrough of the year is listed right under the “synthetic cell” in the Science “Breakthrough of the Year” runners-up article. It is the determination of the sequence of approximately two-thirds of the Neandertal genome by Svante Pääbo (Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.) and his colleagues. This achievement is something that only a few years ago seemed completely impossible. Moreover, this work is of great cultural significance, since it indicates that Neandertals contributed some 1-4 percent of the genome sequences of non-African present-day humans. More recently, Dr. Pääbo and his colleagues followed up the Neandertal studies by using their DNA synthesis methods to identify a third species of humans, known as Denisovans. Denisovans, who were more closely related to Neandertals than to modern humans, were alive at the same time as modern humans emerged from Africa and also encountered the Neandertals. Dr. Pääbo’s new studies indicate that the Denisovans contributed some 4–6% of the genome sequences of present-day Melanesians.
Despite the importance of the Pääbo Neandertal studies, we have not blogged on this work simply because it has nothing to do with drug discovery and development. However, perhaps someday, for example, some of the products of genes that are found in present-day humans but not in Neandertals could emerge as potential drug targets. As discussed in the Science “Breakthrough of the Year” runners-up article, researchers have begun studying some of these gene products in cell culture systems.
Moreover, the types of advanced, next-generation DNA sequencing methods used by Dr. Pääbo and his colleagues are being applied to studies that are relevant to drug discovery. These include the 1000 Genomes Project, which seeks to find all single-nucleotide polymorphisms (SNPs) present in at least 1% of humans. This and other next-generation genomics projects were listed in the Science “Breakthrough of the Year” runners-up article, as the third runner-up. The 1000 Genomes Project, as well as genome-wide association studies (GWAS) that use high-throughput DNA sequencing methods, may enable researchers to identify rare mutations that are involved in complex human diseases. This might in turn lead to the discovery of novel drugs and diagnostics.
Among other life science items in the Science “Breakthrough of the Year” runners-up article was the production of knockout rats. We discussed knockout rats in an October 1, 2010 blog post.
Newsmaker of the Year
Nature also had an end-of-2010 special article, “The Newsmaker of the Year”, in its 23/30 December issue. Unfortunately, Nature chose a U.S. government official as its Newsmaker of the Year.
We would prefer that Nature stick to what it does so very well, and stay out of U.S. politics, whether in its “opinionated editorials” [sic] or elsewhere. Perhaps the low point in Nature‘s political forays was its November 2010 editorial calling for what amounts to a new version of Prohibition. This is despite the ample evidence that moderate consumption of red wine (for example) is healthy for most adults. Readers would be well advised not to believe everything they read in Nature editorials.
Our nominee for Newsmaker of the Year in the life sciences is Dr. Svante Pääbo, for the reasons we discussed earlier.
Deals of the Year
Also as an end-of-year feature, the IN VIVO blog has been running a Deal of the Year competition. The nominees are grouped in three categories: M&A Deal of the Year, Alliance Deal of the Year, and Exit/Financing Deal of the Year.
Only one of the nominees had been featured in an article on our blog: the Celgene/Agios alliance (April 23, 2010).
The IN VIVO Blog invited readers to vote on the Deal of the Year in each of the three categories, by going to their website. The voting closed at 12:00pm on 6 January 2011 (Eastern Standard Time).
The winners of the vote were:
- M&A Deal of the Year: Celgene/Abraxis (50.31% of 1,799 votes)
- Alliance Deal of the Year: Celgene/Agios (55.32% of 3,176 votes)
- Exit/Financing Deal of the Year: Ablexis (46.54% of 1,631 votes)
Congratulations to all the winners, especially Agios and Celgene, which were featured in our blog post.
Happy New Year!
This is our own version of an end-of-year special article, and will be our last blog post of 2010. Best wishes to all of you for a happy, productive, and innovative New Year in 2011.
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.
Citric acid cycle
The 3 December issue of Science featured a Special Section on metabolism, headed by an introductory article entitled “Metabolism is Not Boring”.
Way back in the 1920s through the 1950s, intermediary metabolism was a hot field of biology. This culminated in the awarding of the Nobel Prize in Physiology or Medicine in 1953 to Hans Krebs “for his discovery of the citric acid cycle” and Fritz Lipmann “for his discovery of co-enzyme A and its importance for intermediary metabolism”.
As most of you know, that same year, 1953, Watson and Crick published the structure of DNA, which won them the Nobel Prize in Physiology or Medicine in 1962. This began the great era of molecular biology. As the result of the overwhelming success of molecular biology, the study of intermediary metabolism receded into the background. Answering most questions in leading-edge biology required little or no attention to intermediary metabolism. However, as discussed in the review article by Steven L. McKnight included in the Special Section, metabolism is coming to the forefront of biomedicine again. Research problems that require both consideration of molecular biology and of metabolism now appear as interesting and important challenges.
Considerations of intermediary metabolism have always been important in the study of what are known as metabolic diseases, especially type 2 diabetes and obesity and such related conditions as dyslipidemia. However, as detailed both in the McKnight article and in an article by Arnold J. Levine and Anna M. Puzio-Kuter, the study of intermediary metabolism has now also become important in cancer, with the discovery that alterations in metabolic enzymes can result in the production of “oncometabolites” that support the growth of cancer cells.
In an article on this blog dated December 31, 2009, we discussed research in cancer metabolism that is behind the technology platform of Agios Pharmaceuticals (Cambridge, MA). In that article, we highlighted the discovery that mutations in a metabolic enzyme, cytosolic isocitrate dehydrogenase (IDH1) are a causative factor in a major subset of human brain cancers. The wild-type form of IDH1 catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, the mutant forms of IDH1 catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG appears to be an oncometabolite that is involved in the progression of low-grade gliomas to lethal secondary glioblastomas. Agios researchers and their academic collaborators later implicated mutations in isocitrate dehydrogenase enzymes and the production of the oncometabolite 2HG in the pathogenesis of acute myelogenous leukemia (AML).
Also discussed in our article was the Warburg effect, in which cancer cells carry out aerobic glycolysis (conversion of glucose to lactate, with the production of 2 molecules of ATP even in the presence of oxygen). In contrast, most normal mammalian cells metabolize glucose to CO2 and water via glycolysis coupled to the mitochondrial citric acid cycle, generating 36 molecules of ATP. Agios scientific founder and signal-transduction pioneer Lewis Cantley showed that there is a connection between growth factor-mediated signal transduction and aerobic glycolysis in cancer cells. 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 mitochondrial oxidative phosphorylation to anabolic processes required for rapid proliferation of cancer cells.
The McKnight and Levine and Puzio-Kuter papers also discuss the Warburg effect in cancer cells, and the role of mutations in several metabolic enzymes that contribute to malignant phenotypes. The McKnight article notes that in addition to dominant mutations in isocitrate dehydrogenates, rare recessive mutations in fumarate hydratase and succinate dehydrogenase are also associated with cancer. Mutations in the genes for these enzymes, coupled with loss of the wild-type allele, result in elevated intracellular levels of fumarate and succinate, respectively. These appear to act as oncometabolites that can induce activation of the hypoxia response pathway, which triggers the induction of aerobic glycolysis (the Warburg effect) and angiogenesis.
The Levine and Puzio-Kuter paper also discusses the role of oncogenes and tumor suppressor genes and their signaling pathways in regulating metabolism and in particular in inducing the Warburg effect. For example, p53 regulation suppresses the Warburg effect and promotes mitochondrial oxidative metabolism. Thus the loss of p53 function seen in most human cancers tends to promote aerobic glycolysis. Other signaling pathways that have been implicated in cancer-associated changes in metabolism include the Akt and mTOR pathways, which are frequently altered by mutations in key genes (e.g., mutations in PTEN and amplifications of such growth factor receptors as Her2 and EGFR) in cancer. Deregulation of these pathways activates the hypoxia response pathway, thus triggering the Warburg effect.
Levine and Puzio-Kuter suggest that research aimed at a deeper understanding of how cancer-associated signaling pathways regulate biochemical metabolic pathways and trigger the Warburg effect, and the role of the Warburg effect in the pathogenesis of cancer, may lead to novel drug discovery strategies in oncology.
The Special Section on metabolism also includes an article on autophagy, a process by which cells break down cellular components in order to eliminate damaged biomolecules and organelles or to provide substrates for metabolism in case of starvation. Although autophagy promotes the health of cells and can prevent degenerative diseases, it can also enable cancer cells to survive in nutrient poor tumors.
There is also a review by Jay Keasling on metabolic engineering to produce such substances as natural product drugs, chemicals, and biofuels. Metabolic engineering is a branch of synthetic biology that engineers metabolic pathways to produce such substances, hence the inclusion of this review in the Special Section on metabolism. We have several articles on synthetic biology on this blog, most of which focus on metabolic engineering and its role in drug manufacture and drug discovery.
All in all, the 3 December Special Section on metabolism is worth reading by basic researchers, and by drug discovery and development researchers in biotechnology and pharmaceutical companies. It may broaden your perspectives, and lead to new ideas for R&D or partnering, especially in oncology drug discovery.
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