tag:blogger.com,1999:blog-46827504331592052872024-03-06T12:01:53.439-08:00Biopharmconsortium BlogExpert commentary from Haberman Associates biotechnology and pharmaceutical consulting.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.comBlogger29125tag:blogger.com,1999:blog-4682750433159205287.post-89725837880387080102010-06-11T20:35:00.000-07:002010-09-20T13:49:27.677-07:00We've moved!Haberman Associates' Biopharmconsortium Blog has moved to our own site. You can now find it at <a href="http://biopharmconsortium.com/blog">http://biopharmconsortium.com/blog</a>.<br /><br />Please go to the new site, which has many new posts on it. We invite you to keep reading our blog, to subscribe to it, and to make useful comments to our blog posts if you so desire.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-75517986309970040192010-06-05T13:02:00.000-07:002010-06-05T13:06:01.160-07:00We're moving!Haberman Associates' Biopharmconsortium Blog is in the final stages of moving to our own site. You can now find it at <a href="http://biopharmconsortium.com/blog">http://biopharmconsortium.com/blog</a>.<br /><br />Our new site is now also powered by WordPress. We hope that you like the new format, and the WordPress features. We are new to WordPress, so will be making further improvements as we learn more about the system.<br /><br />We hope that you will also make use of the other resources on our website, <a href="http://biopharmconsortium.com">http://biopharmconsortium.com</a>.<br /><br />As you may have noticed, many blogs that start out as Blogspot blogs (hosted by Google's Blogger) eventually change to WordPress, and migrate to the blogger's own site. Now our blog has migrated as well.<br /><br />We shall keep this old blog online for awhile to help our visitors and subscribers to make the transition to the new site. However, all new posts will appear only on the new blog.<br /><br />We hope that you will continue to visit the Biopharmconsortium Blog at its new home, and to subscribe to our posts. We also welcome your constructive comments as always.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-43120296129415000372010-05-13T15:24:00.000-07:002010-05-13T15:43:33.372-07:00A frog jumps into the animal model lineup<span style="font-family:Arial;">The cover of the 30 April 2010 issue of <i style="">Science</i> bears a photo of a tadpole of the western clawed frog <i style="">Xenopus tropicalis</i>. In that issue is <a href="http://www.sciencemag.org/cgi/content/full/328/5978/633">a report</a> on the draft sequence of the genome of this organism, and a short <a href="http://www.sciencemag.org/cgi/content/full/sci;328/5978/555">companion news feature</a>. The report on the genome emphasizes <i style="">X. tropicalis’</i> role as an emerging animal model in developmental and evolutionary biology and in comparative genomics.<br /><o:p></o:p></span> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p><i style=""><span style="font-family:Arial;">X. tropicalis</span></i><span style="font-family:Arial;"> 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 (“<i style="">Xenopus tropicalis</i>: an emerging model system”) of our book-length report, <a href="http://www.insightpharmareports.com/reports_report.aspx?r=7307&id=97037"><i style="">Animal Models for Therapeutic Strategies</i></a>, published by Cambridge Healthtech Institute in March 2010. <o:p></o:p></span> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The <i style="">Nature</i> news feature, authored by Elizabeth Pennisi, also cites the potential role of this frog in biomedical research. <i style="">X. tropicalis</i> 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 <i style="">X. tropicalis</i> 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. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p><p class="MsoNormal"> <a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjM3gAjI0xxZssEl0YbmQM_M6zLJ0IS3zDSbDMlMMwQX9Yoe1lIII4bTc9qttRKbztPQqS2_RrQqcg85osJxpuhu0XZNinJPgWOi-LWSYi1wsg8NcVu1m41Yb3zVABf1fILFcaIxInXryI/s1600/Xenopus_laevis.jpg"><img style="display: block; margin: 0px auto 10px; text-align: center; cursor: pointer; width: 306px; height: 216px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjM3gAjI0xxZssEl0YbmQM_M6zLJ0IS3zDSbDMlMMwQX9Yoe1lIII4bTc9qttRKbztPQqS2_RrQqcg85osJxpuhu0XZNinJPgWOi-LWSYi1wsg8NcVu1m41Yb3zVABf1fILFcaIxInXryI/s400/Xenopus_laevis.jpg" alt="" id="BLOGGER_PHOTO_ID_5470885327134835554" border="0" /></a><br /><span style="font-family:Arial;"><o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The related frog <i style="">Xenopus laevis</i> (known as the African clawed frog) is an old animal model that has long been used in developmental and cell biology research. However, <i style="">X. laevis</i> (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, <i style="">X. tropicalis</i> is diploid. <i style="">X tropicalis</i> also has a much shorter generation time than <i style="">X. laevis</i>, and is much smaller, thus requiring less space and making breeding and experimentation much more feasible than with <i style="">X. laevis</i>.</span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Some of the same researchers that have been participating in the <i style="">X. tropicalis</i> 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, <i style="">X. tropicalis</i> may join the zebrafish as a lower vertebrate animal model in developing novel therapeutic strategies for human diseases. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Elsewhere on the animal model genome front, researchers recently <a href="http://www.nature.com/nature/journal/v464/n7288/full/nature08830.html">published</a> a draft sequence of the genome of <i style="">Hydra magnipapillata</i>. 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.</span> <br /></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEixar2KLOKWZMb51zKvv1l0ke9Spp7I1L97iNah_IYVPfWKohn53lginEGrfaUOZLwf9I6uPkZOK-HN9gSjfm9H04503aGa1DswJGkz0hb2bLYi5Zyez2shbfu4uF4LlFdkOnjZ8LktH8I/s1600/Hydra001.jpg"><img style="display: block; margin: 0px auto 10px; text-align: center; cursor: pointer; width: 363px; height: 334px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEixar2KLOKWZMb51zKvv1l0ke9Spp7I1L97iNah_IYVPfWKohn53lginEGrfaUOZLwf9I6uPkZOK-HN9gSjfm9H04503aGa1DswJGkz0hb2bLYi5Zyez2shbfu4uF4LlFdkOnjZ8LktH8I/s400/Hydra001.jpg" alt="" id="BLOGGER_PHOTO_ID_5470886447992705538" border="0" /></a><span style="font-family:Arial;"><o:p></o:p>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. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Hydra may also be of interest for biomedical research. As discussed in the genome report, Hydra possesses four homologues of the <i style="">Myc </i>oncogene, which is involved in human cancers and also regulates pluripotency and self-renewal of mammalian stem cells. <i style="">Myc</i> 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. <o:p></o:p></span></p> <!--EndFragment-->Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-52679552648332438012010-05-11T13:23:00.000-07:002010-05-11T13:34:16.411-07:00More on anti-aging research: Continuing controversy, opportunity, and good news<!--StartFragment--> <p class="MsoNormal"><o:p></o:p><span style="font-weight: bold;">1. Continuing Controversy</span></p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">In <a href="http://biopharmconsortium.blogspot.com/2010/02/update-on-anti-aging-biology-sirtuins.html">our blog post on 10 February 2010</a>, we discussed the controversy over Sirtris/GlaxoSmithKline’s reseveratrol formulation, and its second-generation sirtuin-1 (SIRT1) activators. Researchers at Amgen and Pfizer found that the apparent in vitro activation of SIRT1 by these compounds was an artifact of the experimental method used by Sirtris researchers. The Amgen group found that the fluorescent SIRT1 peptide substrate used in the Sirtris assay is a substrate for SIRT1, but in the absence of the covalently linked fluorophore, the peptide is not a SIRT1 substrate. Although resveratrol appears to be an activator of SIRT1 if the artificial fluorophore-conjugated substrate is used, resveratrol does not activate SIRT1 in vitro as determined by assays using two other non-fluorescently-labeled substrates.</p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">Last month, I attended two meetings at which this controversy was discussed. One was the Bio-IT World Conference & Expo in Boston. At that conference, Christoph Westphal (then CEO of Sirtris) gave a <a href="http://www.bio-itworld.com/news/04/26/10/Christoph-Westphal-on-aging-pharmageddon.html">keynote address</a>.<span style=""> </span> In that presentation, Mr. Wesphal stuck with the story that Sirtis’ compounds and its assays are valid. The day after his presentation, Mr. Westphal resigned as Sirtris’ CEO, and now is the head of GSK’s SR One venture fund. He and other Sirtris and Vertex founders also started the Longwood Founders Fund in February of this year. </p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">At the other meeting (which was Harvard-related), one of the most respected leaders of the longevity-related pathway field (whose name I am withholding) stated that the whole resveratrol/sirtuin-activator story is nonsense. He did, however, concur with our views on anti-aging pathways as expressed in <a href="http://biopharmconsortium.blogspot.com/2009/11/anti-aging-biology-new-basic-research.html">our November 8, 2009 article on this blog</a>. We do not go as far as calling the resveratrol story nonsense, but remain unconvinced of the mechanistic basis for resveratrol action pending further evidence. </p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">Meanwhile, Derek Lowe’s “In the Pipeline” blog has a <a href="http://pipeline.corante.com/archives/2010/04/28/sirtriss_compounds_everyone_agrees.php#comments">discussion</a> of Mr. Wesphal’s talk at the Bio-IT conference.</p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">In its 25 March 2010 issue, <i style="">Nature</i> also has a <a href="http://www.nature.com/news/2010/100324/full/464480a.html">News Feature</a> centered upon the controversy. This article (written by Cambridge MA-based Nature reporter Heidi Ledford) basically says that the controversy remains unsettled, but that several laboratories are working to resolve the assay issue. These include corporate researchers at Sirtris, Leonard Guarente of MIT (another leader in the longevity-related pathway field, who is co-chair of Sirtris’ scientific advisory board), and Anthony Sauve of Weill Cornell Medical School (also a member of Sirtris’ scientific advisory board). </p> <p class="MsoNormal"><o:p> </o:p></p> <p style="font-weight: bold;" class="MsoNormal">2. Opportunity</p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">There was <a href="http://www.sciencemag.org/cgi/content/full/328/5976/321">a review of longevity-related pathways</a> in the 16 April 2010 issue of <i style="">Science</i>. It covers all the bases of anti-aging research in yeast, worms, flies, and mammals, with an emphasis on the TOR and insulin-like growth factor-1 (IGF-1) pathways. <span style=""> </span>Sirtuins and resveratrol rate a minimal mention in the review. </p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">Cynthia Kenyon, another leader in the longevity pathway field, published a <a href="http://www.nature.com/nature/journal/v464/n7288/full/nature08980.html">review</a> on the genetics of aging in a special Nature Insight section on aging in the 25 March 2010 issue. In this review, Dr. Kenyon discussed the panoply of aging-related pathways in worms, flies, and mice, especially the insulin/IGF-1 and TOR pathways, as well as several other biomolecules and biological processes. Dr. Kenyon discusses sirtuins, but notes the unknowns in aging-related mechanisms involving sirtuins, especially in mammals. She also notes the difficulties in interpreting results with resveratrol. In addition to the issue with the assays involving the fluorescent substrate, she notes that although (<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538685/?tool=pubmed">in studies conducted by Sirtris researchers and their academic colleagues</a>) resveratrol has been found to extend the lifespan of mice fed a high-fat diet, it did not extend the lifespan of mice fed a normal diet. Dr. Kenyon also cited the results of studies with resveratrol in yeast, worms, and flies that are not consistent with the hypothesis that resveratrol extends lifespan by acting as a sirtuin activator. </p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">The bottom line of the discussion in the two reviews in <i style="">Science</i> and <i style="">Nature</i> is that lifespan is controlled by sets of complex, interacting pathways. Sirtuins represent only one control point in these pathways, which might not be the most important one. Thus no one company “owns” the anti-aging field in terms of drug discovery and development, and there is a lot of opportunity out there. Even Mr. Westphal stated as much in his Bio-IT World presentation. </p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">Interestingly, Dr Kenyon notes that different closely related animals can have large differences in lifespan. For example, rats live for three years, but squirrels for 25. She speculates that differences in longevity might be easily evolvable, and mechanisms by which lifespan changes during evolution (perhaps involving mutations in regulatory genes or that affect rates of respiration) might constitute novel intervention points. </p> <p class="MsoNormal"><o:p> </o:p></p> <p style="font-weight: bold;" class="MsoNormal">3. Good News</p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">Now for some good news about aging. In an <a href="http://www.nature.com/nature/journal/v464/n7288/full/nature08984.html">article</a> in the 25 March 2010 Nature Insight section by James W Vaupel (Max Planck Institute for Demographic Research, Rostock, Germany, University of Southern Denmark, Odense, and Duke University), the author presents evidence that human senescence (i.e., deterioration with age)—at least in advanced countries—has been postponed by a decade. This process, first noted in 1994, is continuing. The factors that are making this possible are prosperity (which promotes good health) and medicine (including medical and surgical interventions to prevent or treat disability, and public health efforts). These two factors enable people to reach old age in better health, as well as promoting better health in older people.</p> <p class="MsoNormal"><o:p> </o:p></p> <p class="MsoNormal">This ongoing postponement of senescence and mortality provides a foundation for ongoing anti-aging research and eventual treatments based on that research. (One must remember, however, that regulatory agencies as well as the practical considerations of drug development will not permit researchers and companies to utilize mortality as an endpoint in clinical trials. Companies must therefore develop putative “anti-aging drugs” for specific diseases associated with aging, such as diabetes, cancer, various cardiovascular indications, and dementia.) The postponement of senescence also has profound implications for how one lives one’s life, as well as for social policy and the practice of medicine. <span style=""> </span></p> <!--EndFragment-->Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-75427011628481124162010-04-23T11:27:00.000-07:002010-05-13T15:56:29.091-07:00Agios Pharmaceuticals partners with Celgene<!--StartFragment--><span style="font-family:Arial;">On December 31, 2009, we posted an <a href="http://biopharmconsortium.blogspot.com/2009/12/cancer-metabolism-as-target-for-drug.html">article</a> on this blog about <a href="http://www.agios.com">Agios Pharmaceuticals</a> (Cambridge, MA). Agios is a private research-stage biotech company that is developing a pipeline of oncology drugs based on targeting metabolic pathways in cancer cells. In our article, we focused on Agios’ research on mutations in the metabolic enzyme cytosolic isocitrate dehydrogenase (IDH1) as a causative factor in gliomas and glioblastomas. We also mentioned Agios’ research on pyruvate kinase M2 (PKM2) and aerobic glycolysis in cancer. <o:p></o:p></span> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">On April 15, 2010, it was announced that Agios and <a href="http://www.celgene.com/index.aspx">Celgene Corporation</a> (Summit, NJ), a public biotechnology company with marketed products, had formed a strategic collaboration in the area of cancer metabolism. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Celgene markets Thalomid (thalidomide), which is approved by the FDA for treatment of multiple myeloma (MM). Thalidomide was notorious for causing birth defects in the late 1950s and early 1960s. However, beginning in the late 1990s, this drug has undergone a rehabilitation, provided that proper precautions are maintained to prevent its use in pregnant women and women who may become pregnant. Celgene has also been developing a class of thalidomide-derivative immunomodulatory drugs (IMiDs), which are designed to have greater efficacy against cancer and lesser toxicity than thalidomide. Of these drugs, Revlimid (lenalidomide) is approved by the FDA for treatment of MM and myelodysplastic syndromes (MDS) (life-threatening diseases of the bone marrow in which abnormally functioning immature hematopoietic cells are made; MDS can progress to acute myeloid leukemia in a substantial percentage of patients.) Celgene is researching additional indications for lenalidomide, and is also developing other IMiDs for various indications in cancer and inflammatory and neurodegenerative diseases. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Celgene’s Vidaza (azacitidine), a nucleoside metabolic inhibitor, is also indicated for the treatment of MDS. Celgene acquired Vidaza via its 2007 acquisition of Pharmion (Boulder, CO), which had developed the drug. Vidaza is an inhibitor of DNA methyltransferases (DNMT), which are enzymes that methylate DNA at specific sites and are important in epigenetic regulation. It was the first approved drug that works via an epigenetic mechanism. (Epigenetics is the study of heritable changes in gene function that do not involve changes in the nucleotide sequence of DNA. Major epigenetic processes include DNA methylation, modification of histones in chromatin, and RNA interference.)<br /></span></p><p class="MsoNormal"><span style="font-family:Arial;">Since Vidaza’s approval in 2004, two histone deacetylase (HDAC) inhibitors, which also modulate epigenetic regulation, have been approved. In late 2009, Celgene acquired the HDAC inhibitor romidepsin (Istodax) [approved in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL)], via its acquisition of Gloucester Pharmaceuticals (Cambridge MA).<o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Celgene is also developing several other anti-inflammatory drugs and kinase inhibitors. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The goal of the Agios/Celgene collaboration is to discover, develop, and commercialize novel oncology therapeutics based on Agios’ innovative cancer metabolism platform. Celgene sees the potential for early drug development opportunities in Agios’ IDH1 and PKM2 programs, as well as future opportunities based on new targets expected from Agios research programs. Celgene also sees opportunities to harness Agios’ R&D to expand its own pipeline in cancer and other diseases. <span style=""> </span><o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Under the terms of the agreement, Agios will receive a $130 million upfront payment, including equity. In return, Celgene will receives an initial period during which it will have the exclusive option to develop any drugs resulting from the Agios cancer metabolism platform. Celgene may also extend this exclusivity period through additional funding. Agios will lead discovery and early development for all cancer metabolism programs. During the period of exclusivity, Celgene will have an exclusive option to license any clinical candidates at the end of Phase I, and will lead and fund global development and commercialization of licensed programs. On each program, Agios may receive up to $120 million in milestones as well as royalties, and may also participate in the development and commercialization of certain products in the United States.<o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The Celgene collaboration continues Agios’ record of success in fundraising, and in gaining the recognition of the scientific and corporate communities. Despite the generally unfavorable financial environment for young biotech companies, Agios has raised, through alliances and investments, over $163 million in less than two years. This is despite the fact that the company has not one drug in the clinic. Agios expects to have a lead compound in the clinic some time in 2010, however. As is always the case, the validation of Agios’ innovative biology-driven platform awaits the results of human clinical trials and the attainment of regulatory approval.<span style=""> </span><o:p></o:p></span></p> <!--EndFragment-->Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-20661306577965350162010-04-19T15:33:00.000-07:002010-04-19T15:43:01.392-07:00Some notes on acute promyelocytic leukemia (APL)In our <a href="http://biopharmconsortium.blogspot.com/2010/04/developing-improved-mouse-models-of.html">last blog post</a> (April 15, 2010), we discussed genetically engineered mouse cancer models, with emphasis on the work of Dr. Pier Paolo Pandolfi (Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center, Boston MA) and his colleagues. Part of that discussion was on Dr. Pandolfi’s earlier work on the construction of genetically engineered models of acute promyelocytic leukemia (APL), and the use of these models in designing therapies for that disease. As the result of these studies and the work of others, the major form of APL (in which leukemic cells express the fusion protein PML-RARα) is now treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As<sub>2</sub>O<sub>3</sub>). What once was an invariably fatal disease now has about a 90% survival rate. <o:p></o:p><p></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">For those of you who are interested in the mechanisms by which ATRA and As<sub>2</sub>O<sub>3 </sub>work in treatment of APL: the 9 April 2010 issue of <i style="">Science</i> has a <a href="http://www.sciencemag.org/cgi/content/full/328/5975/184">Perspective</a> and a <a href="http://www.sciencemag.org/cgi/content/full/328/5975/240">research report</a> that focus on the mechanistic basis for the action of As<sub>2</sub>O<sub>3</sub>. For the mechanistic basis of the action of ATRA in APL, you may read a November 2008 <a href="http://www.nature.com/nm/journal/v14/n12/abs/nm.1891.html">research report</a> published in <i style="">Nature Medicine</i>.<br /><br /><!--StartFragment-->As soon as I posted the blog article on Dr. Pandolfi’s work, I received my 9 April issue of <i style="">Science</i> with the articles on As<sub>2</sub>O<sub>3</sub> in APL. So I am passing this information on to readers of this blog. <o:p></o:p></span></p> <!--EndFragment--><br /><span style="font-family:Arial;"><o:p></o:p></span><p></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <span style=";font-family:Arial;font-size:12pt;" ></span><!--EndFragment-->Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-78415210448076854902010-04-15T16:55:00.000-07:002010-04-19T15:30:56.952-07:00Developing improved mouse models of cancer for drug discovery and developmentThe April 1, 2010 issue of <i style="">The Scientist</i> has an article, entitled <a href="http://www.the-scientist.com/article/display/57237/">“Building a better mouse”</a>, on efforts of researchers to develop improved mouse models of cancer. <o:p></o:p><p></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p>Current mouse models of cancer, mainly xenograft models in which human cancer cell lines are transplanted into immune deficient mice, are notoriously unpredictive of efficacy when oncology drug candidates are tested in them. This is a major factor in the high failure rate of oncology drugs in clinical trials. It is estimated that oncology drugs that enter human clinical trials have a 95 percent attrition rate, as compared to the 89 percent attrition rate for all clinical candidates. (Poorly predictive animal models are a major factor in the failure of clinical candidates in all therapeutic areas, but cancer models are particularly unpredictive.) <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The <i style="">Scientist</i> article focuses on the ongoing <a href="http://www.dfhcc.harvard.edu/news/news/article/3285/334/?PHPSESSID=0d088ea8d5c2ea2fe888f27268fa09a5">“co-clinical mouse/human trials”</a> now being led by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center). Dr. Pandolfi and his colleagues have constructed genetically engineered transgenic mouse strains that have genetic changes that mimic those found in human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In the co-clinical mouse/human trials, researchers simultaneous treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The human clinical trials being “shadowed” by simultaneous studies in mice include Phase III trials of several targeted therapies for lung and prostate cancer. Xenograft models in which tumor tissue from the patients have been transplanted into immunosuppressed mice are being tested in parallel with the genetically engineered mouse models. This two-year project represents the most rigorous test to date of how well genetically engineered mouse models of cancer can predict clinical outcomes.<o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Dr. Pandolfi started in the mouse cancer model field with his <a href="http://www.nature.com/onc/journal/v20/n49/full/1204855a.html">studies of acute promyelocytic leukemia (APL)</a>. Unlike humans, mice do not naturally develop APL. Chromosomal translocations, in which the gene for the retinoic acid receptor alpha (</span><span style="font-family:Arial;">RARα</span><!--EndFragment--><span style="font-family:Arial;">) (located on chromosome 17) becomes fused to one of several partner genes (known as “X genes”) on different chromosomes, are involved in the causation of APL. In over 98% of cases of APL, </span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> is fused to the <i style="">promyelocytic leukemia (PML)</i> gene, located on chromosome 15. In a relatively small percentage of cases, </span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> is fused to other X genes. An example of one of these other genes is the <i style="">promyelocytic leukemia zinc finger (PLZF)</i> gene, located on chromosome 11.<span style=""> </span><span style=""> </span><o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">In studies in the late 1990s, Dr. Pandolfi and his colleagues constructed transgenic mice that expressed either PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> or PLZF-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> transgenes, in a promyelocytic-specific manner. (Expression of these transgenes in every cell of a mouse embryo results in embryonic lethality, and their expression in all early hematopoietic progenitors results in impaired myelopoiesis but no leukemia; these transgenic mice are thus not informative with respect to APL. The researchers were able to model PML only by expressing the transgenes specifically and exclusively in promyelocytes.)<o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The promyelocytic-specific PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Symbol;"></span><span style="font-family:Arial;">-transgenic mice exhibit abnormal hematopoiesis over their first year of life, and between 12-14 months of age 10% of them develop APL.<span style=""> </span>The promyelocytic-specific PLZF-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Symbol;"></span><span style="font-family:Arial;"> transgenic mice also exhibit a long latency period, and a subset of these mice eventually develops a leukemia that has features of human chronic myelogenous leukemia (CML). <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Importantly, the above transgenic mouse models were useful in designing therapies for human patients. The leukemias in both the PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;">-transgenic mice and in patients with the PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> translocation were responsive to treatment with all-trans retinoic acid (ATRA) (Genentech’s Vesanoid, generics). However, both the PLZF-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> transgenic mice and patients with APL bearing the PLZF-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> translocation were not responsive to ATRA. APL patients who initially responded to ATRA developed resistance to the drug, as did the PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> transgenic mice. Using the PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> transgenic mice, the researchers found that a combination of ATRA with arsenic trioxide (As<sub>2</sub>O<sub>3</sub>) (Cephalon’s Trisenox) cured the mice of leukemia. This later proved to also be true for human patients with APL bearing the PML-</span><span style="font-family:Arial;">RARα</span><span style="font-family:Arial;"> translocation. Thus a cancer that once was uniformly fatal now has an approximately 90% survival rate. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Leukemic mice with the PLZF-RARα transgene were not responsive to As<sub>2</sub>O<sub>3</sub>. However, later studies have indicated that histone deacetylase inhibitors such as phenylbutyrate, in combination with ATRA, may be effective in treating these transgenic mice. <span style=""> </span>These drug combinations may therefore be effective in APL patients with the PLZF-RARα translocation. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">The success of Dr. Pandolfi’s genetically engineered mouse model in designing an effective therapy for the major type of APL illustrates the potential power of improved mouse models for cancer. Of course, this is a special case, since researchers were able to use the model to design an effective therapy using already-approved drugs. In most cases, researchers use the models to develop novel therapeutic strategies for a particular cancer, which involves discovery and development of new drugs or design of clinical trials using experimental drugs that have yet to be approved. The “co-clinical mouse/human trials” being run by Dr. Pandolfi and his colleagues may result in additional validation of the power of genetically engineered mouse models of cancer, and may thus encourage their adoption by companies developing new oncology drugs. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Our recently published book-length report, <a href="http://www.insightpharmareports.com/reports_report.aspx?r=7307&id=97037"><i style="">Animal Models for Therapeutic Strategies</i></a>, includes a case study on a genetically engineered model of pancreatic cancer. Pancreatic cancer is one of the most lethal of cancers. Although models bearing transplanted human pancreatic tumors (i.e., xenograft models) are sensitive to numerous chemotherapeutic agents, human pancreatic cancers are insensitive to the same agents. Using a genetically engineered mouse model of pancreatic cancer, researchers hypothesized that the reason for the insensitivity of human pancreatic cancer (and of tumors in the mouse model) is impaired drug delivery. Researchers have been using the mouse model to develop novel therapeutic strategies to enhance drug delivery and thus to achieve improved treatment of this disease. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Our 2009 book-length report, <a href="http://www.insightpharmareports.com/reports_report.aspx?id=90910&r=666"><i style="">Approaches to Reducing Phase II Attrition</i></a>, includes a case study on adoption of genetically engineered cancer models by industry. Most animal models designed to enable researchers to develop novel therapeutic strategies for complex human diseases are developed by academic researchers. This includes genetically engineered cancer mouse models. However, most drugs are developed by industry, not academia. Industrial researchers are hampered in their ability to develop successful new oncology drugs by the poorly predictive xenograft models. Genetically engineered mouse models of cancer may help biotechnology and pharmaceutical company researchers to be more productive in oncology drug development, provided the corporate researchers can adopt these animal models for use in their discovery research and preclinical studies. However, for several reasons, industry has not widely adopted these models. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;">Our report discusses the barriers to adoption of these models, large pharmaceutical companies that are beginning to adopt the models, and the biotechnology company <a href="http://www.aveopharma.com/">Aveo Pharmaceuticals</a>, whose technology platform is based on in-licensing </span><span style="font-family:Arial;">genetically engineered mouse cancer models </span><span style="font-family:Arial;">from its principals’ academic laboratories and developing new models in-house. Aveo uses its models in its own internal drug discovery and development, and also collaborates with several large pharmaceutical companies. Aveo thus serves as a means of technology transfer from academia to industry, including both to its own internal programs and to its partners. The article in <i style="">The Scientist</i> also discusses Aveo’s research on genetically engineered mouse cancer models, and their use in the company’s internal drug development programs. <o:p></o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <p class="MsoNormal"><span style="font-family:Arial;"><o:p> </o:p></span></p> <!--EndFragment-->Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-68417168622322303902010-03-18T17:13:00.000-07:002010-03-18T17:18:34.810-07:00Some notes on this blogWe started the Biopharmconsortium Blog in July of 2009, so it is relatively new. Since that time, we have posted 21 articles (not including this one), 7 of which were posted in 2010.<br /><br />The blog has gradually been picking up a following, and it recently made a <a href="http://phlebotomytechnicianprograms.org/2010/top-50-biotech-blogs/#more-61">"Top 50 Biotech Blogs"</a> list. Thanks to Medicareer for honoring our blog in that way. (Haberman Associates has no business or financial relationship with Medicareer, nor do I even know the people there.)<br /><br />The 21 articles now posted on the blog may at first glance seem to be on random subjects—commentary on recent news and/or recent published scientific reports or business articles, and a few announcements and commentaries on Haberman Associates publications or events. However, there is a strong theme of R&D strategy—especially productive R&D strategies—running through the whole blog.<br /><br />When we first began the blog, the masthead at the top read “Your place for discussion of scientific and business issues in the biotechnology, pharmaceutical, diagnostics, and research products industry". Earlier this month, we changed the masthead to read “Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.” The new heading better reflects what the blog has become since we started it, and also reflects the fact that it is a business blog. Nevertheless, our blog is also a service to the life science community, including companies, academic institutions, and disease organizations and patient advocates. We continue to welcome your comments and discussions of our articles.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-51819175448255434472010-03-12T16:50:00.000-08:002010-03-12T17:05:38.356-08:00“Animal Models for Therapeutic Strategies” published by Cambridge Healthtech InstituteOn March 5, 2010, Cambridge Healthtech Institute (CHI) announced the publication of our new book-length report, <span style="font-style: italic;"><a href="http://www.insightpharmareports.com/reports_report.aspx?r=7307&id=97037">Animal Models for Therapeutic Strategies</a></span>. This new Insight Pharma Report discusses the use of animal models to develop new paradigms for drug discovery and development in important human diseases. The report also discusses strategies for developing more predictive animal models of drug efficacy. Poorly predictive animal models are a major reason for Phase II and Phase III pipeline drug attrition. Thus this new report complements our May 2009 Insight Pharma Report, <a href="http://www.insightpharmareports.com/reports_report.aspx?id=90910&r=666"><span style="font-style: italic;">Approaches to Reducing Phase II Attrition</span></a>.<br /><br />We have an <a href="http://www.biopharmconsortium.com/GEN_91504_allanhab.pdf">article</a>, published in <span style="font-style: italic;">Genetic Engineering News</span> in 2004, on the use of animal models in developing novel therapeutic strategies for the treatment of Alzheimer’s disease (AD), available free on our website. This article, based on our 2004 animal models report that is now out of print, gives examples of the use of animal models (the mouse, <span style="font-style: italic;">C. elegans</span>, Drosophila, and the zebrafish) in developing therapeutic strategies. These animal model studies were key to the eventual development of nearly all the pipeline drugs now in the clinic for AD, as well as the development of alternative hypotheses to the dominant amyloid hypothesis (and therapeutic strategies based on them).<br /><br />The 2010 report includes discussions of using animal models to develop therapeutic strategies for such diseases as Parkinson’s disease, polycystic kidney disease (PKD), autism, and various types of cancer. It also includes discussion of development of emerging animal models, from fish to frogs to mammals.<br /><br />In the “emerging mammalian model systems” chapter, we include a discussion of the “reemergence” of the laboratory rat, an old animal model that had been eclipsed by the mouse in the era of knockout mice and genomics. Many of you have no doubt seen the ads from SAGE Labs (Sigma Advanced Genetic Engineering) in scientific and trade journals, announcing that <a href="http://www.sciencemag.org/cgi/issue_pdf/advertising_pdf/327/5966.pdf">“knockout rats are finally here”</a>. Some of you may also have seen the Nature news article <a href="http://www.nature.com/news/2009/090811/full/460788a.html">“</a><a href="http://www.nature.com/news/2009/090811/full/460788a.html">Return of the rat</a><a href="http://www.nature.com/news/2009/090811/full/460788a.html">”</a>. We cover the technologies behind the reemergence of the rat, and the companies and research groups that are driving this development, in our report. As we also discuss in the report, some of the new technologies used in developing rat models are also being applied to other mammalian species.<br /><br />The report also covers the issue of why it is so difficult to model the complex diseases that are the major focus of current drug discovery and development efforts in the pharmaceutical/biotechnology industry, and strategies that researchers are using to develop more predictive animal models, especially more predictive mammalian models.<br /><br />For more information on the report, or to order it, see the <a href="http://www.insightpharmareports.com/reports_report.aspx?r=7307&id=97037">CHI Insight Pharma Reports</a> website.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com1tag:blogger.com,1999:blog-4682750433159205287.post-61416508085780689632010-03-10T15:10:00.000-08:002010-03-10T20:33:55.949-08:00Plexxikon’s discovery of PLX4032, a selective targeted therapeutic for metastatic melanomaIn our <a href="http://biopharmconsortium.blogspot.com/2010/03/bringing-targeted-therapy-of-metastatic.html">March 2, 2010 blog post</a>, we focused on a Phase I clinical trial of Plexxikon/Roche’s PLX4032, in which clinical researchers led by Keith T. Flaherty achieved a dramatic breakthrough in treatment of metastatic melanoma. Now we shall discuss the discovery of the drug itself, PLX4032.<br /><br />In 2002, a research consortium based at the Wellcome Trust Sanger Institute in the U.K. found <a href="http://www.nature.com/nature/journal/v417/n6892/full/nature00766.html">B-Raf somatic missense mutations in 66% of malignant melanomas</a> (as well as in a subset of other cancers). V600E (valine substituted by glutamic acid at position 600) accounted for 80% of these mutant forms of B-Raf. The V600E mutation causes destabilization of the inactive conformation of B-Raf kinase, shifting the equilibrium toward the catalytically active conformation.<br /><br />B-Raf is a serine/threonine protein kinase that is a component of an intracellular pathway that mediates signals from growth factors. B-Raf is regulated by binding to Ras. In turn, B-Raf activates MEK (mitogen-activated protein kinase kinase), which activates ERK (extracellular signal-regulated kinase). Activated ERK goes on to upregulate transcriptional pathways that promote cellular proliferation and survival.<br /><br /><span style="font-weight: bold;">Growth factors → →Ras→ B-Raf→ MEK→ ERK→ →upregulation of cell proliferation and survival </span><br /><br />Growth factor signaling via Ras also controls other signaling pathways that upregulate cell proliferation, notably the PI3K-Akt (phosphatidylinositol-3-OH kinase-Akt) pathway.<br /><br />The Sanger researchers found evidence that cells carrying B-Raf(V600E) no longer require Ras function for proliferation. This would mean that melanoma cells carrying this mutation could proliferate independently of growth factor signaling, resulting in the runaway proliferation characteristic of the malignant phenotype.<br /><br />These results suggested that B-Raf(V600E) would be a good target for novel kinase inhibitors to treat malignant melanoma. The first such kinase inhibitors to be developed, although they had inhibitory activities at low nanomolar concentrations against B-Raf (both wild-type and mutant), were not successful in the clinic, due to their inhibition of multiple nonspecific targets and/or their poor bioavailability. Plexxikon researchers therefore set out to discover inhibitors that are highly selective for B-Raf(V600E). The result was the discovery of PLX4032.<br /><br />The discovery of PLX4720 (a <a href="http://www.nature.com/nchembio/journal/v6/n3/full/nchembio.330.html">tool compound or chemical probe</a> related to PLX4032) by Plexxikon researchers and their academic colleagues, and its preclinical validation, is described in a 2008 publication, <a href="http://www.pnas.org/content/105/8/3041.long">Tsai et al</a>. Plexxikon used its proprietary <a href="http://www.nature.com/nbt/journal/v23/n2/abs/nbt1059.html">“scaffold-based drug design” </a>technology platform to discover PLX4720. Scaffold-based drug design involves synthesizing sets of low-molecular weight “scaffold-like’” compounds. These compounds interact (typically at low affinity) with many members of a protein family by targeting their conserved regions.<br /><br />In the B-Raf study, the researchers identified protein kinase scaffolds by screening a select library of 20,000 150-350-dalton compounds for inhibition of a set of three structurally characterized protein kinases at a concentration of 200 micromolar (μM). Of this library, 238 compounds were selected on the basis of their inhibition of the kinases by at least 30% at the 200 μM concentration. Each of the compounds was cocrystallized with one if the three kinases, Pim-1. Using this method, the researchers found that 7-azaindole bound to the ATP-binding site of Pim-1 kinase. They further modified this compound by adding side chains on the 3 position of 7-azaindole, resulting in a “scaffold candidate” with increased affinity for the ATP binding site of PIm-1 and other kinases. The researchers further modified this scaffold, based on structural data from other kinases. Ultimately, they cocrystallized their modified compounds with wild-type B-Raf and B-Raf(V600E), and optimized the structure of their compounds to give a compound, PLX4720, with selectivity for B-Raf(V600E) and against wild-type B-Raf and other kinases. This process (including the relevant chemical and protein structures) is illustrated in <a href="http://www.pnas.org/content/105/8/3041/F1.expansion.html">Figure 1</a> of Tsai et al.<br /><br />In biochemical assays, the researchers found that PLX4720 inhibited B-Raf(V600E) at low nanomolar concentrations, and was 10-fold more selective for B-Raf(V600E) than for wild-type B-Raf, and was even more selective for B-Raf(V600E) than for other kinases.<br /><br />Surprisingly, in cellular assays, PLX4720 is over 100-fold (not 10-fold) more selective in inhibiting proliferation of tumor cell lines that bear B-Raf(V600E) as compared to those that bear wild-type B-Raf. Moreover, <a href="http://www.nature.com/nature/journal/v439/n7074/full/nature04304.html">as first found by researchers at Pfizer and their academic collaborators</a>, a specific inhibitor of MEK (Pfizer’s CI-1040) is also similarly selective for tumor cell lines bearing B-Raf(V600E). This suggests that the B-Raf-MEK-ERK pathway is critical for the proliferation of B-Raf(V600E) cells, but not for cells bearing wild-type B-Raf. [For example, tumor cells that bear wild-type B-Raf might use the PI3K-Akt pathway to upregulate pathways that control cell proliferation independent of ERK signaling, while tumor cells that bear B-Raf(V600E) cannot.]<br /><br />The B-Raf-MEK-ERK pathway dependence of B-Raf(V600E) cells may in part be related to feedback inhibition of B-Raf (and other isoforms of Raf). Activated ERK can <a href="http://www.cell.com/molecular-cell/retrieve/pii/S1097276504008019">phosporylate wild-type Raf isoforms at specific inhibitory sites</a>. This results in downregulation of signaling via the Raf-MEK-ERK pathway. However, in cells bearing B-Raf(V600E), <a href="http://www.pnas.org/content/106/11/4519.long">this feedback inhibition is disabled</a>, resulting in uncontrolled signaling.<br /><br />The Plexxikon researchers (Tsai et al.) tested PLX4720 against tumor xenograft models. Oral administration of PLX4720 blocked tumor growth, and in 4 out of 9 cases caused tumor regressions, in mice with tumor xenografts bearing B-Raf(V600E). Treatment with PLX4720 was well tolerated, and showed no adverse effects. Growth of tumor xenografts bearing wild-type B-Raf was not affected by PLX4720. In mice with tumors bearing B-Raf(V600E), PLX4720 blocked B-Raf-MEK-ERK pathway signaling, as demonstrated by immunohistochemical assays.<br /><br />The exquisite specificity of PLX4720/PLX4032 for B-Raf(V600E) as compared to wild-type B-Raf was made possible by Plexxikon’s structure-guided “scaffold-based drug design” technology. Other structure-guided drug design technologies, such as <a href="http://pubs.acs.org/cen/coverstory/86/8629cover.html">fragment-based lead design</a>, as is carried out in several companies, might be used to design comparably specific drugs.<br /><br />The discovery of PLX4720/PLX4032 is an example of the use of new-generation chemistry technologies (or the revival of the old, and now disused natural products chemistry approach), coupled with biology-driven drug discovery strategies, to discover promising new drugs. We have discussed this strategy in several articles on this blog. (For example, see <a href="http://biopharmconsortium.blogspot.com/2009/11/stapled-peptides-for-targeting.html">here</a> and <a href="http://biopharmconsortium.blogspot.com/2009/07/now-for-some-chemistrynatural-products.html">here</a>).<br /><br />Despite the promising results seen in Phase I clinical trials of PLX4032, it must be emphasized that the establishment of the efficacy and safety of this compound awaits the completion of the ongoing Phase III trials. Moreover, despite the dramatic regressions and increased survival seen in the Phase I trials, all the patients apparently eventually suffered relapses. Dr. Flaherty, as discussed in our earlier blog post, sees the need for combination therapies to effectively combat metastatic melanoma. In early 2009, Dr. Flaherty and his colleague Keiran S Smalley published a <a href="http://www.nature.com/bjc/journal/v100/n3/full/6604891a.html">mini-review</a> on potential strategies for developing such combination therapies.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-30031838013314937752010-03-02T16:14:00.000-08:002010-03-08T16:57:24.921-08:00Bringing targeted therapy of metastatic melanoma into the clinic--the crucial role of translational researchersDuring the week of February 22, 2010, the <span style="font-style: italic;">New York Times</span> (NYT) ran a three-part <a href="http://www.nytimes.com/2010/02/22/health/research/22trial.html">series </a>on a Phase I trial in 2008/2009 of a targeted therapy for metastatic melanoma, a disease that is almost always fatal within a year. The trial was led by Keith T. Flaherty, M.D. (then at the University of Pennsylvania in Philadelphia, and now at the Dana-Farber Cancer Center in Boston). The drug was PLX4032, developed by <a href="http://www.plexxikon.com/view.cfm/1/Homepage">Plexxikon</a>, which is co-developing the compound with Roche. PLX4032 is a kinase inhibitor, which specifically targets the V600E mutant of the B-Raf oncoprotein. This is the most common somatic mutation found in human melanomas. Researchers believe that B-Raf(V600E) is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation. PLX4032 entered Phase III clinical trials in 2009.<br /><br />The NYT series, authored by Amy Harmon, focused on the stories of several patients, and on the dogged efforts of Dr. Flaherty to help his patients and to prove the value of targeted therapy. Although the targeted kinase inhibitor imatinib (Novartis’ Gleevec/Glivec) produces complete responses in the majority of treated patients in the chronic phase of CML (chronic myelogenous leukemia) and long-lasting remissions in many of these patients, many researchers believe that this is a special case, and they cite evidence that targeted therapy, especially in solid tumors, almost never produces durable responses. But Dr. Flaherty pressed on with his quest to prove the value of targeted therapy, despite this skepticism.<br /><br />A key point in the story was when the original formulation of PLX4032, at the highest dose that patients could absorb, produced neither adverse effects nor clinical responses. Because of his belief in targeted therapy, and in this particular drug, Dr. Flaherty convinced Roche to reformulate the drug to enable patients to absorb a higher dose. With the higher doses of the drug made possible by the new formulation, the researchers saw dramatic clinical responses in the great majority of patients whose tumors contained B-Raf(V600E). Responses lasted an average of nearly 9 months, a dramatic breakthrough in treatment of metastatic melanoma.<br /><br />As the series ended, Dr. Flaherty was working with his colleagues and the pharmaceutical industry to find ways to enable the testing of combination therapies of targeted drugs (including PLX4032) that might result in long-lasting remissions in patients with metastatic melanoma. Meanwhile, Plexxikon and Roche have taken PLX4032 into Phase II clinical trials and now into Phase III.<br /><br />The NYT series is essentially a human-interest story. I commend it to all researchers, executives, and consultants in the industry whose work does not involve contact with patients, since creating products that can help patients is what our work is all about.<br /><br />Dr. Flaherty reminds me, and others who have commented on this story, of Brian J. Druker, M.D. at the Oregon Health Sciences University in Portland. It was Dr. Druker’s efforts, centered on helping patients and proving the value of targeted therapy, that was the <a href="http://www.ohsu.edu/xd/about/news_events/news/ohsubriandrukerwinslasker.cfm">driving force</a> behind the development of imatinib (Novartis’ Gleevec/Glivec). Without this effort (conducted in collaboration with biochemist Nicholas B. Lydon, then at Novartis), the whole field of kinase inhibitors for targeted therapy of cancer would not have emerged. Dr. Flaherty, as well as several other oncologists, is continuing this worthy tradition.<br /><br />As pointed out to me by a leading Boston-area academic researcher in a cancer-related area, the NYT series did not give credit to the academic researchers who identified the role of B-Raf in cancer, and especially the role of B-Raf(V600E) in human melanoma. (For that matter, it did not credit the Plexxicon researchers who discovered PLX4032.) She said that the series sounded as if only one person, Dr. Flaherty, was responsible for the development of PLX4032. Moreover, the development of imatinib was made possible by decades of academic research on the target of the drug, Bcr-Abl, a fusion protein formed as the result of a chromosomal translocation. Drs. Druker and Lydon thus were not solely responsible for the development of imatinib either.<br /><br />The academic researcher has a point. However, <a href="http://pipeline.corante.com/archives/2005/06/05/biotech_at_last_eh.php">some industry commentators</a> take a contrary point of view, downplaying the role of academic researchers in the drug discovery/development process and giving most of the credit to industry.<br /><br />For years, we have taken the <a href="http://www.biopharmconsortium.com/GEN_1205_allanhab.pdf">point of view</a> that biology-driven drug discovery and development (arguably the most successful drug discovery/development strategy in the post-genomic era) requires the contributions of <span style="font-style: italic;">both</span> academia and industry, and that more effective collaboration between academia and industry would result in more effective drug discovery and development. (See also my 2005 <a href="http://www.businessweek.com/magazine/content/05_27/c3941015_mz004.htm">letter to the editor</a> of <span style="font-style: italic;">BusinessWeek</span>.)<br /><br />It is basic research, usually in academic laboratories, that has resulted in the very best validated targets. Basic research on a particular target typically takes years or even decades (as in the case of Bcr-Abl). Many of the breakthrough drugs that have emerged in the past 10-15 years (as well as numerous promising pipeline drugs now in clinical testing) were made possible by this research. In contrast, large-scale “target validation” testing in industry more often than not results in targets whose role in normal physiology and in disease is poorly understood. This is an important cause of clinical attrition in drug development.<br /><br />Nevertheless, it is industry, not academia, which uses this basic research to create drugs. In particular, it is industry that bears the enormous economic risk of drug development, especially of late-stage clinical trials.<br /><br />Translational researchers, who are involved in taking the results of academic research and/or of discovery research in industry, and translating them into therapies that benefit patients, are—or should be—a key component of the drug discovery-development process. Drs. Druker and Flaherty are two outstanding examples.<br /><br />However, at least some sectors of academia (and of governmental policy-makers and the media) are suspicious of the type of closer industry-academic collaboration that is needed to produce more effective translation of basic and drug-discovery research into the clinic. An <a href="http://www.nature.com/nature/journal/v463/n7284/full/463999b.html">editorial</a> in the 25 February issue of <span style="font-style: italic;">Nature</span> notes that there has been <a href="http://www.boston.com/news/health/blog/2010/02/harvards_new_re.html">criticism</a> of the recent hiring of William Chin, Lilly’s senior VP for discovery and clinical research, to be the executive dean for research at Harvard Medical School. The critics charge that strong research collaborations between academia and industry will inevitably result in conflicts of interest. The<span style="font-style: italic;"> Nature</span> editorial supports institutional policies that require disclosure of links between academic researchers and industry, but deplores the views of influential critics who believe that any collaboration between academic researchers and industry “corrupts” the academic research enterprise.<br /><br />In addition to <span style="font-style: italic;">Nature</span>, some leading academic researchers say that it is time for industry and the academic medical community to <a href="http://online.wsj.com/article/SB123914780537299005.html">fight back</a> against the critics, rather than appeasing them with <a href="http://www.boston.com/business/healthcare/articles/2010/01/03/partners_healthcare_curbs_fees_staff_can_accept_from_drug_makers/">ever more restrictive conflict-of-interest policies</a>. These researchers note that the main purpose of medical research is not to publish scientific papers, but to translate this knowledge into therapies that benefit patients. This requires effective collaboration between academia and industry. We agree.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-76037458480803916152010-02-19T16:36:00.000-08:002010-02-23T08:31:45.091-08:00Across-the-board R&D cuts will not solve the pharmaceutical industry’s productivity crisisThe 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 <a href="http://www.corante.com/pipeline/">“In the Pipeline”</a> 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 <a href="http://pipeline.corante.com/archives/2010/02/17/merck_announces_cuts.php">Merck</a> have been affected.<br /><br />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.<br /><br />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.<br /><br />From the point of view of a financial analyst, the move to cut internal pharmaceutical R&D is a matter of <a href="http://pipeline.corante.com/archives/2010/02/05/sheer_economics_how_we_got_in_this_fix.php">“sheer economics”</a>. 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.<br /><br />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.<br /><br />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.<br /><br />For example, here in the Boston area, <a href="http://www.dyax.com/">Dyax</a>, 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.<br /><br />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.<br /><br />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.<br /><br />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.<br /><br />We recently authored two publications that analyzed the nature of the R&D productivity problem, and which outlined solutions. These are an article, <a href="http://www.biopharmconsortium.com/GEN_PIIAtt_0809.pdf">“Overcoming Phase II Attrition Problem”</a>, published in Genetic Engineering News (GEN) and available free on our website, and a book-length report, <a href="http://www.insightpharmareports.com/reports_report.aspx?id=90910&r=666"><span style="font-style: italic;">Approaches to Reducing Phase II Attrition</span></a>, available from Cambridge Healthtech Institute (CHI). In summary, we proposed a two-part strategy to increase rate of success in drug development:<br /><ul><li>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).</li><li>Employ early stage proof-of-concept (POC) clinical trials to weed out drugs and targets that do not achieve POC. </li></ul>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.<br /><br />In a recent Reuters article entitled <a href="http://www.reuters.com/article/idUSTRE6144GA20100205">“Killing research no certain cure for Big Pharma”</a>, 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."<br /><br />We have discussed Novartis’ R&D strategy in several articles on this blog, notably our July 20, 2009 article <a href="http://biopharmconsortium.blogspot.com/2009/07/biology-driven-drug-discovery.html">“Biology-driven drug discovery: a ‘disruptive innovation’?” </a><br /><br />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.<br /><br />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 <a href="http://blogs.wsj.com/source/2010/02/03/roche-ceo-reckons-the-drugs-will-work/">“poised for a quantum leap into a golden age”</a>, 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.<br /><br />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.<br /><br />With respect to rare diseases, in addition to adopting the <a href="http://web.mac.com/apoorva.bajaj/iWeb/Random%20Musings/Thought%20Joining/321A7C51-34F9-4685-85D0-E288C74D050B.html">“Genzyme strategy”</a> (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.<br /><br />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, <a href="http://www.nature.com/nrd/journal/v8/n1/full/nrd2758.html">kinase inhibitors</a> 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?<br /><br />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.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-30960638059603468382010-02-10T19:10:00.000-08:002010-02-11T07:54:46.225-08:00Update on anti-aging biology, sirtuins, and Sirtris/GlaxoSmithKlineOn November 8, 2009, we posted an <a href="http://biopharmconsortium.blogspot.com/2009/11/anti-aging-biology-new-basic-research.html">article</a> 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).<br /><br />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.<br /><br />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 <a href="http://pipeline.corante.com/archives/2010/01/12/the_sirtris_compounds_worthless_really.php">“In the Pipeline”</a> blog for the information. This issue was also covered in <a href="http://pipeline.corante.com/archives/2010/01/26/a_storm_in_a_teacup.php">a second post</a> on the same blog. It was also covered by articles in the 15 January 2010 issue of <a href="http://www.newscientist.com/article/dn18396-stay-young-on-red-wine-drugs-think-again.html">New Scientist</a> and in the January 26, 2010 issue of <a href="http://www.forbes.com/2010/01/25/longevity-resveratrol-glaxosmithkline-healthcare-business-pfizer-amgen.html">Forbes</a>. <a href="http://www.nature.com/news/2010/100119/full/news.2010.18.html">Nature</a> also covered this story in an online news article.<br /><br />In a <a href="http://www.ncbi.nlm.nih.gov/pubmed/19843076?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1">report</a> 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.<br /><br />More recently, researchers at Pfizer published a <a href="http://www.jbc.org/content/early/2010/01/08/jbc.M109.088682.full.pdf">study</a> 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.<br /><br />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.<br /><br />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.<br /><br />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 <a href="http://www.forbes.com/2010/01/25/longevity-resveratrol-glaxosmithkline-healthcare-business-pfizer-amgen.html%5D">Forbes article</a>, 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.)<br /><br />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.<br /><br />As we discussed in <a href="http://biopharmconsortium.blogspot.com/2009/11/anti-aging-biology-new-basic-research.html">our original blog post</a>, 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 <a href="http://www.sienabiotech.com/index.jsp">Siena Biotech</a> (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.<br /><br />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 <a href="http://www.ncbi.nlm.nih.gov/pubmed/18358225?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2">report</a> 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.<br /><br />The <a href="http://www.nature.com/nature/journal/v444/n7117/full/nature05354.html">efficacy</a> 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.<br /><br />Finally, as we discussed in our <a href="http://biopharmconsortium.blogspot.com/2009/11/anti-aging-biology-new-basic-research.html">November 8, 2009 blog post</a>, 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.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-86246156433999268602010-01-28T16:34:00.000-08:002010-01-28T16:43:49.715-08:00Update on liraglutide (Novo Nordisk’s Victoza)—approved by the FDA for treatment of type 2 diabetesOn October 25, 2009, we posted an <a href="http://biopharmconsortium.blogspot.com/2009/10/liraglutide-novo-nordisks-victoza-for.html">article</a> 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.<br /><br />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.<br /><br />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.<br /><br />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.<br /><br />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.<br /><br />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.<br /><br />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.<br /><br />Our October 2009 <a href="http://biopharmconsortium.blogspot.com/2009/10/liraglutide-novo-nordisks-victoza-for.html">blog post</a> 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.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-4432280023013491822010-01-26T19:43:00.000-08:002010-01-26T20:06:28.687-08:00ApoE4 and Alzheimer’s disease: stratified medicine and development of new therapeutic strategiesIn the December 15, 2009 issue of <span style="font-style: italic;">Neurology</span>, a <a href="http://www.neurology.org/cgi/content/abstract/73/24/2061">research report</a> by Stephen Salloway and his colleagues at the Butler Hospital and Brown University (Providence, RI) and an <a href="http://www.neurology.org/cgi/content/full/73/24/2052">editorial</a> 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”.<br /><br />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.)<br /><br />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.<br /><br />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.<br /><br />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 <a href="http://www.adaptivepharmacogenomics.com/users/fdaMITprogram04OCT2009.pdf">here</a> and <a href="http://www.nature.com/nrd/journal/v8/n12/full/nrd3070.html">here</a>. 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.<br /><br />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 <a href="http://www.biopharmconsortium.com/GEN_91504_allanhab.pdf">2004 article</a> published in <span style="font-style: italic;">Genetic Engineering News </span>(available on our website), and in book-length reports published by Cambridge Healthtech Institute <a href="http://www.insightpharmareports.com/reports/2006/66_Emerging_Targets/overview.asp">in 2006</a> and <a href="http://www.insightpharmareports.com/reports_report.aspx?id=90910&r=666">in 2009</a>.<br /><br />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.<br /><br />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 <a href="http://www.pnas.org/content/105/4/1343.long">here</a> and <a href="http://www.jbc.org/content/284/40/27273.long">here</a>. 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.<br /><br />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.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-58767503113412903512009-12-31T16:35:00.000-08:002010-01-06T12:29:32.792-08:00Cancer metabolism as a target for drug discovery: Agios PharmaceuticalsIn the December 10 2009 issue of <span style="font-style: italic;">Nature</span>, researchers at Agios Pharmaceuticals (Cambridge, MA) and their academic collaborators published an <a href="http://www.nature.com/nature/journal/v462/n7274/full/nature08617.html">article</a> implicating mutations in a metabolic enzyme, cytosolic isocitrate dehydrogenase (IDH1) as a causative factor in a major subset of human brain cancers.<br /><br />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).<br /><br />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.<br /><br />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.<br /><br />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 <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2557065/?tool=pubmed">NMDA (N- methyl-D-aspartate) receptor agonist</a>, and competitive inhibition of enzymes that use glutamate and/or α-ketoglutarate resulting in the <a href="http://www.sciencemag.org/cgi/content/full/324/5924/261">induction of hypoxia-inducible factor-1α</a>, a transcription factor that facilitates tumor growth under conditions of hypoxia.<br /><br />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.<br /><br />The company that led this research, <a href="http://www.agios.com/">Agios Pharmaceuticals</a>, is developing a pipeline of oncology drugs based on targeting metabolic pathways in cancer cells. Interestingly, Agios means <a href="http://www.youtube.com/watch?v=V9HWu2C6cU4">“holy” </a>in Greek.<br /><br />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”.<br /><br />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 <a href="http://www.sciencemag.org/cgi/content/full/324/5930/1029">the connection between growth factor-mediated signal transduction and aerobic glycolysis </a>that is the basis for Agios’ platform. In particular, Dr. Cantley and his colleagues found that pyruvate kinase M2 (PKM2) is <a href="http://www.nature.com/nature/journal/v452/n7184/full/nature06667.html">a link between signal transduction and aerobic glycolysis</a>. 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.<br /><br />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.<br /><br />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.<br /><br />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 <a href="http://www.nature.com/nrd/journal/v8/n8/full/nrd2964.html">one of the most exciting areas of cancer research</a>.<br /><br />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), <a href="http://theoncologist.alphamedpress.org/cgi/content/full/6/3/233">specific targeting of protein kinases was though to be unlikely</a>, 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.<br /><br />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 <a href="http://biopharmconsortium.blogspot.com/2009/09/bristol-myers-squibb-acquires.html">our blog post on monoclonal antibodies</a>, 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.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com2tag:blogger.com,1999:blog-4682750433159205287.post-66889022434440416282009-12-09T14:25:00.000-08:002009-12-09T14:47:07.617-08:00Small-molecule drugs for targeting an intracellular signaling pathway: research and development of new oncology drugsIn our <a href="http://biopharmconsortium.blogspot.com/2009/11/stapled-peptides-for-targeting.html">November 27th blog post</a>, we discussed an innovative new technology, stapled peptides, for use in targeting intracellular protein-protein interactions. In the example we gave, the target was a transcription factor complex in the Notch pathway. As we stated, protein-protein interactions are deemed to be “undruggable”, since they cannot be readily addressed with small molecule drugs.<br /><br />Nevertheless, in some cases, small molecules have been discovered that do address key protein-protein interactions, and which may become clinical candidates.<br /><br />Back in February 2006, Decision Resources published our report, <a href="http://www.researchandmarkets.com/reports/328329">“Protein-Protein Interactions: Are They Now Druggable Targets?"</a> Among the case studies we discussed in that report was one in which researchers were attempting to discover small-molecule agents that targeted the Wnt pathway. The researchers discovered small-molecule agents that, as with the stapled-peptide example we discussed in our previous blog post, targeted a transcription factor complex. As of late 2009, two of these compounds are in preclinical development for treatment of various cancers.<br /><br />Mutations that mediate deregulation of the Wnt pathway are causative factors in several types of cancer, most notably colorectal cancer, as well as multiple myeloma (MM), hepatocellular carcinoma (HCC), and B-cell chronic lymphocytic leukemia B-CLL). In the canonical Wnt pathway, soluble extracellular factors that are members of the Wnt family activate the pathway. A complex that includes the protein adenomatous polyplosis coli (APC) is central to the Wnt pathway. When Wnt receptors are not engaged by their ligands, kinases in the APC complex phosphorylate β-catenin, a multifunctional protein that is involved both in signal transduction and in adhesion between cells. Phosphorylation targets β-catenin for degradation.<br /><br />When Wnt proteins bind to their receptors, the kinase activity of the APC complex is inactivated. This results in the accumulation of β-catenin, which moves into the nucleus. There it binds to proteins of the T cell factor (Tcf) family. β-catenin binding changes Tcf from a transcriptional repressor into a transcriptional activator. Downstream genes controlled by the β-catenin/Tcf complex include the oncogene Myc and other genes that mediate cell proliferation.<br /><br />In precancerous colonic adenomas or the colorectal cancers that they may evolve into, APC is usually mutated. This results in constitutive stabilization of β-catenin and constitutive activation of Tcf and its downstream genes. In other types of cancer that involve constitutive Wnt pathway activation, β-catenin also becomes stabilized, via other means. This makes the Tcf/β-catenin a tempting target for drug discovery. However, it is a protein-protein interaction, and is thus deemed “undruggable”.<br /><br />In 2004, A group led by Ramesh Shivdasani (Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, Boston MA), including researchers from the Novartis Institutes for BioMedical Research (Cambridge, MA), <a href="http://www.cell.com/cancer-cell/retrieve/pii/S1535610803003349">discovered several small-molecule inhibitors of the interaction between human Tcf4 and human β-catenin</a>.<br /><br />Dr. Shivdasani’s group, among others, had previously determined crystal structures of Tcf-β-catenin complexes. The interaction between the two proteins occurs over a large surface area. It is the large, and usually hydrophobic, interface between proteins in protein-protein interactions that forms the theoretical basis for the difficulty of addressing these interactions with small molecules. However, <a href="http://www.jbc.org/content/278/23/21092.long">there is a small hydrophobic pocket that is critical for binding</a> (as also confirmed by site-specific mutation studies), which might accommodate a small molecule inhibitor.<br /><br />Therefore, the researchers screened approximately 7,000 purified natural products from public and proprietary libraries using an enzyme-linked immunosorbent (ELISA) assay involving release of a labeled Tcf4 binding fragment from its complex with a β-catenin fragment absorbed to an ELISA plate. Eight compounds were found that gave reproducible, concentration-dependent release of the Tcf4 fragment at less than 10 micromolar concentration. The structures and purity of these compounds (most of which are complex, multi-ringed planar compounds with multiple hydroxy groups) were then determined. The sources of these compounds include fungi, actinomycetes, and a marine sponge.<br /><br />The researchers performed several additional biochemical assays to confirm the compounds’ specific disruption of the Tcf/β-catenin complex, and also performed cellular assays and an in vivo assay in the Xenopus (frog) embryo to study the activities of these compounds against β-catenin-mediated cellular effects. Each of the eight compounds shows different levels of potency in the different assays used in this study, and the compounds differ from each other in their activities in the different assays.<br /><br />Two fungal-derived compounds, PKF115-854 and CGP04909, gave the best results in all the assays. It is those compounds that have been tested in preclinical studies as potential oncology drug candidates. In <a href="http://www.pnas.org/content/104/18/7516.long">a study published in PNAS in 2007</a>, researchers at the Dana-Farber and at Brigham and Women’s Hospital tested PKF115-584 in human MM cells in vitro and in xenograft models. The compound blocked expression of Wnt target genes, induced cytotoxicity in MM cells in vitro, and inhibited tumor growth and prolonged survival in the xenograft model. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19662654">In a study in HCC </a>at the Asian Liver Center at Stanford University School of Medicine, PKF115-584, CGP049090, and another of the Shivdasani group’s compounds, PKF118-310, also induced cytotoxicity in human HCC cell lines in vitro, and suppressed tumor growth and induced apoptosis in tumor cells in a human HCC xenograft model. Finally, in <a href="http://ash.confex.com/ash/2009/webprogram/Paper21676.html">an abstract presented at the American Society of Hematology (ASH) meeting in December 2009</a>, researchers at the Novartis Institute for Biomedical Research in Basel and their academic collaborators presented data that showed that CGP04090 and PKF115-584 potently inhibited the survival of primary human B-CLL cells in vitro and in vivo. In all three cases, the compounds showed no significant cytotoxicty against normal cells.<br /><br />In the conclusion of the ASH meeting abstract, the authors stated that further investigations are warranted to determine the feasibility of testing these compounds in human clinical trials.<br /><br />Many medicinal chemists <a href="http://medchem.rutgers.edu/mc501/pdfs/druggability.pdf">remain skeptical</a> about the ability of researchers to develop small-molecule drugs that target protein-protein interactions, which have satisfactory pharmacokinetics and can advance through clinical trials and reach the market. However, at least one nonpeptide small-molecule compound that targets a protein-protein interaction, the thrombopoietin receptor agonist eltrombopag (Ligand/GSK’s Promacta), has reached the market. (The FDA approved it in November 2008.) Several other small-molecule drugs that target protein-protein interactions are in clinical development. And Cambridge Healthtech Institute will be sponsoring <a href="http://www.drugdiscoverychemistry.com/ppi">a conference</a> on this subject, which is scheduled for April 2010. This conference is in its third year. Thus, as also shown by the development of stapled peptides, there is renewed interest in discovering and developing drugs that address these “hard targets”.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-47898972317753886072009-11-27T19:53:00.000-08:002009-11-27T20:18:04.098-08:00Stapled peptides for targeting intracellular signaling pathways: research and commercial developmentIn the 12 November issue of <span style="font-style: italic;">Nature</span>, there was a <a href="http://www.nature.com/nature/journal/v462/n7270/abs/nature08543.html">research article</a> and a <a href="http://www.nature.com/nature/journal/v462/n7270/full/462171a.html">News and Views minireview</a> about targeting an intracellular signaling pathway with a novel type of compound called a stapled peptide. <br /><br />Signaling pathways are crucial for cellular physiology, and in the pathobiology of important diseases ranging from metabolic diseases to cancer. In many cases, signaling proteins that work by binding to other proteins in protein-protein interactions are key control points in signaling pathways. However, protein-protein interactions in all but a few cases cannot be readily addressed with small molecule drugs. These targets are therefore called “undruggable”. Some signaling pathways consist entirely of these “undruggable” targets, and can only be addressed indirectly (if at all) via targeting other pathways that interact with them.<br /><br />Several small-molecule drugs that do address protein-protein interactions are natural products. The best known of these is the immunosuppressant FK506 (tacrolimus, Astellas’ Prograf). This is one reason for the new interest in natural products by some companies and researchers, as we discussed in a <a href="http://biopharmconsortium.blogspot.com/2009/07/now-for-some-chemistrynatural-products.html">previous blog post</a>.<br /><br />However, the 12 November <span style="font-style: italic;">Nature</span> article, authored by James E Bradner (Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA, and the Dana-Farber Cancer Institute, Boston, MA), Gregory Verdine (Department of Chemical Biology, Harvard University, Cambridge MA, and the Dana-Farber Cancer Institute), and their colleagues, takes a different approach. The researchers target specific intracellular protein-protein interactions by designing special types of peptides known as stapled peptides.<br /><br />The signaling pathway that is the focus of this article is the Notch pathway. In normal physiology, this pathway regulates various aspects of cell-cell communication, cellular differentiation, cell proliferation, and cellular survival or death. Deregulated Notch pathway function is involved in diseases including cancers of the lung, ovary and pancreas, and in T-cell acute lymphoblastic leukemia (T-ALL), which is a cancer of immature T cells.<br /><br />Notch is a cell-membrane receptor. Binding of one of its ligands (on the surface of an adjacent cell) to the extracellular domain of Notch triggers sequential cleavage of the Notch intracellular domain by a metalloproteinase known as TACE (tumor necrosis factor alpha converting enzyme) and by γ-secretase (an enzyme which is also involved in the amyloid pathway that is implicated in Alzheimer’s disease). The free intracellular domain of Notch, called ICN, migrates to the nucleus, and docks with the DNA-bound transcription factor CSL. The interaction between CSL and ICN creates a groove along the interface of the two proteins, which serves as a docking site for the mastermind-like protein MAML1. The resulting trimolecular complex initiates specific transcription of Notch-dependent target genes.<br /><br />The binding domain of MAML1 that engages the elongated groove formed by the ICN-CSL complex is in the form of an α-helix. The researchers therefore designed a series of peptides derived from portions of the sequence of the MAML1 binding domain. These were stapled peptides in which hydrocarbon moieties are used to constrain, or “staple”, MAML1 binding-domain mimetic sequences into an α-helical conformation. One such stapled peptide, SAMH1, gave the highest affinity binding to ICN and CSL, and competitively inhibited binding of wild-type MAML1 to these proteins.<br /><br />SAMH1 was cell-penetrant, and inhibited intracellular Notch pathway signaling in cultured T-ALL cell lines. Moreover, SAMH1 reduced the proliferation of a variety of T-ALL cell lines <span style="font-style: italic;">in vitro</span>, but was inactive against T-cell tumor lines that were not dependent on the Notch pathway for their proliferation. In SAMH1-sensitive T-cell tumor lines, SAMH1 treatment activated caspases, which are involved in apoptosis. In a mouse model of T-ALL, intraperitoneally injected SAMH1 inhibited leukemic progression, and inhibited Notch pathway signaling in leukemic cells <span style="font-style: italic;">in vivo</span>.<br /><br />Stapled peptides are not conventional “drug-like” compounds. Their molecular weights are several times greater than the 500-dalton maximum prescribed by Lipinski’s rules (developed by the leading medicinal chemist Chris Lipinski), which are used to define “drug-like” properties of small molecule compounds. Moreover, peptides are usually subject to protease degradation <span style="font-style: italic;">in vivo</span>, and thus have short serum half-lives. In most cases, peptides do not enter into cells efficiently, except for those peptides that have specific cell-membrane receptors.<br /><br />However, stapled α-helical peptides, in addition to their improved binding activities to their specific targets, are protease-resistant, have improved serum half-lives, and are cell penetrant. Researchers attribute these properties to the constrained conformation of these molecules, and to the hydrocarbon staples themselves. For example, the hydrocarbon staples may confer lipophilic properties to these molecules, and thus render them membrane-penetrant.<br /><br />In an <a href="http://www.sciencemag.org/cgi/content/abstract/305/5689/1466">earlier study</a>, Dr. Verdine and researchers at the Dana-Farber Cancer Institute and Children’s Hospital in Boston designed a stapled α-helical peptide that initiated apoptosis by specifically binding to and activating a member of the Bcl-2 family, and that inhibited the grown of leukemic cells in a mouse model. The researchers have been <a href="http://www.nature.com/nature/journal/v455/n7216/full/nature07396.html">continuing to develop and to determine the mechanisms of action</a> of their Bcl-2 family-targeting stapled peptides.<br /><br />The discovery-stage biotechnology company <a href="http://www.aileronrx.com">Aileron Therapeutics</a> was founded in 2005 to develop and commercialize stapled peptides. The company’s scientific founders include Dr. Verdine, Loren Walensky (Dana-Farber Cancer Institute), and the late Stanley J. Korsmeyer (Dana-Farber Cancer Institute, a pioneer in the study of the Bcl-2 family and its role in apoptosis and in the biology of cancer). It has a pipeline of stapled peptides that it is developing for the treatment of solid and hematological tumors, the most advanced of which are in the preclinical stage. Aileron has managed to attract venture capital despite the current adverse conditions--in June 2009, the company closed a $40 million Series D financing.<br /><br />Stapled peptides represent an exciting and innovative technology with the potential to address “undruggable” protein-protein interactions, and thus to treat diseases that represent major unmet medical needs. However, this technology is in an early stage, and the therapeutic value of stapled peptides has not yet been confirmed in the clinic.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-26338108147292491752009-11-08T18:25:00.000-08:002009-11-09T07:57:50.272-08:00Anti-aging biology: new basic research, drug development, and organizational strategyIn the 2 October issue of <span style="font-style: italic;">Science</span> (the "<span style="font-style: italic;">Ardipithecus ramidus</span> issue”), there was a <a href="http://www.sciencemag.org/cgi/content/summary/326/5949/55">Perspective </a>(authored by Matt Kaeberlein and Pankaj Kapahi) and a <a href="http://www.sciencemag.org/cgi/content/abstract/326/5949/140">Report</a> (authored by Colin Selman and his colleagues) on recent findings in anti-aging biology.<br /><br />Since the late 1980s, researchers have found that caloric restriction (CR) (reduction in caloric intake while maintaining essential nutrients) slows aging in a variety of organisms—yeasts, nematodes, fruit flies, mice, and most recently rhesus macaques. In the recently published <a href="http://www.sciencemag.org/cgi/content/abstract/325/5937/201?ijkey=8587ed93f6a8e2cc9f30c255477929d69037293a&keytype2=tf_ipsecsha">20-year study in rhesus macaques</a>, CR not only increased lifespan, but also delayed the onset of a suite of aging-related disease conditions—diabetes, cancer, cardiovascular disease, and brain atrophy. This parallels the studies with other organisms.<br /><br />Researchers who have been studying the CR model have been attempting to elucidate the mechanisms by which CR works to slow the aging process and to retard aging-related disease. They hope to find targets for drugs to mimic the effects of CR in humans, since long-term CR is not practical for most people. Over the years, researchers have discovered several pathways by which CR appears to exert its effects. The Report describes new research results on one such pathway, the mammalian target of rapamycin (mTOR) pathway. The Perspective reviews this research in the context of related recent studies.<br /><br />In a <a href="http://www.nature.com/nature/journal/v460/n7253/abs/nature08221.html?lang=en">report published in Nature earlier this year</a> (16 July 2009), researchers found that rapamycin administered in food increased the median and maximal lifespan of genetically heterogeneous laboratory mice, whether it was fed to middle-aged (600 days old) or young adult (270 days old) mice. Rapamycin feeding beginning at 600 days of age led to an increase in lifespan of 14% for females and 9% for males, on the basis of age at 90% mortality.<br /><br />Rapamycin targets mTOR (mammalian target of rapamycin), a kinase that regulates signaling pathways that affect many cellular processes. mTOR forms two protein complexes that are active in intracellular signaling—mTORC1 and mTORC2. It is mTORC1 that is most sensitive to rapamycin. mTORC1 works to coordinate cellular growth and survival responses induced by changes in the availability of nutrients, and also responses to cellular stresses (e.g., hypoxia, DNA damage and osmotic stress). Genetic inhibition of TORC1 in yeast and invertebrates has been found to extend their lifespan. In particular, in the nematode <span style="font-style: italic;">Caenorhabditis elegans</span>, <a href="http://dev.biologists.org/cgi/content/full/131/16/3897">TORC1 interacts with the insulin pathway</a> (via raptor, a component of TORC1) to control lifespan. The role of the insulin pathway in the enhancement of lifespan by CR in <span style="font-style: italic;">C. elegans</span> has been known for many years. The role of mTORC1 at the junction of nutrient and stress sensing pathways, together with these results in invertebrates and now mice, has led researchers to hypothesize that the mTORC1 pathway may be involved in CR-mediated enhancement of lifespan, and that drugs that modulate this pathway may substitute for CR in lifespan extension.<br /><br /><a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1W-4WJ3DRT-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=1f21be6ff54e2f77e68e731e104a55f7">In other studies</a>, inhibition of the mTOR pathway in mice was found to retard development of such aging-related conditions as cancer, metabolic disease, and cardiovascular disease. This effect has also been seen in studies of CR in mice and in nonhuman primates, as stated above.<br /><br />Rapamycin is an immunosuppressant that is marketed as Wyeth’s (now Pfizer’s, since the October 2009 merger) Rapimmune, to prevent organ transplant rejection. More recently, a derivative of rapamycin, temsirolimus (Wyeth/Pfizer’s Toricel) has been approved for treatment of renal cell carcinoma. The authors of the <span style="font-style: italic;">Nature</span> paper therefore hypothesized that rapamycin may have extended lifespan in the mice either by working via CR-related pathways that control lifespan, by postponing death from cancer, or both.<br /><br />The finding that oral rapamycin can retard aging in mice, even when fed to 600-day-old mice (the equivalent of 60 years old in humans) raises hope for the development of anti-aging drugs for human use. However, rapamycin itself cannot be used for this purpose because of its immunosuppressant effects. (In the mouse rapamycin feeding studies, the mice were kept under specific pathogen-free conditions.) If researchers were to attempt to modulate the mTORC1 pathway to extend lifespan, they would therefore need to discover other drugs that modulate that pathway without rapamycin’s side effects. Learning more about specific pathway components that may be targeted to increase lifespan may help researchers discover such drugs.<br /><br />In the new Selman et al. report, researchers endeavored to learn more about how the mTORC1 pathway might extend lifespan in mice. They constructed knockout mice that lacked S6 protein kinase 1 (S6K1). S6K1 is a downstream target of mTORC1, which upregulates mRNA translation and protein synthesis in response to mTORC1 signaling. The researchers found that deletion of the gene for S6K1 resulted in a 19% increase in median lifespan in female mice (as compared to wild-type females), and also increased maximum lifespan. S6K1 deletion had no effect on the lifespan of male mice. This was in contrast to the study with rapamycin feeding, which showed lifespan extension in both sexes, even though the effect in female mice was greater. However, the results of the two studies are not strictly comparable, since mice of different genetic background were used in the two studies.<br /><br />Female S6K1 knockout mice also showed improvement in several biomarkers of aging (e.g., motor and neurological function, level of physical activity, insulin sensitivity, glucose tolerance, fat mass, immunological parameters). Hepatic gene expression in 600-day-old female S6K1 knockout mice resembled that of wild type mice subjected to CR. Female S6K1 knockout mice showed increased hepatic, muscle, and adipose tissue expression (as compared to wild-type mice) of genes associated with other pathways associated with longevity, including genes for sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK).<br /><br />Selman et al. went on to obtain evidence that the effect of S6K1 knockout on lifespan in female mice is due to activation of AMPK. The gene expression profile of muscle tissue of long-lived female S6K1 knockout mice resembled the profile of wild-type mice treated with the AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR). Hepatocytes from S6K1 knockout mice also showed enhanced AICAR activation of AMPK as compared to hepatocytes from wild type mice. A parallel study in <span style="font-style: italic;">C. elegans</span> showed that deletion of the <span style="font-style: italic;">aak-2</span> gene, which encodes a subunit of AMPK, suppresses lifespan extension in mutants that lack rsks-1, the nematode homolog of S6K1. These results suggest that S6K1 knockout may exert its pro-longevity effects via activation of AMPK.<br /><br />AMPK is found in all eukaryotic organisms, and serves as a sensor of intracellular energy status. In mammals, it also is involved in maintaining whole-body energy balance, and helps regulate food intake and body weight. AMPK has been implicated in metabolic response to CR in eukaryotic organisms from yeasts to humans, and it mediates the effects on lifespan of at least one type of CR regimen in <span style="font-style: italic;">C. elegans</span>. Thus the hypothesis that lifespan extension via the mTORC1-S6K1 pathway works via AMPK activation is an attractive one.<br /><br />However, it is not known how deletion of S6K1 (or its inhibition via mTORC1 in rapamycin-treated mice) might activate AMPK. Moreover, as pointed out by Kaeberlein and Kapahi, there are other downstream targets of S6K1 that might play a role in anti-aging effects of SK61 deletion or inhibition. Among these is hypoxia-inducible factor-1α (HIF-1α). Moreover, there are other biomolecules and pathways that have been implicated in the effects of CR on retarding aging. These especially include the sirtuins, an evolutionarily conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases.<br /><br />As shown by the Perspective and Report in the 2 October issue of <span style="font-style: italic;">Science</span>, anti-aging research is an exciting area of basic biological research, and researchers still have much to learn about pathways that mediate the effects of CR on longevity. However, this field is already being applied to drug discovery and development. A basic issue in applying anti-aging research to the development of drugs is that one clearly cannot use increased lifespan as an endpoint in clinical trials. Companies must test putative anti-aging drugs against one or more diseases of aging. The hope is that any “anti-aging” drugs approved for treatment of one disease of aging will have pleiotropic effects on multiple diseases of aging, and will ultimately be found to increase lifespan or “healthspan” (the length of a person’s life in which he/she is generally healthy and not debilitated by chronic diseases).<br /><br />The two principal types of “anti-aging” drugs currently in company pipelines are sirtuin modulators and AMPK activators. Sirtris Pharmaceuticals (Cambridge, MA, a wholly-owned subsidiary of GlaxoSmithKline [GSK]) is developing the SIRT1 activators SRT501 (a proprietary formulation of the natural product resveratrol) and SRT2104 (a novel synthetic small-molecule SIRT1 activator that is structurally unrelated to resveratrol and is up to 1000-fold more potent). SRT501 is in Phase II clinical trials in type 2 diabetes. SRT2104 has been tested in Phase I trials in healthy volunteers, and was found to be safe and well tolerated. Elixir Pharmaceuticals (Cambridge, MA) is developing a preclinical-stage SIRT1 inhibitor for treatment of Huntington’s disease and certain cancers, and a preclinical-stage SIRT1 activator for treatment of type 2 diabetes and obesity. Elixir also has a research-stage SIRT2 inhibitor under development for treatment of type 2 diabetes and obesity.<br /><br />Companies developing AMPK activators include a collaboration between Metabasis Therapeutics (La Jolla, CA; about to be acquired by Ligand Pharmaceuticals, San Diego, CA) and Merck--preclinical oral AMPK activators, for treatment of type 2 diabetes and hyperlipidemia), Mercury Therapeutics (Woburn, MA)--research and preclinical-stage oral AMPK activators for treatment of type 2 diabetes, and Betagenon (Umea, Sweden)--the preclinical-stage oral AMPK activator BG8702, for treatment of type 2 diabetes.<br /><br />The relationship between sirtuin-modulator developer Sirtris and GSK represents a prime example of the attempt of large pharmaceutical companies to become more “biotech-like” in order to improve their R&D performance. We discussed this strategy in <a href="http://www.insightpharmareports.com/reports_report.aspx?id=90910&r=666">our recent report</a>, <span style="font-style: italic;">Approaches to Reducing Phase II Attrition</span>. GSK acquired Sirtris for $720 million in June 2008. In December 2008, GSK announced that it had 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, is now Vice President and the head of the US CEEDD at GSK. Dr. Westphal, who is also a former venture capitalist, remains as CEO of Sirtris, and is based at Sirtris’ Cambridge location.<br /><br />Thus anti-aging research, despite the fact that it is mainly in the basic research stage, is not only beginning to produce drug candidates, but has also been having an impact on the organizational strategy of one of the major pharmaceutical companies, GSK.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-91623241644647137512009-10-25T16:28:00.000-07:002009-10-25T16:53:55.866-07:00Liraglutide (Novo Nordisk’s Victoza) for treatment of obesity?<span style="font-family:arial;">The field of obesity drugs has been a very difficult one for the pharmaceutical industry. Attempts to develop these drugs have been plagued by major safety failures, notably the notorious “Fen-Phen” case that led to market withdrawal and numerous lawsuits. More recently, rimonabant (Sanofi-Aventis’ Acomplia) failed to gain FDA approval due to psychiatric adverse effects, and the company also later withdrew the drug from the market in Europe. Currently marketed drugs have marginal efficacy and troublesome side effects. The complex physiology of weight control, and our inadequate knowledge of pathways that control energy balance, make development of effective agents difficult. </span><br /><br /><span style="font-family:arial;">Moreover, there is a lingering perception that obesity is merely a “lifestyle issue” and a failure of “personal responsibility”. This is despite the consistent finding that weight is as heritable as height, and that there are physiological factors that militate against long-term, medically significant weight loss by overweight or obese individuals. These research results indicate that safe and efficacious obesity drugs will be necessary, in addition to diet and exercise, to ward off obesity and its comorbidities in the rapidly growing, worldwide overweight population. </span><br /><br /><span style="font-family:arial;">Currently, late-stage drugs developed by three small California companies, Vivus Pharmaceuticals, Orexigen Therapeutics, and Arena Pharmacuticals, are approaching NDA submission. This follows a long hiatus, since the FDA has approved no anti-obesity drug since 1999. The companies hope that the drugs will reach the market in late 2010 or early 2011. All three drugs work in the brain to suppress appetite, as does the currently marketed prescription drug sibutramine (Abbott’s Meridia/ Reductil). The other current agent, orlistat, is available in prescription form as Roche’s Xenical, and in a low-dose over-the-counter form, GlaxoSmithKline’s alli. Orlistat works in the gut to reduce absorption of fats. </span><br /><br /><span style="font-family:arial;">Now comes a <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961375-1/abstract">report</a> in the 23 October 2009 issue of the <span style="font-style: italic;">Lancet</span>, comparing the effects of liraglutide (Novo Nordisk’s Victoza) and orlistat on weight loss in a 20-week double-blind, placebo-controlled Phase II trial in 564 obese healthy volunteers on a hypocaloric diet and increased physical activity. (A subscription is required to see the complete article). The researchers found that in the 20-week period, subjects on liraglutide lost a significant 4.8-7.2 kilograms (10.6-15.8 pounds), depending on the dose, as compared to 4.1 kilograms (9.0 pounds) on orlistat and 2.8 kilograms (6.2 pounds) on placebo. 76% of subjects on the 3.0-milligram/day dose of liraglutide lost over 5% of their body weight, as compared to 30% of subject on placebo. All doses of liraglutide reduced blood pressure, and the 1.8 mg through 3.0 mg doses reduced the prevalence of prediabetes (e.g., fasting plasma </span><span style="font-family:arial;">glucose above normal, but below that which is classified as diabetes) by between 84-96%. The most common side effects of liraglutide were nausea and vomiting, which usually occurred during the first month of treatment. However, these effects were mainly transient and rarely led to subjects discontinuing treatment. No serious adverse effects were seen.</span><br /><br /><span style="font-family:arial;">In an open-label extension of the trial, subjects on liraglutide maintained their weight loss, according to Novo Nordisk. Additional questions need to be addressed, including whether subjects on liraglutide maintain their weight loss after they stop taking the drug.</span><br /><br /><span style="font-family:arial;">Unlike the two currently marketed obesity drugs, liraglutide is administered via subcutaneous self-injection. Liraglutide was approved in Europe earlier this year, and is currently marketed in Europe for treatment of type 2 diabetes. However, it is awaiting FDA approval for that indication. It is not yet approved for treatment of obesity in any jurisdiction. </span><br /><br /><span style="font-family:arial;">Liraglutide is a member of a class of drugs called incretin mimetics. An incretin is a gastrointestinal hormone that triggers an increase in insulin secretion by the pancreas, and also reduces gastric emptying. The latter effect slows nutrient release into the bloodstream and appears to increase satiety and thus reduce food intake. The major physiological incretin is glucagon-like peptide 1 (GLP-1), and incretin mimetic drugs are peptides with homology to GLP-1 that have a longer half-life in the bloodstream than does GLP-1. </span><br /><br /><span style="font-family:arial;">The first incretin mimetic to reach the market is exenatide (Amylin/Lilly’s Byetta), which is based on a Gila monster lizard salivary peptide and was approved for treatment of type 2 diabetes in 2005. Physicians sometimes prescribe exenatide off-label for treatment of obesity. Exenatide has a relatively short half-life, and must be self-injected twice a day. Amylin and Lilly are therefore developing a longer-acting, once-weekly formulation for treatment of type 2 diabetes. Researchers working with Amylin and Lilly also reported positive results of a clinical trial of exenatide in treatment of nondiabetics for obesity at a scientific meeting earlier this year. Amylin is also developing two earlier-stage biologics, pramlintide/metreleptin and davalintide, for treatment of obesity. Neither is an incretin mimetic. </span><br /><br /><span style="font-family:arial;">Liraglutide is a GLP-1 analogue designed to bind to human serum albumin in the bloodstream, and thus has a longer half-life than exenatide, and is self-injected only once a day. Liraglutide is thus more convenient for patients to use than exenatide. The results of a study published in the <span style="font-style: italic;">Lancet</span> earlier this year indicate that liraglutide is more effective than exenatide in long-term reduction in blood glucose (measured as hemoglobin A1c) in patients with type 2 diabetes. </span><br /><br /><span style="font-family:arial;">The development of liraglutide for obesity represents part of a larger trend—the development of drugs that treat both type 2 diabetes and obesity. In the case of development of obesity drugs, the regulatory pathway for diabetes is easier than for obesity. Companies therefore tend to develop dual diabetes/obesity drugs first for diabetes. As the drugs prove themselves in the clinic, with respect to safety, antidiabetic efficacy, and effects on weight loss, companies may also develop them for obesity. This is the case with liraglutide. </span><br /><br /><span style="font-family:arial;">In the case of treatment of type 2 diabetes, reducing weight in obese diabetics undergoing drug treatment is a major unmet need. Antidiabetics that also induce weight loss are therefore of special value. We discussed this issue in our 2008 article, <a href="http://www.biopharmconsortium.com/GEN_diabetes_0108.pdf">“Addressing unmet type 2 diabetes needs”</a>.</span><br /><br /><span style="font-family:arial;">There are at least several companies with early stage dual diabetes/obesity drugs. These companies generally prefer to develop these drugs for diabetes. Early stage obesity drug development is mainly on hold, awaiting the regulatory approval of the three late-stage drugs now nearing NDA submission. </span><br /><span style="font-family:arial;"><br />Novo Nordisk is also waiting to hear from the FDA regarding regulatory approval of liraglutide for treatment of type 2 diabetes before proceeding with further development of the drug for obesity. </span><br /><br /><span style="font-family:arial;">We have produced two additional resources for understanding drug development in type 2 diabetes and obesity. These are, <a href="http://www.insightpharmareports.com/reports/2007/80_Diabetes/overview.asp"><span style="font-style: italic;">Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D</span></a> and <a href="http://www.insightpharmareports.com/reports_report.aspx?id=81172&r=653"><span style="font-style: italic;">Obesity Drug Pipeline Report Overview</span></a>, both published by Cambridge Healthtech Institute. </span>Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-66740616421722950162009-09-28T19:32:00.000-07:002009-09-29T15:37:51.393-07:00Bristol-Myers Squibb acquires monoclonal antibody leader Medarex<span style="font-family:arial;">I was quoted in an article entitled “Bristol-Myers Squibb swallows last of antibody pioneers”, by Malorye Allison, in the September 2009 issue of <span style="font-style: italic;">Nature Biotechnology</span>. The article focused on the monoclonal antibody sector, especially on the acquisition of Medarex by Bristol-Myers Squibb (BMS). The acquisition was completed on September 1. </span> <span style="font-family:arial;">To read the article, go to <a href="http://www.nature.com/nbt/journal/v27/n9/full/nbt0909-781.html">http://www.nature.com/nbt/journal/v27/n9/full/nbt0909-781.html </a>(subscription required).<br /><br /></span><span style="font-family:arial;">In January, I gave a presentation to an RNAi conference, drawing lessons for the current therapeutic RNAi field from the evolution of the monoclonal antibody (MAb) field. This was discussed in a <a href="http://biopharmconsortium.blogspot.com/2009/07/rnai-embryonic-stem-cells-and.html">previous blog post</a>, which focused on technological prematurity. In this blog post, we discuss the evolution of the MAb sector, how industry leaders emerged, and the acquisition of these leaders by large pharmaceutical and biotechnology companies.</span><br /><br /><span style="font-family:arial;">MAbs are now the fastest-growing and most successful class of biologics. The majority of the MAbs on the market are indicated for oncology and inflammatory diseases. In 2005, MAbs accounted for 75% of antitumor biologics sales ($7.3B). Fueled by expanded indications and new products, MAbs are the major growth engine of the biologics sector, now and into the foreseeable future. Moreover, as we discussed in <a href="http://biopharmconsortium.blogspot.com/2009/07/biology-driven-drug-discovery.html">another previous blog post</a>, leading biologics (all of which are MAbs) are on track to be the biggest-selling drugs in 2014. Large pharmaceutical companies thus have been seeking to acquire this highly successful class of drugs (including both marketed and pipeline MAbs), in order to fill their depleted pipelines and to make up for lost revenues due to current and impending patent expiries.<br /><br /></span><span style="font-family:arial;">However, the MAb field was not always successful. Therapeutic MAbs went through nearly 20 years of scientific/technological prematurity.<br /><br /></span><span style="font-family:arial;">The period of technological prematurity of MAbs lasted roughly from 1975 to 1994. Georges Köhler and César Milstein published the first paper on MAb technology in 1975, and they received a Nobel Prize for their work in 1984. The first MAb drug, Johnson & Johnson’s Orthoclone OKT3 was approved in 1986 for use in transplant rejection. However, this drug can only be used once in a patient due to its immunogenicity. There were not any further approvals of MAb drugs until 1994. The “deluge” of MAb drug approvals began in 1997, and has accelerated ever since. Prior to 1994, MAb technology represented great science, and it enabled researchers to make great strides in immunology, cancer research, the biology of HIV/AIDS, and other fields. (Some of this research was eventually applied to drug discovery, including the discovery of MAb drugs.) But during this period of scientific prematurity, any MAb drugs seemed to be in the distant future.</span> <span style="font-family:arial;"><br /><br />However, beginning in the early 1980s, several companies and academic labs began to develop enabling technologies designed to move this premature technology up the development curve. Among these companies were those that became the leaders In the MAb field. </span> <span style="font-family:arial;"><br /><br />The original MAbs were made via fusion of mouse B cells with murine myeloma cells, to create hybridomas. The MAbs secreted by these hybridomas contain all mouse sequences. They are highly immunogenic in humans, and are usually rapidly cleared from the circulation. They may also trigger allergic reactions and in some cases anaphylaxis. In order to create less immunogenic MAbs with the potential for efficacy and safety in humans, researchers used recombinant DNA technology to construct MAbs with mainly human sequences, but with the specific antigen-binding site of a mouse MAb. </span> <span style="text-decoration: underline;"><br /><br /></span><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiz1sp2F92v9vZawaLACnx_8sAVwARjuT2Zg37jzijk-7wdfErt5MswlUaPQCe0BirxnI_smnbSnvLBc4Kzlbw3yfwmOpI9mAw4U2_kUMLhnAFcLLgjko6CQ3CVC7vE4ziMEMgIEk6n7ec/s1600-h/AbStructure.jpg"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 400px; height: 362px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiz1sp2F92v9vZawaLACnx_8sAVwARjuT2Zg37jzijk-7wdfErt5MswlUaPQCe0BirxnI_smnbSnvLBc4Kzlbw3yfwmOpI9mAw4U2_kUMLhnAFcLLgjko6CQ3CVC7vE4ziMEMgIEk6n7ec/s400/AbStructure.jpg" alt="" id="BLOGGER_PHOTO_ID_5386722854111278402" border="0" /></a><span style="text-decoration: underline;"><br /></span><span style="font-family:arial;">The progression of MAb technology resulted in the following classes of products:</span><br /><ul><li><span style="font-family:arial;">Chimeric MAbs: mouse variable region and human constant region </span></li><li><span style="font-family:arial;">Humanized MAbs: mouse hypervariable regions and human framework regions and constant regions </span></li><li><span style="font-family:arial;">Fully human MAbs: human sequences only</span></li></ul><span style="font-family:arial;">Development of fully human MAbs required the invention of special technologies (phage display or the humanized mouse) that do not rely on mouse hybridoma technology</span>.<br /><span style="font-family:arial;"> </span><span style="font-family:arial;"><br />Among leading fully human MAb companies, Cambridge Antibody Technology utilized phage-display technology, and Abgenix and Medarex used humanized mouse technology.</span> <span style="font-family:arial;"> </span> <span style="font-family:arial;">The great majority of marketed MAb cancer drugs are chimeric or humanized MAbs. The first fully human MAb cancer drug was approved by the FDA in 2006. </span> <span style="font-family:arial;"><br /><br />The development of MAb enabling technologies began in the early 1980s (early within the period of technological immaturity of MAb drugs). For example, Genentech’s broad Cabilly patents (issued in 1989 and 2001) resulted from the company’s collaboration with academic researchers beginning in the early 1980s. </span> <span style="font-family:arial;">But Genentech’s first MAb products, the antitumor agents Rituxan (codeveloped with Idec) and Herceptin, did not reach the market until 1997 and 1998, respectively. Both are highly successful drugs. </span> <span style="font-family:arial;"> </span> <span style="font-family:arial;"><br /><br />The MAb sector has been characterized by a high degree of litigation over enabling technology patents (e.g., Genentech’s Cabilly patents vs. UCB Celltech’s Boss patent), and a great degree of cross-licensing of enabling technology patents, in part to settle or prevent lawsuits. From this history of technology development, patent disputes and cross-licensing, several MAb sector leaders emerged. </span> <span style="font-family:arial;"><br /><br />Over the course of the last several years, all of the public biotechnology companies that pioneered therapeutic MAb technology and become leaders in the field have been acquired. The acquisition of Medarex by BMS brings this process to a conclusion.</span><span style="text-decoration: underline;"><br /></span><span style="text-decoration: underline;"><br /></span><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-UK7Gap6khx40VFI7bgPg5PoIn1FaFHulpWLMYL_83O3-hC9DZSArsL2XMdW7yCDjfimUkptsEYAVcTekMALunt0glOUhdIUQwIyiIkkUtowepzHPFhbRhwCxVPa8dRlrPOwkAOlUb0Y/s1600-h/AbCompanies.jpg"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 400px; height: 300px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-UK7Gap6khx40VFI7bgPg5PoIn1FaFHulpWLMYL_83O3-hC9DZSArsL2XMdW7yCDjfimUkptsEYAVcTekMALunt0glOUhdIUQwIyiIkkUtowepzHPFhbRhwCxVPa8dRlrPOwkAOlUb0Y/s400/AbCompanies.jpg" alt="" id="BLOGGER_PHOTO_ID_5386723198597753282" border="0" /></a><br /><span style="font-family:arial;">Are there any MAb companies that have yet to be acquired? The Nature Biotechnology article mentions several companies developing antibody conjugates, antibody fragments or antibody mimetics. However, there are also other still-independent firms that have developed proprietary technologies to produce full-length humanized or fully human MAbs. Among these are Facet Biotech (humanized MAbs), and Xoma, MorphoSys, BioInvent, and Dyax (all of which developed fully human MAb platforms based on phage display technology). Of these companies, Dyax is currently focusing on development of its proprietary non-antibody lead product, but also has a pipeline of proprietary research-stage MAbs and partnered research-stage and Phase I MAbs. The other companies are focusing solely on MAbs, and have pipelines of proprietary and partnered MAb drug candidates. </span> <span style="font-family:arial;"><br /><br />Of these companies, MorphoSys appears to have the strongest technology platform, and has used this platform to craft a <a href="http://seekingalpha.com/article/128452-morphosys-a-biotech-rule-breaker-part-1">unique business model</a> that enables the company to be profitable even though it has not yet marketed a drug. Facet Biotech was spun out of PDL BioPharma last year. PDL, formerly known as Protein Design Labs, is a pioneer in humanized antibody technology, whose technology was used in the development of Genentech’s Herceptin and Avastin. In August 2009, Biogen Idec made an unsolicited offer to acquire Facet, which Facet rejected; the attempt of Biogen Idec to acquire Facet is still ongoing. Biogen Idec has been Facet’s partner since 2005, and the two companies have been codeveloping daclizumab, an anti-IL-2 receptor agent for treatment of multiple sclerosis (currently in Phase II clinical development), and volociximab, an anti-angiogenesis agent for treatment of solid tumors (also currently in Phase II). Except for Facet, none of these companies appears to be a near-term acquisition candidate. </span> <span style="font-family:arial;"><br /><br />Nevertheless, large pharmaceutical companies are continuing to work on building franchises in biologics, with an emphasis on MAb drugs. This is, for example, a factor in the Merck-Schering Plough and Pfizer-Wyeth mergers. Schering-Plough has had MAb alliances with such companies as MorphoSys and Xoma, and acquired Dutch company Organon (which had a collaboration in MAbs with Dyax) in 2007 in part because of its capabilities in biologics. Merck also acquired GlycoFi in 2006, for its capabilities in yeast-synthesized MAbs and other biologics. The newly merged Merck plans to make biologics a major focus of the company. Similarly, Pfizer acquired Wyeth in part because of its strength in biologics. </span> <span style="font-family:arial;"><br /><br />Thus, the acquisitions of the leaders in MAb technology represent an important part of a larger picture, the growing emphasis on biologics in large pharmaceutical companies, which have traditionally relied on small-molecule drugs. </span>Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-20637080054864322972009-09-17T19:42:00.000-07:002009-09-17T19:58:01.089-07:00Haberman Associates joins Innovalyst as an Affiliate<span style="font-family: arial;">Haberman Associates has joined <a href="http://www.innovalyst.com/home.html">Innovalyst</a> as an Affiliate. </span><br /><br /><span style="font-family: arial;">Innovalyst is a North Carolina-based consulting consortium. It is led by four Managing Partners with over 20 years of industrial experience as executives at top-tier pharmaceutical or biotechnology companies. Innovalyst’s Intellectual Capital Advisory Network (ICAN) also includes over 75 Affiliates with an extraordinary breadth and depth of life science business skills. </span><br /><br /><span style="font-family: arial;">Since 1997, Haberman Associates has been a member of the <a href="http://www.biopharmconsortium.com/tbpc.html">Biopharmaceutical Consortium (BPC)</a>, a Boston-based life science consulting network. We shall continue to maintain our membership in BPC, and our Boston-area location. However, we shall also expand our network to include Innovalyst. In addition to Haberman Associates, another BPC member, <a href="http://www.trilogyassociates.com/">Trilogy Associates</a> (headed by Joseph Kalinowski), is both a member of BPC and an Innovalyst Affiliate. Trilogy relocated to North Carolina in 2008. </span><br /><br /><span style="font-family: arial;">Haberman Associates will maintain its primary focus on science and technology strategy, and on new product development via internal R&D and partnering. However, we shall be able to draw on our partners in BPC and Innovalyst to form project teams to take on larger, more complex projects requiring multiple areas of expertise, especially for large pharmaceutical and biotechnology companies. We shall also continue to serve life science clients of all sizes, from start-ups to major corporations.</span><br /><br /><span style="font-family: arial;">If you have any questions about Haberman Associates and its expanded consulting network, or would like to discuss your company’s needs, please <a href="mailto:allanhab@biopharmconsortium.com">contact me</a>. </span>Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-43206210512488823262009-09-07T20:01:00.000-07:002009-09-07T20:17:27.059-07:00More metabolic engineering/synthetic biology<span style="font-family: arial;">In a <a href="http://biopharmconsortium.blogspot.com/2009/07/now-for-some-chemistrynatural-products.html">previous blog post</a>, we talked about the role of metabolic engineering and synthetic biology in facilitating a return to natural products as drug candidates in drug discovery and development. In the August 13 issue of <span style="font-style: italic;">Nature</span>, George Church (Harvard Medical School) and his colleagues reported on their <a href="http://www.nature.com/nature/journal/v460/n7257/abs/nature08187.html">new method </a></span><span style="font-family: arial;">for accelerating the optimization of metabolic pathways to produce medically and industrially useful natural products.<br /><br />The Church group calls its technology Multiplex Automated Genome Engineering (MAGE). MAGE is an efficient, inexpensive, automated system to simultaneously modify many targeted chromosomal locations (such as genes or regulatory elements) across a large population of cells, through the repeated introduction of synthetic oligonucleotides. A <a href="http://www.pnas.org/content/98/12/6742.long">bacteriophage-mediated homologous recombination system</a> is used to replace the targeted sequences with sequences of the introduced oligonucleotides. As the result of this process, researchers obtain a heterogeneous, highly diverse population of cells. Researchers may subject this population to selection for a desirable property, such as more efficient production of a desired product. The selected cells may then be subjected to additional rounds of MAGE, followed by additional rounds of selection. The result is the evolution of strains that efficiently produce the desired product. These strains may be scaled up to produce the product for research or commercial purposes. </span><br /><br /><span style="font-family: arial;">The Church group chose to demonstrate their MAGE technology by optimizing a pathway in <span style="font-style: italic;">Escherichia coli</span> for production of the carotenoid lycopene (the red pigment found in tomatoes and watermelons, which is valued as a nutraceutical). These researchers’ approach to utilizing and optimizing this pathway builds upon the work of leading metabolic engineers Jay Keasling (University of California at Berkeley) and Gregory Stephanopoulos (MIT). </span><br /><br /><span style="font-family: arial;">Carotenoids such as lycopene are members of a larger class of compounds called isoprenoids. Another class of isoprenoids is the terpenoids. As discussed in our previous blog post, terpenoids include numerous marketed natural product drugs, and this class of compounds is also of interest to researchers interested in discovering novel drugs. Because of common pathways for biosynthesis of precursors of carotenoids and terpenoids, Church’s work on optimizing production of lycopene in <span style="font-style: italic;">E. coli</span> is relevant to researchers interested in applying synthetic biology to the synthesis and study of terpenoid drugs. </span><br /><br /><span style="font-family: arial;">The pathway in <span style="font-style: italic;">E. coli</span> (and in other prokaryotes) for synthesis of isoprenoids is known as the DXP (deoxyxylulose-5-phosphate) pathway. This is in contrast to the better-known mevalonate pathway, which is found principally in eukaryotes and in archaea. We discussed Dr. Keasling’s engineering of the mevalonate pathway in yeast and in <span style="font-style: italic;">E. coli</span> (the latter of which was engineered to express this exogenous pathway) to produce terpenoid drugs in our 2007 <a href="http://www.decisionresources.com/Products-and-Services/Report.aspx?r=spech50807">synthetic biology report</a>. A review of work on metabolic engineering of both the mevalonate pathway and the DXP pathway by the Keasling group and by others can also be found in a <a href="http://www.springerlink.com/content/p118kp4816486248/">2007 paper by Drs. Withers and Keasling</a>. </span><br /><br /><span style="font-family: arial;">In order to utilize the <span style="font-style: italic;">E. coli</span> DXP pathway to produce lycopene, researchers must engineer the bacteria to express the enzymes that catalyze the final steps in lycopene biosynthesis (i.e., the three enzymes that convert the final product of the DXP pathway to lycopene). The Church group transfected their starting <span style="font-style: italic;">E. coli</span> strain with a plasmid containing the genes (derived from another species of bacterium) for these three enzymes. The resulting <span style="font-style: italic;">E. coli </span>strain produced lycopene at a basal level. It was that strain that the researchers subjected to MAGE. </span><br /><br /><span style="font-family: arial;">The researchers used the MAGE system to target each of 20 endogenous <span style="font-style: italic;">E. coli</span> genes in the DXP pathway. For each gene, they designed 90-mer oligonucleotides that contained variants of the gene’s ribosome binding site (RBS), in order to replace the endogenous RBS with one that would give more efficient translation of mRNA into protein. They also designed oligonucleotides to knock out four endogenous genes that encode enzymes that siphon off intermediates from the DXP pathway, in order to increase the flux through the DXP pathway to improve lycopene production. The total pool of oligonucleotides was in the hundreds of thousands. The goal was to optimize 24 genes simultaneously in order to achieve maximal lycopene production. </span><br /><br /><span style="font-family: arial;">The researchers added the cells and oligonucleotides to the MAGE system, cycling the cells through oligonucleotide delivery (via electroporation), growth, and washing cycles, yielding billions of genetic variants per day. Every 24 hours, the researchers selected the variants that produced the reddest colonies, and thus the most lycopene. After only three days, the procedure yielded variants that exhibited a fivefold greater lycopene production than the starting strain, with a greater yield (approximately 9,000 micrograms per gram dry cell weight) than previously documented. </span><br /><br /><span style="font-family: arial;"><span style="font-style: italic;">E. coli</span> strains with an optimized DXP pathway, as developed by the Church group, could in principle be used to produce other isoprenoid compounds, including terpenoid therapeutics. In order to do so, researchers would need to transfect specific sets of genes to carry out the final steps of the biosynthesis of their desired compounds into the strains, instead of the specific lycopene biosynthesis genes used by the Church group. They might also use methods such as the <a href="http://www.nature.com/nature/journal/v440/n7087/abs/nature04607.html">“designed divergent evolution”</a> technology developed by the Keasling group, to develop variants of enzymes that carry out the final steps of the biosynthesis of terpenoids, in order to discover novel terpenoid drugs that are not found in nature.</span><br /><br /><span style="font-family: arial;">MAGE, which allows researchers to simultaneously optimize the expression of large sets of genes in a metabolic pathway, contrasts with traditional metabolic engineering, which is typically a slow process in which genetic constructs are introduced into cells one at a time. It thus represents a potential advance. However, as in the above MAGE-based optimization of lycopene production, applications of MAGE to natural product drug discovery and production will build on the work of metabolic engineers who use more conventional methods. </span><br /><br /><span style="font-family: arial;"> </span>Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com1tag:blogger.com,1999:blog-4682750433159205287.post-20881957840135611352009-08-21T07:42:00.000-07:002009-11-08T19:09:54.546-08:00Oligonucleotide Therapeutics at IBC Drug Discovery and Development WeekIBC’s Drug Discovery and Development Week was held in Boston on the first week of August, from August 3-6, 2009. This annual event, a highlight of the summer for the Boston biotech community, had always been called “DDT”, for “Drug Discovery Technology” conference. More recently, the name was changed to “Drug Discovery & Development of Innovative Therapeutics World Congress,” but the acronym “DDT” still stuck.<br /><br />This year, IBC changed the format of the conference, hence the name change. The new format no longer was as technology focused, but emphasized drug discovery and the translation of discovery into clinical studies and onto the market. With our consulting group’s focus on science and technology strategy, biology-driven drug discovery and development, and improving the effectiveness of pharmaceutical and biotechnology R&D, I naturally liked the change in format. IBC also intended the conference to focus on networking and discussion of real drug discovery, scientific research, translational medicine, and business issues. As far as I’m concerned, the conference fulfilled that purpose as well. It was good to meet with friends and colleagues old and new, and to have substantive discussions. Even the booths in the exhibit hall were populated with company executives and researchers, as well as salespeople. It seems that the exhibitors got the point of the new conference format.<br /><br />A highlight of the conference was the session on oligonucleotide therapeutics, focused on RNAi. At the conference, the RNAi biotech company RXi Pharmaceuticals (Worcester, MA) presented animal study data on its proprietary self-delivered rxRNA (sd-rxRNA) compounds, which are chemically modified RNAi molecules with self-delivering moieties. sd-rxRNAs are designed to be delivered to cells and tissues without a delivery vehicle. In vivo administration resulted in systemic delivery of sd-rxRNAs to the liver. There are many disease indications that could be potentially treated by specifically targeting disease pathways in the liver using oligonucleotide therapeutics such as sd-rxRNAs. sd-rxRNAs are compatible with subcutaneous administration, and thus might be self-administered by patients. The lack of the need for a delivery vehicle also potentially allows for lower manufacturing costs.<br /><br />I attended the Industry Leadership Forum on RNA therapeutics on August 4. It was like “old home week”, since many of the panelists and attendees had attended (or spoken at) the RNAi conference in Cambridge MA in January at which I had also been a speaker. When I got up to ask a question at the end of the session, panel moderator Jim Thompson of Quark Pharmaceuticals recognized me and asked me a question in return.<br /><br />One of the key discussions in the Leadership Forum concerned assessing progress in the therapeutic oligonucleotide field. Proof of principle has been achieved for aptamer drugs [pegaptanib (OSI/Eyetech/Pfizer’s Macugen) for treatment of age-related macular degeneration], and for antisense agents [fomivirsen (Isis/ Novartis Ophthalmics’ Vitravene), for treatment of cytomegalovirus retinitis in AIDS patients]. These are the two first oliogonucleotide drugs to reach the market, and both treat ophthalmologic diseases and are delivered locally. Another antisense drug, Isis/Genzyme’s mipomersen is a first-in-class apolipoprotein B (apoB) synthesis inhibitor currently in Phase III trials for treatment of homozygous familial hypercholesterolemia (FH). Miopomersen is one of Isis’ second-generation chemically modified antisense therapeutics. These compounds preferentially traffic to the liver when injected intravenously, without the need for a delivery vehicle.<br /><br />The panel at the Leadership Forum predicted that an approved oligonucleotide blockbuster drug, which is likely to be a locally delivered or a liver-targeting drug, is about 2-3 years away. The approval of Quark’s systemically delivered kidney-targeting RNAi drug QPI-1002 (for acute kidney injury) may occur soon thereafter. The first microRNA drugs may be approved a year or two after that. Other systemically delivered oligonucleotide drugs that target organs and tissues other than liver or kidney are “a long way off”, and the timing of their appearance is difficult to predict. This is typical of a technologically premature field, as discussed in <a href="http://biopharmconsortium.blogspot.com/2009/07/rnai-embryonic-stem-cells-and.html">our earlier blog post</a>. Early formulations of oligonucleotide drugs may also fail in Phase III, thus thwarting the panel’s predictions.<br /><br />The panelists agreed that it is important to target the “low-hanging fruit” (i.e., products that are locally delivered or target the liver or kidney) first in order to get the momentum of the field going. However, researchers and companies should also look at other targets, especially if they are developing novel enabling technologies in drug delivery and/or in design of therapeutic oligonucleotides with enhanced potency and specificity.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com0tag:blogger.com,1999:blog-4682750433159205287.post-56844396754662513342009-08-09T12:17:00.000-07:002009-08-09T12:40:59.330-07:00Haberman Associates on Page One of Genetic Engineering News<a href="http://www.genengnews.com/">Genetic Engineering & Biotechnology News</a> (GEN) featured my new article, entitled “Overcoming Phase II Attrition Problem”, on the top of Page One of its August 2009 edition.<br /><br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgLMqvYHEg5p2cJ3zKOoRXF9txPeUvMreUmV8HdHHQm1DV6EuA4IVe4xKGUUW-UtZT7lH3nJomjdwklLtFelODFiSQtnomKKctfMtH2tQmBoh-q_ssTIdN60inuY4rdV9atYB_Kob2TV-4/s1600-h/GEN_Aug09_400Pixels_Cover.jpg"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 250px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgLMqvYHEg5p2cJ3zKOoRXF9txPeUvMreUmV8HdHHQm1DV6EuA4IVe4xKGUUW-UtZT7lH3nJomjdwklLtFelODFiSQtnomKKctfMtH2tQmBoh-q_ssTIdN60inuY4rdV9atYB_Kob2TV-4/s320/GEN_Aug09_400Pixels_Cover.jpg" alt="" id="BLOGGER_PHOTO_ID_5368046402124075282" border="0" /></a><br /> Here is an image of Page One of the August 2009 issue.<br /><br /><br /> <a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjtI5EgAmIOj8VYmADucur7cKmAIhc8gwQDTiCt2fWxrGoh_E8Xy_UI0If2vjp6M5dQUSFC-Rxbfwg0E-tFPmrz4ktMja2lMJI6yYV5E1CklE6TWPWaAP2u8BnLIpUJSRFuLg7MofPw7x0/s1600-h/DSC_0116AH.JPG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 320px; height: 214px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjtI5EgAmIOj8VYmADucur7cKmAIhc8gwQDTiCt2fWxrGoh_E8Xy_UI0If2vjp6M5dQUSFC-Rxbfwg0E-tFPmrz4ktMja2lMJI6yYV5E1CklE6TWPWaAP2u8BnLIpUJSRFuLg7MofPw7x0/s320/DSC_0116AH.JPG" alt="" id="BLOGGER_PHOTO_ID_5368047017632250690" border="0" /></a><br />And here am I, at the IBC Drug Discovery and Development Week conference (formerly known as DDT) in Boston, on Tuesday, August 4, holding a copy of the August issue. Thanks to Keri Dostie of IBC for taking this photo.<br /><br />If you were at the conference, you may have read the article in one of the advance copies of the August GEN that were available there. Or you can look for your own copy, which you should receive in the mail shortly. More immediately, you can read the article by downloading the PDF on our website:<br /><br /><a href="http://www.biopharmconsortium.com/GEN_PIIAtt_0809.pdf">http://www.biopharmconsortium.com/GEN_PIIAtt_0809.pdf</a><br /><br />The article discusses the most important challenge facing the pharmaceutical industry today, the need to improve R&D productivity. It outlines leading-edge strategies for reducing pipeline attrition and for increasing the number of drugs that reach the market and that address unmet medical needs.<br /><br />If you need a more in-depth exposition, you may have your company order a copy of our May 2009 book-length report, <a href="http://www.insightpharmareports.com/reports_report.aspx?id=90910&r=666">Approaches to Reducing Phase II Attrition</a>, an Insight Pharma Report published by Cambridge Healthtech Institute (CHI). The GEN article is based in part on that report.<br /><br />You may discuss issues raised by the article or the report by leaving a comment on this blog post.<br /><br />Thanks are in order to those who helped make the GEN article a success. Four industry executives were quoted in the article-- Charles Gombar and Evan Loh of <a href="http://www.wyeth.com/">Wyeth</a>, Bruce H Littman of <a href="http://transmedassociates.com/">Translational Medicine Associates</a>, and Peter Lassota of <a href="http://www.caliperls.com/">Caliper Life Sciences</a>. (Full transcripts of interviews with these and other executives are included in an appendix to the CHI Insight Pharma report.) Drs. Littman and Lassota also reviewed the article prior to publication.<br /><br />Hearty thanks also to those who served as editors of the article—Laurie Sullivan and Al Doig at CHI and John Sterling and Tamlyn Oliver at GEN. Producing a lead article for GEN (or for other publications) requires an extra level of effort from editors as well as authors, so thanks to all who participated in this effort.Allan B Haberman, Ph.D.http://www.blogger.com/profile/03852820846679752188noreply@blogger.com1