Archive for the ‘New Drugs’ Category
Ion Channels Open Doors to New Drugs Increased R&D Efforts Are Overcoming Obstacles and Showing Potential
Last Updated on Thursday, 8 July 2010 03:20 Written by Editor Thursday, 8 July 2010 03:20
- Nina Flanagan
Researchers at the recent Society for Biomolecular Screening conference and CHI’s upcoming “Pharmacology Driven Assays for GPCRs and Ion Channels†shared information on a cornucopia of topics, including the latest enabling technologies, new screening paradigms, and novel approaches to generate GPCRs.
The IonFlux system from Fluxion Biosciences was recently beta tested by scientists at Novartis Institutes for Biomedical Research (NIBR). “Compounds, buffers, and waste are contained on a single 96-well plate, eliminating robotic handling. Air pressure drives experiments in microfluidic channels in a layer below the wells. This is a novel approach in automated electrophysiology,†explained Andrew Golden, Ph.D., post-doc fellow.
Robustness is enhanced via recordings taken from 20-cell ensembles (IonFlux HT), and pharmacology improved by recording a full range of concentrations from the same group of cells, according to the company. There are two available systems—the IonFlux 16, which uses 96-well plates, and the IonFlux HT, which uses 384-well plates.
Analysis of the prototype (alpha and beta testing) was initially focused on whether IonFlux could reproduce results demonstrated on other platforms. “The microfluidic approach could be helpful for ligand-gated ion channels—especially for subsets of those for fast desensitizing ligand-gated ion channels where you only add a short pulse of the ligand or neurotransmitter,†explained Mats Holmqvist, Ph.D., research investigator in the center for proteomic chemistry at NIBR.
In addition, Dr. Holmqvist said the hope for the new platform is that it should provide selectivity not only by target but also by function. “You can utilize ‘use dependency’—the accumulation of inhibition with repetitive depolarizations. If an ion channel is active, the drug may be much more potent.†With this new technology, one should be able to refine and understand how a compound affects an ion channel. However, it’s still too early to show whether this will be the case.
Since HT platforms for ion channels are fairly new, standardization across different instruments hasn’t been addressed. “There are different quality control parameters, including the way of recording a single cell per well or ensemble recording in parallel. Some machines use Oracle database versus file formats. We’ve been trying to address that in safety profiling. A quick answer is that we make a summary PDF file of every compound in each experiment that can be accessed any time,†noted Dr. Holmqvist.
Parallel Screening
The traditional screening paradigm involves one target for primary HTS. However, this process “wastes a considerable amount of time to get results, and also wastes efforts on compound management in order to get those compounds ready for testing,†said Peter Hodder, Ph.D., senior director of lead identification for the translation research institute at the Scripps Institute, Florida.
His group uses a parallel screening process that screens compounds against the target and antitarget simultaneously. “Antitarget is an all-encompassing name for any assay you would run that’s different from the target—usually to remove compounds from further consideration,†Dr. Hodder explained. “We found most of those compounds are junk compounds anyway.†The antitarget becomes important for the hit compounds, because it provides information on whether it is something specific to the target or whether it is something nonspecific to the assay format.
Time saved via parallel screening can be four to five weeks per target. In addition, and what is more important and what is harder to gauge, he noted, is saved efforts following false trails, which result in smaller, cleaner datasets. Relevant structure activity relationships emerge early in a campaign. For example, Dr. Hodder performed an SF1 (transcription factor) assay and ran the antitarget ROR against it and found potent compounds. “If we had relied on primary screening alone, those compounds would not have been selected.â€
The parallel-screening format is not specific to any target class. “What’s more important is how to apply it to different target classes or different assay formats.†His group was successful in screening ion channels, including TRPML3 with TRPN1 as the antitarget (TRP is transient-receptor potential). HTS probes confirmed that the target is not located on plasma membranes in native cells.
Dr. Hodder added that this approach can be used to help focus on the most important compounds for drug or probe discovery, but it’s key is in choosing the right antitarget. “If it’s too close in relationship to the target, you’re going to start throwing out compounds you don’t want to during the campaign.â€
His group is now performing more sophisticated screening using two or three antitargets and trying to find the overlap of hits that are specific in all three versus two or one of those targets and antitargets. “This challenges us to think about how we present and analyze our data.â€
Novel Assays
Some of the challenges of working with ion channels include controlling activity, whether with a small molecule ligand or voltage. Many ion channels inactivate within milliseconds, making HTS difficult.
David Weaver, Ph.D., director at Vanderbilt Institute of Chemical Biology HTS, has been focusing his research efforts on ion channels—especially 7TM (7-Transmembrane) receptors.
“We are interested in looking at some of the effector systems that are more physiologically relevant and one of these is the GIRK (G-protein regulated inwardly rectifying potassium (K+) channel).†His group developed this assay to measure the activity of GI-coupled 7TM receptors. “The idea was whether we could see any differences in the pharmacology and the fact that we may be using a more physiologically relevant end effector rather than using mutant G proteins to couple the change in intracellular calcium.â€
The success of the GIRK assay encouraged Dr. Weaver to examine ion channels as end effectors that could be used to generate new assays with physiological relevance. Preliminary data demonstrates the ability to detect changes in M-current (muscarinic-modulated potassium current, usually studied in the brain and peripheral nervous system) activity.
He developed an HTS-compatible assay that can measure and quantify the modulation of M-current downstream from the 7TM receptor using thallium-flux. This optical assay platform can use a commercially available kinetic imaging plate reader.
According to Dr. Weaver, the only nonstandard part of the assay is that he extracts a slope from the initial measurement, instead of fitting a peak amplitude. His hope is to use this assay to further understand the pharmacology of 7TM receptors. “It’s my intent that we can demonstrate that these are good, robust assays for use in HT screens to discover novel modulators of 7TM receptors or the ion channels we’re using as effectors.â€
Novel Targets
“Ion channels are terrific molecular targets, and many drugs have been targeted to them,†stated David Clapham, M.D., Ph.D., Aldo R. Castenada professor of cardiovascular research at Children’s Hospital Boston. Yet, one of the biggest challenges is the gold standard assay—the patch clamp.
This is a time-consuming technique—single cell membranes must be broken open and the current must be recorded while controlling voltage in the cell. Although HT assays exist, not all ion channels are suited to them. “The most promising are the very fast, voltage-dependent channels with large, rapid changes and ones less amenable are ones that are similar to each other in their properties, like TRP channels—these are more difficult.â€
Dr. Clapham also presented information on what he thought were good, fairly recent, ion-channel targets and included some recent data on some of his work with these targets.
Many TRP channels are involved in sensory functions, like smell, taste, and hearing. TRPV3 is an ion channel that is well expressed in skin. Dr. Clapham demonstrated that both skin barrier formation and some aspects of hair formation are altered by this ion-channel’s activation or block.
It is activated by subtle temperature changes—temperatures about 32ºC—indicating TRPV3 is sensing heat at the skin surface and relating that to the nerves. This indicates it may help regulate body temperature. Growth factors such as EPGR potentiates TRPV3 to bring calcium into karatinocytes, and, in turn, TRPV3 potentiates EPGR, so there’s a positive feedback loop.
“This is important for the proper formation of skin barriers, so that there is normally a cycle of karatinocytes maturing from deeper in the skin to the surface of the skin.†Dr. Clapham added that TRP channels are difficult to work with because they are fairly slow and their properties are often difficult to distinguish. In addition, they are often small in size, and there is a lack of known ways to activate them.
Additional ion channels that Dr. Clapham thought were worth pursuing were the NAV1.7 to NAV1.9 pain targets, which are voltage-gated sodium channels. A new chloride channel, TMAM16-A, and the ORAI channel, which is important in the immune system, were also on the list. An interesting new target for contraception, called CATSPER, is an ion channel only present in mature sperm and required for male fertility. “This may be a good method of contraception without hormones,†said Dr. Clapham.
“Our job is to find new targets and new molecules, and then other people can work with those molecules to target diseases.â€
New Approach
There are many challenges for the generation of new GPCRs, said Michel Bouvier, Ph.D., professor and chairman in the department of biochemistry at the University of Montreal. These include selectivity and ligand-biased signaling, where one receptor can couple to different signaling pathways in a cell.
“The problem with this is that you are trying to monitor the efficacy of a compound toward one signaling pathway, but since there are multiple ones, we don’t necessarily know which one to follow that will correlate with a disease or particular activity.†His approach is to develop one assay that could encapsulate in one reading all the signaling pathways and by dissecting the signatures, provide information about the pathways being engaged by a receptor.
Utilizing Roche’s label-free xCELLigence platform, his group is able to measure cell impedence. Each well of the plate has electrodes. As the cells grow, the impedance increases, and when the cells are treated with compounds that bind to receptors, many different pathways are triggered.
The readout reflects changes in impedance from the compound over time—providing a global assessment of the various pathways. Different compounds generate different curve shapes. “We can use this technology to differentiate classes of compounds that have different relative selectivity toward different pathways. It’s generating a simpler way to classify compounds in different efficacy profiles toward different signaling pathways.â€
Dr. Bouvier added that they can now, using selective inhibitors of different pathways such as the generation of cyclic AMP, show how the inhibition influences the shape of the impedance curve. “Not only can we start classifying the ligands in different categories or compounds, but we can start making predictions on which pathways these compounds will be actively inhibiting. His group is planning to develop algorithms to apply to the curve and thus, provide a response as to which pathway is being affected. “We first need to confirm which portion of the curve informs us about each pathway.â€
This approach can be used for almost any receptors, reported Dr. Bouvier. It provides a big time savings—one assay instead of four or five. However, he added, “we don’t know yet if all signaling pathways will respond to changes in impedance—from our data so far, we haven’t encountered such a pathway.â€
source: genengnews.com
Posted under Drug Development, New Drugs, Press Releases, R & D | No Comments
Rising to the Challenge in R&D
Last Updated on Monday, 11 January 2010 05:22 Written by Editor Monday, 11 January 2010 05:22
Over the past 20 years there has actually been a decline in NMEs approved by FDA. Furthermore, many of the NMEs approved are “me-too†molecules for disease states where first-in-class drugs are already on the market. Granted, there are other reasons for the dearth of product innovation—including regulatory issues, an increasing focus on short-term returns by some shareholders, and corporate restructuring—but the fact remains that pharmaceutical companies need NMEs with novel mechanisms and better safety and efficacy than offered in currently available drugs. Clearly, new chemistry allowing access to well known targets that have been intractable to older chemistries could provide a kick-start to the malaise in drug discovery.
A New Kind of Chemistry: Allosteric Modulation
Even as biologics, RNAi, and gene and cell therapies may provide value to patients in the short-to-medium term, small molecule drugs may one day offer patients many of the same benefits in a format that is more patient friendly (i.e. oral administration) and, potentially, with easier manufacturing and/or lower costs compared to non-pharmaceutical drugs. Allosteric modulators are an emerging class of orally available small molecule drugs that may have multiple advantages compared to traditional orthosteric drugs, including biologics.
Allosteric modulators have been shown to achieve greater selectivity, successfully modulating previously intractable therapeutic targets. In addition, orally available small molecule allosteric modulators have been discovered for targets for which only injectable biologic drugs are available. It is easier to achieve selectivity when targeting more heterogeneous allosteric binding sites on targets with therapeutic potential—such as G-Protein Coupled Receptors (GPCRs) and cytokine receptors—than an “active site,†which is often highly conserved across multiple related receptors.
Simply put, the active site on receptors acts as a switch that controls turning receptor signaling. Unlike orthosteric drugs, which turn receptors completely on or off, allosteric modulators act like a dimmer switch to mediate the intensity and frequency of receptor signaling. However, the trigger for signaling remains under the control of the endogenous ligand, which binds the target according to the physiological rhythm determined by the body. In many cases, allowing the body to retain control over initiating signaling while simply increasing or decreasing the amplitude of that signaling may offer a competitive advantage over other approaches. Although it has often been attempted with orthosteric drugs, comparable functional control over receptor signaling cannot be achieved simply by modifying the dose or delivery of orthosteric drugs.
Key Advantages of Allosteric Modulation
- Because they do not compete for the endogenous ligand binding site and exert their effects even in the presence of endogenous ligands, lower doses of allosteric modulators may have greater potency than orthosteric molecules with similar affinity for the same target. Lower dosing often leads to fewer side effects.
- Allosteric modulators can be devoid of activity in the absence of endogenous ligands, offering a less disruptive way to influence the functioning of biological systems and therefore could lead to greater safety and fewer tolerability issues.
- Because they bind on a distinct site, it is possible to create new chemical entities with unfettered intellectual property that re-address well validated GPCR targets for which there are marketed products. In such cases, the goal would be that the allosteric mechanism offer clear differentiation in terms of efficacy and/or side effects.
- It follows that highly selective allosteric modulators can be made for targets where it has been difficult to make selective orthosteric modulators. For example, orally available small molecule allosteric modulators against GLP-1 and FSH receptors—for which only peptide, protein or hormonal therapies are available—have been discovered.
- Because they bind at a separate site, it is possible to combine allosteric modulators with orthosteric drugs. For example, a positive allosteric modulator, or PAM, could be used to potentiate an orthosteric agonist. This could alleviate side effects associated with off-target effects seen at high doses of some orthosteric drugs or simply reduce cost of goods for other orthosteric drugs, especially with biologics.
History of Allosteric Modulators
The concept of allosteric modulation is not new; scientists have been discussing it since the first half of the 20th century, and some suspected such a mechanism even earlier. In the 1960s, Roche introduced the tranquilizer Valium, which later was discovered to act by allosteric modulation of gamma-aminobutyric acid (GABA) receptors. More recent allosteric modulators include Sensipar (cinacalcet, from Amgen), a calcium-sensing receptor PAM, and Selzentry (maraviroc, from Pfizer), a CCR5 NAM.
But these first-to-market drugs were found more through serendipity than through focused searches for allosteric modulators. Indeed, the industrialization of allosteric drug discovery is something that many pharma companies and venture capitalists have shied away from due to the risks and the magnitude of investment.
The search for new drugs has long focused on GPCRs, but of roughly 850 known GPCRs less than 200 have been drugged. Compounds identified through screening have typically worked at the orthosteric site, but after finding the so-called “low hanging fruit,†this approach delivers fewer and fewer hits. In the late 1990s, researchers made some breakthroughs, identifying mGluR selective ligands that didn’t bind to the active sites on glutamate receptors, including allosteric modulators, targeting the metabotropic glutamate receptor 5 (mGluR5), which was discovered by researchers at SIBIA Neurosciences in collaboration with Novartis.
The goal soon became finding similar allosteric drugs; and for this, a new type of screening assay was needed. In the mid-1990s, screening assays evolved to include biological function. When the resulting compounds started to show different types of effects on the receptor, researchers concluded allosteric modulation may be playing a role.
In 2001, Vincent Mutel, CEO of Addex Pharmaceuticals, was a pharmacologist at Roche. Almost by chance, he and his colleagues discovered an allosteric molecule that enhanced the activity of the metabotropic glutamate receptor 1 (mGluR1). This glutamate receptor subtype was not tied to any particular disease, but the finding convinced Mutel that allosteric molecules could enhance an effect as well as block.
Addex was founded in 2002 and initial discovery work focused on targeting mGluR5 for addiction. As mGluRs had been intractable to orthosteric chemistry, Dr. Mutel and his team developed biological screening tools that would detect allosteric modulators of mGluR5 and other mGluR subtypes. It turned out that the tools developed could be adapted to almost any GPCR, and eventually to other types of receptors, like cytokine receptors. GPCRs are the targets of more than 30 percent of all medicines currently on the market . The company has disclosed discovering receptors in all three GPCR families and, more recently advances in the discovery of small molecules targeting receptors such as TNF-R1, IL-1R1, GIPR and GLP-1R, targets that have previously only been addressed by injectable protein or peptide therapeutics .
Future of Allosteric Modulators
The role of specific receptor sub-types has been elucidated in many diseases; however, in many cases, it has been challenging to develop sub-type specific drugs. These cases are the low hanging fruit for allosteric modulators. For example, metabotropic glutamate receptor 5 (mGluR5) has been implicated and clinically or preclinically validated in multiple diseases for more than two decades. But it took Big Pharma more than 20 years after the cloning of the mGluR5 receptor to identify and begin testing selective molecules against this high value target. In the end most if not all the molecules targeting mGluR5 are allosteric modulators. These molecules have progressed into the clinic and are now showing efficacy in humans in a variety of indications.
Addex’s lead compound ADX10059, a negative allosteric modulator of mGluR5, has shown efficacy in separate early Phase II studies for gastroesophageal reflux disease (GERD) and migraines. Clinical and preclinical data from Addex and other groups suggest that the product also has potential in Parkinson’s disease, and certain chronic forms of anxiety and depression. Other companies already are working on mGluR5 inhibitors to treat Parkinson’s disease, Fragile X, and neuropathic pain.
The allosteric drugs also could be combined with conventional orthosteric drugs against the same target to maximize the efficacy of the orthosteric and/or allow use of lower doses. This could be a desirable strategy to minimize dose-related, off-target side effects associated with the orthosteric product while potentially also reducing the cost of goods (especially if it is a biologic).
Allosteric modulators may become a life-cycle management strategy for biologics drugs. In the future, orally available small molecule allosteric modulator may be able to replace or complement many biologic drugs. The cost of a prescription allosteric modulator could, in some cases, obviate the opportunity for bio-generic competition while preserving the profit margin of the prescription biologic.
Allosteric drug discovery and development has only just begun. Many skeptics are being won over and it is beginning to become a mainstream approach. With more than 70,000 potential allosteric modulators in its unique biased library and a growing number of proprietary biological screening tools, Addex is leading the field. Its growing pipeline and partnerships serve as increasingly irrefutable validations. The approach, however, is much bigger than one company, with many in the industry predicting that allosteric modulation will become a new therapeutic class in the medical armamentarium.
Source: findpharma.com
Posted under Drug Development, New Drugs, Press Releases, Reports | No Comments
AIDS Drugs – HIV
Last Updated on Monday, 14 December 2009 05:19 Written by Editor Monday, 14 December 2009 05:19
In the early 1980s, the human immunodeficiency virus (HIV) was identiÂfied as the etiologic agent of acquired immune deficiency syndrome (AIDS). More than 3 million people worldwide died from HIV/AIDS in 2003, according to a July 2004 United Nations report. During the same period, about 5 million people contracted the human immunodeficiency virus, bringing the total number of people living with HIV worldwide to 38 million. Although AIDS was called the «gay men’s disease» at the beÂginning of the outbreak, it was soon discovered that sexual intercourse was not the only way of transmission. Blood transfusions and mother-to-baby transmission also spread the virus.
In comparison to the scourges caused by other viruses in history, we were more prepared and have achieved astonishing milestones against AIDS, thanks to our accumulated knowledge and efforts around the globe. HIV was identified and shown to be the cause of AIDS in less than 2% years. It took only another 2 years for blood tests to become commercially available. In 1987, the first anti-HIV drug, AZT, was introduced. With the arrival of the HIV protease inhibitors and triple drug therapy (the cocktail therapy) in 1995, many patients who would otherwise have died are still alive. In 1996, Time magazine named AIDS researcher David Ho «Man of the Year» for his revolutionary idea of the cocktail therapy.
Who discovered HIV was such a contentious isÂsue that it took the President of the United States and the Premier of France to settle the dispute.
In 1983 Francoise Barre-Sinoussi and Luc Montagnier, in the laboratory led by Montagnier at the Institut Pasteur de Paris, first detected and later isoÂlated a retrovirus, lymphadenopathy-associated virus (LAV), which they believed was the cause of AIDS. During their research on the virus, Montagnier’s labÂoratory collaborated with Robert C. Gallo, a renowned virologist at the National Cancer Institute (NCI), who was one of the most widely referenced scientists in the world in the 1980s and 1990s. Montagnier and Gallo frequently exchanged virus sampies and information. In April 1984, Gallo held a press conference anÂnouncing that his laboratory had isolated a retrovirus, human T-lym-photrophic virus (HTLV-III), that he believed to be the cause of AIDS. Gallo was basking in scientific glory and was widely considered a leading contender for the Nobel Prize. Soon it was confirmed that Gallo’s HTLV-III and Montagnier’s LAV were identical. In 1986, a nomenclature comÂmittee was set up, chaired by Harold Varmus, an expert in avian retrovirus and then director of the NIH. The NIH committee settled on the name of human immunodeficiency virus (HIV).
In April 1984, Gallo’s laboratory filed a patent on an HIV blood test kit using his HTLV-IIIB-ELISA (enzyme-linked immunosorbent assay), which was issued in a record 13 months via a special category involving naÂtional security. Although Institut Pasteur had filed a patent in the United States much earlier, in December 1983, it was not granted until a later date. Gallo’s HIV test kit was approved by the FDA in 1985. An acrimonious leÂgal battle ensued for the priority of the discovery of the HIV between the French and American teams. The contentious scientific and legal controÂversies came to an end in March 1987 when a historic agreement was signed by the directors of the NIH and the Institut Pasteur and ratified by Ronald Reagan and Jacques Chirac. The patents would become the joint properties of the two institutions, which would share the royalties. The three inventors from the NIH, including Gallo, would receive $100,000 annually from the royalties earned.
Even the intervention by two heads of state did not put the matter to rest. In November 1989, a Pulitzer Prize-winning investigative reporter, John Crewdson, published a 50,000-word article in the Chicago Tribune on the Montagnier-Gallo priority dispute. He concluded that Gallo had either stolen or allowed his samples to be contaminated with Montagnier’s virus. The controversy generated resulted in congressional investigations. In the end, it was found that Mikulas (Mika) Popovic from CzechoslovakÂia, a cell biologist in Gallo’s laboratory, had isolated HTLV-III from a pool by mixing several blood samples from different sources, including Montagnier’s sample, which contained LAV. Pooling blood samples was an unusual practice in virology. In 1991, Gallo admitted in Nature that he had not discovered the new virus. In 1996, he left the NCI, where he had worked for 30 years, to become the director of the Institute of HuÂman Virology at the University of Maryland Biotechnology Institute in Baltimore.
In 1987, the first anti-AIDS drug, AZT, was introduced by Burroughs Wellcome. AZT, which blocks HIV reverse transcriptase activity, stands for azidothymidine, with the generic name of zidovudine and the trade name of Retrovir. Popular media often give the credit to Gertrude Elion of Burroughs Wellcome for having discovered AZT. In fact, alÂthough Elion and George Hitchings (see chapter 1, page 19) developed the concept of using nucleotides as antimetabolites in treating cancers, AZT itself was synthesized by a group led by Jerome Horowitz of the Detroit Institute of Cancer Research in 1964 as a possible anticancer drug. Horowitz, now a professor at Wayne State University, published his synÂthesis as a note in the. Journal of Organic Chemistry in 1964.
Since its birth, AZT had a checkered life as a drug looking for a disease to treat. AZT did not show efficacy in treating cancers; the drug also failed to prolong the lives of leukemic animals. In 1974, a German laboratory found it effective against viral infection in mice—Wolfram Ostertag of the Max Planck Institute for Experimental Medicine showed that leukemia helper virus (LLV-F) replication by AZT occurred via phosphorylation of AZT to the corresponding triphosphate, which cannot be incorporated into the growing strand of DNA. Ostertag correctly concluded that AZT-triphosphate worked by binding to the growing strand of DNA. BurÂroughs Wellcome acquired AZT and explored the possibility of using it to treat the herpes virus under the guidance of Gertrude Elion, although it did not make it to the market.
In 1984, shortly after Gallo announced his discovery of the retrovirus, HTLV-III, the head of the NCI, Samuel Broder, organized a team to screen antiviral agents as possible treatments for AIDS. In all, more than 50 pharmaceutical companies submitted their possible antiviral drug canÂdidates to Broder’s team for screening. Together with Dani Bolognesi, an AIDS researcher at Duke University, Broder obtained some of the potenÂtial antiviral compounds from Burroughs Wellcome. In February 1985, usÂing an assay developed by Hiroaki «Mitch» Mitsuya, AZT was found to be active in vitro in the NCI laboratories in Bethesda. Wellcome patented AZT as an antiviral drug in June 1985 and promptly commenced the cliniÂcal trials. As with cancer drugs, the Phase I trials for AIDS drugs are done with patients rather than with healthy volunteers. The first trials to test AZT in patients with HIV showed dramatic efficacy. For ethical reasons, the company terminated the trials and switched patients on placebo to AZT immediately. The FDA approved the use of AZT on March 19,1987, within 22 weeks. The recommended dose was one 100-mg capsule every 4 hours around the clock. Thus AZT established itself as the first antiviral drug in the arsenal against HIV. The mechanism of action of AZT is the blockade of the HIV reverse transcriptase activity. Reverse transcriptase, first isolated by David Baltimore and Howard Termin in 1970, is the enÂzyme that transcribes RNA into DNA. The success of AZT incited the deÂvelopment of many nucleotide anti-HIV drugs in an effort to minimize the toxicities that AZT displayed.
Among the newer reverse transcriptase inhibitors, Ziagen represents a vast improvement over AZT, a nucleotide whose gycosidic core structure is metabolized rapidly. Whereas AZT has to be taken every 4 hours around the clock, Ziagen allows a twice-daily regimen. When the oxygen on AZT is replaced with a methylene group, carbocyclic nucleoside analogs such as Ziagen are metabolized much more slowly by the body. Ziagen was develÂoped by Glaxo Wellcome (now part of GlaxoSmithKline) using a technolÂogy developed by Robert Vince of the University of Minnesota, who licensed the patent to Glaxo Wellcome in 1993.
Robert Vince is a professor of medicinal chemistry and director of the Center for Drug Design at the University of Minnesota. After completing his Ph.D. training in 1966, he began his independent research in the field of antiviral medicine. In the mid-1970s, he designed an antiviral comÂpound, carbocyclic Ara-A (cyclaradine), that was more effective in comÂbating herpes virus than acyclovir was. Because he did not patent his discovery, it was difficult to entice the pharmaceutical industry to develop it. That experience taught him a lesson on the importance of intellectual properties. In the mid-1980s, inspired by the success of AZT, Vince started to tinker with nucleosides as HIV reverse transcriptase inhibitors. In retrospect, it was logical for him to replace the oxygen on the nucleoÂsides related to AZT with a methylene group in order to improve bioavail-ability. But at that time, it represented a significant improvement. Along with a visiting researcher from China, Mei Hua, he synthesized a group of carbocyclic nucleoside analogs, which they called carbovirs. The NIH tested the carbovirs and found them to be the most active compounds in their screen against HIV since AZT. In fact, the carbovirs were the first compounds found active against HIV that were specifically synthesized for that purpose. In 1987, the University of Minnesota patented their synthesis and a group of antiviral drugs, listing Vince and Hua as coin-ventors. The university subsequently licensed the patent to Glaxo Well-come, which arrived at Ziagen by substituting a propyl cyclopropyl group for the purine ring using the synthetic route developed by Vince. Because of Ziagen’s favorable pharmacokinetics profile, it allows a twice-daily regÂimen and has brought in hundreds of millions of dollars in sales for the company.
The credit for any important discovery often seems to be a contentious issue. In this case, the stakes were high, as both AIDS and a large sum of money were involved. Glaxo claimed that Ziagen was not covered by the Vince-Hua patent because the patent did not cover Ziagen per se, whereas Minnesota contested that alkyl surely included cyclopropyl. In October 1999, the University of Minnesota and Glaxo settled this dispute, and as part of the settlement Glaxo agreed that the University patents were valid and enforceable. The settlement brought a financial windfall for MinÂnesota and the inventors. With the Ziagen money, estimated at $250 milÂlion thus far, Minnesota established a Center for Drug Design, with Vince as its director. Vince is putting his share of the Ziagen money to work on potential new AIDS drugs and other potential antiviral and anticancer agents at the center.
In addition to AZT and Ziagen, many HIV reverse transcriptase inÂhibitors exist. An organic chemistry professor at Emory University, Dennis Liotta, and his virologist colleague, Raymond Schinazi, discovered another reverse transcriptase inhibitor 3TC (lamivudine, Epivir), which allows a once-daily regimen. BMS’s d4T was licensed from Yale University. The drug gained international fame when activists at Yale persuaded the uniÂversity to rewrite a license agreement with BMS so that generic d4T could be sold in South Africa. BMS’s ddl was approved in mid-1991, and nevi-rapine (trade name Viramune) by Boehringer Ingelheim was approved by the FDA in June 1996.
Posted under HIV Research, New Drugs, Press Releases | No Comments
Researchers find candidates for new HIV drugs
Last Updated on Tuesday, 1 December 2009 11:26 Written by Editor Tuesday, 1 December 2009 11:26
While studying an HIV protein that plays an essential role in AIDS progression, researchers at the University of Pittsburgh School of Medicine have discovered compounds that show promise as novel treatments for the disease.
HIV drug discovery efforts have met with little success in finding compounds that interact with an important HIV virulence factor, called Nef, because it lacks biochemical activity that can be directly measured, explained Thomas E. Smithgall, Ph.D., William S. McEllroy Professor and Chair, Department of Microbiology and Molecular Genetics, and senior author of the paper, which was published last week in the early, online version of ACS Chemical Biology.
To get around that problem, Dr. Smithgall’s team developed an assay to measure Nef function indirectly by coupling it to another protein, called Hck, which Nef activates in HIV-infected cells. Because Hck activity can be easily measured, the investigators were able to use it as a reporter for Nef activity in an automated high-throughput screening process. In collaboration with the University of Pittsburgh Drug Discovery Institute, they screened a library of 10,000 chemical compounds against the coupled proteins to see which ones influenced Nef-induced activation of Hck.
After further testing, they confirmed that three compounds inhibited the activity of the Nef-Hck complex and, more importantly, all of them also interfered with HIV replication. One compound was so effective that it suppressed HIV replication to undetectable levels in cell culture experiments.
“So we now have a way to rapidly and efficiently screen for inhibitors of Nef signaling through Hck,” Dr. Smithgall said. “But the surprise was that some of those inhibitors also showed strong antiviral activity in cell culture models.”
There is evidence that people infected with HIV variants that have mutations in the Nef gene take substantially longer to develop disease symptoms or AIDS, he said. In animal models, disrupting the production of Nef from the virus or its interaction with Hck also delays or prevents disease symptoms. The next challenge for the researchers will be to determine whether these compounds also interfere with progression of AIDS-like disease in animal models by blocking Nef function.
“Most current therapies for HIV infection use drugs that interfere with the function of viral enzymes such as reverse transcriptase or with the interaction of the virus and the host cell,” Dr. Smithgall said. “Targeting Nef represents an entirely new approach that could be useful to deal with issues such as drug-resistant HIV strains, and may slow the progression to AIDS.”
He added that Nef is just one of several so-called “accessory proteins” encoded by HIV which are important virulence factors in AIDS. Inhibitory compounds against some of the others might be revealed using a similar coupled protein approach for high throughput screening.
Source: labspaces.net
AIDS Study Flushes Out Hidden Virus, Pointing to Possible Cure
Last Updated on Wednesday, 14 October 2009 10:02 Written by Editor Wednesday, 14 October 2009 10:02
Oct. 2 (Bloomberg) — Scientists, moving closer to a cure for AIDS, identified a way to find medicines that would help rid patients of the hardest-to-treat pockets of HIV.
Current anti-HIV drugs reduce the virus to undetectable levels without eradicating it. The virus survives by lying dormant in immune-system cells, where the medicines don’t reach them. Scientists from Johns Hopkins University and the Howard Hughes Medical Institute reported yesterday that they developed a way of luring out these cells in laboratory experiments, an achievement they said may lead to a cure if repeated in humans.
In 2007, about 2.7 million people were newly infected with HIV, the virus that causes AIDS, and 2 million died of the disease, making it the world’s deadliest infectious malady, according to the Geneva-based World Health Organization, an arm of the United Nations. Scientists looking to stop HIV have turned to attacking so-called latent reservoirs of the virus after efforts to prevent infection, such as vaccines and gels, largely failed.
“This is a way in which you could envision finding a drug that would, in conjunction with existing treatment, allow us to cure patients,†said Robert Siliciano, the professor who led the study at Johns Hopkins’s medical school in Baltimore. More research is needed, he said.
For about 12 years, doctors have known that HIV, or human immunodeficiency virus, can lie dormant in immune-system cells called resting CD4s found in the lymph nodes, spleen and blood. There the virus stops replicating, avoiding the drugs designed to kill it.
Roaring Back
Studies have shown latent HIV comes roaring back when treatment is interrupted, condemning patients to a lifetime on drugs such as Abbott Laboratories’ Kaletra that can cause side effects including nausea, liver damage and fat buildup. Eliminating the last vestiges of the virus could cure patients of the disease, allowing them to stop treatment.
Siliciano’s team mimicked HIV latency in a lab dish using a gene called Bcl-2 to turn normal CD4s into resting cells capable of hosting the dormant form of HIV.
The researchers used the model to test 2,400 chemicals, finding 17 that coaxed the virus out of hiding, kick-starting its normal process of replication. In a human, that would make the virus susceptible to drugs. The best performer was a compound called 5HN found in the leaves, bark and roots of the black walnut tree.
‘Key Thing’
“They’ve found a way to find drugs — that’s the key thing,†said Stephen Kent, a professor of immunology at the University of Melbourne, in a telephone interview yesterday. “We’ve really just been guessing up to this point about ways to get at this. Having a system for screening drugs is a big advance over what we’ve had so far.â€
The result was achieved without rousing non-infected CD4 cells, avoiding a potentially fatal scenario called a cytokine storm in which the body’s immune system overreacts.
The study has limitations, Siliciano said. First, 5HN may be too toxic for use in humans, he said by phone.
“It’s going to require additional research to find something that does the same thing but doesn’t have lots of other effects,†Siliciano said. “We’re pretty confident that we’ll find lots of compounds that work, but whether any of those will be sufficiently free of other effects — that’s not clear,†he said.
Second, recent studies have pointed to another reservoir of latent HIV that has yet to be identified, Siliciano said.
No Test
“We may have to find another drug to target that reservoir,†he said. “First we have to identify what it is.â€
There’s no test for identifying whether a patient has latent HIV, meaning the only way to be sure a drug has polished off the virus is to cease treatment and see if it returns, the University of Melbourne’s Kent said.
The findings are an advance that may allow researchers to come up with a drug they could start testing in humans, Kent said.
“To get something like that into clinical trials is only a few short years — it’s not decades,†he said. “Then it’s got to work.â€
The study was published yesterday in the Journal of Clinical Investigation, a peer-reviewed journal published by the American Society for Clinical Investigation, of Ann Arbor, Michigan.
The research was funded by the National Institutes of Health in Bethesda, Maryland; the Doris Duke Charitable Foundation in New York; and the Howard Hughes Medical Institute in Chevy Chase, Maryland.
To contact the reporter on this story: Simeon Bennett in Singapore at sbennett9@bloomberg.net
Source: bloomberg.com
Posted under Discoveries, Innovations and Patents, HIV Research, New Drugs, Press Releases | No Comments
Sirona Biochem Optimizes Key Test for Diabetes and Obesity Drug Development
Last Updated on Friday, 21 August 2009 01:26 Written by Editor Friday, 21 August 2009 01:26
VANCOUVER, BC — (Marketwire) — 07/16/09 — Sirona Biochem Corp. (TSX-V: SBM) announced today it is now ready to begin testing its novel new compounds to fight diabetes and obesity.
The completion of the company’s key SGLT biological assessment test and testing will be done under contract with Richmond, BC based SignalChem.
Sirona Biochem owns the worldwide rights to a library of potential new sodium glucose transporter (SGLT) inhibitors developed to treat diabetes and obesity. SGLT Inhibitors are a novel new drug class currently under development that block the reuptake of excess sugars from urine in the kidney which can then reduce high blood sugar to normal levels. Excess sugar in the blood is a primary medical challenge associated with treating diabetes and obesity.
Sirona has a research and development agreement with TFChem (Rouen, France), where a significant number of SGLT drug analogs are being prepared for first stage evaluation. Preliminary primary stage testing conducted earlier this year provided positive indications to support Sirona Biochem’s project and provided key insights to optimize the new test that is now ready for use to evaluate the next library set of molecules.
Mark Senner, President, explained, “SGLT inhibitors are a new and exciting class of compounds that have great promise to treat both diabetes and obesity which are now at epidemic levels worldwide. This new drug class is one considered to have extraordinary market potential in the fight against diabetes and obesity.
“Development of this new drug class however is challenging due to the fragile nature of these ‘sugar’ based molecules that render them unstable and difficult to develop for clinical use. Given this challenge, it is believed that the use of the patented GlycoMim® technology, licensed from TFChem to develop SGLT Inhibitors, will increase drug stability and, therefore, improve their overall clinical effectiveness. Potential licensing and development partners have expressed interest in our concept of improving molecules in this new drug class. We intend to develop ‘best in class’ SGLT Inhibitors through use of this technology.
“The key and critical first test has been developed and optimized for use by SignalChem under contract from Sirona Biochem. Through use of this proprietary test, the company will be able to determine which molecules have the desired potency and selectivity compared to a reference standard. Screening of the current library of compounds will generate key data for ongoing drug development and provide first stage proof of concept necessary to secure future partnering opportunities. Sirona’s scientific team aims to identify lead compounds by the end of 2009,” continued Senner.
“The results from our new optimized test will be critical to direct our ongoing development of novel new SGLT inhibitors. The development and optimization of this sophisticated test, completed by SignalChem, is a significant and key milestone achievement for us. We are very pleased with the progress that we are making on our SGLT drug development program,” commented Senner.
Upon selection of compounds with the desired potency and selectivity for the SGLT 2 carrier protein, further preclinical screening for cytotoxicity, ADME properties, pharmacokinetics and in vivo efficacy will need to be carried out to select compounds for future clinical development. The primary objective of this critical first stage development plan with SignalChem was to develop, qualify and optimize the key test required for the initial development of SGLT inhibitors.
Investors are invited to visit the Sirona Biochem website at: http://www.sironabiochem.com where we feature the most recent information about the company and its activities. Alternatively, investors are able to e-mail all questions and correspondence to info@sironabiochem.com where they can also request to be added to the investor e-mail list to receive all future press releases and updates or call John Dougherty, Corporate Development at 604-641-4466.
About the Company:
Sirona Biochem Corp. (TSX-V: SBM) is a emerging biotech company dedicated to the discovery and development of novel drug compounds. The current focus is on treatments for Type II Diabetes and Obesity. Sirona has entered into a license agreement with TFChem S.A.R.L., a Drug Discovery company based in Rouen, France. TFChem licenses its technology of fluorinated carbohydrate mimics: GlycoMim®, and products in development to biotech companies. The license agreement with TFChem provides for research and development of new compounds known as S.G.L.T. inhibitors. S.G.L.T. inhibitors are a new and exciting class of compounds that have great promise and potential to treat both diabetes and obesity.
About SignalChem:
SignalChem, based in Richmond, B.C., Canada is a biotechnology company focused on the research, development and production of innovative cell signaling products to advance basic research and drug discovery efforts, with specific emphasis on the production of highly purified biologically active human recombinant proteins. SignalChem is emerging as a leader and a key contender in the life science recombinant protein market place. SignalChem offers a comprehensive discovery service which includes: gene cloning & expression of therapeutic ‘targets,’ custom assay & antibody development and compound profiling for drug ‘potency’ & ‘selectivity.’
Mark Senner President and Director
Neither the TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release.
Sirona Biochem
950-789 West Pender Street
Vancouver, B.C., V6C 1H2
Direct: 604-641-4466
Fax: 604-608-5471
info@sironabiochem.com
Source: www.sys-con.com
Posted under Compound Screening, New Drugs, North America, Press Releases, USA and Canada | No Comments
CytRx Unveils Clinical Development Plan for Pipeline Assets
Last Updated on Friday, 12 December 2008 02:47 Written by Editor Friday, 12 December 2008 02:47
Names World-Renowned Cancer Drug Expert Dr. Joseph Rubinfeld as Chief Scientific Advisor
LOS ANGELES–(BUSINESS WIRE)–CytRx Corporation (NASDAQ: CYTR) today unveiled its corporate strategy to focus its internal resources on the clinical development of oncology drug candidates tamibarotene and INNO-206, which the Company believes offer the greatest mix of near-term and medium-term revenue potential among its clinical assets. CytRx will pursue partnerships to advance the clinical development of INNO-406 (bafetinib) and its clinical molecular chaperone portfolio, where it continues to see significant future revenue potential. The Company further intends to use its proprietary high-throughput, high-content drug screening Master Chaperone Regulator Assay (MaCRA) platform to discover additional molecular chaperone drug candidates, including those that may inhibit cancer growth, which will support internal efforts to build an oncology drug franchise or future out-licensing possibilities.
CytRx also announced that Board of Directors’ member Dr. Joseph Rubinfeld has accepted the additional responsibility of Chief Scientific Advisor, and will consult on all aspects of the Company’s oncology development programs while serving as an important interface between the Company and investors, clinicians and industry thought leaders. Dr. Rubinfeld brings substantial expertise in oncology and drug development through his distinguished career. Dr. Rubinfeld was employed at Bristol-Myers Company International Division as Vice President and Director of Research and Development. While at Bristol-Myers, Dr. Rubinfeld was instrumental in licensing the original anticancer line of products, including Mitomycin and Bleomycin. Among other accomplishments, he was among the four co-founders of Amgen, Inc., and founded SuperGen, Inc., where he previously served as CEO, President and Chief Scientific Officer. In his career he has been instrumental in the development of several blockbuster cancer drugs including cisplatinum, etoposide, erythropoietin, decibitene and pentostatin, and the antibiotics amoxicillin and cefadroxil.
Steven A. Kriegsman, CytRx President and CEO said, “We feel that our stockholders are best served by a focus on potential therapeutics for cancer. We believe tamibarotene has strong potential as a revenue generator with a high likelihood for rapid U.S. approval as a third-line treatment for acute promyelocytic leukemia (APL). Our view is based on the substantial clinical history of tamibarotene as an approved treatment of relapsed APL, in Japan and the existing special protocol assessment (SPA) in place with the U.S. Food and Drug Administration (FDA) for our ongoing U.S. registration clinical trial. We are accelerating enrollment in this clinical trial, with the expectation of filing an NDA with the FDA as early as 2010. We are also taking steps to move into a Phase 2 clinical trial with INNO-206, our highly promising targetable pro-drug for the commonly prescribed chemotherapeutic doxorubicin. We believe that INNO-206 could be effective in a wide variety of cancers, including small cell lung cancer, sarcoma, breast and ovarian cancer and Non-Hodgkins Lymphoma.
“Importantly, we expect that we have ample financial resources with our current cash position and investment in RXi Pharmaceuticals Corporation to support this strategy,†according to Mr. Kriegsman. “We have strong oncology expertise within CytRx and are delighted that Dr. Joseph Rubinfeld, our long-time board member who has enjoyed an illustrious career developing cancer drugs, will be taking a leadership role in our oncology programs.â€
Dr. Rubinfeld said, “Having reviewed the extensive data on tamibarotene and INNO-206, I am excited about the potential for these two cancer drug candidates and look forward to working closely with the CytRx management team to advance their clinical development to potential commercialization. I am also encouraged by the Phase 1 data we announced earlier this month with INNO-406, now known as bafetinib, which demonstrated positive, clinical responses in 35% of patients with refractory chronic myeloid leukemia. I believe these results will be instrumental in our search for a partnership for bafetinib.â€
Mr. Kriegsman added, “We also stand behind our view that our orally administered molecular chaperone drug candidates, arimoclomol and iroxanadine, provide enormous potential in addressing large, underserved markets and are convinced that the prudent course to maximize stockholder value in this economic climate is to pursue pharmaceutical partners to share additional development costs for these longer-term programs. We intend to complete our ongoing arimoclomol animal toxicology studies and work aggressively toward lifting the current clinical hold in order to enable this drug candidate to move back into the clinic. At that point, we will seek partners for further development of arimoclomol as a therapeutic treatment for both ALS and stroke recovery. Additionally, iroxanadine has shown significant potential as a therapeutic treatment for diabetic foot ulcers and other diabetic complications, and based on Phase 2 data, we will pursue potential partnerships in cardiovascular conditions.â€
CytRx’s drug portfolio includes the following:
Oncology Drug Candidates:
Tamibarotene: CytRx holds the North American and European rights to tamibarotene, a rationally designed, synthetic retinoid compound designed to potentially avoid toxic side effects of the current first-line APL treatment trans-retinoic acid (ATRA). CytRx is actively enrolling patients in a Phase 2 registration clinical trial, known as STAR-1, with tamibarotene to evaluate its efficacy and safety as a third-line treatment for APL. The registration study is being conducted under a Special Protocol Assessment. The FDA has granted Orphan Drug Designation and Fast Track Designation for the use of tamibarotene in patients with relapsed or refractory APL following treatment with ATRA and arsenic trioxide.
There are currently no approved third-line treatment options for refractory APL patients. CytRx estimates the U.S. market opportunity for tamibarotene in refractory APL at approximately $20 million annually. CytRx scientists are also evaluating clinical strategies for developing tamibarotene as a first-line or second-line APL therapy. The estimated annual market potential in the U.S. and Europe for an expanded label including refractory, maintenance and front-line therapy is $150 million. CytRx also retains an option to expand its licenses for the use of tamibarotene in other cancers including multiple myeloma, myelodysplastic syndrome and certain solid tumors in the U.S., and multiple myeloma, myelodysplastic syndrome and solid tumors, other than hepatocellular carcinoma, in Europe.
INNO-206: This pro-drug derivative of the commonly prescribed chemotherapeutic agent doxorubicin is designed to reduce adverse events by controlling drug release and preferentially targeting the tumor. In a Phase 1 study, INNO-206 was administered in doses at up to six times the standard dosing of doxorubicin without an increase in observed side effects over those historically seen with doxorubicin. Objective clinical responses were seen in patients with sarcoma, breast and lung cancers. The Company plans to evaluate further clinical development of INNO-206 in a wide variety of cancers, including sarcomas, breast and ovarian cancer, and Non-Hodgkins Lymphoma.
INNO-406 (bafetinib): INNO-406 (bafetinib), a potent, orally available, rationally designed, dual Bcr-Abl and Lyn-kinase inhibitor, is being evaluated for the treatment of patients with chronic myeloid leukemia (CML) and other leukemias that have a certain mutation called the Philadelphia Chromosome (Ph+) and are intolerant of or resistant to imatinib (Gleevec®) and second-line tyrosine kinase inhibitors (i.e. dasatinib (Sprycel®) and nilotinib (Tasigna®)). In November 2008, CytRx announced that bafetinib demonstrated positive, clinical responses in 35% of patients with CML in Phase 1 clinical testing. The Phase 1 clinical trial was used to determine the optimal dose prior to Phase 2 clinical efficacy testing.
CML is a type of cancer that starts in blood-forming cells of the bone marrow and invades the blood. In 2007, the American Cancer Society estimated that approximately 4,600 new cases of CML were diagnosed in the U.S. and that the number will increase as the population ages. Current estimates are that worldwide CML prevalence will increase by 10,000 patients a year, reaching a population of 110,000 in 2010. The global market will grow to an estimated $5.5 billion by 2012.
Molecular Chaperone Regulation
CytRx is a leader in molecular chaperone regulation technology. The Company currently has two orally administered, clinical-stage, drug candidates and recently discovered a series of additional compounds that may provide a pipeline for additional drug candidates. The Company’s drug candidates are believed to function by regulating a normal cellular protein repair pathway through the activation or inhibition of “molecular chaperones.” Because damaged proteins are thought to play a role in many diseases, activation of molecular chaperones that help to reduce the accumulation of misfolded proteins may have therapeutic efficacy in a broad range of disease states. Similarly, CytRx believes that the inhibition of molecular chaperones that normally help protect cancer cells from toxic misfolded proteins may result in the selective destruction of cancer cells.
- Arimoclomol: This molecular chaperone regulator drug candidate is being considered as a treatment for amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and stroke recovery. Arimoclomol has been studied in seven Phase 1 and two Phase 2 clinical trials without any significant adverse events. CytRx’s Phase 2b clinical trial with arimoclomol as a treatment for ALS was placed on clinical hold by the FDA in January 2008, unrelated to any data generated by human studies, and additional preclinical toxicology studies are underway to resolve this issue.
- Iroxanadine: CytRx believes that this orally available small molecule compound represents a potentially powerful breakthrough in the treatment of vascular diseases that are caused in part by damage to “vascular endothelium” that lines the inside of blood vessels. CytRx believes that endothelial dysfunction plays a key role in the development of various vascular diseases or their complications including diabetic ulcers, thrombosis, retinopathy, and peripheral artery disease. Preclinical and clinical studies with iroxanadine indicate that it has therapeutic potential for the treatment of cardiovascular atherosclerosis. According to the National Heart, Lung & Blood Institute, atherosclerosis is a leading cause of illness and death in the U.S. and affects approximately 4.6 million people annually.
CytRx San Diego Laboratory: The CytRx San Diego Laboratory is using the Company’s proprietary Master Chaperone Regulator Assay (MaCRA), a cell image-based screening tool that enables the rapid and quantifiable screening of large numbers of small molecule compounds. This technology is used to identify potential drug candidates that modify the activity of a protein known as heat shock transcription factor 1 (Hsf1) and consequently control entire groups of molecular chaperone proteins that repair or degrade toxic misfolded proteins present in diseased cells. Evaluation of the compounds identified in the screen has shown that they exhibit cytoprotective properties in cell culture models of disease. This platform has broad applicability to a range of therapeutic areas, through its ability to identify drug candidates that can either inhibit or amplify molecular chaperone activity. Information related to the development of MaCRA for compound screening was published in the November 2008 issue of the peer-reviewed Journal of Biomolecular Screening.
CytRx Oncology Expertise
Collectively, CytRx’s management and its Board of Directors have brought numerous cancer drugs to market. In addition to Dr. Rubinfeld, the senior managers and directors of CytRx who hold significant oncology experience include: Max Link, Ph.D., Chairman of the Company’s Board of Directors since 1996, who served for a number of years as Chairman and CEO of Sandoz Pharma as well as a director of Alexion Pharmaceuticals, Inc., Celsion Corporation and Discovery Laboratories, Inc.; Jack R. Barber, Ph.D., Chief Scientific Officer, who has significant R&D experience in oncology at Immusol and Viagene, where he most recently served as Head of Oncology; and Shi Chung Ng, Ph.D., Senior Vice President of Research and Development, who has substantial R&D experience at companies such as Abbott and ArQule, Inc., and most recently served as Vice President of Molecular Oncology at Ligand Pharmaceuticals.
About CytRx Corporation
CytRx Corporation is a biopharmaceutical research and development company engaged in the development of high-value human therapeutics. The CytRx drug development pipeline includes programs in clinical development for cancer indications, including tamibarotene in a registration study for the treatment of acute promyelocytic leukemia (APL). CytRx is developing two drug candidates based on its industry-leading molecular chaperone technology, which aims to repair or degrade misfolded proteins associated with disease. The Company owns and operates a research and development facility in San Diego. CytRx also maintains a 45% equity interest in publicly traded RXi Pharmaceuticals, Inc. (NASDAQ: RXII). For more information on the Company, visit www.cytrx.com.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. Such statements involve risks and uncertainties that could cause actual events or results to differ materially from the events or results described in the forward-looking statements, including risks relating to the outcome or results of any pre-clinical or clinical testing of CytRx’s potential oncology or molecular chaperone drug candidates, including tamibarotene as a third-line treatment for APL, risks related to CytRx’s ability to enter into partnerships to advance the clinical development of INNO-406 and its clinical molecular chaperone portfolio, uncertainties related to the impact of the FDA’s clinical hold on the Company’s arimoclomol clinical trial for ALS on the timing and ability to resume clinical testing at the desired dosage of arimoclomol, the risk that any requirements imposed on the Company’s planned clinical trial designs for ALS or stroke recovery by the FDA as a result of the concerns expressed in their clinical hold of the Company’s ALS program might adversely affect the Company’s ability to demonstrate that arimoclomol is efficacious in treating ALS or stroke patients or cause the Company to cancel one or both of those trials, risks related to CytRx’s need for additional capital or strategic partnerships to fund its ongoing working capital needs and development efforts, risks related to the future market value of CytRx’s investment in RXi and the liquidity of that investment, and the risks and uncertainties described in the most recent annual and quarterly reports filed by CytRx with the Securities and Exchange Commission and current reports filed since the date of CytRx’s most recent annual report. All forward-looking statements are based upon information available to CytRx on the date the statements are first published. CytRx undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
MorphoSys and Galapagos Enter Alliance to Co-develop Novel Therapeutic Antibodies in Bone and Joint Disease
Last Updated on Monday, 1 December 2008 12:59 Written by Editor Monday, 1 December 2008 12:59
Combination of Proprietary Drug Targets and Unique Technologies to Create Range of New Therapeutic Antibodies
MUNICH, GERMANY — (Marketwire) — 11/26/08 — MorphoSys AG (FSE: MOR; Prime StandardSegment, TecDAX) and Galapagos NV (Euronext: GLPG) announced today the launch of a long term co-development alliance aimed at discovering and developing antibody therapies based on novel modes of action in bone and joint disease, including rheumatoid arthritis, osteoporosis and osteoarthritis.
The alliance spans all activities from target discovery through to completion of proof of concept clinical trials of novel therapeutic antibodies. Both companies will contribute their core technologies and expertise to the alliance. Galapagos will provide antibody targetsimplicated in bone and joint disease in addition to its adenoviral target discovery platform to discover further targets for antibody development.MorphoSys will contribute its HuCAL antibody technologies to generate fully human antibodies directed against these targets. The initial goal is to further validate the targets through disease-specific in vitro and in vivotesting of the antibodies. After successful validation, the alliance will select antibody programs for pre-clinical and clinical development.Following proof of concept in human clinical trials, programs will be partnered for subsequent development, approval and marketing.
Under the terms of the agreement, Galapagos and MorphoSys will share the research and development costs, as well as all future revenues equally.Decisions will be made by a Joint Steering Committee comprising members of both companies. An initial set of three targets implicated in bone and joint disease has been selected for the collaboration, and Galapagos isalready commencing with production of these proteins for the alliance.Generation of antibodies directed against these targets will start in2009. More targets will be selected using Galapagos’ target discovery platform to fuel the alliance in the coming years. If successful, the first antibody programs based on these novel targets could enter the clinic within four to five years.
“With this alliance, we are adding a biologics strategy to our small molecule drug discovery. Galapagos is the world leader in discovery ofnovel targets, and this alliance with MorphoSys enables us to explore the potential of proprietary antibody targets. Antibody approaches have provento be successful in developing new therapies for major diseases, including rheumatoid arthritis. Having both approaches, small molecules andantibodies, to fill our product pipeline in bone and joint disease willfurther establish Galapagos as the leader in this field,” said Onno van deStolpe, Chief Executive Officer of Galapagos. “With our cash position and revenue streams from both BioFocus DPI and our pharma alliances, we are in a good financial position to enter into this alliance to create value for our shareholders.”
“This alliance represents a major step in our efforts to gain access to novel antibody targets for proprietary drug development in disease areas with a high unmet medical need. The partnership with Galapagos combines both the scientific and financial strength of two leading companies in their space,” said Dr. Simon Moroney, Chief Executive Officer of MorphoSys. “We are excited to combine our broad antibody expertise with Galapagos’ target discovery capabilities and disease know-how to form a successful partnership. The access to novel disease-related target molecules from a renowned partner accelerates the expansion of our proprietary antibody pipeline. This alliance also complements our development efforts in the field of inflammation and arthritis includingour lead program MOR103.”
With this strategic alliance, MorphoSys gains access to a proven target discovery engine as well as to Galapagos’ expertise in bone and joint disease, to support its therapeutic antibody pipeline expansion. The threemain indications of bone and joint disease – rheumatoid arthritis,osteoporosis and osteoarthritis – all represent very significant marketopportunities with several million people affected worldwide and combinedsales of drug treatments of more than US$ 15 billion in 2006.
Through the alliance with MorphoSys, Galapagos enters the rapidly growingmarket for therapeutic antibodies. In 2007, total sales for the 20antibody drugs on the market amounted to more than US$ 25 billion andantibody sales are forecast to increase to approximately US$ 50 billion in 2013. Fully human antibodies are recognized as the next generation and the majority of therapeutic antibodies currently in development are humanized or fully human. The average industry timescale from discovery to pre-clinical development of antibody therapies is only two to three years, considerably shorter than the average six years for small molecules.Antibodies also incur lower attrition rates than small molecules.
Galapagos and MorphoSys will conduct a conference call and live audio webcast today at 02:00 p.m. CET (8:00 a.m EST) to provide detailed information on the alliance.Dial-in number for the Conference Call (listen-only):Germany & U.K. residents: +32 2 401 53 06For U.S. residents: +1 866 931 1567 Please dial in 10 minutes before the beginning of the conference.Approximately two hours after the press conference, the archived webcast will be available for replay of the conference on http://www.morphosys.comand http://www.glpg.com.
For further information please contact: Dr. Claudia Gutjahr-Löser, Head ofCorporate Communications & Investor Relations, Tel: +49 (0) 89 / 899 27-122, gutjahr-loeser@morphosys.com or Mario Brkulj, Manager CorporateCommunications & Investor Relations, Tel: +49 (0) 89 / 899 27-454,brkulj@morphosys.com
About Galapagos:
Galapagos (Euronext Brussels: GLPG; Euronext Amsterdam: GLPGA; OTC: GLPYY)is a drug discovery company with pre-clinical programs in bone and jointdiseases and bone metastasis. Its BioFocus DPI division offers a fullsuite of target-to-drug discovery products and services to pharmaceuticaland biotech companies, encompassing target discovery and validation,screening and drug discovery through to delivery of pre-clinicalcandidates. BioFocus DPI also provides adenoviral reagents for rapididentification and validation of novel drug targets, compound libraries fordrug screening as well as chemogenomics and ADMET database products toselect targets and compounds. Galapagos currently employs about 450 peopleand operates facilities in six countries, with global headquarters inMechelen, Belgium. More information about Galapagos and BioFocus DPI canbe found at www.glpg.com and www.biofocusdpi.com.
About Galapagos’ target discovery technology:
Galapagos’ target discovery engine is based on adenoviruses thatefficiently introduce human gene sequences into a wide variety of humancells to knock-down specific proteins. High-throughput assays thatrepresent a selected human disease state are then used to functionallyselect for those proteins that have a causative effect in those models ofhuman disease. After rigorous validation of these protein targets, theyform the basis for the development of novel drugs.
About MorphoSys:
MorphoSys is a publicly traded biotechnology company focused on thegeneration of fully human antibodies as a means to discover and developinnovative antibody-based drugs against life-threatening diseases.MorphoSys’s goal is to establish HuCAL as the technology of choice forantibody generation in research, diagnostics and therapeutic applications.The Company currently has therapeutic and research alliances with themajority of the world’s largest pharmaceutical companies includingBoehringer Ingelheim, Centocor/Johnson & Johnson, Novartis, Pfizer andRoche. Within these partnerships, more than 50 therapeutic antibodyprograms are ongoing in which MorphoSys participates through exclusivelicense and milestones payments as well as royalties on any end products.Additionally, MorphoSys is active in the antibody research market throughits AbD Serotec business unit. The business unit has operations in Germany(Munich), the U.S. (Raleigh, NC) and U.K. (Oxford). For further informationplease visit http://www.morphosys.com/
HuCAL® and HuCAL GOLD® are registered trademarks of MorphoSys AG
Main Menu
- Home
- About Bioscreening.net
- Glossary
- Biotechnology Glossary A-I
- Biotechnology Glossary J-Q
- Biotechnology Glossary R-Z
- Bird Flu
- Cheminformatic Glossary
- Endotoxins
- Fullerenes
- Genipin
- Gossypol (Gossipol)
- Grants, Venture Capital, and Government Funding
- High-throughput screening
- Lipinski Rule-of-Five
- Mumie
- Natural Medicine
- Rule-of-Three (Ro3)
- Targeted Libraries
- Web Directory