Karen Honey

Microbicide trial screeches to a halt.

A phase III clinical trial to test the effectiveness of the HIV microbicide Ushercell was recently stopped because interim analysis indicated that the rate of infection with HIV in women using the microbicide was higher than the rate of infection in those using the placebo. Ushercell, which was being developed by the nonprofit reproductive health organization CONRAD, is a cellulose sulfate compound that blocks viral entry into the cell. Its inhibitory function is thought to be due to the fact that it is polyanionic and can interfere with the charged interaction between positive charges on the viral envelope and negative charges on the cell surface. The women who enrolled in the double-blinded randomized trial, which was being conducted in India, Uganda, Benin, and South Africa, were randomly assigned to use either Ushercell, which comes in gel form and is inserted vaginally up to one hour before intercourse, or a placebo gel. The trial was halted when the independent group of experts analyzing the interim data noted a higher rate of HIV infection in women using Ushercell than in women using the placebo. The interim results of the trial came as a shock to researchers in the field, including those conducting the study, such as Lut Van Damme, who led the trial and told the JCI, “We are extremely disappointed by the results of the trial and were very surprised by the increased risk of becoming infected with HIV.” Much of the surprise about the trial results arose because no safety concerns had been noted in the 11 previously completed safety and contraceptive trials of Ushercell involving more than 500 patients in Africa, India, Belgium, and the United States. This lack of prior indication that Ushercell use might raise safety issues contrasts with the case of the detergent nonoxynol-9, another microbicide that failed in clinical trials because it increased the rate of infection with HIV. Going into the clinical trials, nonoxynol-9 was known to create lesions in the mucosal lining of the vagina; ultimately these lesions were shown to result in the increased rate of HIV infection. By contrast, no data regarding Ushercell even hinted that its use might present problems. Although researchers involved in the trial currently have no idea why Ushercell increased the rate of infection with HIV, CONRAD is determined to establish why this happened. One of the ways in which they are hoping to address this issue is to “put together a blinded panel of compounds, including cellulose sulfate, and send it out to various individuals working on different models and see if they can come up with any clues,” according to Henry Gabelnick, CONRAD’s executive director (1). Van Damme added that they “hope to learn from the experience and perhaps understand how preclinical models differ from the clinical situation.” In the view of Michael Lederman, an expert in HIV microbicide research at Case Western Reserve University, the fact that “they are clearly committed to learning as much as possible about why cellulose sulfate failed or was harmful will only help the field.” Other researchers are concerned about the impact that the failure of this trial will have on the development of other microbicides, the most advanced of which are Carraguard (Population Council) and PRO 2000 (Indevus Pharmaceuticals), both polyanionic microbicides in phase III clinical trials. The trial with Carraguard was completed at the end of March 2007, and although the results will not be available until the end of 2007 at the earliest, the independent group of experts monitoring the interim results of the trial has not noted any safety issues. Despite the assumption that Carraguard and PRO 2000 will be safe, some researchers are asking whether the microbicides currently being tested in clinical trials are the best ones; many are favoring a move to a more specific approach, such as the topical application of antiviral drugs (2). Indeed, as Lederman told the JCI, “The good news is that there are microbicide candidates in the pipeline that target critical viral or host elements and there is reason to be more optimistic about their chances for success.” Another criticism of the current approach to developing microbicides is that the process is not streamlined enough: experts have questioned whether 3 polyanionic microbicides needed to be tested in phase III clinical trials or whether the best candidate should have been singled out at an earlier stage of development (1). However, others, such as Gabelnick, counter that, “We don’t know enough to say these [drugs that target HIV in the same way] are all the same” (1). The one thing that researchers do agree on is the need for an effective microbicide, as women in Sub-Saharan Africa and elsewhere are more likely than men to become infected with HIV, and many social issues in these regions do not allow them to easily protect themselves from infection.

The comeback kid: TYSABRI now FDA approved for Crohn disease

The US FDA recently approved the monoclonal antibody TYSABRI (natalizumab) for use in the treatment of adults with moderately to severely active Crohn disease (CD) who do not respond to, or do not tolerate, conventional therapies for CD and inhibitors of TNF-α. This represents a comeback for a drug that was temporarily pulled from the market in February 2005. TYSABRI is a monoclonal antibody specific for the α4 integrin that pairs with either the β1 integrin or β7 integrin to form α4β1 (also known as VLA4) and α4β7, respectively. These integrin heterodimers are expressed by distinct subsets of T cells, and binding of α4β1 and α4β7 to their respective ligands is important for directing T cell migration to different tissues. Interactions between α4β7 and MAdCAM-1 direct T cells to the intestine, both under steady-state conditions and during inflammation, whereas interactions between α4β7 and VCAM-1 are important for directing T cells to the inflamed CNS. Given its specificity for the α4 integrin, TYSABRI blocks T cell homing to the intestine and the inflamed CNS. Two randomized, placebo-controlled phase III clinical trials indicated that TYSABRI markedly reduced the number of relapses in individuals with MS (1). The results were so promising that the FDA approved TYSABRI for the treatment of individuals with relapsing forms of MS in November 2004, only halfway through the phase III clinical trials. However, Elan Corp. and Biogen Idec, the manufacturers of TYSABRI, pulled the drug from the market and halted all ongoing clinical trials only 3 months later, after two patients developed progressive multifocal leukoencephalopathy (PML) — a demyelinating brain disorder caused by a polyomavirus known as the JC virus. Although one patient was successfully treated for the disorder (2), the other died. An additional fatal case of PML was uncovered when the data from one of the halted clinical trials, which had been assessing the efficacy of TYSABRI as a treatment for CD, was retrospectively reviewed (3). A review of the data from all clinical trials (i.e., the completed and halted trials assessing the efficacy of TYSABRI in patients with MS as well as the halted trials assessing the efficacy of the drug in patients with CD) revealed no more cases of PML. The FDA therefore reapproved the use of TYSABRI to treat individuals with relapsing forms of MS in June 2005 (4). However, because the two affected patients with MS were also being treated with IFN-β and the affected patient with CD had a history of being treated with immunosuppressive drugs, the FDA restricted the use of TYSABRI such that even today, it can only be given to individuals with relapsing forms of MS who have not responded adequately to, or cannot tolerate, other treatments for MS, and it must be given as a monotherapy. Furthermore, TYSABRI remains available in the US only through a risk management program developed by the manufacturers of TYSABRI in conjunction with the FDA known as the TOUCH (TYSABRI Outreach: Unified Commitment to Health) prescribing program. In the European Union, where TYSABRI was approved for the treatment of individuals with relapsing forms of MS in June 2006, there is no restrictive prescribing program. The TOUCH prescribing program facilitates the appropriate use of TYSABRI and ensures that patients are monitored very closely for any new sign or symptom suggestive of PML. Under the program, TYSABRI can only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program. Furthermore, patients receiving the drug must be educated about the risks and benefits of TYSABRI and enrolled in the TOUCH prescribing program. Through the TOUCH prescribing program, more than 12,000 individuals with MS are being treated with TYSABRI. A similar CD-TOUCH prescribing program will be the only way that individuals with CD who fit all the criteria for receiving treatment with TYSABRI can receive the drug. Implementing this restricted distribution program for the network of physicians, nurses, and patients with CD has meant that although the drug is already FDA approved, as the JCI went to press, Elan Corp. and Biogen Idec anticipated that TYSABRI was likely to be available to individuals with CD only by the end of February 2008 (5). It is estimated that there are 500,000 individuals in the US with CD, a substantial proportion of whom either fail or cannot tolerate current therapies. In clinical trials, TYSABRI has been shown to induce and maintain disease remission in individuals with moderate to severe CD for longer than two years (6 ). Therefore, as Stephen Hanauer, chief of the Section of Gastroenterology at the University of Chicago, said, “The FDA’s approval of TYSABRI is an important step forward in the treatment of Crohn’s disease,” because, as he explained, “The unique mechanism of action of TYSABRI affords us a new class of therapy in our fight against this debilitating disease” (5 ).

Drug designed to raise HDL levels falls down

On December 2, 2006, Pfizer halted the development of torcetrapib, the drug that was once considered by the company and pharmaceutical analysts as the most promising drug in its pipeline. The development of torcetrapib as a treatment for heart disease was brought to an end because preliminary data from a 15,000-patient phase III clinical trial indicated that individuals receiving the drug had higher risks of death and heart failure than did individuals not receiving the drug. The trial was organized such that 7,500 patients taking torcetrapib and the statin Lipitor (atorvastatin) were compared with 7,500 patients taking Lipitor alone. It was hoped that the drug combination would decrease the risk of coronary heart disease and stroke more than Lipitor alone. However, the independent panel of experts monitoring the trial noted that 82 patients receiving the drug combination had died compared with only 51 receiving Liptor alone and advised Pfizer to halt the trial, which it did immediately. The news came as a surprise to many people, including Jeffrey L. Kindler, the new chief executive officer of Pfizer, who only days earlier at a meeting for investors was quoted as saying, “This will be one of the most important compounds of our generation” (1). Similarly, Daniel J. Rader, a preventative cardiovascular specialist at the University of Pennsylvania who was senior author on the first published manuscript on torcetrapib, told the JCI, “Although there were legitimate questions about whether cholesterol ester transfer protein (CETP) inhibition with torcetrapib would substantially reduce atherosclerosis progression and cardiovascular events, I personally did not anticipate that the drug would result in increased cardiovascular events and mortality.” The reason that many people, such as Rader, had high hopes for torcetrapib is that it substantially increases levels of HDL, which is generally considered “good cholesterol,” and decreases levels of LDL, which is generally considered “bad cholesterol.” Low levels of HDL are associated with an increased risk of developing coronary heart disease, and so it had been hoped that combining torcetrapib with Lipitor, which mainly works (as all statins do) by decreasing LDL levels, would further decrease the risk of coronary heart disease and strokes. Torcetrapib, in development since 1990, works by inhibiting CETP, which transfers cholesterol esters from HDL to other lipoproteins. One early indication that developing such drugs would increase HDL levels and therefore be useful for treating coronary heart disease was the observation that humans with a defect in the gene encoding CETP have increased levels of HDL (2). However, a later study, published in the JCI, showed that despite an increase in HDL levels, Japanese-American men with a defect in CETP had an increased risk of coronary heart disease (3). Alan Tall at Columbia University, who was the senior author on both these studies (2, 3), told the JCI that despite the observation of increased risk of coronary heart disease in Japanese-American men with a defect in CETP (3), further genetic studies “showed no clear increase or decrease in coronary heart disease [linked to a defect in CETP].” It is currently unclear why torcetrapib had such a devastating effect, and the future development and utility of other CETP inhibitors depends on the answer to this question. One possibility lies in the observation that torcetrapib has been shown to actually increase systolic blood pressure. Other CETP inhibitors in development have not been reported to have this effect, so it might not be the end of the road for all CETP inhibitors. Additional possible explanations for the failure of torcetrapib include other potential off-target effects of torcetrapib, insufficient blockage of CETP function, and unwanted interactions between torcetrapib and Lipitor. It might also be that the strategy of increasing HDL levels per se is not enough, and some researchers believe that it is the function of HDL that needs to be improved rather than its levels (4). Indeed, some researchers are actively pursuing this as an approach to decrease the risk of individuals developing coronary heart disease. Whatever the reason for the failure of torcetrapib, coronary heart disease remains the number one killer in the United States, and as Tall remarked, “[Statins] have not solved the problem of coronary heart disease; we still need more research and to continue the development of new drugs to tackle this problem.” As for Pfizer, analysts believe that the loss of torcetrapib from its pipeline is a major blow to the company, which was hoping that the combination of torcetrapib and Lipitor would extend the life of Lipitor past the expiry of its patent protection in 2011. Despite this, and the upcoming loss of patent protection on other high-income drugs such as Viagra, Kindler told the New York Times that the company still expected to report higher profits in both 2007 and 2008, mainly due to cost cutting (5).

Translating medical science around the world.

Improving the translation of basic research into the clinic is fast becoming a priority not just in the US but also in Europe. In the US, one of the biggest initiatives to enhance translational research is sponsored by the NIH through its Clinical and Translational Science Awards (CTSAs). The first CTSAs were awarded to 12 institutions in October last year, a second series of recipients was, at press time, set to be announced in September this year, and applications for next year’s awards are soon to be evaluated. Funding is for a 5-year period, and a total of almost

Good bugs, bad bugs: learning what we can from the microorganisms that colonize our bodies

100 million was provided to the 12 institutions for the first year alone. The goal of CTSAs is to eliminate barriers between clinical and basic research, in part by assembling interdisciplinary teams covering the spectrum of research (1). At the University of Pennsylvania (Penn), Garret FitzGerald — professor of medicine and pharmacology, director of Penn’s Institute for Translational Medicine and Therapeutics (ITMAT), and principle investigator for Penn’s CTSA — told the JCI that “the CTSA award has enabled ITMAT to broaden its focus and become a transinstitutional and trans-school enterprise.” He says this is bringing together people from diverse disciplines, something he considers essential if academia is going to successfully reenter the drug discovery arena and safely translate basic science into therapeutics. FitzGerald is also in a position to assess the changes that are occurring in translational research on the other side of the Atlantic — he served last year, for example, on the panel that advised the National Institute for Health Research (NIHR) in the United Kingdom on where to establish their comprehensive Biomedical Research Centres (BRCs) (2, 3), a venture that he considers “very healthy for UK biomedicine,” and he is about to chair a review committee for the British Heart Foundation to establish interdisciplinary Centres of Excellence, again focused on translational enterprise. He told the JCI that these two approaches build on earlier Wellcome Trust initiatives to fund translational research and are an impressive step forward for biomedical research in the UK. Each BRC is a partnership between a university and a National Health Service (NHS) trust — a regional unit of the publicly funded health care system in the UK. Funding was provided to five comprehensive BRCs (three sited in London, one in Cambridge, and one in Oxford), which will cover a wide range of areas, and six specialist BRCs, which will work in very defined areas such as cancer, ophthalmology, and mental health. Funding began in April of this year and will provide more than Σ450 million (approximately

Tales from the gene pool: a genomic view of infectious disease

900 million) over the next five years. One big difference between the money provided to researchers in the US through CTSAs and that provided to researchers in the UK at the BRCs is that in the UK, the money cannot be used for preclinical studies; it must all be used for patient-based clinical research. As Graham Lord, professor of medicine and deputy director of the comprehensive BRC at King’s College London, noted to the JCI, “This provides a challenge to do something different.” As one of the five comprehensive BRCs, the partnership between King’s College and Guy’s and St. Thomas’ NHS Foundation Trust created a new Faculty of Translational Medicine to help them achieve the overall goal of the BRCs of improving patient care. Lord believes that creating the new faculty, which will be based on two floors of Guy’s and St. Thomas’ Hospital and colocated with new clinical research facilities, will provoke interactions among faculty members and others from different backgrounds (senior NHS clinicians, university academics, dentists, healthcare professionals, NHS managers, and patients) and that fostering such interactions is necessary to effect the cultural shift required to generate novel ideas and approaches to patient care. Although the five comprehensive BRCs competed against each other for UK funding, one of the requirements of the recipients is that they engage with each other to compete with clusters of biomedical research facilities around the world, such as the cluster found in Boston. To help achieve this, the UK government is creating a Global Medical Excellence Cluster, which will foster interactions among the five centers that were awarded comprehensive BRC status as well as between these centers and biotechnology and pharmaceutical companies (4). Other countries in Europe are also developing strategies to improve translational research (5). For example, the Center for Drug Research, Development, and Safety (ZAFES) in Germany was founded at the Johann Wolfgang Goethe University in Frankfurt am Main in 2002 as a center of excellence intended to more rapidly develop innovative drugs by combining insights from academia, the pharmaceutical industry, and biotechnology. FitzGerald pointed out to the JCI that one of the current limitations is human capital and that attracting the best clinicians and scientists of the future might be difficult until the community comes up with a unifying, global tag for this type of research and training (6). Unfortunately, coming up with a name is only one of many challenges facing the translation of basic research into the clinic.

HIV vaccine trial no longer PAVEs the way

The NIH recently announced the first recipients of funding for its Human Microbiome Project. The number of microorganisms that live inside or on the body of a healthy adult human is thought to be least 10 times greater than the number of human somatic and germ cells (Figure ​(Figure1).1). Some of these microorganisms are beneficial to the human host (e.g., some bacteria in the intestines break down carbohydrates that humans would otherwise not be able to digest), and some can cause illness (e.g., Streptococcus pneumoniae, which can be found in the nasopharynx of healthy individuals but causes disease if it colonizes other parts of the body, such as the lungs, where it causes pneumonia). However, the effects on human health of most of these microorganisms are not known; as Martin Blaser, Professor of Medicine and Microbiology at New York University School of Medicine, told the JCI, “We need to know who these microorganisms are and what they do.” In an attempt to answer these questions and increase our understanding of how these microorganisms influence human health and disease, the NIH launched the Human Microbiome Project at the end of 2007 (1). Figure 1 The genome of Lactobacillus acidophilus is part of the human microbiome, as L. acidophilus can be found in the mouth, intestines, and vagina. The human microbiome consists of all the genomes of all the microorganisms that live inside or on the body of a healthy adult human. The idea behind the Human Microbiome Project is to use metagenomic and traditional genome sequencing approaches, which enable the analysis of all the DNA of all the microbes recovered in an environmental sample and of single clonal microbial cultures, respectively, to determine whether individuals share a core human microbiome and to understand whether changes in the human microbiome correlate in any way with changes in human health. Other goals of the project include developing new technological and bioinformatic tools to address the central issues and determining the ethical, legal, and social effects of research into the human microbiome. The initial goal is to sequence 600 genomes from both cultured and uncultured bacteria as well as several nonbacterial microorganisms, focusing on the genomes of microorganisms in the digestive tract, mouth, skin, nose, and female urogenital tract. The aim of this goal is to provide researchers the background information to investigate the relationship between the microorganisms that contribute to the microbiome and human disease. Upon completion, the total number of microbial genomes sequenced will be raised to around 1,000, as some have already been completed, some are underway, and some will be sequenced as part of other projects that are already planned. An estimated

GINA: making it safe to know what’s in your genes

115 million will be distributed to researchers as part of the Human Microbiome Project over 5 years. Most of the recently announced initial round of funding, which will provide approximately

True dedication to clinical research: the Clinical Center of the National Institutes of Health receives the 2011 Mary Woodard Lasker Award for Public Service

21.2 million, is to support researchers developing innovative technologies — specifically technologies that should help improve and refine the way in which researchers identify the microorganisms that contribute to the microbiome — and computational tools. According to Alan Krensky, director of the Office of Portfolio Analysis and Strategic Initiatives, which oversees the NIH Roadmap for Medical Research, the NIH targeted initial funding in this area because “The development of new tools and technologies is central to our ability to meet the goals of the Human Microbiome Project. An exceptional amount of information will be generated by this project and we need robust technologies and analytical tools that are equal to the task” (2). The remainder of the money awarded in this round of funding is going toward establishing the Human Microbiome Project Data Analysis and Coordination Center and to researchers examining ethical, legal, and social implications of human microbiome research. The Data Analysis and Coordination Center will act as a repository for all the data generated by the Human Microbiome Project, which will also be deposited in other public databases, including those supported by the National Center for Biotechnology Information (3). The importance of the Human Microbiome Project was highlighted to the JCI by Blaser, who thinks that understanding how the microorganisms that contribute to the microbiome affect human health and disease is an area of research as exciting as stem cell research, with as much therapeutic potential. He continued that the microbiome is likely much more diverse than the human genome and that it changes over time as the microorganisms that colonize the human body change. By understanding these changes and taking a census of the microorganisms present under different conditions of health and disease, Blaser hopes that the Human Microbiome Project will lead to the identification of new drugs from microorganisms — just as drugs have been developed using botulinum toxin and cyclosporine A from the bacterium Clostridium botulinum and the fungus Tolypocladium inflatum Gams, respectively — and the use of approaches to manipulate the populating microorganisms to benefit human health; there is a “lot of potential” there, he says.

HPV vaccine gets a shot in the arm

Research into the pathogenesis, prevention, and control of infectious and parasitic diseases remains a global priority, as these scourges continue to be a substantial cause of mortality and morbidity. The plethora of molecular tools that are now readily available has facilitated a genome-wide approach to studying the pathogenesis of such diseases, with direct implications for disease prevention and treatment. The articles in this Review Series describe how genome-wide approaches have provided insight into a range of human pathogens, leading to greater understanding of the human diseases that they cause, and highlight some of the challenges that must be overcome if we are to maximize what we learn from the wealth of genomic information now available.