Considerable research in the field of immunotherapy for melanoma has demonstrated that this tumor type can be responsive to therapeutic immune activation strategies. In early clinical trials, vaccine strategies using dendritic cells (DCs) and adenovirus (Ad) vectors (AdVs) were safe and immunogenic, and induced clinical responses in a minority of patients. Research from the past several years has yielded an improved mechanistic understanding of DC biology, AdV effects on DCs and the crosstalk that occurs between antigen-loaded DCs and specific lymphocyte subsets. This knowledge base is being combined with technological advances in cytokine delivery, AdV design and in vivo DC targeting. These developments are leading to novel AdV-transduced DC-based therapeutic modalities that may further advance melanoma immunotherapy. Interactions between AdVs and DCs, initial clinical trial results, and new developments in DC engineering and in AdV biology are reviewed.
The use of MRI-based imaging in drug development has received increased interest recently because of the difficulties associated with the development of CNS pharmacotherapies. While not yet routine, there have been significant advances in imaging that allow this technology to be used for evaluating disease state and drug effects. For disease states, both single and longitudinal studies of non-invasive measures may be obtained to provide a read-out of disease processes and, potentially, to predict the disease state and its evolution. In addition, imaging has enabled the development of improved preclinical disease models based on changes in brain circuitry. Pharmacological MRI, the imaging-based evaluation of drug effects, includes measures of direct effects on the brain, as well as the effects of chronic dosing on brain changes and neurochemical changes associated with these brain effects using magnetic resonance spectroscopy. Thus, imaging may become an integrated process in drug development, during both the preclinical and clinical stages. However, validation, the implementation of good clinical practices and regulatory acceptance are hurdles that remain to be overcome.
Oralair Birch is a dissolving tablet being developed for sublingual immunotherapy (SLIT) of allergic rhinitis caused by birch pollen allergy. Oralair Birch is being developed by Stallergenes SA and Canadian licensee Paladin Labs Inc. Oralair Birch is a recombinant protein that is synthesized from the DNA coding region of Bet v 1a, the major birch pollen allergen. During preclinical characterization, Oralair Birch had comparable structural and biological properties to the natural Bet v 1 allergen. However, Oralair Birch was more homologous than the natural Bet v 1 allergen, making a greater level of quality control possible. The administration of SLIT in tablet formulation provides a more uniform dose compared with liquid drops and better local application, which might enhance local uptake into dendritic cells of the sublingual submucosa and efficacy. Using skin prick testing, the performance of recombinant Bet v 1 was comparable to the natural Bet v 1 allergen. The results of a dose-finding phase IIb/III clinical trial of Oralair Birch were positive, with the primary endpoint met by all three tested doses. A confirmatory phase III trial was planned for 2011. Oralair Birch is a very promising treatment option for patients with birch pollen allergic rhinitis.
Advances in immunology and genetics have identified new therapeutic targets to control inflammation and symptoms in patients with inflammatory bowel diseases (IBD). Despite the success of anti-TNF therapies in the treatment of IBD, a considerable proportion of patients are refractory to treatment, highlighting an unmet medical need for new therapies. Molecules that direct the trafficking of inflammatory cells, such as the α4β7 integrin, are attractive targets for new drug candidates. The α4β7 integrin is involved in lymphocyte recruitment to the normal and inflamed gut mucosa, and the lymphoid tissue. The pan-α4 integrin neutralizing mAb, natalizumab, is not gut-selective but has demonstrated efficacy in IBD. However, treatment was associated with the occurrence of progressive multifocal leukoencephalopathy, which has limited its use, especially in Europe. Vedolizumab (MNL-0002), Millennium Pharmaceutical's gut-specific, α4β7 integrin-neutralizing mAb, does not affect peripheral blood cell counts and appears to lack systemic effects. Data from phase II clinical trials of vedolizumab demonstrated efficacy with an attractive safety profile, especially in ulcerative colitis. Large phase III, multicenter trials in both ulcerative colitis and Crohn's disease will provide valuable data for the ongoing development of vedolizumab, which might evolve as a new anti-inflammatory treatment option for the management of therapy-refractory patients.
Drug addiction is a chronically relapsing disorder that is characterized by a compulsion to take drugs and loss of control in limiting intake. Medications that are on the market for the treatment of drug addiction target either the direct reinforcing effects of abuse (eg, naltrexone) or the consequent protracted abstinence syndrome (eg, acamprosate). Both conceptual and neurobiological advances in research have suggested that brain stress systems contribute to the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle that promote the compulsivity of drug-taking in addiction. Validated animal models of the stress component of addiction and improved understanding of the neurocircuitry and neuropharmacological mechanisms involved in perturbations of this component suggest that corticotropin-releasing factor systems are a viable target for the development of future medications for drug addiction.
The scarcity of new innovative drugs in the development pipeline for combating HIV replication may signal a change in direction for HIV researchers and drug developers. The model of introducing drugs with incremental improvements within existing drug classes is no longer commercially viable. While an argument can be made that drugs aimed at novel targets may have a greater impact, the list of such targets is limited and the scientific challenge of intervening at another stage in the HIV replication cycle is high. It is difficult to envision a realistic risk/reward scenario that will ensure continued investment in the discovery of novel HIV drugs that simply block replication and suppress plasma viral load. Recently, it has been suggested that the scientific community should move research in a new direction, with the goal of attacking the reservoirs of latent HIV that persist despite treatment with current drugs to achieve a functional cure, if not a sterilizing cure. This process will have to be a long-term commitment, primarily funded by the NIH, with some involvement by the pharmaceutical and biotechnology industries. While most individuals infected with HIV can achieve viral suppression with the current approved therapies, treatment is lifelong, side effects are significant and resistance will eventually render more of these drugs less effective. New and innovative approaches must be developed to prevent viral infection and further improve the quality of life for those individuals who are already infected.
Accumulating evidence suggests that vitamin D deficiency is associated with cardiovascular disease, and that vitamin D therapy may have significant mortality and morbidity benefits in the treatment of congestive heart failure. However, the potential protective role of vitamin D in the heart, as well as the mechanism of action of the hormone in this organ, are poorly understood. In this review, the potential mechanisms of action of vitamin D in cardiac dysfunction are discussed, and the experimental and clinical findings that provide evidence for a role of vitamin D in the treatment of cardiovascular diseases are reviewed.Accumulating evidence suggests that vitamin D deficiency is associated with cardiovascular disease, and that vitamin D therapy may have significant mortality and morbidity benefits in the treatment of congestive heart failure. However, the potential protective role of vitamin D in the heart, as well as the mechanism of action of the hormone in this organ, are poorly understood. In this review, the potential mechanisms of action of vitamin D in cardiac dysfunction are discussed, and the experimental and clinical findings that provide evidence for a role of vitamin D in the treatment of cardiovascular diseases are reviewed.
The treatment of thyroid cancer is evolving. The molecular mechanisms of carcinogenesis for many thyroid cancers have been investigated, and have yielded targets for potential therapies. These targets include VEGFR in the treatment of all thyroid cancers, BRAF in the treatment of papillary thyroid cancer, and RET in the treatment of medullary thyroid cancer (MTC). Many promising drugs that target one or more of these proteins are currently being evaluated, including sorafenib and sunitinib, both of which are still under development for the treatment of thyroid cancer but which have been approved for use in other malignancies. In addition, compounds such as vandetanib (AstraZeneca plc) and XL-184 (Bristol-Myers Squibb Co/Exelixis Inc) have demonstrated activity in early-phase clinical trials of MTC and are being tested further in randomized trials.
Apelin is a peptide that has been identified as the endogenous ligand for the receptor APJ. The apelin/APJ system may be an important factor in the regulation of vascular tone and cardiovascular function. Studies on cultured cells and small animal models have revealed that apelin and APJ are localized in cardiomyocytes and vascular cells. The infusion of apelin affects vascular tone and blood pressure, with both central and peripheral actions. In clinical conditions such as heart failure and atherosclerosis, the gene expression of APJ and apelin, as well as the levels of circulating apelin, may be altered. The only known active homolog of ACE, ACE2, hydrolyzes apelin with similar potency to angiotensin II and, therefore, is responsible for the degradation of both peptides. Emerging data on a potential interaction between the two pathways suggest that the function of apelin/APJ in the vasculature may be relevant to cardiovascular disease, and identifying how this system is regulated could be useful clinically.
Recent studies have demonstrated a role for appetite- and volume-regulating neuropeptides in alcohol dependence, particularly in association with alcohol craving. The peptides leptin, ghrelin, adiponectin, vasopressin and the atrial natriuretic peptide (ANP) have been of particular interest because of their central effects on various brain circuits, including the hypothalamic-pituitary-adrenocortical (HPA) axis. In addition, pro-opiomelanocortin (POMC) plays an important role in linking appetite regulation with the HPA axis. Recent research has also demonstrated that the expression of these peptides in alcohol dependence is, at least partially, regulated by genetic and epigenetic mechanisms. These peptides and their associated circuits provide an intriguing new field for future pharmacological approaches for treating depression, anxiety and, potentially, addictive disorders such as alcohol dependence.
Comparative effectiveness studies of medications or, more appropriately, studies comparing the safety and efficacy of drugs have been conducted for decades, particularly for cancer chemotherapy. Research oncologists can stratify individuals participating in studies using prognostic criteria based on tissue diagnosis and disease staging. Conversely, research cardiologists, in particular those evaluating drugs for atherosclerotic vascular disease, have had to stratify individuals using criteria based on the risk of having a vascular event (ie, coronary heart disease risk). During the past 20 years, new imaging techniques, such as coronary calcium scoring, that are able to screen asymptomatic populations for atherosclerosis have been developed. In the future, studies comparing drugs for cardiovascular disease should be based on the presence of disease, such as atherosclerosis, rather than on the risk of a vascular event.
Oxyntomodulin, a product of the proglucagon gene, is released from the enteroendocrine L-cells of the gastrointestinal tract after the digestion of food, and acts via glucagon-like peptide 1 receptors in the arcuate nucleus to induce satiety. The administration of oxyntomodulin to animals and humans causes weight loss by reducing food intake in combination with increasing energy expenditure. Thus, the development of potent and long-acting analogs of oxyntomodulin is an exciting new therapeutic avenue for addressing the global obesity epidemic. This review discusses the role of oxyntomodulin in the physiological control of appetite, and presents the currently available evidence suggesting its potential as an obesity treatment.
Aprela, in development by Pfizer Inc, is a once-daily, orally administered, tissue-selective estrogen complex that contains the selective estrogen receptor modulator bazedoxifene (BZA) and conjugated equine estrogens (CE). Aprela was designed as an alternative to combination estrogen and progestin therapy to treat the vasomotor symptoms associated with menopause without the potential safety concerns associated with combination estrogen/progestin therapy, and with better tolerability. Both estrogens and BZA bind to estrogen receptors (ER)alpha and beta, but when BZA binds to an ER, the result may be an estrogen agonistic or antagonistic effect. In contrast, progestins antagonize the effects of estrogen in the uterus, but along with estrogen, stimulate breast tissue increasing the risk for breast cancer. In phase III clinical trials, Aprela significantly reduced the number and severity of vasomotor symptoms, reduced vaginal atrophy and increased bone mineral density. However, higher doses of BZA tended to attenuate these positive effects of CE. At the time of publication, there were no clinical data from women taking Aprela for > 2 years, and no definitive trials to determine the effects of Aprela on the risks for cardiovascular events, stroke, breast cancer, venous thromboembolism or cognitive function had been completed. Nevertheless, at the time of publication, Aprela was under consideration by the FDA for approval to treat vasomotor symptoms in postmenopausal women.
Current standard-of-care therapy for HCV infection, comprising a combination of IFNalpha and ribavirin (IFN/Rib), is ineffective in more than 50% of patients, and is associated with poor patient compliance and high cost. The recent development of an infectious culture system for HCV has allowed investigators to target the complete life cycle of the virus in an attempt to develop new, virus-specific drugs. Compounds specific for classical HCV targets, such as the viral protease and polymerase, have reached phase II/III clinical trials, and encouraging results have indicated that these virus-specific compounds may complement and eventually replace therapy with IFN/Rib. However, the variable nature of HCV (quasispecies and genotype variation) and the limited number of compounds developed thus far have prompted research aimed at expanding the repertoire of available targets, resulting in processes such as virus assembly being targeted therapeutically. The viral ion channel p7 is critical for the release of HCV virions, and the sensitivity of this channel to small-molecule inhibitors renders p7 a promising target for novel therapies. Small-molecule p7 inhibitors, although at an early stage of development, block virion production in culture effectively, and limited clinical data, although controversial because of the variable antiviral effects observed, suggest that p7 inhibitors could represent effective additions to combination therapies with other virus-specific drugs.
Diabetic kidney disease, or diabetic nephropathy, is the leading cause of kidney failure in developed countries and is projected to place an increasingly heavy burden on medical, social and economic systems worldwide. Existing therapies can slow, but do not stop, disease progression. Recent data from preclinical models and patients with diabetes emphasize the need for reducing excess metabolic flux through aldose reductase, an enzyme that plays a critical role in transducing the metabolic abnormalities that cause fibrosis in the diabetic kidney. The background and developmental history of aldose reductase inhibitors are reviewed briefly, as are metabolic, hemodynamic and genetic data linking aldose reductase to diabetic kidney disease. A new paradigm defining the pathogenic role of aldose reductase, the 'metabolic flux hypothesis', is presented, along with updated pharmacological goals for achieving success with this class of inhibitors in diabetic kidney disease.
Since the development of the first vaccines, modern medicine has been consistently aiming to improve the efficacy of immune responses. Traditionally, adjuvants have been used as non-specific immune modulators to enhance recognition and activation against a desired antigen. By providing 'danger' signals to the immune system, adjuvants activate innate immunity, which enhances the development of protective and therapeutic adaptive immune responses. The newest class of immune modulators bypasses the innate response and targets cells of the adaptive response directly. Targeted immunomodulatory therapy is focused primarily on the activation of costimulatory receptors (eg, 4-1BB, OX40 and GITR [glucocorticoid-induced TNF receptor-related gene]) or the blockade of co-inhibitory receptors (eg, CTLA-4, PD-1 and PD-L1) on T-cells during activation and/or effector responses. With promising clinical results obtained to date, immunomodulatory therapy is becoming an integral part of immunotherapeutic approaches. The modulation of GITR is listed as one of the top 25 most promising research areas by the NCI, and has demonstrated potential in both antitumor and vaccine settings. This review discusses the role of GITR as a potential target for immunomodulatory therapy, as well as the research involved in understanding the mechanisms of anti-GITR therapy and current progress in translation into the clinic.
The response to the first influenza pandemic of the 21st century benefited from the extensive preparation for an avian influenza pandemic and the mild nature of the 2009 A/H1N1 swine influenza virus. However, the pandemic demonstrated the limited ability to predict influenza pandemics, to anticipate levels of cross-protection, and to deliver vaccines in a timely manner, particularly to low income countries. The lessons learned from the 2009 H1N1 pandemic are of paramount importance to develop more effective preparations against future pandemics.
Systemic lupus erythematosus (SLE) is an autoimmune disease that is associated with the production of autoantibodies, and with considerable morbidity and mortality. There has been much interest in developing more specific therapies for this disease, which is currently managed with immunosuppressive drugs, predominantly corticosteroids, azathioprine, methotrexate and cyclophosphamide, in combination with hydroxychloroquine. Mycophenolate mofetil has been demonstrated to be as efficacious as cyclophosphamide in patients with lupus nephritis, and is being used increasingly in the clinic despite not being licensed for this indication. Novel methods of reducing autoantibody formation in SLE include the use of mAbs that modulate and/or deplete B-cells (anti-CD22 and anti-CD20 antibodies, respectively), or that interfere with the stimulatory effects of the soluble factor B-lymphocyte stimulator (anti-BLys antibodies). Alternative approaches include the use of atacicept (Merck Serono), a transmembrane activator and calcium modulator ligand interactor (TACI)-Ig fusion protein, which inhibits B-cell stimulation by binding to BLys and a profileration-inducing ligand (APRIL), or toleragens such as abetimus. Blocking costimulatory molecule interactions, such as the CD40-CD40 ligand interaction with mAbs and the CD28-B7 interaction with a soluble cytotoxic T-lymphocyte antigen 4 (CTLA-4)-IgG1 construct (abatacept), has also been attempted as a therapeutic strategy for SLE. The most promising strategy for a new drug for SLE is belimumab (Human Genome Sciences/GlaxoSmithKline), an anti-BLys antibody, as two phase III clinical trials with this drug recently met their primary endpoints. In this review, these novel approaches to the treatment of SLE, including the potential of targeting cytokine pathways involved in autoimmunity, are discussed.
HMG-CoA reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in the plasma. Statins are substrates for several membrane transporters that may mediate drug interactions. Inhibitors of the organic anion transporting polypeptide 1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Potent inhibitors of cytochrome P450 (CYP)3A4 can significantly increase the plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin, rosuvastatin and pitavastatin are not susceptible to any CYP inhibition. An understanding of the mechanisms of statin interactions will help to minimize drug interactions and to develop statins that are less prone to adverse interactions.
