Filibuvir (PF-868554), being developed by Pfizer, is an orally administered, non-nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase for the potential treatment of chronic HCV infection. An estimated 180 million people worldwide are infected with HCV and at risk of developing chronic liver diseases that can lead to cirrhosis or hepatocellular carcinomas. HCV infection is the main cause of liver transplantation in industrialized nations. Filibuvir is a potent and specific inhibitor of the virally-encoded NS5B polymerase, and inhibited genotype 1 subgenomic HCV replication in the cell-based replicon system. Filibuvir demonstrated a good pharmacokinetic profile and oral bioavailability in preclinical animal studies, which is consistent with twice-daily dosing in humans. In phase I and a IIa clinical trial in treatment-naïve patients infected with genotype 1 HCV, filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin (the standard of care [SoC] for HCV infection) for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone. The incidence and severity of adverse events were similar to SoC and placebo. At the time of publication, phase I pharmacokinetic clinical trials were ongoing in healthy volunteers and a phase IIb clinical trial was assessing filibuvir in combination with SoC for up to 24 weeks in treatment-naïve patients infected with genotype 1 HCV. Results of this trial will help to characterize the potential of this drug class for the treatment of HCV infections.

Remimazolam (CNS-7056) is a short-acting GABA(A) receptor agonist, under development by PAION, in collaboration with Japanese licensee Ono Pharmaceutical, as an intravenous sedative agent for potential use in day-case procedures, and the induction and maintenance of anesthesia. A member of the benzodiazapene class of drugs, the structure of remimazolam was modified to produce a drug that displays organ-independent metabolism. The incorporation of a carboxylic ester moiety into the benzodiazapene core of remimazolam renders it susceptible to non-specific tissue esterases and it is rapidly metabolized into its pharmacologically inactive metabolite CNS-7054. Preclinical studies in sheep demonstrated that remimazolam produced a more rapid onset of action, and a shorter duration of action, compared with midazolam. In a phase IIa clinical trial evaluating remimazolam as a procedural sedative for upper gastrointestinal endoscopy in patients, the time to recovery from sedation was shorter and more consistent with remimazolam, relative to midazolam. Because of its organ-independent metabolism and rapid and predictable onset and recovery, remimazolam appears to have potential advantages over other currently available short-acting sedatives.

LX-1031, being developed by Lexicon Pharmaceuticals, is an oral, small-molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces 5-HT synthesis peripherally. LX-1031 is being developed for the potential treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), which is characterized by excess 5-HT. In preclinical studies, LX-1031 dose-dependently reduced expression of 5-HT in the duodenum, jejunum and ileum, but had no effect on brain 5-HT levels. In ascending single-dose and multiple-dose (14 day) phase I clinical trials in healthy volunteers, LX-1031 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA; a marker of 5-HT metabolism) levels, starting by day 5 and persisting over the duration of exposure. In a phase II clinical trial in patients with IBS-D, a 1000-mg qid dose of LX-1031 was associated with improved weekly global scores and stool consistency, and lower urinary 5-HIAA levels over a 28-day treatment period. LX-1031 was well tolerated in trials to date. In conclusion, LX-1031 appears promising for IBS-D. Optimal doses, efficacy in IBS clinical trials and safety need to be fully elucidated.

Dexpramipexole (KNS-760704), the R(+) enantiomer of pramipexole, is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. Pramipexole, exclusively the S(-) enantiomer, is a non-ergot dopaminergic autoreceptor agonist that is currently marketed for use in the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity. More recent work has suggested that pramipexole possesses anti-excitotoxic properties, raising the possibility of beneficial effects in patients with ALS. However, pramipexole has high intrinsic dopaminergic receptor activity and, consequently, dose-limiting side effects, including orthostatic hypotension and hallucination, are frequent. Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects. In clinical trials to date, dexpramipexole has been safe and well tolerated at doses up to 67-fold higher than the maximum recommended daily dose of pramipexole in patients with Parkinson's disease, and has demonstrated signs of neuroprotective benefit. This report summarizes the chemical and pharmacological properties of dexpramipexole and describes the potential utility of the drug in the pharmaceutical development pipeline.

Lu-AA21004, an oral, multimodal serotonergic agent, is currently under development by H Lundbeck and Takeda Pharmaceutical, for the potential treatment of depression and anxiety. Lu-AA21004 belongs to a novel chemical class of antidepressant agents, the bisarylsulfanyl amines, and possesses a novel pharmacological profile, with activity at serotonergic receptors 5-HT3, 5-HT7 and 5-HT1A, and also at the 5-HT transporter. Acute administration of Lu-AA21004 in rats inhibited the firing activity of serotonergic neurons of the dorsal raphe nucleus through 5-HT3 receptor blockade, with rapid recovery of firing activity upon cessation of treatment compared with an antidepressant of the SSRI class. Results from phase II clinical trials have reported improvement in depression and anxiety symptoms after 6 weeks of treatment. Lu-AA21004 was generally well tolerated, with adverse events related to sexual dysfunction occurring in a lower number of patients receiving Lu-AA21004 compared with venlafaxine. Phase III clinical trials with Lu-AA21004 in patients with major depressive disorder are underway and phase III trials in patients with generalized anxiety disorder have been completed. If initial outcomes from these clinical trials prove positive, Lu-AA21004 may pave the way for new multimodal therapies for the treatment of depression and anxiety.

Florbetapir (18F), being developed by Avid Radiopharmaceuticals, is an 18F-labeled PET tracer binding to amyloid-β (Aβ) plaques for the potential detection of Alzheimer's disease (AD). Preclinical studies indicated high binding affinity of florbetapir (18F) to Aβ fibrils and specific labeling of Aβ plaques in the cortical regions and hippocampus. In phase I and II clinical trials, florbetapir (18F) clearly differentiated patients with AD from healthy controls and uptake was most prominent in the precuneus. The neocortical-to-cerebellar tracer uptake ratio reached a plateau within 50 min post-injection and high-quality images were acquired with 5 to 10 min image acquisition time with 370 MBq of florbetapir (18F). Results from an ongoing phase III clinical trial confirmed a strong correlation between florbetapir (18F) PET images and postmortem assessment of Aβ deposition. No serious adverse events were reported in any of the clinical trials of florbetapir (18F). At the time of publication, a marketing application for florbetapir (18F) had been submitted to the US FDA. The fast kinetics and strong evidences of radiological-pathological correlation are advantages of florbetapir (18F) over other 18F-labeled amyloid PET tracers. This tracer has a potential to serve as an agent for preclinical detection of AD-related pathology in the large elderly population.

This feature article discusses the basic principles of patentability as related to vaccine research, and outlines recent cases in the US and EU in which vaccine patents have been considered. Issues regarding eligibility for supplementary protection, as currently being considered by the Court of Justice of the EU, are also outlined, as well as the implications of such issues in protecting future vaccine research.

Flaviviruses comprise a diverse family of viruses that are cumulatively responsible for hundreds of millions of cases of infection annually. The Flavivirus genus includes both insect-vectored viruses, such as yellow fever and dengue, and non-vectored viruses such as HCV; the viruses have a broad range of disease presentation and geographic distribution. No specific antiviral therapies are currently available for the diseases caused by insect-vectored flaviviruses. Thus, efforts have been focused on the prevention of disease, through either vaccination or vector control, rather than on the treatment of infected individuals. While vector control can occasionally be successful in controlling the spread of flavivirus outbreaks, vaccines appear to be a more cost-effective, sustainable, and environmentally friendly approach. A review of vaccines for the medically important flaviviruses presents the full spectrum of vaccine options and complexity levels, and provides examples of successes and major challenges. The insect-borne flavivirus vaccine field is dynamic, with new and improved vaccines being advanced to replace existing vaccines, and novel vaccine approaches being developed for those targets that currently lack an approved vaccine. Advances in scientific knowledge and in the application of new technologies are helping to overcome some of the key challenges that have stymied the field for decades. New, safe and effective vaccines to protect against yellow fever, Japanese encephalitis, tick-borne encephalitis, West Nile and dengue viruses will likely result.

Key methodologies such as HTS and combinatorial chemistry have allowed pharmaceutical discovery to focus on identifying promising drug candidates through the use of statistics. Thus, amassing large data sets from large-scale screening campaigns of ever-increasing corporate compound collections was expected to deliver unprecedented success for the pharmaceutical industry. This feature review explores aspects of how the reliance on using numbers to drive discovery has gone awry. Building knowledge equity from the integration of multiple parallel screening assays, workstreams and data sources provides an alternative to driving discovery through statistics. Thus, a more rational approach to creating and inventing new leads and drug opportunities may be pursued.

Rising expenditure in pharmaceutical R&D has not been matched by increased productivity. There is an urgent need to solve the current high levels of pipeline attrition. Changing the current failed model of drug discovery and development, in which high numbers of candidate drugs are produced and high attrition is accepted, is essential. A different model is needed, in which the focus shifts to identifying better-quality candidate drugs that allow scientifically robust testing of disease and targets in humans. Lowering the risks of compound-based attrition in small-molecule drug discovery and development (ie, addressing toxicity, specificity, potency, duration and exposure) is achievable by improved control of physical properties and by setting more demanding candidate criteria. Separating the key scientific experiment--proof-of-concept clinical trials in humans--from commercial development imperatives is a necessary step for the industry.

The application of chemical proteomics to new target discovery can lead to a rapid understanding of disease mechanism and new therapeutic methods. Successful application includes a thorough understanding of SAR and the validation of target relevance using multiple genetic and biochemical methods. This feature review highlights several successful applications of chemical proteomics and outlines the strategy and approaches that lead to the discovery of novel therapeutic targets.

Although the benefit of early ADME screening is widely recognized in the pharmaceutical industry, the implementation of this paradigm is often performed with insufficient resources and poor collaboration between functions. Dedicated and consistent integration efforts of ADME knowledge during the lead generation (LG) phase of drug discovery enables informed resourcing decisions and also increases the quality of initial starting points for discovery projects. To facilitate the efficient and consistent application of ADME resources to early projects at Eli Lilly and Co, a team of scientists was formed to provide dedicated ADME support to the LG phase of the discovery portfolio. This feature review discusses the working construct of the team, the general philosophy that was employed, and the outcomes of this endeavor.

The search for an HIV vaccine began following the discovery of the virus more than 25 years ago. Despite important progress, an effective vaccine remains an elusive goal that will likely require many more years of R&D to achieve. Following recent advances in research, however, there has been increased optimism that a prophylactic HIV vaccine is feasible. A consensus is forming among researchers to support a larger role for proof-of-concept efficacy clinical trials, conducted in parallel with invigorated basic research efforts and testing in animal models, to accelerate the discovery of key principles that will guide rational vaccine development.

Recently, cellular mechanical properties have received increasing attention as a potential biophysical marker for cancer cells. The analysis of mechanical profiles at the single-cell level may provide information that is potentially useful to assess tumor prognosis and response to therapy. This feature review discusses a novel nanocytology approach that combines traditional morphology assessment, molecular analysis and nanomechanical analysis of cancer cells.

MicroRNAs (miRNAs) are 19- to 24-nucleotide, non-coding RNAs that have been implicated in both solid and hematological malignancies. Given the ability of miRNAs to target multiple genes and key biological processes, these molecules have received intensive research interest both as biomarkers and as therapeutic agents. The prospect of leveraging miRNAs to complement current therapeutic strategies in cancer is appealing, but is also complex. Simultaneously targeting multiple genes has both advantages and disadvantages for miRNA therapeutic delivery, and achieving target organ specificity while limiting off-target effects remains a major challenge in the translation of novel discoveries in research to the successful therapeutic delivery of miRNA in the clinic. This feature review discusses the current status of therapeutic approaches for miRNA in cancer, as well as potential challenges and future strategies.