Late-stage Compounds Research Articles

Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes

To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify “toxic” and “non-toxic” drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition.

Factors Related to Regulatory Approval of Late-Stage Development Compounds: Analysis of Japanese Pharmaceutical Company Activities, 1995-2007.

Japanese pharmaceutical companies invest resources in their internal research and development (R&D) activities and in-licensing activities especially from Western companies, for the local market. The objective of this research is to investigate the fate of late-stage compounds developed by them and to identify company profiles and compound characteristics that could relate to regulatory approvability. Using publicly available information for late-stage compounds that were developed by Japanese companies in 1995-2007, logistic regression analysis was conducted to investigate the company characteristics and regulatory approval ratio, as well as compound characteristics and probability of approval, for late-stage development compounds. Compound approvability was correlated to the time when the compound was developed (ie, the approval ratio of compounds in phase 3 or later in 1995-1998 was lower than that in 2001 or later); also, in-licensed compounds from large pharmaceutical companies received a higher approval ratio. Company size and R&D expenses were not correlated to their approval ratio.

Investigating Mitochondrial Dysfunction to Increase Drug Safety in the Pharmaceutical Industry

Drug-induced mitochondrial dysfunction is a contributor to both late-stage compound attrition and post-market drug withdrawals. This review outlines the mechanisms which lead to drug-induced mitochondrial dysfunction and discusses the tremendous advances that have been made in the development of in vitro methods to identify mitochondrial impairment. Potentially useful animal models and in vivo methods to detect drug-induced mitochondrial impairment are also discussed.

Pluripotent Human Stem Cells

The need for new and improved pharmacotherapies in medicine, high late-stage compound attrition in drug discovery, and upcoming patent expirations is driving interest by the pharmaceutical industry in pluripotent stem cells for in vitro modeling and early-stage testing of toxicity and target engagement. In particular, human embryonic and induced pluripotent stem cells represent potentially cost-effective and accessible sources of organ-specific cells that foretell in vivo human tissue response to new chemical entities. Here we consider the potential of these cells as novel tools for drug development, including toxicity screening and metabolic profiling. We hold that despite various challenges to translating proof-of-concept screening platforms to industrial use, the promise of research is considerable, and close to being realized.

BIG PHARMA’S YEAR-END SPREE

AS 2009 DREW to a close, pharmaceutical companies opened their pocketbooks for several drug candidates. The highest price tags were on late-stage compounds intended to help offset revenue losses when generic drug competition hits key products. In the biggest end-of-season deal, AstraZeneca is paying up to $505 million for Novexel, a private French anti-infectives company. When the deal is complete, Forest Laboratories will pay AstraZeneca half of the acquisition costs in exchange for the rights to codevelop two of Novexel’s antibiotic therapies. One combines ceftazidime and NXL-104, Novexel’s β-lactamase inhibitor for gram-negative infections. The other combines NXL-104 with ceftaroline. The ceftazidime/NXL-104 combination is likely to move into Phase III trials by late this year. Both Forest and AstraZeneca are in dire need of new drugs. Forest loses exclusivity on the antidepressant Lexapro in 2012 and on the Alzheimer’s drug Namenda a year later. AstraZeneca’s antipsychosis drug, Seroquel, is slated to...

GSK and XenoPort to Collaborate on Late-Stage Compound for RLS and Neuropathic Pain

GSK and XenoPort to Collaborate on Late-Stage Compound for RLS and Neuropathic Pain

TEACHING AN OLD DRUG NEW TRICKS

WITH THE NUMBER OF NEW drugs approved dipping in 2005 to its lowest level in more than a decade, the pressure on pharmaceutical companies to bulk up their late-stage pipelines is acute. In-licensing is a popular solution, but the number of late-stage compounds up for grabs is limited, and competition has pushed the cost of licensing deals to exorbitant levels. Gaithersburg, Md.-based Gene Logic is trying to persuade big pharma to add another approach to its drug development efforts: looking within their own cupboards to find new value in drugs that have been shelved after disappointing trial results. The idea is that compounds that were found to be safe in Phase I trials but not effective in Phase II or beyond could still be useful in other indications. The underlying concept, known as drug repositioning or repurposing, is not new. Several blockbuster drugs have resurfaced under new guises after setbacks. For example, Pfizer's Viagra ...