June 15, 2007 (Vol. 27, No. 12)

MipTec Highlights Reveal Industry Focus on Characterization for Turning Hits into Leads

Kurt Stoeckli, Ph.D., vp, member of the global discovery board, and head of lead identification technologies, Sanofi-Aventis (www.sanofi-aventis.com) sciences and medical affairs, opened the 10th “MipTec” conference in Basel, Switzerland, last month with a perspective on drug discovery as seen by big pharma. There have been several challenges in recent years, including the requirement to show more differentiation and improvement of new products when it comes to addressing unmet medical needs. There is also the greater burden of chronic degenerative diseases that needs to be addressed, and regulatory concerns and pharmacovigilance are playing a bigger role as well.

Meanwhile, there continues to be a high rate of attrition at a late stage of development and insufficient translation from R&D. “The consequence of this is stagnation of productivity as R&D costs continue to soar,” said Dr. Stoeckli. There are three dimensions to improvement in big pharma: efficiency, quality, and innovation. “In coming years, we will see these addressed through consolidation, for efficiency; alignment between research and development, for quality; and diversification, to address the need for innovation,” he added. “Our fundamental issue is that of translation—deliverables are far under expectations. For the enormous input, the output is not sufficient.”

Dr. Stoeckli went on to describe how the drug discovery paradigm has changed. The classic model, based on phenotypic targets, worked well for the discovery of anti-infectives and oncology drugs. This shifted to the current paradigm, which is based upon isolated targets and has led to high attrition. There will be a future shift to a drug discovery paradigm based on molecular pathology and molecular epidemiology, with an increasing emphasis upon pathways and more feedback from the later stages of development into the earlier stages. There will also be an increasing focus upon stratified medicine, where a genetic profile is part of a drug’s efficacy and can be a way of rescuing drug candidates and differentiating new ones.

Looking to the future of drug classes, Dr. Stoeckli acknowledged the importance of mAbs, of which there are 400 in clinical development—half in cancer—and 12 already approved. But these molecules are complex to manufacture, and it is necessary to think earlier about developing them than for a small molecule drug. These days, most big pharmas have 10–20% of their portfolios devoted to biologics, including vaccines and RNA drugs as well as monoclonals.

Stem cells are of great interest, of course, but Dr. Stoeckli advised caution as they are hard to isolate and screen. Finally, he highlighted a need for better screening assays for ion channel and transporter targets and also suggested that natural products should still play an important role in drug discovery, as they cover a large structural space that is not well addressed by synthetics.

Threat of Antiobiotic Resistance

Jutta Heim, Ph.D., CSO of Basilea Pharmaceutica (www.basilea.com), a Roche drug discovery spin-off, described how they are responding to the growing threat of antibiotic-resistant bacteria. Basilea is focused on antibacterials, antifungals, and anticancer drugs, with three products currently in Phase III—ceftobiprole, alitretinoin (for dermatitis), and isavuconazole, an anti-fungal. Ceftobiprole is being developed as an anti-MRSA (methicillin-resistant Staphylococcus aureus) broad-spectrum antibacterial with Johnson and Johnson.

“Emerging antibiotic-resistant infections are one of the most serious problems our hospitals face today,” Dr. Heim said. “Many people are dying from this cause, regardless of their underlying illness.” The antibacterial market was worth $29 billion in 2005, of which $8 billion was spent in hospitals. There are already many powerful antibacterials, but, even while resistance has increased the need for new drugs, several big pharmas pulled out of this area. Between 2002 and 2006, only a few new antibacterial drugs came onto the market.

Only four drug targets appear to be useful for antibacterials: cell wall biosynthesis, transcription, translation, and metabolism. Bacteria can develop resistance against all antibacterials, regardless of their target or class, explained Dr Heim. They then disseminate this resistance through horizontal gene transfer. MRSA has also become coresistant to other antibacterials.

The mechanism of resistance to marketed beta lactam antibacterials, which target the cell wall, is attributed to the presence of an extra penicillin binding protein (PBP2´) in the resistant strain, to which beta lactams bind only weakly, allowing it to continue producing cell wall.

Dr. Heim described how Basilea has attempted to overcome this with the development of ceftobiprole, which is a re-engineered cephalosporin. Clinical trial data published earlier this year show comparable efficacy with combination vancomycin/ceftazidime control in complicated skin infections, including diabetic foot ulcer and MRSA infections.

“The most important result for us was that in serial passage experiments, where resistance might be expected to develop, ceftobiprole showed a low propensity for the development of resistance, compared to fluoroquinolones and linezolide,” said Dr. Heim. A detailed analysis of the interaction between the PBPs and the new antibacterial shows how it converts PBP2´ from being resistant to being sensitive again.

Meanwhile, the Infectious Disease Society of America has warned against a second wave of antibiotic resistance, coming from the Gram negatives, with Klebsiella, Pseudomonas, and Acetinobacter being the new danger bugs putting patients’ lives at risk. These species have a variety of different mechanisms with which to fight antibiotics, Dr. Heim warned. Basilea’s approach to the Gram negative threat is to develop new antibiotic combinations, similar to amoxicillin/clavulanic acid and piperacillin/tazabactam, which have been successful in the past. This approach requires industrial scale profiling and generation of millions of datapoints to hit upon the optimal combination of many potential antibacterials.

In early work, the Basilea team says it obtained promising results with one combination against a pan-resistant strain of K.pneumoniae from Greece.

Screening Success

In the technical arena, Beckman Coulter(www.beckmancoulter.com) presented some new products that can add benefit at all stages of the drug discovery process, particularly screening. “Our core strategy is to simplify and automate to improve productivity,”explained Christoph Krüll, Ph.D., product manager, automated solutions, Beckman Coulter Europe.

The company added new SAMI EX software to its range of Biomek® liquid handling to control integrated systems. “We added the support of an industrial robot, Motoman, to this software, which provides multiple transportation options that help speed up processes and hence improve productivity,” explained Andreas Hahn, project manager, automated solutions.

The company has also been working on the detection aspect of screening. Rainer Mühlbacher, sales and marketing of the Center of Excellence Microplate Detections Systems, Beckman Coulter Austria, introduced the Paradigm™, a plate reader that supports several kind of fluorescence and visible light detection technologies for screening. “Paradigm introduces a new level of modularity into the detection platform,” he explained. “The system can now be upgraded as and when needed for specific applications.” The key feature of the new instrument is a series of plug-and-detect cartridges, each containing label-specific optics and a light source, which can be configured into the machine in less than five minutes, says Mühlbacher.

Meanwhile, Beckman Coulter has acquired technology that allows the extension of work on the Biomek to smaller volumes using the bioRAPTR and the picoRAPTR, two sub-microliter liquid-handling systems. “There are several drivers towards miniaturization, including reduction in reagent and plate usage and increase in throughput and efficiency,” explained Dr. Krüll. “This all allows an increase in the collection of high-content information at earlier stages of screening, but getting an assay into a miniaturized format can be a challenge.”

The bioRAPTR is a pressurized, non-contact, bulk dispenser, which is particularly useful in dispensing cells from a bottle onto a plate, being designed so the cells cannot settle or be disrupted in any way says the company. The picoRAPTR is for work on the nanoliter scale but has a range of scales that allows for a speedier alternative to serial dilution. This may be applied to generating dose-response curves at an early stage of development.

The company has also introduced the ChemLib ™ series of 1,536- and 3,456-well plates made of a cyclo-olefin polymer, which gives an especially inert, rigid, and flat product. One interesting feature is the presence of additional perimeter wells to control evaporation from sample wells by providing a vapor headspace.

Beckman Coulter has also been looking at the software side because data collection in automated systems can become complicated. The company devised the Data Acquisition and Repository Tool as an add on to the Biomek. The company reports that the Tool can collect data from any instrument and will have advantages in improving data security and lab management and will preserve all the information generated in a process for future use.

Nanoliter Assay System

Bart Van de Vyver, Ph.D., CEO of SpinX Technologies (www.spinx-technologies.com), described another new technology for improving productivity. Both Piero Zuchelli, CSO, and Dr. Van de Vyver have a background in particle physics at CERN (the European particle accelerator facility) and have used this as inspiration for developing a nanoliter assay system to address the space in drug discovery between target and lead. The resulting gStack™ system is based upon an advanced microfluidics system, linking an array of 300-nL chambers through a network of programmable channels. The set-up allows multiple assays to be carried out on multiple compounds at multiple concentrations.

A virtual laser valve, shown not to damage cells or DNA, provides connections between the channels as and when needed. Dr. Van de Vyver calls this a “walk away hit-to-lead characterization system” because it is so highly automated. “Any assay that can be done on a microtiter plate can be transferred onto our nanoliter card system,” he explained. At present, the gStack is going through trials with big pharma, mainly on enzyme assays, and there is also an ongoing publicly funded collaboration on whole cell assays.

Béla Kelety, Ph.D., CEO of IonGate Biosciences (www.iongate.de), introduced the SURFE2R, which is a cell-free electrophysiology platform for screening transporters and ion channels. This is an important group of targets, both for their involvement in cardiovascular, neurology, metabolic, and other major indications and for their role in transporting drugs across membranes.

Until now, screening of transporters/ion channels has had severe limitations. Dr. Kelety says the SURFE2R overcomes these by fixing membranes or liposomes expressing such proteins onto a gold surface, which gives a higher concentration and more sensitivity than a cell-based assay can. When the protein is activated in SURFE2R, an electrical signal is generated, which can be detected by standard electronic amplification.

The IonGate team has been developing the assay with PEPT1—a drug uptake transporter that moves peptides across the intestinal epithelial cell membrane; this is an important factor in a drug’s bioavailability. Experiments with SURFE2R have distinguished between drugs like cefadroxil and captopril, which are transported, and acyclovir, which is not. “SURFE2R can help you change the properties of a drug, so it can be taken up systemically,” explained Dr. Kelety. That is, it is a tool that can allow early selection of drug candidates that are going to work through oral absorption via their binding to PEPT1. The platform is also available in a 96-well plate format for high throughput.

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