Helping to ensure that the drug discovery and development process continues evolving, contract research organizations (CROs) are of increasing value to biotech and biopharma. These guardians of the pipeline keep the process alive by providing the best-in-class assay and technological support to insure that viable, new drug candidates are commercialized.
The support needed at each phase of the drug pipeline is available from a CRO, whether it be a small niche organization that has specialized in a specific assay or platform technology, or a large organization that serves as a one-stop-shop with extensive technologies/services to take an optimized lead candidate through clinical trials to full commercialization.
Indigo Biosciences was born out of expertise with a specific assay technology, in this case one focused on nuclear receptors. This small CRO was spun out of Penn State University when Jack Vanden Heuvel, Ph.D., founder and CSO, realized that his nuclear receptors expertise could be leveraged for drug discovery.
Of the 48 known human nuclear receptors, Indigo has developed a reporter gene assay system using a mammalian cell line for 25 of them. The most notable receptors in this class are the PPAR receptors, a family of nuclear receptors whose activity is associated with on target effects for many metabolic diseases including diabetes, obesity, and chronic inflammation. These receptors are also valuable as off target markers for toxicological studies and for the analysis of drug-drug interactions.
The nuclear receptor assays are now also available in kit formats, so the luciferase-based reporter assay can be run in a firm’s own lab if it chooses not to outsource.
“We’ve come to be known as the ‘Nuclear Receptor CRO’. We use a single point assay in medium to high throughput to screen tens to hundreds of compounds across a panel of up to 25 receptors in 384-well plate format,” says Dr. Vanden Heuvel.
“The assay is run in 15–30 µL reaction volumes and yields results within 24 hours. We work closely with the customers on both ends of the analysis, first to develop the study plan and then to help with the interpretation of the results. The completed study is usually turned around in two weeks.”
In Vitro ADME/Tox Services
The focus of BD Biosciences’ Gentest™ contract research services is on metabolism of drug candidates as measured by the induction or inhibition of cytochrome P450, a superfamily of drug-metabolizing enzymes. “BD has a large suite of drug-metabolizing enzymes with more than 50 different P450, UGT, and other enzyme products sold under the BD Gentest brand,” shares Roseann Vardaro, product manager, BD Biosciences—Discovery Labware.
“The services business is closely integrated with the product business. This helps assure that datasets are comparable whether customers do the work themselves or outsource it to us.” Another key focus area for both products and services is transporter proteins. Like cytochrome P450 enzymes, ATP-binding cassette and solute linked carrier transporter proteins can mediate drug-drug interactions.
“A trend that we’ve noticed recently is more repurposing of established drugs. These drugs often have little or no data applicable to newer standards of in vitro drug-interaction testing, such as those outlined in the FDA’s 2012 drug-drug interaction guidance document,” says David Stresser, Ph.D., program manager, BD Gentest contract services. “Before investing in another round of clinical trials, our customers want to confirm there are no drug-drug interaction or safety issues.”
Molecular Imaging (MI) is dedicated to the use of small-animal imaging in the drug discovery process. “We use a full range of imaging modalities for anatomical, functional, and molecular outputs, enabling us to provide our customers with combined pharmacology and imaging biomarkers that assist in their go/no-go decision-making process,” says Patrick McConville, Ph.D., co-founder and CSO.
“We customize our approach with every project. The customer brings us their compounds and we do the rest; we order the animals, acclimatize them on-site, induce the disease state, and interrogate the pharmacology. Imaging is then performed using one or more modalities usually over multiple time points to extract predictive biomarker(s) with the aim to perform the analysis in real time.”
The increasing reliance on imaging in the pharmaceutical industry as well as parallel improvements in the technology has enabled MI to add a broad base of imaging assays. These assays are validated and applied to the noninvasive study of disease in the context of the otherwise normal physiology of the animal.
MI is currently primarily focused on oncology and inflammation diseases. The latter also extends its reach to the broader area of metabolic and cardiovascular disease. It plans to expand its offerings by developing expertise in other disease areas, and this expansion will occur in parallel to the addition of emerging imaging platforms. Using ancillary technologies such as MRI contrast agents, PET tracers, and optical probes to study these disease states, it is looking to pull together richer, more reliable datasets.
Another trend is the use of whole-animal imaging for drug safety and toxicology studies. MI is an active participant in the consortium set up by the Health & Environmental Science Institute to define guidelines and set the industry standard for imaging in preclinical safety assessment.
Avacta Analytical was spun out of the University of Leeds in 2005. The business focuses on providing extended protein-characterization services, specializing in biophysical and physico-chemical analytics. Avacta offers a range of techniques not traditionally found in every lab or even at CROs.
Its experience of using these techniques and applying them to different types of therapeutic proteins is central to its success. It provides smaller organizations with the ability to access additional analytical resource and provides extra capacity for larger multinationals.
“We mainly work in the R&D phase of drug development, looking at stability, comparability, aggregation, formulation selection, and general protein characterization,” explains Richard Perkins, business development manager.
“We advise our customers on the pros and cons of various analytical techniques, making sure the package we provide is fit for purpose. Techniques such as analytical ultracentrifugation, FTIR (fourier transform infrared spectrometry), and circular dichroism are not familiar to most, so we have learned that extensive consultation and open communication with the customer before and after projects is vital."