Multidisciplinary approaches optimize contract drug discovery

Headquartered out of Indiana and operating multiple sites in the US, Inotiv Inc is a contract research organization (CRO) providing non-clinical and analytical drug discovery and development services to the pharma and medical device industries. Inotiv is innovating with multidisciplinary approaches that optimize drug discovery and approval for its clients in a unique way.

The process of drug discovery never stands still. The pharmaceutical industry is constantly on the lookout for better ways of doing things, be it improved disease models, de-risking by earlier elimination of drug candidates or improving screening for drug metabolite toxicity. All these things save time and money and are vitally important to CROs looking to deliver high value services to their pharma industry clients.

Traditionally, CROs have focused singularly on clients’ specific needs, providing technical support and a specific dataset in a highly commoditized manner. However, that is now changing, with CROs shifting focus to more integrated and value-added partnerships. We spoke with three members of Inotiv who are at the forefront of the company’s new approach: Brian Bond, Vice President of drug discovery sciences and an in vivo physiologist and pharmacologist; Mark Hoenerhoff, senior director for investigative and molecular pathology who oversees histology, immunohistochemistry, digital imaging analysis and discovery pathology; and Chris Null, associate director of investigative toxicology.

A new paradigm

Between them, Bond, Hoenerhoff, and Null are helping Inotiv to bring the three key disciplines of disease pharmacology, toxicology, and pathology together in an integrated service offering to its pharma clients. As Bond explains, “The service and the value that contract laboratories provide has evolved over the years. When I was initially operating as a client, it was highly commoditized with a fairly focused deliverable of study execution.”

According to Bond, Inotiv is evolving the paradigm by offering greater value to its clients, through integrated packages which can involve multiple components. “Instead of providing a singular dimension of support, we strive to understand and support broader program objectives and then craft a fully integrated data package involving elucidation of pharmacology, target engagement, pathway activation, and early exploratory toxicology – all supported by drug metabolism, pathology, and histology,” he says.

Mechanism of action

With its evolution in approach, Inotiv attaches greater importance to understanding the mechanisms of action of candidate drugs as opposed to simply focusing on toxicity alone. Hoenerhoff explains, “Mechanism of action is critically important because it gives us knowledge of the causal pathway by which a drug acts on the body. It helps us understand what targets a drug acts upon, what pathways downstream from that target are engaged, and what downstream effects on tissues and endpoints there are that are relevant to efficacy.”

All of which of course provides information regarding a drug candidate’s appropriate use, its effectiveness, and any possible adverse effects or contraindication. But Hoenerhoff’s investigative and molecular pathology team adds much more to the equation. “Discovery studies can be complex, often requiring a great deal of work on the front end to understand a particular animal model of a human disease and the subsequent effects of drug candidates on that model,” he asserts. “From histology to immunohistochemistry, pathology evaluation, and digital image analysis, we really seek to understand how that drug candidate impacts the disease model,” he adds.

Hoenerhoff explains that his team often use specialized tissue preparation techniques that are specific to a disease target and employ a variety of assays including in situ hybridization to understand how a drug affects target cells. They evaluate the expression of many molecular endpoints using digital image analysis and, ultimately, it is a multidisciplinary endeavor. “We work across pharmacology, toxicology, and proteomics teams in a multi-platform approach to understand disease pathogenesis, mechanism of action, and efficacy,” he says.

Toxicity for risk management

The exploratory toxicology lab at Inotiv has the task of de-risking clients’ assets in non-GLP studies, before progressing to the much more expensive GLP development studies. In other words, catching problems early, as Null elaborates, “We identify toxicity risks early in the drug discovery cycle, establish safety margins, and estimate dose tolerability because we want these assets to go into development with as few unanswered questions as possible.” Null adds that as most drug candidates fail the grade before making it to the clinic, “the earlier you can identify a no-go-decision, the more cost saving there is for the client who is then able to reinvest money on an alternative viable approach.”

Null’s lab performs all the non-GLP pharmacokinetics and the absorption, distribution, metabolism, and excretion studies for early-stage projects. Understanding the mechanisms of toxicity is critical to moving a drug candidate on into enabling studies. Null explains, “If you have a compound that metabolizes and that metabolite drives toxicity that is not associated with the target you are trying to hit with your drug, you might approach it through a backup compound that does not metabolize in the same way to remove the toxicity risk. But you have to understand what that risk is first.”

Null elaborates that toxicity can simply arise due to overstimulation or over inhibition of an intended drug target, in which case experimenting with dose modulation can be sufficient to adjust the safety margin for progression into enabling studies.

Inotiv now has a very broad array of tools, assays, and techniques to identify toxicity risks much earlier in the timeline than could previously be achieved. These include cell-based assays, biomarker examination, digital imaging, exploratory pathology, gene expression and proteomics, leading Null to assert, “We can identify potential liabilities very early. The ability to bring all these disciplines to bear makes the drug development process much more cost-effective for our clients.”

Integrating new technology

According to Bond, Inotiv’s team of senior scientists are expected to continually appraise new technologies that would bring added value for its clients. He concludes with a couple of examples. “The application of targeted proteomics for confirming target sufficiency, and in vitro cell and organoid assays for confirming translational relevance are being actively incorporated into our programs now,” he enthuses. “It’s very important that we stay current because our clients are looking for cutting-edge support.”

Learn more about how Inotiv’s integrated exploratory toxicology, pathology, and disease pharmacology approaches could help to take your research to the next level.