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Envigo’s new program to aid drug R&D
PRINCETON, N.J.—Since 1980, more than 30 drugs have been removed from the market due to concerns about hepatotoxicity and possible drug-induced liver injury (DILI) in patients. Several others have had their use restricted for the same reason. Currently, pharmaceutical companies spend valuable time and money on drug candidates only to have them withdrawn in late-stage clinical trials due to DILI.
In May 2015, a group was set up at Envigo to assess new and developing technologies which did not involve the direct use of animals, resulting in the Non-Animal Technology program, or NAT, which focuses on assessing new developments in in-vitro models and techniques and facilitating drug development. As part of this process, Envigo scientists investigated some of the major risks new drugs face during development and how they could use new in-vitro techniques to effectively gauge the drug’s susceptibility to various risks, including non-approval. Two aspects were chosen for further investigation: de-risking programs and an assessment of what assays are currently used to satisfy a regulatory requirements and those tests currently being developed.
Recently, Envigo announced the launch of its new DILI assessment program, an integrated program of in-vitro technologies designed to help predict the likelihood of compounds causing DILI. The program is run by using either some or all of its three key tests as needed to identify whether a drug exhibits possible risk factors associated with drug-induced liver injury.
“Envigo’s battery of in-vitro tests, typically using human cells, enables our customers to determine if a compound carries a DILI liability. A compound that is negative in our in-vitro testing program is considerably de-risked from one of the failure factors newly approved drugs face. This allows our customers to make more informed choices as to whether they should progress the compound. The de-risking approach serves to increase patient safety, provides confidence to invest and aids the in/out-licensing of new drugs,” commented Guy Webber, scientific manager of the In Vitro and Drug-Drug Interaction Sciences Group at Envigo.
The tests used for the program—covalent binding, reactive metabolite formation and time-dependent inhibition (TDI) of cytochrome (CYP) enzymes—require mere milligrams of material. This makes them ideal for early discovery research, Envigo notes, where typically only small amounts of compound are available.
“If a compound comes up negative in these assays, we then use this data, in conjunction with other information, such as lipophilicity, transporter inhibition, structural alert analysis and likely human dose, to make an educated assessment as to whether a compound may carry a DILI liability or not,” Webber noted.
“Ultimately, the DILI assessment package forms part of Envigo’s larger de-risking program for new drugs. This broader initiative, driven by the company’s Science and Technology Advisory Group, comprises DILI assessment, drug-to-drug interactions, genotoxicity and cardiotoxicity,” added Brian Burlinson, principal scientist for safety assessment at Envigo. “As our de-risking studies can be carried out very early on, there is time for chemists to re-examine their molecules and assess potential changes that could be made to reduce the DILI liability while maintaining efficacy. Once the molecules are re-engineered, they can then be checked again against the Envigo assays.”
Currently, Evigo does not expect this program to affect how the FDA approaches new drugs or re-evaluate any that had previously been withdrawn or restricted, but added that information provided to customers will ultimately be of interest to the FDA, and that could potentially become a part of the approval process. The hope is that the highly focused and visible way Envigo provides customers with this type of information will help them better judge both risks and benefits of new drugs efficiently, leading regulatory bodies to do the same.