Optivia, UCSF receive SBIR grant to develop transporter-based assay system

Optivia Biotechnology Inc., a leading provider of in vitro transporter assay services, today announced that the company and the University of California, San Francisco (UCSF), have received a Small Business Innovation Research (SBIR) grant from the National Institutes of Health (NIH) to develop an innovative system for characterizing the role transporter proteins play in the disposition of drugs by the liver. The $430 thousand Phase I grant will leverage the expertise of Leslie Z. Benet, PhD, , an internationally recognized drug development expert and Professor and Chairman Emeritus, Department of Bioengineering and Therapeutic Sciences, UCSF, along with Optivia's novel transporter technology platform to study the effects of transporters on drug disposition and the interplay of transporters and metabolizing enzymes in the liver. The goal is to develop a transporter-based assay system capable of predicting the absorption, distribution, metabolism and excretion (ADME) of drug candidates - a key step to optimizing a drug's safety and efficacy.

“Transporters likely contribute to the observed discrepancies. Considering transporters when assessing metabolism will result in the generation of better in vitro models.”

ADME models are increasingly influential in determining whether a new molecular entity (NME) should advance through R&D, and one of the fastest growing ADME research areas of the last decade is transporter proteins. The importance of transporters to drug safety was highlighted in a recent published report by the International Transporter Consortium ("Membrane Transporters in Drug Development," Nature Reviews-Drug Discovery, March 2010), which stated that understanding the interplay of drug-metabolizing enzymes and transporters in the disposition of an NME is crucial in determining the safe and effective use of the NME. Drug-induced liver toxicity is the primary cause of clinical failures, and is one of the most common reasons for marketed drugs to be withdrawn. Such failures have translated into increasing costs of drug discovery and development. For example, according to the FDA's 2004 Critical Path Initiative white paper, it was estimated that clinical failures based on liver toxicity alone have cost one major pharmaceutical company more than $2 billion in the last decade.

"This grant will allow us to build on UCSF's previous work suggesting that we can predict how drugs will behave in the body, specifically the liver, based on transporter biology," said Dr. Benet, who is a member of the International Transporter Consortium. "We intend to provide a body of systematic data based on the in vitro profiling of a large number of drugs against a panel of key human transporters as the first step toward building transporter-based predictive models for the assessment of ADME and drug-drug interactions (DDIs)."

According to Yong Huang, Ph.D., president and chief executive officer of Optivia Biotechnology, "This collaboration reflects our response to the specific call from the pharmaceutical industry and regulatory agencies for systematic data, both in vitro and in vivo, with respect to how drugs interact with multiple transporters expressed in various human organs, and how such interactions alter drug pharmacokinetics in the human body. Integrating analysis of drug transporters is increasingly becoming a core requirement in ADME assessments and is anticipated to become a regulatory standard for new drug applications." (2010 EMA Drug Interaction Draft Guidance and 2010 International Transporter Consortium (ITC) Report)

In the Phase I study, Optivia Biotechnology and UCSF will systematically test 40 marketed drugs against ten major hepatic transporters, then correlate the in vitro drug-transporter interaction data with in vivo information on the disposition of drugs in the liver, with the aim of building a more definitive, earlier-stage model for predicting actions of drugs in humans. The Phase I study will also address the interplay between transporters and drug metabolizing enzymes.

"The industry has long observed discrepancies between measuring drug metabolism in existing experimental systems," says Dr. Huang, "Transporters likely contribute to the observed discrepancies. Considering transporters when assessing metabolism will result in the generation of better in vitro models."

"A model that correlates in vitro data to in vivo results would be of incalculable value to the pharmaceutical industry, since it will allow drug developers to make better decisions on the ADME properties of drug candidates prior to performing in vivo studies, most likely reducing development costs and decreasing the number of failures related to the ADME properties of drugs," stated Dr. Benet. "The unique capabilities of the Optivia platform will allow us to move forward on this critical step in building transporter-based predictive models for ADME."

This research collaboration further advances Optivia Biotechnology's leadership position in applying its understanding of transporter-mediated mechanisms to the development of practical, efficient and predictive in vitro assays and services that more closely model human biology. Optivia is the only company that offers a polarized mammalian cell assay panel for all seven transporters cited by the ITC and the Food & Drug Administration as most clinically relevant to transporter-related drug-drug interactions.

It is estimated that more than 86 percent of all compounds and about 40 percent of clinical stage drugs fail due to unsatisfactory ADME, toxicity and clinical safety properties. Drug-induced hepatotoxicity is estimated to be responsible for as many as five percent of all hospital admissions and 50 percent of all acute liver failures. It is well-established that transporters greatly influence the hepatic disposition of a number of commonly used drugs (e.g. antibiotics, statins, and hypoglycemic agents) and others that were subsequently removed from the market (e.g. the antidepressant nefazodone).