[All tables and figures appear after the references]
Risk management has become an important discipline for firms developing new prescription drugs. Analysts estimate that for every 10,000 molecules entering drug discovery, only one will become a successful marketed drug. Even then, it is not certain development costs will be recouped. Couple this extraordinarily high attrition rate with a lengthy, complex and expensive process (average 12 years in development and cost of £1.15 billion [about $1.9 billion]1) and it is clear that drug development is an industry where the risk of expensive failure is very high.
So, is it possible to turn these odds a little more in our favor? Can we better select new molecules that will have a greater than a 1:10,000 chance of progressing through development and making a successful, safe, marketed product?
The liability risks under focus in this paper are metabolically driven and comprise just one area of potential attrition risk. Drug metabolism is one of the most important and yet sometimes under-appreciated parameters of drug development. Having a full understanding of how a new molecule is metabolized in the body, and by which enzyme(s), is crucial to successful drug development. For small molecules, drug metabolism will often drive clearance, pharmacokinetics (including population exposures in poor and rapid metabolizer sub-groups), drug-drug interaction potential and some forms of toxicity.
An adverse liability in any of these parameters is highly undesirable, in the best case leading to approval delays and at worst potentially catastrophic post-market withdrawal, as illustrated in Table 1.
The de-risking strategies discussed in this paper are designed to investigate if a molecule may have potential risks based upon how it is metabolized and how it interacts with CYP enzymes (and drug transporters). If a molecule is tested and is low or negative using in-vitro assays, it can be considered somewhat “de-risked” from these metabolically driven potential problem areas. However, if a molecule is positive in these tests, then drug developers can use this knowledge to better assess the risk-benefit ratio before deciding whether or not to continue to progress the molecule further in development.
The individual in-vitro assays applied in a de-risking strategy are sometimes not wholly predictive on their own, and the chance of a false negative always exists if a single assay approach is used. However, applying a full matrix of in-vitro tests will very often identify a “red flag” somewhere, making the metabolic de-risking program a powerful tool to detect major risk alerts.
If a liability is detected early enough, it may be possible to make changes to the structural chemistry of the discovery program without altering the pharmacophore. This would reduce the metabolic liability by blocking certain metabolic pathways and prevent particular reactive or toxic metabolites from forming.
Ultimately it is the aim of the pharmaceutical industry to develop medicines which are safe and efficacious for use in humans. In addition to the enhanced safety profile, a de-risked molecule is intrinsically more valuable than a similar molecule with unknown risk liabilities. A de-risked molecule provides an increased measure of scientific confidence and ultimately further investment in its progression.
The primary aim of an early de-risking strategy is to provide a comprehensive and rigorous data set, which allows a rational, scientifically based assessment to be made about the likelihood that a molecule may carry a liability before major investment decisions are made. With this in mind, integrating metabolic de-risking into drug discovery would seem to be an advisable strategy given that the pharmaceutical industry operates in an increasingly risk-adverse environment.2
The three main elements of metabolic de-risking are discussed below.
Drug-induced liver injury
Drug-induced liver injury (DILI) is a major concern for the pharmaceutical industry. It is the single greatest cause of liver transplant in humans and a major cause of safety-related drug withdrawal post-market. DILI is also a major cause of drug attrition during development.
The decision to progress a molecule that is displaying DILI-positive characteristics is an extremely high-risk decision and should only be made after taking into account multiple factors including the therapeutic area, whether the molecule will be meeting a currently unmet need (first-in-class product) and likely human dose (lower human doses significantly reduce the risk of DILI).
Although precise mechanisms of DILI are still being understood, one pathway increasingly believed to contribute is via the formation of reactive metabolites (RMs). RMs are short-lived, highly reactive, electrophilic (+ve) metabolites (sometimes radicals) which can bind to macromolecules such as hepatic proteins, antibodies and DNA causing both Type A (direct, e.g. genotoxicities) and Type B (idiosyncratic, e.g. DILI) toxicity. If the binding is covalent (irreversible), then this can trigger immune-related, hapten-like anaphylactic shock responses resulting in tissue/organ necrosis.
The detection of RM formation is therefore a key component of de-risking strategy. Today, RM formation can be assessed using various in-vitro assays, either directly using so-called RM trapping assays or via surrogate markers such as covalent binding or time-dependent inhibition of CYP enzymes.
If the test drug is low/negative in these DILI detection assays, then it is likely considerably de-risked from major safety-related issues, including attrition and drug withdrawal post-market.
Potential DILI impact scenarios are outlined in Table 2; the overall DILI de-risking strategy used at Envigo is presented in Figure 1.
Drug-drug interactions
The assessment of pharmacokinetic-based drug-drug interactions (DDI) is a major element of modern drug development. Drugs with a high DDI potential, particularly as a victim drug, may be at risk of non-approval, excessive labelling or post-market withdrawal.
To test a new drug for DDI potential, regulatory authorities recommend the initial use of a range of in-vitro studies (basic models) designed to assess interactions of new drugs as both a victim and perpetrator of DDIs.3
Often, it is assumed that the greater risks are as a perpetrator drug—medicines that cause pharmacokinetic changes in other co-administered medicines. Generally, however, for drug approval, this can be an incorrect assumption. Perpetrator interactions such as reversible CYP inhibition or CYP induction can be tolerated to a certain extent by dose adjustments and/or labelling. The greater risk lies as a victim drug.
If a drug has a single enzyme (or transporter) dominating its clearance, then this will be of regulatory concern unless the drug has an established wide therapeutic window.
Without a wide therapeutic window, a “single substrate” drug may be heavily labelled (reducing competitiveness), not approved (e.g. debrisoquine, perhexilline) or even withdrawn from the market (e.g. terfenadine, cerivastatin, astemizole, cisapride).
The overall DDI de-risking strategy used at Envigo is presented in Figure 2.
Metabolites in safety testing (MIST)
One of the principal recommendations of the FDA’s 2016 Safety Testing of Metabolites Guidance4 is to encourage the identification of differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible during the drug development process. This will help ensure the relevance of the animal species used in safety assessment to identifying potential human toxicity.
The definitive human metabolism data set is obtained from conducting a human radiolabelled (14C) AME study (absorption, metabolism, excretion), where a radioactive form of a drug is given to a small number of human volunteers (n = 6 to 8 cohorts). Typically, this crucial study is conducted during late-phase development (after Phase 2/proof of concept). This may seem a prudent approach, given human radiolabelled studies are expensive to run. However, if the definitive human data set is obtained too late and it reveals a disproportionate human metabolite to which animal models used in safety assessment were not adequately exposed, it can result in significant delay(s) in the NDA/approval process.
To assess this MIST risk and potential for late-stage approval delay, an integrated use of both in-vitro (hepatocytes) and in-vivo (animal) studies should be employed (see Figure 3) to understand if human-specific metabolism is potentially an issue. If it is, then the human 14C AME in-vivo study should be prioritized and conducted with some urgency to obtain the definitive human metabolite profile.
Summary
De-risking is the intelligent application of early in-vitro testing to investigate areas of major risk for new molecules in development, helping to avoid spending time and resources on a compound that may possess high potential liability of non-approval or market withdrawal. De-risking provides information that allows for more informed decision-making and stronger investment confidence in the high-risk arena of drug development.
Guy Webber is the scientific manager for in-vitro and drug-drug interaction sciences at Envigo. He manages the In Vitro Sciences Team and also future scientific strategy and services. His main research interests include developing the use of primary human cell models to better predict human DDIs, drug transporters and the role of biotransformation in drug-mediated toxicity.
References
1 www.pharmaceutical-journal.com/publications/tomorrows-pharmacist/drug-development-the-journey-of-a-medicine-from-lab-to-shelf/20068196.article
2 Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework, David Cook et al. Nature Reviews Drug Discovery 13, 419–431 (2014)
3 Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labelling Recommendations, Draft Guidance, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), February 2012.
4 Guidance for Industry Safety Testing of Drug Metabolites, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Revision 1, November 2016, Pharmacology and Toxicology
