The impact of early ADME profiling on drug discovery and development strategy

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The increased costs in the discovery and development of new drugs, due in part to the high attrition rate of drug candidates in development, has led to a new strategy to introduce early, parallel evaluation of efficacy and biopharmaceutical properties of drug candidates. Investigation of terminated projects revealed that the primary cause for drug failure in the development phase was the poor pharmacokinetic and ADMET (Absorption, Distribution, Metabolism, Discretion and Toxicity) properties rather than unsatisfactory efficacy. In addition, the applications of parallel synthesis and combinatory chemistry to expedite lead finding and lead optimisation processes has shifted the chemical libraries towards poorer biopharmaceutical properties. Establishments of high throughput and fast ADMET profiling assays allow for the prioritisation of leads or drug candidates by their biopharmaceutical properties in parallel with optimisation of their efficacy at early discovery phases.This is expected to not only improve the overall quality of drug candidates and therefore the probability of their success, but also shorten the drug discovery and development process. In this article, we review the early ADME profiling approach, their timing in relation to the entire drug discovery and development process and the latest technologies of the selected assays will be reviewed. Discovery and development of a new drug is a long, labour-demanding process. Recent studies1 revealed that the average time to discover, develop and approve a new drug in the United States has steadily increased from 8.1 years in the 1960s to 14.2 years by the 1990s. The actual time may be even longer as the above calculation considered the starting point from chemical synthesis, thereby not including the time for target identification and lead finding/selection process, which in general takes a minimum of two more years. Typically, the whole process is fragmented into ‘Discovery’, ‘Development’ and ‘Registration’ phases. The ‘Discovery’ phase, routinely three to four years, involves identification of new therapeutic targets, lead finding and prioritisation, lead optimisation and nomination of new chemical entities (NCEs). In the ‘Development’ phase, the drug candidates are subject to preclinical testing in animals (also known as ‘Phase I’) for about two years. In addition, the preliminary clinical trials in man and the subsequent full clinical trials (known as Phase II and III) will take a much longer time (~8.6 years)1. According to DiMasi, the ‘Registration’ phase averaged around 1.8 years in the late 1990s. Each pharmaceutical firm has their own collection of drug candidates which are being allocated to different phases of the discovery and development process, often referred to as the ‘pipeline’. Discovery scientists primarily focus on ‘hunting’ for drug candidates, whereas in Development one is trying to ‘promote’ NCEs as novel and safer commercial medicines. Discovery and development of a new drug are also extremely costly. Despite the drastic upsurge in R&D expenditures (by a factor of 20-50), the output of pharmaceuticals (number of new drugs launched per year) remains virtually flat from 1963 to 19992-3. Concurrently, the productivity of the pharmaceutical industry, as measured by NCE output per dollar, declined continuously during the past decades4. As a result, the average cost to discover and develop a new drug, taking into account the drug candidates dropped along the way, soared to $800-$900 million in 20032-3,5, in comparison to that of $138 million in 1979 and $318 million in 19912. A separate analysis estimated the cost at $1.3-1.6 billion in 20056. Despite the recent strong performance in earnings7, major pharma firms still have the urgency to improve the efficiency and effectiveness of the drug discovery and development strategy in order to appeal to the investors and to secure continuing growth. In addition to the increasingly tight regulatory hurdles, big pharmaceutical firms also suffer from their failing discovery of NCEs. However, the genomics approach was counteracted by a large number of novel but risky targets which attributed to a 50% rise in the failure rate over the clinically validated approaches8. The downside of combinatorial chemistry is to shift the discovery compound libraries towards large ‘greasy’ and biologically inactive molecules which can rarely survive in the development phase. Indeed, Lipinski’s recent drugability analysis of NCE collections from Pfizer and Merck led to the findings that new NCEs tend to have higher molecular weight and higher LogP and in turn, poorer solubility and permeability9. Therefore, eliminating compounds with the worst ADMET assay properties as early as possible has become an attractive approach10-14. Alternatively, expert advice concerning ADME properties could guide chemists to structure-activity relationship (SAR) based modifications to optimise for ‘drug like properties’ (eg, good absorption, high bioavailability with metabolic stability, required distribution). What is behind the high attrition rate? Even when a candidate reaches the development ‘pipeline’, this will not guarantee the launch of a commercial drug. This milestone indicates nothing else but a probability for success, as many development candidates will not pass through the preclinical and clinical testing. Companies reserving a large number of candidates with a higher probability for success in development phases are viewed as possessing ‘strong pipelines’. Attrition rate analyses of NCEs in the development phases of 10 big pharma companies in the US and Europe over 1991-2000 led to interesting findings8. Albeit distinct among therapeutic areas, the average success rate for drug candidates entering development Phase I will only be around 11% (Figure 1). In other words, the vast majority of the compounds that are being worked on in the development phases will end up in the ‘waste bin’, with no return on the expenditure for the investment. As the development process advances, the potential for the surviving candidates to become a drug gradually escalates, in proportion to the growing expenditure for development per target. A couple of comparable studies led to similar conclusions14-15. Drug candidates might fail during development because of numerous reasons. Kennedy analysed the causes by which 198 NCEs failed in clinical development15 and found that the most prominent cause of the failures was associated with poor pharmacokinetic (PK) and ADME properties (Figure 2). Although lack of efficacy was still one of the main reasons for terminations, the unsatisfactory PK/ADME study, toxicology and adverse effects accounted for up to two-thirds of the total failures. A separate analysis8 also led to a similar conclusion, particularly true for the early 1990s. However, Kolo & Landis’s report revealed that even with the latest improvement in PK/Bioavailability aspects, the total loss of drug candidates in development due to ADME (PK/bioavailability, formulation), toxicology and pharmacology (safety) remains near 50%. Where did the traditional drug discovery and development process go wrong? In principle, most of the above issues might have been foreseen in early discovery by using ADME, toxicological and pharmacological profiling tools. However, it takes time and effort to reform the mindset of scientists and managers in drug discovery and development. Traditionally, optimisation of efficacy was strongly associated with discovery and drugability with development, applied sequentially in their own ‘kingdoms’. Specifically, the majority of the project teams in discovery concentrated on the improvement of in vitro efficacy during lead selection and optimisation. In the end, the champion NCEs, always those with most potent inhibition or binding properties to the in vitro target in test tubes/microplates, were ‘pushed over the wall’ to the development phase, as if the world leading universities picked their best candidates simply by the criteria of nothing else but the academic record of the applicants. From the discovery point of view, the goal was achieved with the identification of active candidates relative to the therapeutic target. However, from the development point of view, excellent in vitro efficacy would not always translate into in vivo potency. First, full in vitro characterisations of the drug candidate including pre-formulation assessment, biopharmaceutics, toxicology and safety pharmacology give a fair prognostic picture for in vivo performance. As a next step, preclinical experiments provide confirmation of pharmacodynamic (PD)/pharmacokinetic (PK) behaviour of the compound in selected animal species. To complete the evaluation, pharmaceutical development has to assess the developability of the candidates as potential commercial drugs (eg, optimisation of drug delivery by various formulations, etc). Although these processes are scheduled way before the more challenging and costly clinical trials, many NCEs display signs of poor ‘drugability’. For example, some NCEs could neither dissolve in aqueous media nor permeate across the gastrointestinal membrane to reach the concentration at the required therapeutic level, often referred to as ‘brick dust’ by development colleagues. Fast (metabolically unstable) or ultra-slow (potential accumulation) metabolism, toxic and adverse effects are not necessarily obvious from animal experiments executed at single dose most of the time. As a consequence, these matters are frequently misinterpreted during the assessment of the in vivo efficacy, which (without mechanistic data) imposes additional challenges during the development process. No wonder, that the late discovery of poor druglike properties and adverse side-effects is heartbreaking for both development teams, often referred to as ‘teams with licences to kill’, and drug discovery teams. Under such a condition, the question is whether to continue the development of the NCE and try to optimise it with great hardship, or just kill the compound and start from scratch. However, the latter decision, (to throw the NCEs back over the wall) is always hard to make, as this means potential delays to the product launch, loss in exclusive patent protection and deterioration of competitive position against other pharmaceutical firms that are working on the same therapeutic target. The matter is made worse by the discovery teams which beg their development colleagues to rescue their ‘babies’. Unfortunately, there is very little that development teams can do to salvage NCEs with inadequate drug-like properties and adverse side-effect profiles. For instance, development of proper formulations may help address drug delivery issues of poorly soluble compounds. However, such improvement can also be very costly and time-consuming and miracles may not always take place. Some notorious GPCR antagonists were classic examples for these efforts. Frequently, the clinical dose format may have to be approved by marketing teams and/or patients. Eventually, such projects may not survive after struggling for years and end up with a big expenditure and disappointed scientists.