Failing faster

Failing faster and cheaper is becoming increasingly important to the pharmaceutical industry. But how? Rebecca Goozee reports.

As many as one in three drugs fail in phase I trials, despite extensive pre-clinical testing and the screening of potential drugs in various in silico, in vitro, in vivo and animal models. In phase II trials 10 percent of potential drugs fail due to pharmacokinetics with an additional 25 percent failing for safety reasons. It seems that re-engineering the drug discovery and development pipeline is crucial for pharma budgets and reputations.

In phase II trials

With regulations getting tougher and the associated costs of research and development soaring, now more than ever there needs to be a solution to this growing problem of productivity. To dramatically change drug development and discovery at least two areas need to be looked at – models of screening drugs and risk. New technologies are helping reduce failure times for drugs. Pharma companies need to look at what these technologies could do for them and act on it.

Two solutions that could prove vital to failing faster models are earlier ADME-Tox testing and human microdosing.

Early ADME-Tox

Many pharmaceutical companies are now integrating ADME-Tox (absorption, distribution, metabolism, excretion and toxicology) programmes with high-throughput assays earlier in the drug screening process in order for these to be carried out at an initial stage of the drug discovery pipeline.

“We’ve been doing this for about five or six years now with greater visibility throughout the drug discovery process and what we’ve seen is that as programmes are trying to develop compounds against their targets, the earlier they use ADME-Tox technology the sooner they can make decisions about which ones fail and which ones to progress, and this makes the whole process much faster,” explains Janet Kolb, Senior Research Investigator at Bristol-Myers Squibb.

Previously people would look for compounds that were active against the target and then they would do certain safety evaluations, move into animal testing, and then more safety evaluations would be performed. “Now, things are done in parallel,” says Kolb, “and there is actually less work overall to be done. Therefore less money is spent before you find out things that you should have known earlier.”

Toxicology is a difficult area; most of the traditional ADME-Tox assays were done in small numbers of compounds at later stages in the drug discovery pipeline and a lot has been done to bring this to an earlier stage with high-throughput technologies. Although some types of toxicity can now be done via a high-throughput assay there are still types of tox that are very low-throughput. Kolb: “It’s important to bring most toxicology studies down to an earlier, more-throughput stage, but I’m not exactly sure when these technologies will become widely available. Many companies are working on it and trying to design assays that can be done at an earlier stage, which are both general and specific indicators of different types of toxicology. Within a year or two, we should have access to some very high quality toxicology assays.”

ADME-Tox produces a large mass of multi-faceted data that needs to be thoroughly analysed and interpreted, enabling scientists to predict what will happen in an animal or a clinic. But this analysis can be time consuming. “To take advantage of high-throughput technology, including all the databasing and all the abilities to analyse data quickly, automatically insert the manual review only where necessary,” suggests Kolb. “Just put the person in there to do the interpretation at the crucial point, which is done here and in several other places.”

Asked her opinion on the future of ADME-Tox in the pharmaceutical industry, Kolb says, “We’ve seen this early ADME-Tox take hold in a couple of companies first and then become more widespread. There is certainly a lot more interest in it industry wide than there has been, even a year ago. This area is opening up and will make the entire drug discovery process more efficient. It will end up being a process to progress drugs at an earlier stage by leveraging the technology that was developed in other areas for high-throughput screening and genomics and informatics.”

Microdosing

Microdosing is a so-called phase 0 trial, although this is not strictly true. Microdosing is a term applied to administration of very small doses and sits equally well within Phase I and II as it does in the space prior to Phase I. There is a misconception that microdosing is only used in compound selection. Microdosing involves administering a sub-therapeutic dose to a human subject to provide adsorption and pharmacokinetic data. With this data a decision can then be as whether this drug should be selected for further testing.

The microdosing approach offers early human screening and a greater predictability of a drug. It could potentially reduce the time of pre-clinical testing from 18 months to four to six months and cut down associated expenses by 10 times according to the European Union Microdose AMS Partnership Programme (EUMAPP).

Dr Lloyd Stevens, Principal Scientist at Pharmaceutical Profiles, explains the concept: “Microdosing is a new technology or a new process of evaluating very small doses of drugs in man. It has come about because of the availability of a very sensitive and specific analytic method. The introduction of Accelerator Mass Spectrometry (AMS); allows the measurement of drug concentrations down to 10-18 molar. Because we have this extremely sensitive methodology it means we can actually give much lower doses to healthy volunteers in order to define the pharmacokinetics.”

Dr Graham Lappin, Head of Research and Development at Xceleron adds, “You actually use the target species, in other words human, as opposed to animal or an in vitro system. You are doing this at a very, very low dose; so it’s right species, low dose as opposed to a higher dose with the wrong species. It’s meant to be a tool in the toolbox. It’s meant to be applied intelligently, in light of all the other information and data that you may have.”

Microdosing is only possible due to new technological advances in detecting almost single molecules. AMS is a technique that measures long-lived radio-nuclides that occur in our environment naturally, using a particle accelerator in conjunction with ion sources, magnets and detectors to single out the presence of specific atoms. The Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) trial was set up to show whether microdosing could predict the pharmacokinetic properties at therapeutic doses of five drugs with various properties.

Dr Lappin believes, “The CREAM trial made a very important contribution to our understanding of how microdosing can contribute to the drug development process. It’s probably the first microdose publication which has been done to that extent, asking very specific questions of how microdosing might have predicted those particular drugs we used, in a clinical setting, in humans.”

Dr Stevens is slightly more apprehensive: “The results of the CREAM trial are a little bit confusing in that they’ve been able to validate the extrapolation from microdose to therapeutic dose, but it doesn’t necessarily mean that you can extend that to any other drugs. We really have to wait another two or three years until there is a lot more information in the public domain before we can put the predictive capability of microdosing in its true context.”

There are criticisms that microdosing may not be able to accurately predict the behaviour of clinical doses. Dr Stevens believes the validation of using microdosing in a predictive capacity “is something that occurs retrospectively”. He says, “You have to go through the whole process for testing your new drugs in man at therapeutic doses to see whether your microdosing did have true predictive capability. Nevertheless the experience gained with particular classes of drugs with a similar chemical structure can be used predicatively providing that they are behaving in a similar way when they are administered to animals and to man.”

Dr Lappin sees the criticisms in questions of linearity. “There seems to be an expectation amongst some critics of microdosing that you have to have perfect linearity between a microdose in order to get an appropriate answer. Now if you compare that level of stringency against in vitro and animal models then the in vitro and animal models do not stack up either. It doesn’t have to be perfectly scaleable.”

In order to understand how microdosing could be applied in early drug development, Dr Stevens asks us to assess the utility of microdosing in two situations.

Firstly, is in compound selection and characterisation, as discussed above. Compound selection in microdosing allows for the characterisation of molecules and could be particularly useful for small pharma companies who want to give confidence to investors by selecting specific drug candidates to minimise the risk of early clinical failure. There is also evidence the suggest that some companies are using microdosing to characterise back-up compounds in parallel to clinical evaluation of the lead molecule. This would facilitate rapid substitution for a failed lead compound.

The second would be as a method for defining the pharmacokinetics of drugs after intravenous administration. Intravenous application of 14-C-microdoses is, he says, “going to have much wider application across all molecules. It is certainly possible with microdosing studies nowadays to undertake intravenous dosing at exactly the same time as oral dosing. Intravenous pharmacokinetics are defined by AMS detection of the intravenously administered 14C-drug, whereas the oral kinetics are defined by the more usual LC-MS/MS assay. This dosing strategy removes the argument against extrapolation from a micro- to macro-dose and therefore, will provide information on systemic pharmacokinetics in man, to quantify clearance and volumes of distribution, plus differentiate between disposition kinetics after iv-dosing from the oral bioavailability issues due to metabolism and formulation. Applications of intravenous dosing within early clinical development include determination of absolute bioavailability, quantification of drug-drug interactions occurring for drug absorption and/or clearance and description of the metabolite profile very early in the phase I program.”

Asked for his opinion on the future of clinical trials within the pharmaceutical industry, Dr Stevens adds, “There is a big change taking place at the moment within the pharmaceutical industry and in general terms the future is healthy for those pharmaceutical companies that embrace and implement new technologies.”

The importance of new technologies

Kolb believes it is “absolutely crucial” to look to new technologies allowing drugs to be failed faster. “It takes so long to develop a drug that we want to do everything we can to do that faster and safer. What we need to do is develop that technology to allow us to allow us to look at a great number of compounds while selections are still being made for what chemo-type and what kind of drug to push forward. It saves time in getting those drugs out to the public and it saves the company money.”

Dr Lappin agrees: “ I think that the pharmaceutical industries need to be a lot more courageous in adopting a lot of this technology. They are conservative by nature and some of them are very risk averse and new technologies always come with a risk.”

Source: Xceleron

Janet Kolb: “It is absolutely crucial to look to new technologies in helping reduce failure times for drugs”

Dr Lloyd Stevens: “It is vital, absolutely vital and the industry should do nothing but push the boundaries of new technologies more and more”

Dr Graham Lappin: “The pharmaceutical industries need to be a lot more courageous in adopting a lot of this technology”