I recently realised that although ‘translation’ and ‘translational science’ have become part of the daily lexicon of drug discoverers everywhere, the way I was using the terms differed from others. I routinely use the words to describe the whole process of moving a project (asset) forward through the drug discovery phases depicted in simple form below.
Since our community seems to have hi-jacked a commonly used word and given it a new meaning, I checked on the perceived meaning of ‘translation’ with the man in the street (well it was actually a few men and a few women in a pub).
The consensus was some form of paraphrase of the Oxford English Dictionary first meaning:
‘a written or spoken rendering of the meaning of a word or text in another language’.
However, this vox pop was in a Cambridge pub, so naturally there were a few strange people in the group! One was a mathematician and she went for the third OED meaning:
‘movement of a body from one point of space to another such that every point of the body moves in the same direction and over the same distance, without any rotation, reflection, or change in size’.
And, of course, I couldn’t escape all of the biologists so there was one who was convinced it meant:
‘the process by which a sequence of nucleotide triplets in a messenger RNA molecule gives rise to a specific sequence of amino acids during synthesis of a polypeptide or protein’.
I was the only drug discoverer present so only I came up with the equivalent of meaning number 2 in the OED:
‘the conversion of something from one form or medium into another: example; the translation of research findings into clinical practice’.
I find that pubs are usually educational, and this exercise taught me that we members of the new medicines discovery community should be careful in our use and explanation of the language, particularly when communicating with funders, policy makers, etc.
The research findings involved in our form of translation usually come from an exploration of disease pathology or genetics. From my point of view there are three major barriers to the translation of these outputs, and the resulting ideas for disease intervention, into clinical practice:
- Proof of the concept that intervention in a particular biochemical process or pathway can ameliorate disease.
- The production of a suitable new molecular entity (NME) that can modulate the disease.
- Identification of a financially viable route to making the new medicine available to the patient population.
Let’s look at each of these issues:
The proof of the biochemical hypothesis is often misleadingly referred to as ‘target validation’. I try to reserve this term for the point at which the translation process is complete. A drug discovery target becomes valid only when a new medicine is generally available to patients.
Many experimental approaches are used to support the biochemical hypothesis. These include familial susceptibility to disease, identification of disease-specific mutations, and gene knock-out/knock-in studies in laboratory animals.
Some researchers attempt to use what they call ‘chemical tools’ to achieve this proof of concept. This is dangerous ground. A ‘tool’ is perceived not to be a drug candidate because it has some known liability which would prevent its development as a drug. A couple of common liabilities are insufficient on-target selectivity or an inadequate pharmacokinetic profile. In the second case the tool could indeed assist the validation process if it is biochemically selective and can be administered in a way so as to achieve effective concentrations at the proposed site of action; but in the first case, the off-target activity will always compromise the confirmation of the hypothesis. Most worryingly in terms of the finances of drug discovery, a failure to prove the concept with a ‘tool’ compound is rarely taken to show invalidation of the target. A well designed experiment could indeed invalidate the approach and would dramatically reduce the costs of drug discovery by allowing projects to be stopped at an early stage. Advocates of the approach will usually find some excuse to continue the project; such as ‘the tool was not good enough’. In order to be a useful tool, it must be accepted to be ‘good enough’ to invalidate the target before such ‘proof of concept’ studies are initiated.
The quality of the NME is critical to its success as a medicine.
Quality covers many areas. The target product profile will determine acceptable routes of administration and frequency of dosing, and within these constraints, the molecule must be able to access the target and engage the target for sufficient time and at sufficient concentration to produce the desired functional effect.
Other quality factors include safety, stability, ease of formulation and production capability at scale.
In safety terms, the therapeutic margin (the ratio of the exposure following an effective dose to the exposure at the maximum safe dose) is critical. Also important are the dose-proportionality of exposure, the variability of exposure between individuals, and the effect of food on bioavailability.
The translational step which exposes humans to the NME is increasingly a major issue for drug discovery programmes. Many diseases previously thought to be homogeneous are now known to be segmented into sub-types, and selection of an appropriate sub-group of the patient population generates increased accuracy and statistical power in the interpretation of clinical trial results. Patient genotype also contributes to the way in which an NME behaves in terms of pharmacokinetics and safety and this can also aid intelligent patient selection for drug evaluation.
The use of biomarkers and imaging technology is now seen to be an essential facet of early stage clinical evaluation and contributes greatly to improved decision-making in this phase of the translation. These biomarkers can provide measures of disease progression, pharmacodynamic indicators or surrogate measures of both therapeutic efficacy and side-effect liability .
Much of public ‘translational science’ funding is directed to the first time in human studies and to the first demonstration of human efficacy. Indeed many policy makers think that this is the whole of ‘translational science’ and forget about the requirement for a high quality NME whose invention in fact takes a significant part of the 15 year lifespan of the translation process.
Pharmaceutical companies are encouraged by their stock analysts to focus on return on R&D investment. This causes them to limit the overall size of their research investment and to focus only on medicines that they forecast to be profitable enough to recover a return on the estimated $1.5bio cost for each successful drug launched. This has resulted in whole areas of disease being underserved by the commercial community.
Present advances in medicine are providing much improved knowledge on which drug is likely to be effective in particular patient sub-groups as described above. The identification of a well-defined responding patient population is a significant part of the translation process today. This fragmentation/segmentation/personalisation of the marketplace further compromises the financial return for the inventors of new medicines.
The pharmacos’ only response in this situation is to increase the price for treatment of an individual patient. This is fine in some circumstances, but is widely recognised to be inadequate for the whole landscape of new medicine discovery.
New business models are emerging in which other stakeholders collaborate with pharmaceutical companies. In rare, but likely to become more frequent, cases these alternative agencies carry out (or pay for) the whole translation process from discovery to development to delivery to patients. These other stakeholders (‘social investors’) today include governments, medical charities, patient advocacy groups and venture philanthropists. In collaboration mode, these stakeholders provide funding that allows pharmaceutical companies to reduce their costs and also their risks. However, in cases where the patient population is unable to pay realistic prices for new medicines, the whole process will need to be covered by the ‘social investors’. These alternative stakeholders will increasingly emphasise social return along with the straightforward financial return on the investment in a new medicine.
As the pharmaceutical companies search for different economically viable ways of introducing new medicines, they are increasingly supporting ‘open innovation’ and entering into a large number of collaborations with other players. So far, most of these ‘collaborations’ have usually involved the pharmaco trawling the outside world for ideas that it can support relatively cheaply until the point at which the asset has been sufficiently de-risked to justify bringing it into the internal portfolio. This one-way traffic will increasingly be superceded by a two-way traffic system. Assets in the internal portfolio which either no longer fit a changed strategic direction for the company, or are forecast to give insufficient financial return, will be out-placed to be further ‘translated’ by other more suitable stakeholders.
The field of new medicines discovery is rapidly moving. We have real opportunities, through science advances and business innovation, to efficiently and effectively ‘translate’ the evolving understanding of disease biology to provide the drugs that will support and promote the health and well-being of future patients.
These exciting developments have encouraged One Nucleus to initiate a series of conferences on the topic. The first ON Helix Conference will take place on 9 July this year at the Wellcome Trust Genome Campus. Sign up now to hear experts in the field and to join the debate.
Written by Geoff Lawton, Founder, INMedD
Geoff Lawton is a founder of INMedD which will establish a drug discovery social enterprise.
The One Nucleus blog is written by individuals and is not necessarily a reflection of the views held by One Nucleus.
