The best objective of the session was to look at the various ways in which we are developing drugs in different phases, different indications and with different mechanisms of action which give us, if you look at quite a different landscape, depending on the type of drug that you are developing and the stage in which we are. Clearly we have many, many things to do still. We have to improve the clinical development path that we have at present and we have to face a number of challenges related to identifying the best patients to be treated with the optimal drug for them and at the same time be able to deliver the best option for the patient.
How do the objectives of maximum tolerable dose and monotherapy efficacy come into this?
They come into this because this is a standard way of developing drugs, if you want. If you still see in many studies that the target is officially the MTD, this is partly embedded in the guidelines, partly not. But, as a result, in studies in which you say we have identified a dose for treating patients in phase II etc. etc. and in further early development we didn’t reach the MTD which technically means the study failed because you didn’t reach it. In reality it’s a full success because you have been able to show that the drug is safe and active at a dose that will never put anybody, or is unlikely to put anybody, at risk of any side effect.
Further than that in certain areas like, for example, the development of antibodies, especially for antibodies that are not conjugated to a cytotoxic or any other drugs, the concept of the MTD simply doesn’t work because they are so targeted that we don’t have side effects linked to other organs unless there is a crossover activity between the tumour and the normal organ. Funnily enough, this is happening now also with tyrosine kinase inhibitors because we are reaching a level of specificity with a simple chemical molecule for the target that we are trying to address that rarely you see an effect on, at least for some of them, other organs than the tumour.
What would be a good supplementary endpoint?
There is a good supplementary endpoint that already exists for several years is the biological effective dose which is essentially the dose at which you get the best biological effect against the target, in this case the tumour. It can be identified – I gave some examples during my presentation. What you need is a good pharmacodynamics marker, we have in a few cases, and when we have it I think we should use it.
Tell us about the MERCURY trial.
MERCURY is an evolution, an evolution of several trials – of WINTHER, of TAPUR and partly also by our experience in phase I. Essentially it has incorporated a couple of novelties, one is that, as said, we look also at the normal tissue. By looking at the normal tissue you are able to identify the presence or absence of a target for the drug in the tissue. This is important because it tells us if this particular mutation, for example, or over-expression of a receptor is a driver of the tumour or not. If you have the same level of expression in the normal tissue and in the tumour likely it’s not. That will allow us to not treat those patients but concentrate on the patients that have the higher probability of having a tumour response which is a further selection of patients and hopefully should increase the level of patient benefit from treatment from the 30-35% of WINTHER to even higher.
The second is that we are considering MERCURY as a combinatory trial, trying to select as fast as possible rational combinations to be then applied on a larger population, again in selected patients which have the highest probability of benefitting from treatment. I’m saying probability because nothing is guaranteed at the end of the day.
The third characteristic that we would like to include in the studies is to use it as a non-competitive space so that different companies can put their drug in and eventually even combining which we already did and I think I show an example. The PI3K that we combined with the MEK inhibitor was not from Merck, was in fact from Sanofi, and it was a collaboration between two companies. So if we did it that way I think we can do it in the context of a study like MERCURY.
