Q&A with Laurent Servais
Could you clarify the connection between the Natural History Study and the clinical trials? Obviously, when a patient is in the Natural History study and is eligible to go into the trial, they just drop out of the Natural History Study and go straight into the trial. That’s what we’ve done for Spinal Muscular Atrophy and it’s extremely efficient. So please feel free to drop me an email if you’re interested in the trials or in the Natural History Study. And both are quite compatible. Obviously, it’s much easier to include patients when they are in the Natural History Study because we know them, we know where they are.
There is already the global Angelman Syndrome registry, does it not cover the same questions as the upcoming Natural History Study? Not at all. A registry and a natural history study are two different measures, but you can get into both. And please do it, feel free to do it. But this is a completely different methodology and we need both because they don’t use the same kind of metrics. They don’t have the same objective.
I know the GTX-102 trial has arrived to the UK even without the Natural History Study being initiated, what will be the impact of the Natural History Study? Well, actually, as you might imagine, we have been in discussions for more than one year and this trial and the Natural History Study are very related to each other. The impact from the Natural History Study is extremely positive, as soon as I can drop off patients from the Study to include these very patients in the trial, I will be more than happy to do it. So, I consider the Study as a list of potential patients for the trial.
Do you have clinical centres for the Natural History Study already identified or are you looking for interested clinicians to participate? Today this study is monocentric. If we can get more funding we could consider an extension. The centre is Oxford. Dora Markati will be the person in charge, and myself or course as the coordinating investigator. The principal investigator is Dr Usha Kini. Dora will certainly be the hands-on person, so you can connect with one of us.
What defines the number of participants in the natural history, is it the cost or something else? It’s two things. The first one is cost. The second is methodology. My experience is in Duchenne when you want to validate an outcome in a rare disease, there is a kind of a magic number which is 30. Because when we have more than 30 patients, from a longitudal perspective, you can use different statistics vs when you have 10 patients. With 30 patients, it’s globally admitted that you can use parametric statistics. So if we want 30 patients over one year, we know it’s better to start with 40 and then you have penetration rate and you have patients that you take out of the natural history study to put them in clinical trials. So that if you want to have 30 patients and to have a full application to be able to go MHRA or EMA or FDA it’s better to have at least 30 patients. So that’s actually why. This also costs a lot of money, I can tell you, because everything is super expensive. And so, at the end of the day, you must have a pragmatic approach and say, Oh, how many patients can be coming?
Given the frequencies of some of the subtypes, and I’m biassed our daughter is UPD, so UPD is 3%, and if we’re taking a randomised snapshot, if that’s the approach for the Natural History Study, then you’re talking about a single UPD participant in the study. But I have a feeling that you’re not taking this approach and that you might have a larger representation of this smaller class than 3%. Yeah, good question. The good thing is that we are very connected with other investigators through FAST US and that we have shared openly the protocol of the natural history study with many investigators around the world: in Latin America, Belgium, France, in many other countries. We are also connected with two pharma companies, which are not GeneTX and Ultragenix, who also want to use Oxford protocol together. So the idea is that if there are several countries and several investigators using the same protocol that they have shared openly as a community, then you can increase, without increasing the cost, the number of patients and gather a much broader amount of patients. So, at the end of the day, you will always have very where genotypes. But the good news is that this is something that exists for other diseases also. If you consider Spinal Muscular Atrophy, there are 5% of patients with a deletion on one allele and a point mutation on the other one. 5% of something that affects 1 out of 10,000. In Duchenne there’s a patient who is the only one in the world with this very specific mutation. It’s something we are used to in the rare diseases, and what we need is to show that these patients either model the behaviour of the others in the spectrum, or try to figure out how special is special. I’m not saying that this will solve all the issues but we need data that. And that’s why we have shared openly our protocol with many other countries, and many other countries are starting with the same kind of protocol and the same kind of outcomes.
Can the protocol be shared with the general public, or is it for special audiences only for now? No, when you have this kind of protocol, you have what we call a confidential disclosure agreement, and this is not something we can share. On top of that, you cannot distribute to a patient anything that has not been approved by the ethics committee. Everything that is patient-facing must be approved by the ethics committee. So, there is the informed consent which recapitulates that everything must be in plain English, everything that’s important for the trial. On top of that when you are included in the trial as a patient, it is your right, and it is the duty of the investigator to take the time you need to answer all the questions. But the protocol itself is a confidential document.