Novartis AFQ056 trials in fragile X syndrome

Published Feb 2015


Fragile X syndrome is the most common monogenic (meaning linked to a single gene) cause of intellectual and developmental disability. The DNA changes in this single gene, the gene FMR1, lead to the creation of an incomplete or missing protein (called FMRP) that is essential for brain development. The brain changes due to this missing protein themselves lead to the intellectual and learning difficulties experienced by people with fragile X syndrome, as well as behaviour and cognitive difficulties, anxiety, or seizures.  A company called Novartis created a new medicine, AFQ056 (or Mavoglurant), which they hoped would have some effects similar to the missing protein


Why did we do this study?

In pre-clinical studies (in laboratories, with animal models), researchers found that AFQ056 indeed interacted with neurons in the brain, and stimulated certain social and cognitive behaviours. Early human studies also showed some benefit so this study was being run by Novartis to see whether AFQ056 really helped people with fragile X syndrome. 


What did we do?

Novartis were running two trials to see if their new medicine, AFQ056, was helpful for difficult behaviours in fragile X syndrome; one trial was in adults, the other in adolescents (12 – 17 year olds). Both lasted for 4 months and the aim was to see if AFQ056 was more helpful than a placebo. In these studies, some volunteers were given the active medicine, AFQ056, while the rest were given placebo. During the trial neither the volunteers nor the doctors prescribing the medicine knew whether they were given placebo or AFQ056.


What did we find?

The results from these trials are negative, i.e. AFQ056 was not found to be effective for the treatment of difficult behaviours in fragile X syndrome. More information is given below.


Results of the Randomised Controlled Trials

The researchers found that almost everyone in the studies felt they had benefitted in some way regardless of whether they had been given AFQ056 or placebo. The conclusions from these trials are that AFQ056 does not work in any useful way for people with fragile X syndrome.

Novartis also wondered whether they simply had not measured the correct behaviours to show an improvement – if you don’t measure the right things then how can you tell if they are better? So they asked researchers to write a description of how each volunteer improved then looked to see whether certain types of improvements were more common in those on AFQ056 or placebo. They did not find any difference between the two meaning that the lack of benefit was not just because they did not look in the right place.

Finally, they checked to see whether there was any evidence that AFQ056 worked for younger people in the trials and not for older people. There was no evidence that this was the case.


Results of the continuation trials

Those people who were in the 4 month trials described above were offered the chance to stay on the medicine; some people have therefore been taking AFQ056 for more than 2 years. These continuation studies do not have a placebo – i.e. everyone is taking AFQ056. Almost everyone in these studies reported some improvement; however these improvements were no larger than those seen in people taking placebo in the randomized trials. The conclusions from these continuation studies is that even if taken for a long time AFQ056 does not lead to more improvements than would be seen with a placebo.


The Future for AFQ056

As a result of these studies, Novartis have discontinued their research into AFQ056 for fragile X syndrome. The continuation studies have stopped and the medicine has become unavailable in 2014. The lack of any evidence that younger people did better means that they have decided that they will not run the trial in 5 – 11 year old children that they had previously talked about doing.

What does it mean for the future?

The Future for Research into Medical Treatments for Fragile X Syndrome

There are a number of other medicines that are currently being considered as potentially helpful for people with fragile X syndrome. Some of them affect the brain in a similar way to AFQ056, some of them affect it differently. At least one of these medicines is being tested in children aged 5 years and over in the USA. Although the results of the Novartis trials are very disappointing the work towards finding medicines that help people with fragile X will continue.


Future Trials in the UK

At the moment we do not have any other trials running in the UK, but the Patrick Wild Centre hopes to run trials of other medicines in the not too distant future. Any research that we do relies upon people volunteering to take part so before we start another trial we sought the views of families about whether this sort of research is important to them and if so how we could go about maximising the chance of success.  You can read about this research here


The findings of the clinical trial were published in a peer-reviewed journal:

Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents.

Hagerman R, Jacquemont S, Berry-Kravis E, Des Portes V, Stanfield A, Koumaras B, Rosenkranz G, Murgia A, Wolf C, Apostol G, von Raison F. Sci Rep. 2018 Nov 19;8(1):16970. doi: 10.1038/s41598-018-34978-4.

Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.

Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, Barth GM, Jaecklin T, Apostol G, von Raison F. Sci Transl Med. 2016 Jan 13;8(321):321ra5. doi: 10.1126/scitranslmed.aab4109.

Who conducted and funded the project?

The study was conducted by a large group of researchers from around the world. In the UK the study was run by Andrew Stanfield, here at the Patrick Wild Centre. It was funded by Novartis. 

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