A single mutation of one gene can greatly influence a person’s life. One such mutation causes achondroplasia, characterized by disproportionate short stature, reduced space for the brain and debilitating respiratory complications. Currently, it has only been possible to treat the symptoms by limb lengthening, an extremely painful surgical procedure. Now scientists have discovered a molecular trap that can capture the proteins that cause the disease. This treatment is already on the way in a Phase 1 trial.
Growth is normally good, but not if it is unimpeded. This is why the human body is equipped with mechanisms that can inhibit growth. About 1 in 25,000 children have a genetic mutation in this inhibition mechanism at birth, resulting in the person being considerably shorter than average. What’s worse is that infants with achondroplasia have life-altering complications because the cranium has insufficient space for the brain and other body systems do not develop in a proportionate way, causing, for example, breathing problems. Today, only the symptoms can be treated. However, in the near future the cause of the disease can hopefully be treated.
“These children are affected because the mechanisms that help to inhibit their growth are constantly active. This new research has shown the promise that trapping the growth-inhibiting signalling protein with the protein TA-46 and treating children from infancy can normalize their growth so they can avoid complications in the brain, spine and airways,” explains Luca Santarelli, Therachon’s Chief Executive Officer, who is responsible for developing and testing this new treatment.
Life-threatening brain condition
One gene mutation in the FGFR3 gene, which codes for fibroblast growth factor receptor 3 (FGFR3), causes 97% of achondroplasia cases. For most people, fibroblast growth factor 3 (FGF3) binds to the receptor on the cell surface, sending a signal to inhibit growth. Once the signal has been sent, FGF3 is absorbed and broken down in the cell. However, people with achondroplasia have a mutation in the receptor that results in FGF3 not being absorbed and broken down.
“These children’s bone growth is therefore constantly inhibited, and the only known treatment is limb lengthening, an extremely painful and invasive surgical procedure to make them taller. We hope that the new drug will be able to treat the actual cause of the disease so that children can fully or partly avoid these potentially lifelong symptoms.”
Short stature is the most visible sign of achondroplasia. Men with achondroplasia average only 131 cm in height and women 123 cm. Being shorter and having shorter arms can make daily life challenging for everything from driving to shopping. Even worse, however, are the serious symptoms affecting infants with achondroplasia.
“One life-threatening condition is an abnormality of the junction between the cranium and the spine that reduces the space for the lower brain stem. This can result in death, and we therefore hope that our treatment can ensure that children grow normally from infancy,” explains Aled Williams who is Chief Commercial Officer in Therachon.
A eureka moment
The idea for the new treatment dates back to 2013, when Elvire Gouze, Stéphanie Garcia and their research colleagues from the Mediterranean Centre for Molecular Medicine in Nice, France noticed that people with bladder cancer also had these problems with the FGFR3 receptor. These researchers had some success using antibodies against FGF3 but had an even more brilliant idea.
“They produced a soluble form of the FGFR3 receptor that could bind to FGF3 and ‘trap’ it to prevent it from binding to the cells’ receptors. Treating mice with the liquid receptor reduced the growth-inhibiting signals so that the bones of the mice developed almost normally. This was a eureka moment, because the results were so clear.”
The soluble FGFR3 receptor traps the surplus FGF3 molecules, solving the problem that the receptors on the cell surface do not function optimally. The research results were so convincing and unequivocal that investors were eager to convert the research into an actual treatment. Therachon came into the picture at that point.
“It's rare to find a disease in which the cause and treatment are so obvious and easily quantifiable. In addition, medicine has previously been used to trap problematic molecules so this presented no problems. Further, the initial trials showed no noticeable side-effects.”
Early treatment possible
Although the results and methods are simple, there are the usual major challenges associated with drug development and the path to a marketable medicine. The French prototype was especially challenging because it was unstable. The researchers therefore had to work on developing new and more stable versions of the soluble receptor.
“In recent years, we have further developed the drug into a version that is stable both when stored at hospitals and when injected into the human body. In early 2016, we were finally satisfied with the TA-46 candidate with which we had been working, and in early 2018 we began a Phase 1 trial with healthy participants to assess the safety, side-effects and dosage.”
It is still too early to predict when the testing of this new treatment will be complete because this involves both Phase 2 and Phase 3 trials. However, the researchers hope to be able to offer treatment as part of the clinical trial programme to people with achondroplasia within the next year or so. The initial plan is to inject the medicine into children and adolescents with achondroplasia once a week.
Increasingly, however, children can be diagnosed through prenatal ultrasound scanning. So in time, it may be possible to treat children very early in their life, thereby avoiding the complications and greater risk of death in the first years of their lives.
“Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice” has been published in Science Translational Medicine. In August 2018, Novo Holdings and co-investors Cowen Healthcare Investments, Pfizer Ventures and funds managed by Tekla Capital Management LLC invested USD 60 million in Therachon’s ongoing development of a treatment for achondroplasia.