3rd Meeting around Achondroplasia in Málaga

The scientific sessions of the 3rd meeting of the Achondroplasia Unit

of Málaga University Hospital that was held on the 18th November in Málaga, south of Spain, presenting a significant range of content. The official language of the meeting was Spanish and just one presentation was conducted in English. The participation was intense, with more than 300 participants and nearly 80 children with achondroplasia. The program of the meeting was diverse, from the current surgery approach in limb lengthening to the Therachon presentation of TA-46 ending in a roundtable about the challenges faced by brothers of children with achondroplasia.

In this article, we present the scientifical and medical highlights of the 3rd meeting.

The first roundtable was about the "Current state of lengthening surgery in the achondroplastic patient", chaired by Dr. Felipe Luna, the head orthopedic surgeon from Malaga Central hospital "Virgen de la Vitoria". The orthopedic surgeons that participated in this roundtable started to explain the basics of achondroplasia, which was followed by the evolution of lengthening process for skeletal dysplasias, with more relevance to achondroplasia. The roundtable ended with the presentation of the intramedullary nail as a new resource in the Malaga University Hospital. 

Figure 1. Achondroplasia, exploratory protocol and follow-up. From left to right: Dr. Antonio Leiva, Dr. Francisco Delgado, Dr. Felipe Luna and Dr. Alfonso Queipo

 

The second roundtable was about "Rehabilitation in the lengthening process in the achondroplastic patient", presented by Gustavo Pérez, a physiotherapist with experience in these cases.

Figure 2. Gustavo Pérez during his presentation

 

During this roundtable were presented the major goals of action by using physiotherapy after lengthening surgery in achondroplasia. Physiotherapy was presented as being the first line intervention to avoid joint stiffness, favor support, body weight loading and walking, to help strengthen the not directly affected body areas and avoid soft tissues retractions.

Figure 3. Techniques used by physiotherapy in limb lengthening

 

Gustavo Pérez also emphasized some of the techniques used during the recovery process namely: active mobilizations of the implied joints; postural control exercises standing; walking correction and mesotherapy of the soft tissues and muscle-tendon stretches

This roundtable was followed by a presentation from Christian Meyer, MD, Ph.D. and Chief Medical Officer of Therachon BioTech. with the theme "Preclinical research: An Orphan drug for Achondroplasia". 

Therachon was represented at this meeting also by Elvire Gouze, head researcher of iBV and Therachon, and Celine Saint-Laurent, Ph.D. student and one of the young researchers of Elvire Gouze team.

Figure 4. Therachon presentation front slide. 

Figure 5. Christian Meyer, did his presentation in English and Belén Pimentel, Scientific Adviser of FIMABIS, followed up by doing the translation to Spanish.

Figure 6. Preclinical data of the product for achondroplasia in development by Therachon, the soluble FGFR3, TA-46

Christian Meyer showed in a very visual and clear presentation, evident data of efficacy of the soluble FGFR3 (TA-46) in the mouse model with achondroplasia. The TA-46 was already granted by EMA and FDA an Orphan Drug designation and the company wants also to conduct a natural history study, also known as an observational study in 2018 with children with achondroplasia. In this particular study, no investigational drug will be administered. 

In figure 6, on the left, are shown 3 mice with the same age. There is a mouse with no mutation at the top (called wild-type), other on the left that has with achondroplasia, much smaller than the other two and the one below, has achondroplasia, but received 3 doses of TA-46, one per week, during an interval of time of 18 days. The TA-46 will also be administered once a week to children with achondroplasia.

Christian Meyer said that TA-46 will be heading to phase 1 in the first half of 2018, that is conducted with healthy adult volunteers, and that will be announced at the website www.clinicaltrial.gov. The company is aiming to start phase 2, the trial with children with achondroplasia, in 2019 and the selected centers for the Clinical trial will be announced on the same website.

Figure 7. Predicted timeline of the TA-46 development

Figure 8. The summary of the presentation on the TA-46 development

 

The following session was presented by António Leiva, orthopedic surgeon, in a representation of BioMarin, with the following theme  "Clinical Research. Achondroplasia Natural History Multicenter Clinical Study". In this meeting, BioMarin was represented by José Luís Hornillos, Associate Country Manager and by Charlotte Roberts, Senior Manager for Dev Sci Patient Advocacy.

Firstly, it was presented the ongoing studies for achondroplasia, the phase 2, the BMN 111-202 study, that started in 2014 and will end in 2019, which includes children from 5 to 14 years old and also the phase 3 interventional study, 111-301, that will start in January 2018 with 110 children all over the globe, with children from 5 to 18 years-old. The children enrolled in this study must have been at least for 6 months in the Natural history study, BMN 111-901.

In the 111-301 study, children will be randomly divided into two groups: the interventional group, that will receive 15 μg/kg/day of Vosoritide and the placebo group. This study will be conducted during 1 year with the goal to test efficacy and security of BMN111 (Vosoritide). The following data will be collected during this period of time: Changes in the annual growth curve, height, trunk-limbs proportionality, security and tolerability, pharmacokinetics, biomarkers and daily life activities.

The novelty in this session was the presentation of the BMN 111-501 study, that will approach the "Impact of achondroplasia on Quality of life, healthcare resource use, clinical, socioeconomic and psychosocial state of individual".

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Figure 9. The BMN 111-501 study

Figure 10. The BMN 111-501 study description

 

The BMN 111-501 study will be an observational, multinational, epidemiologic, retrospective and transversal study with patients with achondroplasia. A transversal study, also known as a cross-sectional study, is used to analyze data collected from a selected population at a specific point in time. It will be conducted in Denmark, Germany, Sweden, and Spain.

The theme of the fifth roundtable was the Research initiatives in achondroplasia and other bone dysplasias.

First, Laura Garde, dietitian-nutritionist, presented a study on the "Analysis of the resting energy expenditure in children with achondroplasia, quantified with indirect calorimetry".

Figure 11. Laura Garde poster on Analysis of the resting energy expenditure in children with achondroplasia, quantified with indirect calorimetry, 2017

 

Children with achondroplasia tend to develop obesity from early childhood which is a cause of aggravation of psycho-social problems, usual medical complications and high morbidity-mortality due to cardiovascular problems. Currently, there are not any validated and specific predictive models to estimate the resting energy expenditure in children with achondroplasia, that can allow the initiation of a diet intervention to treat obesity in these cases. This study was conducted with the collaboration of 18 children, from 6 to 13 years-old. Results obtained from children below 6 years old were not ideal due to some respiratory distress children showed while performing the study. This was a limitation to include younger children than 6 years-old. The full poster can be seen here (in Spanish).

The study team concluded that is very important for clinicians to have available methodological resources to diagnosed and treat obesity in order to improve patients quality of life. Is very relevance to keep studying about this topic, and learning from the limitations that were found during this study to improve further research.

Next, it was time for Karen Heath, clinical molecular geneticist from the Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, to talk about how the genetic diagnosis of skeletal dysplasias is now performed.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 12. Karen Heath giving a practical example of challenges in genetic diagnosis

 

Karen talked about the latest and currently most used technology to perform genetic diagnosis called Next Generation Sequencing. In the case of achondroplasia on mutation in FGFR3 can explain 98% of cases but it is very different in other skeletal dysplasias. To explain this complex method of reading the DNA flaws, Karen explained that it is similar to searching for a needle in a haystack. She went onto to describe what genetic studies can be performed using an example of an apple. The apple pips represent what we use currently in routine genetic diagnosis, i.e. all the genes known to cause a skeletal dysplasia. Then if we don´t identify the gene we can then look at a portion of the apple (genetic term “exome”) which is just a piece of the full amount of genetic information that each person carries. In the future, we will be able to look at all the apple (genetic term “genome”) but this is currently difficult especially when you don´t have many apples (i.e. individuals with the same skeletal dysplasia).

 

Figure 13. Achondroplasia is a single point mutation. In Karen Heath presentation

Figure 14. Searching for the genetic defect. In Karen Heath presentation

Figure 15. Genome sequencing to identify new genes. In Karen Heath presentation

 

Overall, the main topic of this presentation was to express that even with the best geneticists and the most modern systems, the challenge of genetic diagnosis of skeletal dysplasias is very high due to the complexity of the clinical features and not all the genes involved are presently known.

Closing this roundtable, Antonio Leiva also presented an innovative project that will take place in the south of Spain, that aims to collect daily life data directly from patients with achondroplasia through the app "My leaf".

And to finish, a Thank you note to Laura Garde and Karen Heath for kindly sharing documentation that was presented at the meeting.