Treating achondroplasia: from dream to reality

The future is at our door

We are now less than two weeks from Voxzogo's PDUFA* date, the day when the Food and Drug Administration (FDA) will release its response to vosoritide's application for commercialization. Vosoritide has been under clinical development for about ten years now, being investigated as a therapy for achondroplasia, the most common form of dwarfism. This long run has been taken with several humps and bumps throughout the way and, now that the drug is already approved in Europe, the expectations are all on how, and if, the decision by the FDA will truly open new doors for families interested in improving the health of their affected children. But let's see what these expectations are all about since the next steps may come with surprises.

As the 17 readers of this blog certainly know, achondroplasia is caused by a mutation on the gene that encodes an enzyme called fibroblast growth factor receptor 3 (FGFR3). I know, I know, I might become a little bit repetitive, but I think that the circle I will be doing here might help us to understand what we may expect on that vosoritide's breakthrough date (PDUFA). 

Causes and consequences

FGFR3, along with many other enzymes, plays a fundamental role during the phase scientists call development. Development starts with the fertilized egg and goes up until the end of puberty, and it is comprised by biological processes tightly regulated by hundreds of enzymes like FGFR3. You could call these processes standard operating procedures (SOPs). These enzymes work in concert to make the SOPs to run smoothly, but when one of them is modified (mutated) either working more than planned or not working at all, then the development process is deranged. 

FGFR3 is particularly important in bone development because it works by reducing the pace of bone growth, modulating the growth stimuli produced by several other enzymes. In a car, while those other enzymes would work as an accelerator, FGFR3 is a brake. If there was no FGFR3, bones would grow without control and cause several medical problems. In fact, mutations in FGFR3 that inactivate it do cause an overgrowth syndrome known as CATSHL syndrome  (camptodactyly, tall stature, scoliosis and hearing loss) (1).

A brake is important in a car, so its speed can be controlled. However, the mutation in FGFR3 that causes achondroplasia makes it to work too much, so the car can barely move (the brake rules over the accelerator). The result is that, in achondroplasia, bones, and especially the long bones and vertebrae, grow just a fraction of what they were supposed to, in contrast with all other body tissues. Individuals with achondroplasia have short adult stature but this is not the only key characteristic since restricted skeletal growth has consequences beyond height. 

The imbalance between shorter or narrow bones compared to all the other normal tissues will frequently lead to clinical complications that are listed in the published guidelines about achondroplasia. Due to their bone growth impairment, on average individuals with achondroplasia require more healthcare utilization, including surgical treatment to common orthopedic and neurological complications (e.g.: foramen magnum stenosis, spinal stenosis, joint problems, etc.) among others, while adults are also prone to obesity, higher incidence of cardiac disorders and have a shorter life span compared to the general population. (2)

As the knowledge about the natural history of achondroplasia improves it becomes clear that it is a genetic disorder affecting much more than the final height. 

Developing the first therapy for achondroplasia

The gene alteration that leads to achondroplasia was identified almost 30 years ago (3-5), but only more recently efforts have been directed to find ways to correct the bone growth defect caused by the overactive FGFR3 mutation. This became possible because the chemical networks regulated by FGFR3 have been identified (Figure 1) as well as of most of those pathways driven by the other agents involved in bone development and growth. This in turn allowed scientists to find out which of those pathways were impacted by mutations in FGFR3. (6)

Figure 1. FGFR3 relevant pathways in the chondrocyte.

One of those other bone development agents is an enzyme called natriuretic peptide receptor B (NPR-B). Both FGFR3 and NPR-B are located in the cell membrane of the chondrocytes, the cells that govern bone growth. They can be seen as power switches in our home walls that are turned on and off when we move them up and down. In the body, FGFR3 is turned on by FGFs while NPR-B is activated by the C-type natriuretic peptide (CNP). Scientists have discovered that CNP is a positive bone growth agent that works precisely reducing the activity of FGFR3 in the chondrocyte. (Figure 2). They have also seen that the FGFR3 pathway may downregulate the CNP+NPR-B axis. (7)

Figure 2. Crosstalk of FGFR3 and CNP pathways in the chondrocyte.

 

Having learned that CNP modulates FGFR3 activity and that it was working less than normal in achondroplasia, it was natural to check out if providing supplemental CNP would help reducing the effects of the mutated FGFR3. In fact, this was readily seen: adding CNP to cell cultures, bone explants and animal models of achondroplasia restored, at least partially, bone growth. (8) A first potential therapy for achondroplasia was at hand.

However, one problem that scientists faced when dealing with CNP is that this is a fragile molecule. Peptides like CNP are very active and must stay under control. When in the blood CNP will last less than three minutes circulating as it is an easy target for natural clearing systems we have. So, how to solve this problem? They learned that another natriuretic peptide called BNP is naturally more resistant to the clearing system due to having a slightly different structure. They adapted CNP to "look like" BNP and this change rendered the invention of vosoritide. (9) Therefore, vosoritide is a modified version of CNP, also called an analogue.

Vosoritide lasts about 20 minutes in the blood, enough time to reach the bone growth zones (the growth plates) and to exert its effects. So, what are these effects ? By reducing FGFR3 activity the NPR-B axis restores the chondrocyte capability to proliferate and enlarge (hypertrophy), which are the two key steps they need to take to make the bones grow. (8)

One hard challenge in the beginning of the clinical development of vosoritide must have been how to measure its efficacy. In humans, bone growth constitutes a long and slow process so changes are not identified in a day-to-day basis, but can only be seen when two distant time points are compared. This slow development makes it difficult to set objectives when someone is trying to correct a derangement in the bone growth process. Even harder would be to confirm whether the improved bone growth under the experimental drug would provide additional benefits in terms of reducing the frequent medical complications that result from the short and narrow bones, such as spinal stenosis. So, how can we measure those effects? After long discussions, as we can see described in the many public calls (mostly those financial conferences) throughout the years, the agreed endpoint between the developer and regulators that would allow determining if vosoritide was beneficial (efficacy) in the treatment of achondroplasia was bone growth velocity.

Vosoritide has been under tests in children with achondroplasia for years now and, according to the data already available, it helps to restore bone growth to an extent that is close to what happens in an average child. (10-12) The data that have been submitted to the European Medicines Agency (EMA) have been analyzed and, in last August, vosoritide was approved for the treatment of achondroplasia in the European countries that work with that agency. The same data have also been submitted to the Food and Drug Administration (FDA) which will be delivering their feedback in a few days more, as I mentioned above.

The future is present

The approval of vosoritide in Europe is a landmark for the treatment of achondroplasia and very likely to many other skeletal dysplasias where bone growth is impaired. One important characteristic of the CNP+NPR-B axis is that it works independently of FGFR3. The use of CNP analogues like vosoritide (there are others in development) may help improve bone growth in those other genetic disorders, thus not only improving height, but also medical complications related to other restricted growth conditions, as we expect to see in achondroplasia.

It may take a few years more to see whether children being treated with vosoritide will suffer fewer complications such as middle ear infections, sleep apnea, spinal stenosis, genu varum, etc. than what is frequently seen today, but the long term expectations about these potential benefits should not drive any conclusion that this drug, and all the other candidates to come, would not help to reduce those complications. 

And why is that so? Simply because the treatment is systemic, meaning that the drug reaches all bones at the same time. There is no logic in thinking that only one type of bone would be affected by the treatment. Therefore, the treatment not only should increase the length of long bones but also should help widening other bones such as the vertebrae, which grow through growth plates, too.

Children's health

Here is the World Health Organization definition of health:

• Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.

The accumulating evidence about the natural history of achondroplasia shows that both children and adults with this skeletal dysplasia endure impacts not only on the physical aspect but both in the mental (emotional) and social well being fields, too.(13,14) It will be good to see how the upcoming pharmacological treatments for achondroplasia will affect these aspects of health. Based on published evidence, individuals submitted to limb lengthening have improved quality-of-life after the surgery (15, 16), implying that the improved height was beneficial on those other aspects of health highlighted in the WHO definition. Someone pondering about this improvement seen after lengthening surgery needs to recall that the surgery only increases height, not having any effect in other characteristics of achondroplasia and its common complications, in contrast with what is expected with pharmacological therapies.  

We can foresee a time when babies and toddlers with achondroplasia won't need MRIs to rule out foramen magnum stenosis, or children attending repeated visits to a ENT specialist to insert ear tubes, or undergo amigdalectomy to improve their sleep apnea, just to cite a few of the stressful situations they frequently endure early in life. They might also be able to do anything an average child does, without common challenges they face today due to their restricted growth.

In conclusion, based on the current evidence, I believe that with improved bone growth, children with achondroplasia under treatment with vosoritide, and in the future with other potential therapies, will achieve benefits that go beyond the reduction of the risk of medical complications but also to improvement in mental and social aspects as well. These potential benefits must be kept in mind by stakeholders that will be in charge to decide whether to adopt therapies for achondroplasia or not. For me, the simple answer is yes.

References

* From Wikipedia: PDUFA date: In United States pharmaceutical regulatory practice, the PDUFA date is the colloquial name for the date by which the Food and Drug Administration must respond to a New Drug Application or a Biologics License Application.

1. Toydemir RM, Brassington AE,  Bayrak-Toydemir P et al. Novel mutation in FGFR3 causes Camptodactyly, Tall Stature, and Hearing Loss (CATSHL) Syndrome. AGHG 2006; 79 (5): 935-41. Free access.

2. Hoover-Fong J, Scott CI, Jones MC et al. Health supervision for people with achondroplasia. Pediatrics 2020 Jun;145(6):e20201010. Free access.

3. Rousseau F, Bonaventure J, Legeai-Mallet L et al., Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994; 371 (6494); 252–54. Free access.

4. Shiang R, Thompson LM, Zhu YZ et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78 (2): 335–42.

5. Bellus GA, Hefferon TW, Ortiz de Luna R et al. Achondroplasia is defined by recurrent G380R
mutations of FGFR3. Am J Hum Genet 1995; 56:368-73. Free access.

6. Legeai-Mallet L and Savarirayan R. Novel therapeutic approaches for the treatment of achondroplasia. Bone 2020; 141:115579. Free access.

7. Ozasa A, Y. Komatsu A. Yasoda M et al. Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 2005; 36: 1056-64. Free access.

8. Lorget F, Kaci N, Peng J et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia Am J Med Gen 2012; 91(6):1108-14. Free access.

9. Wendt DJ, Dvorak-Ewell M, Bullens S et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 2015;353(1):132-49.

10. Savarirayan R, Irving M, Bacino CA et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med 2019; 381(1):25-35. Free access.

 

11. Savarirayan R, Tofts L, Irving M. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; 396(10252):684-692. Free access.

12.  Savarirayan R, Tofts L, Irving M. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med 2021 Aug 2;1-5. doi: 10.1038/s41436-021-01287-7. Free access.

13. Witt S, Kolb B, Bloemeke J et al. Quality of life of children with achondroplasia and their parents - a German cross-sectional study. Orphan J Rare Dis 2019;14(1):194. Free access. 

14. Yonko EA, Emanuel JS, Carter EM et al. Quality of life in adults with achondroplasia in the United States. Am J Med Gen 2021; 185(3):695-701.

15. Moraal JM, Elzinga-Plomp A, Jongmans MA et al. Long-term psychosocial functioning after Ilizarov limb lengthening during childhood, Acta Orthopaedica 2009; 80 (6): 704-10. Long-term psychosocial functioning after Ilizarov limb lengthening during childhood: 37 patients followed for 2–14 years. Free access.

16. Kim, SJ., Balce, G.C., Agashe, M.V. et al. Is Bilateral Lower Limb Lengthening Appropriate for Achondroplasia?: Midterm Analysis of the Complications and Quality of Life. Clin Orthop Relat Res 2012; 470: 616–21. Free access.

Treating achondroplasia: nine years online

 The blog "Treating achondroplasia" turned nine years old this year. When I started to write the articles for the blog the landscape was completely different: there was really nothing in the horizon towards therapeutic strategies for achondroplasia. Individuals with achondroplasia could only - and, as matter of fact, this is still true today - rely on surgical procedures to correct or improve skeletal problems which come with the typical bone growth impairment caused by the overactive fibroblast growth factor receptor 3 (FGFR3) mutation. Infants with foramen magnum stenosis, children with bowed legs, teens and adults with spinal stenosis sometimes must undergo several surgical interventions to control these and other common neurological and orthopedic complications seen in achondroplasia.

However, things are changing. There are now several potential pharmacological therapies in several stages of development as you can see in the last article published in January in the blog. One of them, vosoritide, is in the last sprint towards approval by two of the most important world regulatory agencies, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Others still have to prove their safety and efficacy in clinical trials and most of them should reach the stage where vosoritide is now. If vosoritide data provided by the developer to EMA and FDA is sound and reliable it is expected that it will be approved and made available next year. This will become a turning point. 

Achondroplasia is a genetic disorder of bone development, meaning that the effects of the mutation in FGFR3 are restricted to the life interval when bones grow. FGFR3 is a natural inhibitor of the bone growth process and, because of the mutation, in achondroplasia it is working too much leading to growth arrest.The end of puberty also represents the end of the bone development process. Unfortunately, because of this, adult individuals would have no benefits in receiving a therapy against FGFR3, at least with the intent of achieving bone growth.

Therapies for achondroplasia will benefit children and teenagers and it is expected that the earlier they start a therapy the better would be the outcomes, although this expectation still needs to be confirmed with data coming from the studies in younger children currently ongoing. 

Why is important to start the therapy early?  Because it is during the first two years of life (and specially during the first year) that children experiment their highest growth velocity rate. Of course, achondroplasia is already identifiable before birth but it is unlikely that a pharmacological intervention so early in life will be available soon. It is during the first two years of life that most of the clinical features of achondroplasia will be established so, if a therapy can be initiated early, it might more efficiently reduce or mitigate those features, which in turn might prevent the common complications I mentioned above.

The Treating Achondroplasia blog is active and I will keep publishing updates as relevant information is released. I really hope that the blog is helping the interested reader to better understand achondroplasia, FGFR3 and what to expect with the new therapies. See you soon. ;)

 

Treating Achondroplasia: how to improve the healthcare for achondroplasia

A conference and a survey

A few months ago I was invited to speak at a conference about how the community sees the healthcare and general support for achondroplasia. The conference had clinical and scientific experts from all over the world.

Given my involvement with achondroplasia, I have my own perceptions about the ups and downs of care, but I wanted to have a broader view that I could present to the other experts during my talk. I wanted to hear from families and people who deal directly with health issues, so I started a short survey in three achondroplasia-related groups in Facebook (Fb; two international and one based in Brazil). The survey was not about calculating rates of this and that, but to understand people's view about the healthcare for achondroplasia.

In summary, the purpose of the survey was to gather impressions of what works well and what doesn't when someone needs healthcare or support from the healthcare system. I have extracted the feedback received from Fb group members from different countries around the world and collated them, and also added real testimonies collected from Fb groups. All information that could lead to personal identification was redacted. More than giving my own opinion, the way I presented the data had one single goal, which was to provide the experts in the conference with points-of-view about healthcare that are not frequently shared with them in their daily practice.

Of course, the message, or messages, given during that presentation are far from approaching all aspects involved in the care and support individuals with achondroplasia and their families need and deserve. My talk basically emphasized an important issue people all over the world face when seeking for healthcare and/or support. However, I believe that what I showed was able to move the audience towards the right direction. I promised to publish the results of the survey, which is what I am doing now, by sharing with you the presentation I gave and I am really grateful to all those members that provided their opinions and insights. Thank you!

Treating Achondroplasia: seven years online and counting

A bit of history

The blog Treating Achondroplasia is celebrating seven years online. The blog has received over 350K visits so far and I hope it is being useful for the visitors. It was created to share knowledge and empower those interested in driving the changes we need for achondroplasia.

I can't help feeling amazed about all the developments I've seen since I published the first article here. The annual number of scientific publications about achondroplasia did not really increase in the last ten or fifteen years (just a bit, as we see in Pubmed; Figure 1), but the scope of the publications has clearly changed over the years.

Figure 1. Number of publications/year about achondroplasia.

Information provided by Pubmed, based on the search for the term "achondroplasia".

For instance, a significant number of studies helped to better understand the molecular mechanisms underlying the FGFR3 mutation leading to achondroplasia. New growth charts (Argentina, Australia, Europe, US) became available to help parents and healthcare providers to track the development of affected kids. Several other works were published about development milestones, and also focusing in management of medical complications, including surgical aspects, from dealing with spinal stenosis and leg bowing to the limb lengthening techniques. We also see that quality-of-life and early diagnosis have also been given more attention lately. Although it is clear that the research for specific therapies has also grown, the number of them is still relatively low. Therapies for achondroplasia might certainly be useful for other dysplasias, but the risk to develop them is high, so...

The low hanging fruit 

The risk is high. This makes me recall a passage of my own development curve. Back to 2009, during a visit to one of the world greatest experts in FGFR signaling and the inventor of one of the first tyrosine kinase inhibitors, in the heart of one of the most renowned US universities, I heard that the research for therapies for genetic disorders like achondroplasia was scarce because it was too risky. He said that large companies would not focus on rare disorders where the landscape was yet to be mapped. Instead they would prefer to drive on paved roads, taking less risk in their endeavors (picking the fruit at the reach of their arms). Tackling rare conditions was a sort of venture reserved for small biotechs (it still is, indeed!). You can imagine how I was feeling when I left that meeting. Some mix between a sense of privilege to have just talked to and learned from that master and at the same time hit by that disheartening concept he told me. Yes, I was already in the pharma industry, but still had an academic heart. What he said was a kind of revelation for me.

Just after that meeting I went to Boston for the International Skeletal Dysplasias Congress, a wonderful opportunity to meet experts from all over the world. The achondroplasia I knew till then was mostly that described in the literature and from my little previous experience in assisting a few affected patients over the years. Talking with those passionate scientists and physicians and watching their presentations gave me new perspectives. One of those physicians, when hearing that I was in the pharma industry, immediately reacted with some sort of contempt: "oh, you work for pharma", followed by one of those looks we easily find in our emoji libraries. I asked him why he was, let's say, upset about that, and he replied saying that "we" (pharma) were not trustworthy. Another punch in just a couple of days. His previous experience with the industry made him reacting that way, a kind of communication gap between them. I told him I was not simply a physician, and I was not simply a pharma R&D professional. I was also a father. This was the kind of combination not easy to find.

It took me one year more to gain his respect. We have met several times after that first congress, but in the end, it was his hand which pointed out to the right direction towards the first clinical trial for achondroplasia when the opportunity came.

The fruit not easy to pick

There are more than seven thousand rare disorders described, and less than 10% have any therapy approved. Despite several incentives promoted by regulatory agencies aiming to increase the research towards therapies for genetic and rare disorders, there is still little effort applied to find solutions for them.

Nevertheless, the interest about achondroplasia has grown in the last five years, with several new approaches being explored, and some being seriously taken into clinical development. I believe this happened as a consequence of the preliminary positive results showed by studies with the C-type natriuretic peptide (CNP) and its first analogue in development, vosoritide. You see, someone needs to chart the new territory and to show that there is potential there. For achondroplasia, cheers for the pioneer Japanese developers of the CNP concept and to the biotech which brought it into the clinic in the form of vosoritide. Others are following, and we now have a second CNP analogue (this road is already paved) and a couple of other strategies already in the clinic (see below). More could be done but, for a rare disorder, these are great news.

A busy year ahead

The new year has just started but we already have news in the horizon. Biomarin announced that the phase 2 study in infants and toddlers is ongoing, and that there were no adverse events in the older cohort so far (Figure 2). 

Figure 2. Biomarin, slide 15 from the presentation on January 7 (2019).

Full presentation can be accessed here.

Meanwhile, Ascendis announced that the start of the phase 2 study with their TransCon CNP is planned for the third quarter (Figure 3) and QED, the developer of infigratinib, is showing in their "Pipeline" webpage that they are planning the start of their natural history study during 2019 and that the next steps would include a phase 1/2 trial (Figure 4).

Figure 3. Ascendis Pharma, slide 56 from the presentation on January 7 (2019).

This slide summarizes results from the phase 1 study with TransCon CNP and lists the next development step. The full presentation can be accessed here.

 
Figure 4. QED Therapeutics pipeline.

Adapted from QED Therapeutics website (free access to the public). Original image can be found here.

The interesting piece here is that the way this expression "phase 1/2 trial to follow" was used could imply that the plan would be to perform an integrated phase 1/2 study, in a potential adaptative design, where after establishing PK and PD in a first group of volunteers (possibly affected children?), subsequent cohorts of participants could start being dosed in a typical phase 2 study fashion. This would only be possible because infigratinib has already all the pre-clinical work done and several clinical trials performed for cancer. Such a design may help expediting the development of infigratinib towards approval, if proven safe and efficient in achondroplasia. 

The change 

Just ten years ago there was no sign for any potential treatment for achondroplasia and, for long time, people with achondroplasia, and by extension, with many other forms of skeletal dysplasias, had no sight that their bone disorders one day would be considered for therapy. Generations have grown under this perspective and dealing with many daily social and medical challenges to say the least, so nothing more natural than the people to build a strong sense of identity. This sense of identity helped creating a solid and fierce community that has been key for many conquers in the social, political and healthcare space.

Science evolves and drives human progress, although it is not linear or necessarily constant. There are jumps and falls in between. However, many chronic and debilitating diseases now have treatments that control or slow down their pace or even revert them. In our days, more and more forms of cancer can be cured with the right therapies, and new and more specific drugs are being developed to beat this once devastating disease.

 

Although a little behind, the knowledge on genetics is growing exponentially, and genetic therapies are already being designed to treat diseases of all sorts, from cancer and diabetes to infectious diseases and genetic disorders. In the near future, we will be able to conquer even more diseases that were unbeatable in the past. This is true for cancer, this will be true for skeletal dysplasias.

So, the change is coming and it's time to see beyond the status quo. Let's embrace the future we see ahead of us, and let's help the new generations to benefit from all the knowledge and progress that are on the horizon. Let's work to give our kids a better future, with more health, more quality of life and more possibilities. Let's give them hope. This is what this blog is about. This has been my pledge from the beginning. It is still mine for 2019 and beyond.

Tratando la acondroplasia: Sexto año en línea y novedades

Original en Portugués publicado en 02/02/2018
 
Traducción al español María Cristina Terceros S.
 
Nueve años atrás, me encontraba participando de un pequeño grupo de discusión en-línea, en una época en la que los blogs y los medios sociales todavía no eran tan populares como lo son ahora, y publiqué un pequeño resumen de lo que estaba leyendo sobre la acondroplasia. En aquella época, habiendo ya conversado con varios investigadores dentro del área y con algunos representantes de asociaciones de padres y pacientes, noté que la información técnica y los avances que yo veía en la literatura no eran fáciles de ser alcanzados por la comunidad interesada. En ese pequeño artículo, mi foco era la perspectiva futura y no reproducir revisiones que los especialistas ya estaban realizando muy bien. Reuní, en unos pocos párrafos, todas las estrategias potenciales que encontré en la literatura, que podrían ser usadas para tratar la acondroplasia.

Como la mayoría de los participantes de ese grupo de discusión no contaba con antecedentes médicos, intenté usar menos jergas y traducir el lenguaje técnico hacia un vocabulario más digerible. Yo tenía esperanzas. 

Ese texto recibió algunos comentarios positivos y fue adoptado por una de las asociaciones. Y también fue la semilla para la creación de este blog. 

Y,… ¡he aquí! Hace seis años comencé el blog Tratando la Acondroplasia, para compartir lo que aprendía con todos los interesados en entender la acondroplasia y el trabajo en camino para vencer la mutación genética que lleva a esa displasia esquelética. 

Existen dos tipos de artículos publicados en el blog. El primero se refiere a revisiones de los mecanismos del desorden genético y en el segundo se encuentran aquellos artículos que analizan potenciales estrategias de tratamiento. Sin embargo, continúo intentando mezclar ambos tópicos en los textos, para dar un poco de base sobre los mecanismos involucrados en cada estrategia. 

Hasta el día de hoy, el blog ha recibido más de 300 mil visitas. Cuando reviso las estadísticas, puedo ver que la mayoría de los visitantes está más interesada en las potenciales terapias y soluciones para la acondroplasia, lo que me hace concluir que el blog está en el camino correcto. 

El blog estuvo un poco silencioso últimamente, como mencioné en un artículo anterior. Y, como dije antes, eso tiene más que ver con mi percepción de una ligera disminución en tópicos que pueden ser interesantes para los lectores que por cualquier otro motivo. Novedades, novedades, novedades. 

Y, apenas para mantenernos atentos y actualizados, estoy feliz de compartir con ustedes que hay una nueva estrategia que puede llegar a convertirse en una fuerte opción para el tratamiento de la acondroplasia. Hace apenas dos días, una empresa de inversión de riesgos en biotecnología (venture capital), llamada BridgeBio anunció el establecimiento de QED Therapeutics, una nueva iniciativa para continuar la investigación con el BGJ398, una pequeña molécula, ahora llamada infigratinib, que fue proyectada para bloquear FGFRs, pero que tiene más afinidad con el FGFR3. Ella fue proyectada con el propósito de tratar varios tipos de cáncer que usan FGFRs para crecer. Para saber más sobre la QED, visiten la página web aquí. 

El infigratinib ya fue probado en un modelo animal de acondroplasia y mostró resultados promisorios convincentes (1). Este estudio, liderado por Laurence Legeai-Mallet, una maestra en displasias relacionadas con el FGFR3, también fue revisado aquí en el blog en 2016: Tratando la acondroplasia: NVP-BGJ398, un inhibidor de tirosina quinasa, restaura el crecimiento óseo en un modelo de acondroplasia. Esta revisión comienza con un pequeño resumen de la acondroplasia y de la biología por detrás de esa displasia esquelética. Ella puede ayudarles a tener una mejor visión de la cuestión (como dije anteriormente… mezclo tópicos). 

Resumiendo, infigratinib fue administrado en dosis inferiores a las destinadas al tratamiento del cáncer y, básicamente, consiguió rescatar el crecimiento óseo en el modelo probado. Es importante notar que, habiendo alcanzado ensayos clínicos para el cáncer, infigratinib mostró un perfil de seguridad equilibrado. Ahora, deberá ser probado en el contexto del cuerpo en desarrollo y el motivo es simple. Si bien la molécula muestra más afinidad con el FGFR3, también puede bloquear otros FGFRs, entonces necesitamos entender si habría problemas de seguridad en el organismo en crecimiento expuesto al infigratinib antes de alcanzar el desarrollo clínico en niños. Si se prueba que es seguro, entonces la justificativa para su uso sería fuerte, ya que bloquea directamente la proteína que causa la acondroplasia, en comparación con otras drogas, como el vosoritide, que funciona indirectamente. 

Éstos son tiempos muy movidos. Pocos años atrás, escuché a un renombrado investigador diciendo: “En el futuro cercano, el problema no será tratar o no tratar la acondroplasia. El problema será qué medicamento usaremos para tratarla”. Esto será una realidad para las nuevas generaciones. 

¡Gracias! ¡Muchas gracias por su interés en el blog Treating Achondroplasia! (Tratando la Acondroplasia). ¡Espero que continúe siendo útil para ustedes!
 
Referencias

1. Komla-Ebri Det al Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016;126(5):1871-84. Acesso livre.

Tratando la acondroplasia: quinto año en-línea

Original en Portugués publicado en 5 de marzo de 2017
 
Traducción: Maria Cristina Terceros
 
El blog Tratando la acondroplasia (www.tinyurl.com/achtion) cumplió cinco años en enero de este año.

Durante todo este tiempo he publicado artículos en los cuales revisamos la biología de la acondroplasia y todas las potenciales estrategias terapéuticas que ya fueron desarrolladas para ayudar a los niños a rescatar su crecimiento óseo, que es severamente afectado por la mutación en el gen FGFR3.

Sin embargo, tratar la acondroplasia, es mucho más que hacer simplemente con que crezcan los huesos para aumentar la estatura final.

Mucho más importante es reducir las muchas complicaciones que los individuos con acondroplasia eventualmente enfrentarán en la vida, desde la estenosis del foramen magnum y de la apnea del sueño en la primera infancia hasta las muchas complicaciones ortopédicas a lo largo de sus vidas.

El blog y, por extensión, el grupo Achondroplasia en el Facebook, son exclusivamente dedicados a compartir con todas las personas interesadas en el conocimiento sobre la acondroplasia que he reunido a lo largo de estos años.

Al escribir los artículos intento traducir la pesada nomenclatura y lenguaje científico en un texto más fácil de ser comprendido (si bien que siento que puedo haber fallado de vez en cuando…).

Últimamente, el blog ha estado menos activo, pero eso tiene más a ver con la escasez de informaciones nuevas, que por cualquier otro motivo o razón. Generalmente, todos los artículos publicados hasta ahora están aún actualizados, y prefiero no escribir solo por repetir informaciones ya publicadas.

Desarrollar terapias para enfermedades comunes es difícil, pero la inversión en ellas es elevada porque el potencial retorno también es elevado. En el terreno de las enfermedades raras, desarrollar un nuevo medicamento es aún más difícil por muchos motivos. Por ejemplo, apenas por mencionar el lado financiero, la población a ser tratada es pequeña (así, hay menor retorno a la inversión realizada). Algunos otros desafíos están relacionados con la forma como las mismas reglas y reglamentos para el desarrollo de fármacos que son aplicados a las enfermedades comunes también son aplicados a las enfermedades raras.

Por ejemplo, el estudio de fase 3 con el análogo del péptido natriurético tipo C (CNP), vosoritida, que es la droga experimental más avanzada en desarrollo clínico para el tratamiento para la acondroplasia, fue iniciado en diciembre en Australia. Las agencias reguladoras solicitaron que el desarrollador siguiera um diseño padrón (estándar) para estúdios de fase 3, que incluye um diseño doble ciego, controlado por placebo.

Aun comprendiendo totalmente la necesidad de un estudio controlado por placebo para certificarse de que los efectos (buenos y malos) vistos con la droga son realmente causados por la droga y no debidos al azar, es complejo ver este tipo de diseño aplicado en el contexto de las enfermedades raras. Y especialmente porque, para un niño con acondroplasia, ésta es una carrera contra el tiempo. Existen otras maneras de rastrear la eficacia y la seguridad de una droga, aparte de someter a niños a placebo por un año para confirmar los efectos de la droga experimental. Este concepto puede ser aplicado a muchas otras condiciones raras (por ejemplo: piense en la distrofia muscular de Duchenne).

Es cada vez más evidente que la participación activa de la comunidad interesada, padres y pacientes, es fundamental para impulsar el desarrollo de nuevas soluciones para estas enfermedades huérfanas. Existen más de siete mil enfermedades raras ya clasificadas. El número de individuos con cada una de estas enfermedades es pequeño, pero colectivamente estas condiciones raras representan un gran grupo que debería ya estar contando con una voz más poderosa.

Agradezco su interés en los artículos que publico aquí. Espero sinceramente que estén ayudando a la comunidad interesada a entender lo que está sucediendo en la investigación para tratar la acondroplasia y los desafíos relacionados con traer esas nuevas terapias para los niños que de ellas necesitan.

Treating achondroplasia: sixth year online and news

Anniversary

Nine years ago, I was participating in a small online discussion group, in a time when blogs and social media were not yet as popular as now, and published a small summary of what I was reading about achondroplasia. 

At that time, having already talked with a number of investigators in the field and with a few representatives of advocacy groups I realized that the technical information and advances I was seeing in the literature were difficult to reach by the interested community. In that short article, my focus was perspective rather than reviewing what experts were doing already so well. I put together all potential strategies I found in the literature that could be used to treat achondroplasia in a few paragraphs. As most of the participants on that discussion group had no medical background I tried to use less heavy jargon and translate technical language to a more digestible vocabulary. I had hope.

That text received some positive feedback and was adopted by one of the advocacy groups. And was the seed for this blog.

That's it! Six years ago I started the Treating Achondroplasia blog to share what I was learning with all those interested in understanding achondroplasia and the ongoing work to beat the genetic mutation that leads to this skeletal dysplasia.

There are two kinds of articles published in the blog. The first type comprises reviews of the genetic disorder mechanisms and in the second there are those reviewing potential strategies. Nevertheless, I keep trying to mix both topics, to give a bit of background on the mechanisms involved in each strategy.

As of today, the blog has received more than 300K visits. When I review the statistics I can see that most visitors are more interested in the potential therapies and solutions for achondroplasia, so I think the blog is in the right track.

The blog has become a bit silent lately, as I mentioned in a previous article. And as I said then, this has more to do with my perception of a slight decrease in topics that may be interesting for the readers than for any other reason.

News, news, news

And, just to keep us on track and aware, I am happy to share with you that there is one more strategy that may become a strong option for the treatment of achondroplasia.

Just two days ago, a biotech venture called BridgeBio announced the establishment of QED Therapeutic, a new initiative to continue the research with BGJ398, a small molecule now called infigratinib, that was designed to block FGFRs, but which has more affinity with FGFR3. It was designed aiming to treat several kinds of cancer that use FGFRs to grow. To learn more about QED, visit their website here.

Infigratinib has been already tested in an animal model of achondroplasia and showed compelling promising results (1). This study leaded by Laurence Legeai-Mallet, a master in FGFR3-related dysplasias, was also reviewed here in the blog in 2016: Treating achondroplasia: NVP-BGJ398, a tyrosine kinase inhibitor, restores bone growth in a model of achondroplasia. This review starts with a tour through achondroplasia and the biology behind this skeletal dysplasia. It may help you to have a better view of the landscape (as I said, I mix topics...). 

In short, infigratinib was given in doses lower than those intended for the treatment of cancer, and basically was able to rescue bone growth in the tested model. It is important to note that, having already reached clinical trials for cancer, infigratinib showed a balanced safety profile. Now, it must be tested in the context of the developing body and the reason is simple. Although the molecule shows more affinity to FGFR3, it can also block other FGFRs, so we need to understand whether there would be safety issues in the developing organism exposed to infigratinib before it reaches the clinical development in children. If proven to be safe, then the rationale for its use would be strong as it directly targets the protein that causes achondroplasia compared to others such as vosoritide, that works indirectly.

These are exciting times. Some years ago, I heard from a renowned investigator that "in the near future the problem won't be to treat or not achondroplasia. The problem will be to decide which drug we will use to treat it". This will be true for the new generations.

Thank you

Thanks for your interest in the Treating Achondroplasia blog. I hope it keeps being useful for you!

References


1. Komla-Ebri Det al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016;126(5):1871-84. Free access.