Thursday, January 24, 2019

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.

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