Thursday, July 19, 2018

Treating achondroplasia: news on vosoritide, meclizine, TA-46, and the question about placebo


There have been new developments for three of the most advanced therapeutic strategies for achondroplasia after the last blog's article in April.


On last May, the FDA held an advisory board committee meeting to address questions related to the clinical development of vosoritide in achondroplasia, such as which parameters should be chosen to follow treatment's response, duration of studies, use of placebo and other technical topics. You can watch a recording of that meeting through this link provided by the FDA (~5 hours; available through 30Sep2018).

Soon after that meeting, the developer of vosoritide announced the start of the infant/toddler study, and published a description of this study at

What does this mean in practical terms?

First, it seems that safety concerns over vosoritide and about the endpoints to be followed in future studies have been addressed, resulting in the FDA authorizing the infant study after a considerable delay. This authorization also allows me to think that, at this point, there is enough evidence that a positive effect of vosoritide does exist, even if it was not consistent enough for now (broad data variability due to small number of participants in the phase 2 study?).

Given the natural history of achondroplasia, a genetic condition that starts impacting bone growth before birth, there is an expectation that beginning a therapy as soon as possible after birth may result in better growth response, not only by promoting better bone development but also by reducing several clinical complications that are common early in life in affected children. Therefore, it is indeed good news that they are starting this infant study.


Meclozine is an old non-prescription drug for long used to alleviate motion sickness in adults and children over 12 year old. Recently, it has been shown to promote bone growth in an animal model of achondroplasia. After additional pre-clinical studies performed in the last few years (1-4), the Japanese group working with meclozine will soon start a phase 1 study in children with achondroplasia. This study is designed to help understanding what is the fate of meclozine in younger children (pharmacokinetics).

The clinical development of meclozine is facilitated by the fact that it is an old drug with a known safety profile, so the phase 1 study should not bring any surprise, although we might see eventual metabolic differences in the younger population compared to what is seen in adults. Based on the scarce information provided in their registry, it seems also that this study will help to set the right dosing (once vs. twice a day?) for the eventual phase 2 trial. Good news here, too, specially because meclozine, if proven effective, even if weaker than vosoritide, would be a reasonable option for achondroplasia: it is an oral drug with a very affordable price and available as a generic drug in many countries, so it would be accessible to all.

TA-46 (soluble FGFR3)

The developer of TA-46 recently announced that they would be starting the natural history study with children with achondroplasia in Belgium. The description of the study, called Dreambird, is yet to be published in clinical trial registries (as of 18Jul2018), but I think it will not be different from the similar one conducted by the developer of vosoritide, which you can check here.

TA-46 was being tested in a phase 1 clinical trial earlier this year and, since there has been no information at all about safety issues until now, I see this as an evidence that the developer will progress TA-46 to phase 2 in short term. The natural history study for vosoritide requires that children should be followed for at least six months before being enrolled in an active drug study, so I can deduct that the same could happen in Dreambird in prepapration for the TA-46 phase 2 study. Given these assumptions, one can predict that the phase 2 study with TA-46 could be starting in the first quarter of 2019. Let's see.

No news from the developers of TransCon-CNP and infigratinib, or statins as of 19Jul2018.


Using placebo in clinical trials for achondroplasia

Achondroplasia, as the readers of this blog know, starts before birth, and affects a tightly controlled bone growth program which has an expiry date. The longer it takes to start any therapy for achondroplasia, the shorter is the time for meaningful therapeutic responses in the context of this genetic disorder, which has an expiry date (repeating just to reinforce the concept).

I was there at the FDA meeting watching while the advisory committee debated about the use of placebo for achondroplasia. I disagree with the general course of their rationale. I keep the question whether it is appropriate to use placebo in studies with drugs targeting achondroplasia (watch the FDA recording!). It is disappointing that regulators and medical experts won't find alternative strategies to define a meaningful therapeutic response without the use of placebo as a comparator. 

Basically, placebo is used to confirm that responses to a given active treatment are a result of the effect of that treatment and not caused by biases of any kind, or by chance or serendipity. It is fair enough when there is no predictable harm for the participant, but in certain settings such as in rare diseases and conditions, the use of placebo in a study could be considered inappropriate for posing unfair burden on participants taking an inactive comparator, that cannot be compensated later. And this is exactly the case of achondroplasia. 

One could argue that there is no proven therapy for achondroplasia yet, as well as that the experimental drug has not been proven safe and efficient yet, so there would be no predictable harm in allowing the use of placebo in a study with that drug. However, in the case of the only drug right now in clinical trials for achondroplasia, vosoritide, there are two pieces of evidence pointing that it will, at least partially, improve bone growth in this condition without major concerns on safety aspects. First, as I mentioned above, there has been no relevant safety issue so far, according with the published information and what I can infer from the later FDA decisions. Second, the available information about efficacy endpoints also lists positive outcomes, even if they have not be convincing enough till now, as we can deduct by watching the FDA meeting recording, from brief references during the open session to what has been discussed during the closed session among the FDA, the advisory committee and the vosoritide's developer.

The Belmont Report (1979), one of the most influential documents that helped creating regulations for ethical clinical research, set three pillars of ethical clinical research:
  • beneficence
  • non-maleficence
  • justice
While other more recent documents such as the updated Declaration of Helsinki (DH) and the The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), main sources for today's ethical clinical research, do not specifically use the word justice, the notion of justice is embedded in several sections of those documents (e.g.: DH: principles #17 and #33; ICH E10: Sections 1.3.5 and 2.5).

The ICH E10 provides other options to assess efficacy and safety in special situations. There are other methods that can be implemented to prevent or mitigate bias or undue interference on data quality and reliability while protecting study participants (see ICH E10) from predicted harm. In the case of achondroplasia, predicted harm refers to the entire year of additional growth that children exposed to placebo in a study will lose and that cannot be compensated later.

Considering the short timeframe children with achondroplasia have to grow (as all non-affected children), the question remains whether it is appropriate to submit them to one year of exposure to placebo before allowing them to receive appropriate therapy. This is now the case of vosoritide. This will be also the case for the upcoming therapies, if  requirements for studies with an inappropriate target population and questionable study designs don't change.


1. Matsushita M et al. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One 2013; 8(12):e81569.

2. Matsushita M et al. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene. Endocrinology 2015;156(2):548-54.

3. Matsushita M et al. Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia. J Neurosurg Pediatr 2017;19(1):91-95.

4. Matsushita M et al. Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia. Sci Rep 2017;7(1):7371.

No comments:

Post a Comment