Wednesday, December 3, 2014

Treating achondroplasia with meclizine / meclozine

Before starting

Sometimes, for the non-technical readers it might be difficult to copy with the language used in articles like this one. If you start to feel like a bit lost in the jargon, don't give up. This blog contains many other articles which have been written with the goal of sharing knowledge while simplifying the language of the science behind the bone growth biology and achondroplasia. Try to visit the index in your preferred language on top of this page. The first articles present the basics in a more digestible way (at least, I tried to make it so) and may help you to follow the more recent ones.

Following the publication in 2013 of the exciting study about the use of meclizine to treat achondroplasia (1; reviewed here), the Japanese group leaded by Matsushita has just published the results from their continuing exploration of the use of this compound to treat this bone growth disorder. The conclusions of this study will help to define the next steps for meclizine in this new therapeutic indication: could it be used in the clinical settings, i.e., can it be tested in children with achondroplasia? So, let's see what the researchers found in their study and think about their results and potential next steps.

Old dog, new trick

Repurposing or repositioning of old drugs is a strategy more and more recognized as a viable way to find therapies for new indications across the vast existing drug armament. The goal is to help reducing the ever increasing costs of drug development by using medicines that have their mode of action and safety profile already established and are approved for the market, thus reducing the development burden. A drug falling in this category could proceed to clinical testing for a new indication in far lesser time than that needed for a new molecular entity (this is the way the regulatory agencies such as the FDA call a brand new compound).

Interested in achondroplasia, in 2103 Matsushita and coworkers published the article (1) where they describe that they screened among almost 1200 old compounds from a FDA approved list available for drug repositioning, for one which could be used to treat this skeletal dysplasia, and identified meclizine as a candidate. 

Meclizine, or meclozine, (Figure 1) pertains to the large familiy of anti-histamine drugs and is an old medicine currently indicated for motion sickness.

Figure 1. Molecular structure of meclizine.

From Wikipedia

In that study, they tested meclizine in mice bone explants and found that the drug was capable to partially restore the bone growth by reducing the activity of one of the main chemical cascades fibroblast growth factor receptor 3 (FGFR3) uses to exert its effects in the growth plate chondrocyte, the mitogen activated protein kinase (MAPK) pathway (Figure 2). As you may already know, FGFR3 acts as natural negative modulator (a brake) in the bone growth machinery and due to the mutation found in achondroplasia, it becomes much more active, leading to bone growth arrest. The MAPK cascade (or pathway) includes the enzymes RAS, RAF, MEK and ERK (and others), which are activated (ignited) in sequence by FGFR3, like in a domino chain.

Figure 2. Meclizine site of action.

Matsushita M et al. (2013). PLoS ONE 8(12): e81569. doi:10.1371/journal.pone.0081569.
 Reproduced here for education purposes only.
What is new?

In the current study, they made new tests, this time exploring the effects of meclizine in a mouse model of achondroplasia. In summary, they verified that meclizine did exert a positive effect in bone growth, making the mutated animals treated with this drug to grow more compared with those animals not treated. However, the amount of the effect, although statistically significant, can't be classified as a full growth rescue.

Meclizine was administered in doses equivalent to the therapeutic doses used to treat motion sickness in humans. This means that the effect was observed in doses that would be unlikely to be toxic for children with achondroplasia.

They treated animals carrying the mutation from the third week of life, when part of the cranial bones have already achieved its final development. I refer here to the cranial bone sutures. These parts of the cranium close earlier in achondroplasia than in the average child, leading to potential clinical complications and to some of the typical head features seen in this genetic condition. They found that the therapy with meclizine couldn't rescue the growth pattern of the cranial bones, confirming one of the findings of another important study recently published. (3) 

This has key implications about the timing to start the therapy for achondroplasia. Since FGFR3 is already causing growth disturb in utero the sooner a therapy for achondroplasia could start the better. Theoretically, this would be important for all bones to allow a better development, but would be indeed more relevant for the bones of the head. So, as part of the investigation, the authors also gave meclizine to pregnant wild type (not affected by the mutation) animals. They found that the offspring of these animals grew more than the those from animals not given the drug. The authors didn't describe if there was any sign of toxicity with the use of meclizine neither in the pregnant females nor in the offspring. However, the observed results warrant the tests in affected animals, which they state they will be doing in the next step of their research.

In summary, these are the major findings in the new study by Matsushita et al.:
  • Mice carrying the achondroplasia mutation grew significantly more when exposed to meclizine;
  • The effect was observed specially in long bones. The cranial bones have not responded to the therapy;
  • The bone growth effect was significant but didn't restore in full the expected bone growth;
  • The effect in bone growth was obtained with doses considered achievable in the therapeutic range;
  • The effect in bone growth was also observed in normal animals.
More food for thoughts 
(see the review about statins, recently published)

The unveiling of some old drugs that may have a role in the therapy for achondroplasia is fantastic.
If proven to work in its known therapeutic dose range (in other words, to be safe and efficient in usual doses) meclizine might represent one major achievement for the treatment of achondroplasia, having at least three key advantages against new compounds in development right now:

1. It is readily and easily available worldwide;
2. It is cheap;
3. It is an oral drug.

Nevertheless, it is good to keep a realistic view about the research with meclizine performed so far. Although several tests are still in the line before assuming any effect in children with achondroplasia at any degree, given the current results, it looks like it will not be able to rescue the full potential growth in affected individuals.

This open the option of associating drugs which also have the potential to beat the mutated FGFR3, specially if they have distinct modes of action. This is exactly the case of the statins, which have been recently showed in another study to promote bone growth in achondroplasia. Combining these drugs may result in a synergistic effect, while keeping the drugs in their safe dosing range.

Another aspect is that they could also be combined with other therapies in research right now. For instance, in theory meclizine could be used with C-type natriuretic peptide (CNP) analogues, antibodies or other compounds targeting FGFR3. 

And finally 

As I have been pointing out in previous articles, one major concern about new therapies for any medical condition is about how they will be made available for the individuals in need after they are approved by the regulatory authorities. A number of recent analyses made by the specialized press have been showing that clinical development is becoming more and more expensive in the last decades, strongly pushing higher and higher the costs of the medicine in the consumer end. This is reality for common diseases such as diabetes or hypertension. This is indeed even more serious issue for rare conditions.

On the other hand, this poses a challenge to drug developers. How they will make the new drug useful if few can afford to pay the price? A rational agreement must be found among all the stakeholders involved, from the drug makers, the health authorities, to the interested population and their representatives.

Therefore, (re)discovering meclizine and other compounds may represent good options and fair argument over excesses we might see in the future with the arrival of newly developed compounds. In the end of the day, balance between the industry sustainability speech (and the deserved reward for the good discovery job) and fulfilling the very one goal of any new therapy - to treat those in need - is much desired.

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. doi:10.1371/journal.pone.0081569. Free access.

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 2014 Dec 2:en20141914. [Epub ahead of print]. Free access.

3. Matsushita T et al. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 2009;18(2):227-40. Free access.

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