Sunday, September 8, 2013

Repurposing of old drugs: is there an opportunity for achondroplasia?

Old drugs, new uses

With the exponential increase in the discovery of the molecular basis of diseases, an amazing number of new compounds targeting causative agents have been designed and/or created in the last decades. However, from thousands of molecules tested only a tiny fraction of them succeed to reach clinical development many years after they have been spotted in a lab. Even among those new compounds that reach the clinical research phase only another small fraction will prove to work and to be safe enough to be given to real patients. Many of them will fail to give convincing outcomes and will be abandoned. You can read more about drug discovery and development in this previous article of this blog.

The rate of failure is high, and this is considered one of the reasons why the average cost of the development of a single drug is now estimated in more than USD 1 billion. (1) With this high attrition across the pharma industry (high costs vs. low productivity), new programs have been designed to help improving drug discovery.


One of these programs which have been given more attention lately is Drug Rescue or Repurposing. (2,3) The strategy is to review data acquired from the research made on abandoned or old drugs and identify new potential uses of those compounds in other clinical indications with unmet needs, such as rare diseases. One good example of drug rescue is AZT, a drug developed to treat cancer without success, which turned to be the first drug to treat HIV. (4)

Several initiatives are ongoing right now for many diseases, especially those that do not have efficient therapies available (e.g. Alzheimer).(5) With one exception, menatretenone, (MK-4, reviewed here), until today I have never found a single work on drugs that could be targeting achondroplasia.

When I was reviewing the program of the 11th International Skeletal Dysplasias Society Meeting to prepare the previous blog's article about the latest BMN-111 tests presented there, I also identified one study exactly taking advantage of the repurposing strategy. The study by Matsushita et al. (6) described tests performed in chondrocyte cell cultures and bone explants bearing an altered, overactive fibroblast growth factor receptor 3 (FGFR3), using meclizin (or meclozin), a low cost anti-histaminic used to treat vertigo and motion sickness. They found that meclizine worked inhibiting one of the enzymes located in the signaling cascade of FGFR3, called external signal-regulated kinase (ERK). Having obtained positive results, they concluded their summary proposing the use of meclizine to treat achondroplasia.

Meclizine for achondroplasia?

The wording in the study's abstract is prudent, mentioning only an attenuation of the  FGFR3 signaling. How much change does attenuation stand for? Before anyone starts to think meclizine should be given to children with achondroplasia, more information is needed in order to allow a fair statement about it. It will be good to learn if the investigators tested if any other signaling pathway was affected by ERK inhibition. The figure below shows the FGFR3 pathway. ERK is located several steps downstream of FGFR3 and also responds to other signals originated by other receptors. 


Meclizine pertains to the piperazine family. In fact, it is not completely a surprise that drugs of this familiy could have effects in the signaling of receptor enzymes like FGFR3: the core structure of piperazine has been already explored to become other drugs, including receptor enzyme inhibitors used to treat cancer (e.g.: imatinib).

Nevertheless, these are outstanding news. We have already talked about the great challenge for achondroplasia or any other rare condition in previous blog's articles. In few words: access to the therapy

Think about this: medicines for rare conditions use to be extremely expensive for several reasons, from the cost of their development (as outlined in the beginning of this article) to their limited market. According to a summary released by Terrapinn - Total Biopharma, the most expensive one is called Soliris (eculizumab), developed by Alexion. It is a kind of antibody developed to treat paroxysmal nocturnal hemoglobinuria and costs USD600,000 per person, per year. Reuters also published an article mentioning a gene therapy for another rare disorder called lipoprotein lipase deficiency that is supposed to cost more than USD 1 Million per patient. (7) Therefore, if a low cost drug with a known safety/toxicity profile, such as meclizine or menatetrenone, is proven to exert effects against the excessive activity of FGFR3 in achondroplasia, then the access challenge would be solved, granting appropriate therapy for all those in need.

Let's wait for the publication of the complete work by Matsushita and coworkers to learn more about the effect of meclizine in chondrocytes and also see if they progressed their work by testing appropriate living models.


1. Paul SM et al. How to improve R&D productivity: the pharmaceutical industry’s grand 
challenge. Nature Rev Drug Discov 2010; 9 (3): 203-14. Free access.

2. National Centers for Advancing Translational Sciences (NCATS). Rescuing and Repurposing Drugs. Accessed on Sep 7, 2013.

3. Food and Drug Administration. A Valuable Resource for Drug Developers: The Rare Disease Repurposing Database (RDRD). Accessed on Sep 7, 2013.

4. Collins FS. Mining for therapeutic gold. Nature Rev Drug Discov 2011 (10):397.

5. Nalr PDrug repurposing gets a boost as academic researchers join the search for
 novel uses of existing drugs. PNAS 2013; 110 (7): 2430–2. Free access

6. Matsushita et al. Meclozine facilitates chondrocyte proliferation and differentiation by attenuating abnormally activated fibroblast growth factor receptor 3 (FGFR3) signaling in achondroplasia. Presented at the 11th International Skeletal Dysplasias Society Meeting, August 28-31, 2013, Bologna, Italy.

7. Hirschler B. Analysis: Entering the age of the $1 million medicineReuters, published on Jan 3, 2013. Accessed Sep 7 2013.

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