Amlexanox

Question

Dear expert team,
I got aware of the following publications:
http://www.ncbi.nlm.nih.gov/m/pubmed/22938201/
and
http://www.google.com/patents/EP2437741A1?cl=en
I would like to know if there is any data yet concerning the correction of CF nonsense mutations? Respectively, if there are any clinical studies, yet?
A patent seems to have been requested at least.
As this substance is used for more than 20 years in humans, could one expect a quick market authorization in case of proven efficacy for nonsense mutations in CF?
Our daughter has i.a. the R553X mutation.
Many thanks and best regards!

Answer

Dear parents,
many thanks for the very interesting and actual question about the correction of so-called stop- or nonsense mutations.
As you for sure already know, mutations of CF - there are meanwhile more than 1600 - are today devided into 5 classes.
The stop- or nonsense mutations belong to class I and are characterized by the finding, that no functional protein and therefore no chloride channel is produced. In case of the stop-mutations, this production impairment is caused by a preterminal stop in the production of the protein in the cell, so that the assembly of the protein is incomplete.
In Germany, 13% of patients show either one or two class I mutations.
The company PTC has developed a drug (Ataluren), that has shown in CF cells, that it is capable of overreading the stop and therefore produce a complete protein molecule, which can then be included in the cell surface. In a little group of CF patients with stop-mutations it could be shown, that the flow of chloride ions, that had been measured over the nasal mucosa (nasal potential difference measurement) could be improved markedly under the treatment with Ataluren. Like you know for sure, before market authorization, all drugs have to be tested for their clinical efficacy and it has to be shown, that their usage is not accompanied by any severe side effects.
This is done in the frame of large clinical studies, hereby mostly half of the patients receive a placebo and the other half the real drug. This study has in the meanwhile be accomplished by the company PTC, however was not able to show the desired clinical result, thus an improvement of the lung function. There have not been relevant side effects. Many reasons have later be identified for the not sufficient clinical efficacy. Therefore, a new study will start in summer this year (2014) - also in several German CF centers - that will take into account the experience that has been made during the first study.

The by you mentioned substance Amlexanox is licensed in the USA for the treatment of skin ulcera and in Japan as an anti-inflammatory drug. In Germany there is until now no licensed drug, that contains Amlexanox. In the by you cited publication of Gonzalez-Hilarion in the Journal "Orphanet Journal of Rare Diseases" the efficacy of Amlexanox is tested in CF cells, that contain a class I (stop) and a class II mutation. It could have been shown that Amlexanox could increase the amount of produced chloride channel and also the operability of the chloride channel. Restrictively it has to be said, that these were only experiments with cell cultures.
As the publication has been submitted 2.5 years ago, it is striking that one has not heard anything new about this substance. In the international register of studies, where all studies have to be announced, 3 studies with Amlexanox have been listed so far, two in case of diabetes and one in case of cancer treatment.
In spite of this I believe, that there will be substances in the future, that will also have a measurable clinical effect in single patients with stop-mutations. However the way from cell culture to a licensed drug is a long one.

PD. Dr. Ernst Rietschel
Head of the CF Center, Cologne, Germany

12.05.2014