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Vertex-770 potentiator

Dear expert team, my son's genotype is DF508 and R347P. As VX-770 only studies effectiveness in G551D (and DF508) at the moment I wonder what the probability is that this drug also works for other (class III-V) mutations with a certain functionality of the CFTR protein (my son must have some functionality as he is pancreatic sufficient). I guess that further studies have to be done but I would like to understand the working method of the drug and if it can be applied to other mutations. I would also like to understand why the company only focus on one specific mutation.

Thank you.
Dear Questioner,
This is an excellent question.

The answer is, however, somewhat complicated.

1. VX-770 is a small molecule “potentiator” which can increase chloride
transport via defective CFTR. This effect is most pronounced in individuals with the class III mutation G551D.
2. In vitro (in a test tube) there is data which suggests that VX-770 has activity on R117H mutant CFTR (a class IV mutation). We have not been able to find published data on the less common Class IV mutations, such as R347P. This does not mean these data do not exist. There is a strong possibility that some level of activity will be seen on other mutations in this class.
3. To study a drug in a clinical setting (and thereby bring a drug to market) narrow parameters are required such that conclusive data can be generated. As G551D is the third most common mutation in CF and that in which VX-770 has most potent activity, it is logical to study the agent initially in this setting (although studies in dF508 homozygotes are also underway).
4. Should clinical studies prove this agent to be effective it will likely receive approval for clinical use in late 2012 or 2013 (accelerated, owing to its orphan drug status).
5. Positive data for VX-770 in individuals with G551D mutations will
result in researchers looking at other mutations for potential efficacy. The same rigorous study clinical design would neither be required nor necessary to support this use. This can then prompt “off-label” use of these products in certain, appropriate clinical scenarios.

In summary, while the current VX-770 study design may look somewhat exclusionary – this is required to give the best opportunity for this new product to demonstrate efficacy in stabilizing the clinical course of CF.
This is the necessary process involved in bringing drugs to market (not just in CF). Should positive results be obtained for VX-770 in those with
G551 D mutations we will be looking for opportunities to expand its use in other mutations in which clinical benefit might be predicted based on laboratory data. Analogously, TOBI and DNase were both studied in very strictly defined populations, but physicians use this “licensed product”
in a much more broad capacity guided by both on going research in new situations and clinical experience.

Thank you for your inquiry.
Best Wishes,

The answer is edited by: Prof Stuart Elborn