VX-770

Question

Hello,
The VX770 molecule (Ivacaftor) acts on the G551D mutation and, also, positively effects on 9 other class 3 mutations. Which ones?
Thank you for your response.

Answer

Hello,

VX-770 is actually also known as Ivacaftor which is its International Common Denomination (ICD). If the structure of Ivacaftor is currently protected by trade secret, we do know that the molecule acts as a "potentiator", ie as an activator of chloride channel function. This mode of action explains the positive effects highlighted by a clinical trial whose primary condition of participation (or inclusion criteria) was to be a cystic fibrosis patient and carry at least one mutation G551D. This mutation is known as a class 3 mutation. It means that, despite the CFTR protein is normally synthesized and transported into the the cell membrane, it does not work as a normal chloride channel. Because of the mutation, the energy input needed to open the gate of the chloride channel is indeed disrupted.There are other class 3 mutations which have the same effect but are much rarer or exceptional: G551S, G1349D, G1244E, S1255P, G178R, S549N, G549R, G970R, S1251N. Those mutations including the G551D total 164 patients in France say 3% of patients identified by the French Cystic Fibrosis Registry (2009 data). All those mutations are grouped under the term of "gating mutations." The G551D mutation, by far the most common, is present in approximately 2% of patients. This may explain the choice of this mutation to set up the first clinical trial with VX-770. Significant effects, observed in patients "G551D" treated (1), and positive results for other "gating mutations" in animal models (2), open indeed the prospects for a therapeutic trial in patients who carry one of those gating mutations.

At the launch of Ivacaftor in the U.S., the company Vertex Pharmaceuticals announced in January 2012 (3) that it planned to undertake mid 2012, three other clinical trials with this molecule:


-A study using a pediatric formulation of this molecule in children aged 2 to 5 years with gating mutations including G551D is expected to evaluate the safety, tolerability and effect on sweat chloride and other measures of clinical activity.
-A study in patients with R117H, a class 4 mutation, which represent about 3% of patients in the U.S. and 2.1% (118 patients) in France.
-A study in patients with another gating mutation than G551D or R117H : they are much rarer (1% of patients have one of these mutations).

We do not know, to date, either the detailed study protocols or investigation centers that will be involved. However, since those mutations are much rarer than the main F508del mutation, it is much likely that a large international collaboration will be established.
Hope I have answered your question.

Dr. Gilles Rault

References:

(1) A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. Bonnie W Ramsey et al. N Engl J Med 2011; 365:1663-1672November 3, 2011.
(2) VX-770 of CFTR Forms With Channel Gating Defects In Vitro. F Van Goor, H Yu, B Burton, B Hoffman, P Negulescu. Vertex Pharmaceuticals Incorporated, San Diego, CA, USA. Poster, 35th NACF Conference, Anaheim, November 2011.
(3) Vertex News, Jan 2012

28.02.2012