Molecules and mutations

Question

Hello
Main research studies focus on personalized treatments. But could you specify if
- In case of success, will Miglustat and Vx809 be effective only on f508 mutation or all class 2 mutations as d507?
- Could PTC124 be effective on the New1 class mutation 1811+1,6 Kb A>G (splicing mutation and not stop codon)?
- Would Vx770 be effective only on 551D mutation? Is that sure that patients with the mutation 1811+1,6 Kb A>G that allow production of some protein (even if in New1 class) would never be concern by Vx770?
In general, could one say that rare mutations will never have any treatment because no studies are specifically conducted for these mutations?
Many thanks for your answer.

Answer

Novel therapies have recently emerged in cystic fibrosis targeting the defective CFTR protein. Several molecules are currently studied to correct the effects of specific CFTR mutation classes:

- Miglustat (Zavesca®, Actelion) and Vx809 (Vertex) are 2 CFTR correctors, that target the class II CFTR mutations (as F508del and I507del). Clinical trials evaluating efficacy of these agents are underway and have concerned so far homozygous F508del patients. For patients with other class 2 mutations (like I507del), new trials will have to be realized to propose such therapies. Promising results have been observed in cell cultures with Miglustat. One advantage with this treatment is that it has already been given in Gaucher disease patients, another rare disease. The first clinical trials with Vx809 have shown that it was well tolerated and allows normalization of the chloride secretion; analyses of other clinical parameters are underway.

- Trials evaluating efficacy of PTC124 (Ataluren®, PTC Therapeutics) are also underway. This treatment targets nonsense CFTR mutations, which are premature stop codons. The first encouraging results of these trials have reported improvement in chloride transport in adults and children with CF. Efficacy on other clinical parameters are underway like lung function, pulmonary exacerbations and quality of life. The 1811+1.6 Kb A>G is not related to a stop codon and, as such, it is actually unknown whether PTC124 could target this mutation.

- Vx770 (Vertex) is a CFTR potentiator; and targets the class 3 mutations by enhancing gating at the cell surface. Clinical trials are underway and have so far concerned patients with at least one G551D mutation. To date, no trial has been done in patients with mutations of other classes and, particularly with the 1811+1.6 Kb A>G mutation; as such, actual results are not applicable to these patients. A recent paper describes the results of the trial in patients with the G551D mutation (Accurso and colleagues, N Engl J Med 2010). They have shown that Vx770 increased the chloride secretion and the lung function. These encouraging results allowed future trials with a combination therapy of Vx770 and Vx809. Preclinical trials have indeed shown that this combination had superior impact on CFTR function compared to one alone.

Taking in account all these encouraging results of clinical trials with target-protein therapies in cystic fibrosis, we could think that, in the next future, such molecules will be proposed to patients with rare mutations like the 1811+1.6 Kb A>G. I hope to have answered your questions. Regards,

Dr Harriet Corvol

24.03.2011