1. UNITA’ OPERATIVA DI PEDIATRIA
Centro Regionale per la diagnosi, la cura e la riabilitazione della Fibrosi Cistica
Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni
09/11/2013
Donatello SALVATORE

2. CF Foundation: le linee di ricerca terapeutica
For this reason, the CF community led by the CF Foundation, continues to support a wide range of therapeutic approaches. Although all approaches are important, today’s presentation will only cover anti-infectives and anti-inflammatories.
cff.org
clinicaltrials.gov

3. How much CFTR is enough? CF Carriers Normal
Pancreatic Insufficient CF
Pancreatic Sufficient
Carriers
Normal
Scott showed you this figure yesterday, explaining that we now know from both natural history studies and initial clinical trials of CFTR modulations, that recovering at least 30% activity of the CFTR protein is associated with a significant impact on symptoms. Please remember this 30% activity threshold as we proceed today.
≈ 30% CFTR activity associated with symptom reduction
Adapted from Accurso et al JCF 2013 in press

4. CF is Not One Genetic Disorder CFTR mutation classesX
Cl -
Class IV
conductance
Class V
quantity
Cl -
Cl -
Cl - X
Class I
synthesis
Class II
maturation
Class III
regulation
Normal
Normal CFTR protein is trafficked to the surface and activated as a Cl- channel. We also know that there are over 1000 CF genetic mutations, most of which can be placed in functional classes shown here. The classes on the left (I, II, III) are associated with more severe disease, including pancreatic insufficiency and the right side (IV, V) with a milder disease. Every patient has 2 mutations and if one is mild, fortunately, it will dominate.
‘severe’ mutations
‘mild’ mutations
pancreatic insufficiency
pancreatic sufficiency
Adapted from

5. So, there must be mutation specific treatment approaches
Reduced Quantity
Reduced Function
MacDonald et al. Pediatr Drugs 2007;9:1-10; Zielenski. Respiration 2000;67:117-33; Welsh et al. Cystic fibrosis In: Valle et al, eds. OMMBID. McGraw-Hill Companies Inc;2004:part 21,chap 201; O’Sullivan et al. Lancet 2009;373:
Class I
Class II
Class V
Class III
Class IV
Little to no
CFTR
Gating
Some
Conductance
Normal CFTR quantity and function
Because of this range of mutations, treatment approaches must be directed to specific functional classes. As shown on the left, in severe classes, reduced levels of CFTR reach the cell surface requiring small molecules – termed correctors -- to assist in proper transport and folding of the protein, milder mutations on the right reach the cell surface but need a potentiator to permit proper function of the salt channel. Severe mutations will require a potentiator in addition to a corrector.
Treatment
approaches
Correctors
Potentiators

6. Class I nonsense mutations
Readthrough compound
Full-length protein
Shortened protein
The most prominent class remaining is Class I or nonsense mutations. Here the nascent protein is never made correctly and is stopped prematurely in the translational process.
Adapted from Schmitz A, Famulok M. Nature 2007

7. Mean Relative Change in %-Predicted FEV1 at Week 48 by Chronic Baseline Inhaled Antibiotic Use
No Inhaled Antibiotics
Any Inhaled Antibiotics
Week 48 ∆ = 6.7%
p = 0.013*
Week 48 ∆ = 0.0%
p = 0.88*
A further evaluation of the inhaled antibiotic sub-group demonstrated a larger treatment effect in the group of subjects who were not receiving chronic inhaled antibiotics at baseline vs. those who were on inhaled antibiotics at baseline. 
The graph on the left shows a 6.7% difference in relative change in % predicted FEV1 in the ataluren-treated group compared with placebo, with an unadjusted p-value of
In contrast, the graph on the right shows that there is no difference between ataluren and placebo in the inhaled antibiotics group.
In 2014, PTC is initiating an ataluren Phase 3 efficacy and safety trial in patients not receiving inhaled aminoglycosides
See Abstract 193
*Nominal p-values

8. Therapeutic Approaches by Class
F508del CFTR Processing Corrector
Adapted from New Engl J Med 352(19): , 2005

9. CFTR proteins with Class II mutations do not reach the cell surface
Cultured F508del/F508del-human bronchial epithelial cells
Cl -
Cl -
Cl -
Cl -
Cl -
Cl -
cilia X
F508del
Class II mutation
cytoplasmic
F508del CFTR
The Class II mutations are very important in reaching our goal. These severe mutations do not reach the cell surface as shown in the photomicrograph of a human bronchial epithelial cell (or HBE) with the green stippling in the cytoplasm.
nuclei
Normal
CFTR
Van Goor et al., PNAS 2011

10. Lumacaftor increases the amount of F508del-CFTR at the cell surface
Cultured F508del/F508del-human bronchial epithelial cells
cilia
CFTR
Lumacaftor, a corrector, also discovered through HTS, and the first to reach Phase 3 testing, demonstrates successful trafficking of F508del CFTR to the surface in HBE cells as shown here. Please note that the green staining is now concentrated at the cell surface.
nuclei
untreated
+ lumacaftor
Van Goor et al., PNAS 2011