Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni

UNITA’ OPERATIVA DI PEDIATRIACentro Regionale per la diagnosi, la cura e la riabilitazione della

Fibrosi Cistica

09/11/2013 Donatello SALVATORE

cff.org clinicaltrials.gov

CF Foundation: le linee di ricerca terapeutica

How much CFTR is enough?

Carriers

Adapted from Accurso et al JCF 2013 in press

Normal

CFPancreatic Insufficient

Pancreatic Sufficient

≈ 30% CFTR activity associated with symptom reduction

CF is Not One Genetic DisorderCFTR mutation classes

Adapted from http://www.umd.be/CFTR/W_CFTR/gene.html

Cl -Cl -Cl -

Cl -

Cl - Cl -

Normal

XClass I

synthesis

X

Class IImaturation

X

Class IIIregulation

X

Cl -Cl -

X

Class IVconductance

Cl -Cl -

Class Vquantity

‘severe’ mutationspancreatic insufficiency

‘mild’ mutationspancreatic sufficiency

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;373:1891-1904

Class I Class II Class V Class III Class IV

Little to noCFTR GatingSome

CFTR Conductance

Normal CFTR quantity and

function

Correctors PotentiatorsTreatment

approaches

Class I nonsense mutations

Adapted from Schmitz A, Famulok M. Nature 2007

Nonsense mutation

Readthrough compound

Shortened proteinFull-length protein

Mean Relative Change in %-Predicted FEV1 at Week 48 by Chronic Baseline Inhaled Antibiotic Use

No Inhaled Antibiotics

Week 48 ∆ = 6.7%p = 0.013*

Week 48 ∆ = 0.0%p = 0.88*

Any Inhaled Antibiotics

*Nominal p-values

8 16 24 32 40 48-8

-6

-4

-2

0

2

4

6 Ataluren (N=64)

Placebo (N=63)

BL

Time, weeks

-4.4%-4.4%

8 16 24 32 40 48-8

-6

-4

-2

0

2

4

6 Ataluren (N=52)

Placebo (N=53)

BL

Time, weeks

Ch

ang

e in

%-P

red

icte

d F

EV

1, M

ean

-0.2%

-6.9%

= 6.7%

See Abstract 193

In 2014, PTC is initiating an ataluren Phase 3 efficacy and safety trial in patients not receiving inhaled aminoglycosides

Therapeutic Approaches by Class

F508del CFTR Processing Corrector

Adapted from New Engl J Med 352(19): 1992-2001, 2005

cytoplasmicF508del CFTR

Cultured F508del/F508del-human bronchial epithelial cells

Van Goor et al., PNAS 2011

CFTR proteins with Class II mutations do not reach the cell surface

Cl -Cl -Cl -

Cl -

Cl - Cl -

NormalCFTR

XF508del

Class II mutation

cilia

nuclei

Van Goor et al., PNAS 2011

Lumacaftor increases the amount of F508del-CFTR at the cell surface

Cultured F508del/F508del-human bronchial epithelial cells

CFTR

cilia

nuclei

untreated + lumacaftor