L8 Cystic Fibrosis II

give the approaches used to treat the ‘basic anion permeability defect’ in CF

• CFTR modulator therapy

• Genetic therapy

• Alternative channel therapy

what does 50% CFTR function mean

heterozygote

• risk for pancreatitis, sinusitis, lung disease, ABPA

what are endpoints to measure for how a new therapy is assessed in vivo

• lung function - e.g. FEV_1.0 (percent predicted)

• Sweat chloride (sweat test)

• Number of hospitalisations

• BMI -weight gain

• Quality of life

describe the function of the secretory coil of the sweat duct

• primary NaCl -rich isotonic secretion from acinar (CC) cells

• mostly Cl- secretion via TMEM16A

describe the function of the reabsorptive duct of the sweat duct 

• transcellular NaCl absorption but not water, producing a hypotonic fluid

• both ENaC and CFTR are involved in transcellular NaCl reabsorption

describe regulation of ion and fluid transport in a normal sweat gland

mostly via ACh (control via hypothalamus) as well as catecholamines

why is CF sweat salty

NaCl is not re-absorbed due to faulty CFTR

what is normal sweat Cl- concentration at maximum rates

below 60 mM

what is CF sweat Cl- concentration at maximum rates

120 mM

what does CFTR modulator therapy use chemicals (drugs) to do

‘correct’ mutant CFTR

how is CFTR modulator therapy used

• alone

• in combination with Genetic Therapies or Alternate Channel Therapy

what does the CFTR modulator therapy required effect depend on

mutation

what does CFTR modulator therapy possibly require

designer (personalised) therapy

how do you calculate total Cl- current (I)

I = N x Po x i

what is N in the equation to find total Cl- current (I = N x Po x i)

number of CFTR channels at cell surface (increase)

• e.g. Class II

what is Po in the equation to find total Cl- current (I = N x Po x i)

CFTR channel gating (enhance)

• e.g. Class III

give an example of Vertex pharmaceuticals as CFTR modulator therapy

VX-770

give an example of high throughput screening vertex pharmaceuticals

VRT-484

list the types of CFTR modulators

• potentiators

• correctors

• termination suppressors

• amplifiers

• stabilisers

where are potentiators and correctors

in clinical use

where are tumour suppressors, amplifiers and stabilisers

still under development

what do potentiators do

increase the activity (Po) of Class III ‘gating’ mutants and some RF mutants

what is a natural potentiator

Genistein

what is a man made potentiator

Vertex VX-770

give examples of Vertex VX-770

• Kalydeco (US)

• Ivacaftor (UK)

how do potentiators increase the activity of class III ‘gating’ mutants and some RF mutants

increasing opening rate or duration of openings

what do potentiator channels need to work

to be phosphorylated

what channel activity (Po) does VX-770 increase

G551D CFTR Po

what does other research show about VX-770

it increases the opening of G551D CFTR channels via an ATP-independent mechanism

what happened in June 2011 for CF patients

Phase III STRIVE trial, carrying a copy of G551D

what happened for Ivacaftor/Kalydeco approval in CF patients

• Aug/Dec 2012 EMA and NHS approval

• March 2013 RVI-Freeman enrolled 10pwCF onto Ivacaftor- cost per patient was 150 thousand pounds per year

• 2017 FDA approved for mutants- clinical trials werent used to get approval

what did the FDA use for more Kalydeco data

in vitro cell-based data (Ussing chamber/patch clamp)

what happened in May 3, 2023 for Kalydeco

approved for infants as young as 1 month old who have atleast once copy of 97 mutations that respond to Kalydeco

what do correctors do

promote processing of class II mutants to the plasma membrane

what do vertex correctors do

improve the processing of mutant CFTR from the ER to the Golgi, by increasing folding efficiency of the channel in the ER

what does Mutant CFTR escape

the ER quality control (ERQC) machinery and so is not degraded

what does ‘rescued’ CFTR (rCFTR) do

traffics to the apical membrane, increasing the number of channels (N) and anion secretion

what are the conditions for correctors

• low temperature

• 4-phenylbutyrate (4-PB)

• VX-809 (lumacaftor)

what is lumacaftor’s other name

VX-809

what does VX-809 increase at the apical plasma membrane of human airway cells in vitro (Ussing expts)

F508del CFTR

what was the time length of treatment of human airway cultures

49hrs VX-809 treatment

what is Chloride secretion (I_T) measured in Ussing chambers after

stimulation with a cAMP agonist

what was the EC₅₀ of VX-809 in the Ussing expt

81

what did phase II studies from patients homozygous for F508del treated with VX-809 show

little effect on lung function or sweat chloride

how many defects does F508del-CFTR have that need to be corrected

at least 3

list the defects that F508del-CFTR have that need to be deleted

• processing defect

• gating defect

• rescued F508del CFTR (rCFTR) has shorter resident time in plasma membrane

what is the F508del-CFTR processing defect due to

Low N

what is the F508del-CFTR gating defect due to

lower Po than WT

what is the F508del-CFTR rescued F508 CFTR (rCFTR) having a shorter resident time in the plasma membrane due to

stability

what is the time of F508del-CFTR rescued F508 CFTR (rCFTR) having a shorter resident time in the plasma membrane

2 hours compared to ~20 hours

why was a combination therapy tested for F508del CFTR

results showed VX-770 increased rescued F508del CFTR channel activity

what do you combine VX-770 with

VX-809

what are the phase III results of those homozygous for F508del, treated with both VX-770 and VX-809

~3% improvement in ppFEV₁

VX-809

lumacaftor LUM

VX-770

Ivacaftor (IVA)

what was the results of pulmonary exacerbations/hospitalisations phase III for F508del CFTR treatment with both VX-770 and VX-809

~30% reduction

what happened in 2015 for FDA approved double drug combination

Orkambi

• EMA in the same year

why did UK’s national institute for health and care excellence (NICE) not initially approve use of Orkambi (2015)

because of cost/benefit analysis

• until 2019

when was triple combination (TC) therapy accessed

2018

what is the Phase II triple combination trial

2 correctors and 1 potentiator

what are the correctors and potentiators used in triple combination therapy

• VX-445

• VX-661

• VX-770

VX-445

elexacaftor

VX-661

tezacaftor

what did triple combination therapy see a decrease in

• sweat [Cl-] and hospitalisations

• BMI improved

who does triple combination therapy phase III combination represent

~90% of CF population in the US/UK

give 4 examples of highly effective CFTR modulators

• ivacaftor

• orkambi

• symkevi

• kaftrio

give 6 examples of new CFTR modulators in clinical use

• ivacaftor

• deutivacaftor

• lumacaftor

• elexacaftor

• tezacaftor

• vanzacaftor