L29- Modulators

Question 1

What kind of nonspecific treatments are there

Answer 1

Pert, antistaph/anti pseudomonas’s, physiotherapy, mycolytics, dnases

Question 2

What was the first modulator found and for whcih mutation

Answer 2

Ivacaftor for class 3 eg gly551asp (problems with gating)

Question 3

What does it do

Answer 3

Augments Cl transport, asl volume increase, cilia beat frequency increase and sweat cl reduction

Question 4

Which article discusses ivacaftors effect more

Answer 4

Ramsey et Al 2011

Question 5

By how much was sweat Cl reduced in 48 weeks

Answer 5

48.1 mmol/L

Question 6

What was the exacerbation reduction rate

Answer 6

55%

Question 7

How much did fev1 increase by

Answer 7

10.6%

Question 8

What weight gain was there

Answer 8

2.8kg

Question 9

What did brodlie et al 2015 find about ivacaftor

Answer 9

Works for other type 3 mutations like arg117his

Does not work for phe508 mutation

Question 10

Ivacaftor is a potentiator what is this

Answer 10

Increase the open probability of CFTR channel ie better gating

Question 11

What are correctors

Answer 11

Modulators which increase processing and trafficking of the CFTR eg for class 2 mutations

Question 12

When Ivacaftor was tested for the phe508 what happened (brodlie 2015)

Answer 12

No change in fev, sweat Cl or weight

Question 13

What was the first corrector-potentiator treatment and which article talks about it

Answer 13

Lumacaftor-ivacaftor

Wainwright et al 2015

Question 14

What was the fev1 improvement

Answer 14

4% which was still much less than Ivacaftor for the g551d

Question 15

What other changes were there in early clinical trials

Answer 15

BMI , exacerbation rate and sweat Cl

Question 16

What was the issue with it

Answer 16

Was no cost benefit to it and 4.2% reported side effects like dyspnoea and liver problems

Question 17

What was the next corrector looked at

Answer 17

Tezacaftor

Question 18

What does it do (brodlie 2015)

Answer 18

Helps correct folding and processing to the surface

Question 19

What sort of effects did it have (brodlie 2015)

Answer 19

Reduced sweat Cl and better fev sligjtly and less side effects than lumicaftor

Question 20

What was found in people with heterozygous mutation for phe508

Answer 20

Tezacaftor didn’t work, no sig change to fev

Question 21

Which therapy was first for heterozygous phe508 patients

Answer 21

Triple therapy (elexacaftor-Tezacaftor-Ivacaftor)

Question 22

Which article talks more about this triple therapy

Answer 22

Middleton 2019

Question 23

What % reduction in exacerbations were there

Answer 23

63% (even more than Ivacaftor)

Question 24

What did the fev increase by even more than Ivacaftor

Answer 24

14.3% change

Question 25

What we’re the side effects like

Answer 25

Very mild only 1% discontinued

Question 26

Why is there no drugs for class 5 and 6

Answer 26

Too rare to find patients for the clinical trials

Question 27

Which other mutation has issues in finding treatments

Answer 27

Class 1