L5 - CF and Small Molecules (Part 2) Flashcards

1
Q

VX-809

A

Lumacaftor

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2
Q

VX770

A

Ivacaftor

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3
Q

Describe what was seen when western blotting for CFTR in rat thyrouid cells that had the f508 mutation

A

Decreased ammout of CFTR (band C) shows that degradation of CFTR was occuring the F508 mutant

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4
Q

How many bands for CFTR on a blot, why?

A

Two
Mature and heavy

Heavy band - mature - fully glycosylated

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5
Q

What is the impact of the F508 mutation

A

In a blot the lower band prodominates - not glycosylated

This immature protein is sent for degradtion

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6
Q

Describe what was seen when applying Lumacaftor (809) to rat thryoid cells (f508) on the western blot

A

Total ammount of mature (band C) had increased and the degradation that normally happens here has been bypassed

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7
Q

When looking at Cl secretion why is it nescesary to add amiloride

A

Prevent any contaimination

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8
Q

Describe the results when looking at lumacaftor on SSC

A

As lumacafotr concentration increases in presence of cAMP then short circuit curretns are bigger and bigger

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9
Q

Lumacaftor clinical trials were

A

Randomised
Double blind
Placebo controlled

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10
Q

Lumcafotr (809) stats

A

18-19 CF patients
Homo F508
28 days
Once placebo group

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11
Q

Lumacaftor clinical trials - effect on lung function

A

NO EFFECT

Results all over the place

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12
Q

Lumacaftor clinical trials - effect on sweat chloride

A

Only a 8mM drop

But this is just a diagnostic marker - unlikely to have any effects on the patients

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13
Q

Compare the sweat chloride drop in the 770 and 809 trial

A

In 809 (luma) onl a 5mM drop compared to 55mM in the (iva)

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14
Q

Were the results from the lumacaftor trials positive or negative - what were the next steps

A

Negative - nothing really changed

Next step was a combination therapy

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15
Q

What was the combination therapy proposed

What made up the therapy and what was the role of each of the components?

A

ORKAMBI

Ivacaftor and lumacaftor

Ivacaftor the potentiator
Lumacaftor the corrector

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16
Q

Evidence for Ivacaftor acting as a potentiator

A

Single channel recordings - in the presence of 770 increased frequency of channel openings

17
Q

Evidence for Lumacaftor acting as a corrector

A

In the western blot of F508 cells

Increased band c in presence of 809

18
Q

N number of orkambi trials

19
Q

Orkambi clinical trials stats

A

1108
Homo F508
12 years
Placebo control

20
Q

Orkambi clinical trials - lung function

A

After 15 days there is an improvement

Peak improvment around 3%

21
Q

What can be said about the variance of the lung function data

Was the 10% improvement (seen in G551D treated with ivacaftor) seen

A

Data had high variance

Mixed spread of dosing protocols and improvements

Some had 10% improvement - others not

22
Q

What does a forrest plot allow

A

Us to compare a huge number of parameters

23
Q

What was the main conclusion that could be made from the forrest plot

A

Combination therapy DOES have a positive effect

24
Q

Orkambi clinical trials - time to first pulmonary exacerbation

A

generally took longer for the treatment groups to have an event compared to the placebo

25
Orkambi clinical trials - events leading to hospitalisation or requiring IV antibiotics
Reduced number of events in both treatment groups relative to the placebo
26
What is the effect of 809 on F508
Can traffic it to the membrane and here it is fucntional
27
In F508 is 809 alone enough to improve symptoms
No
28
Describe how the 770, 809 combination can relieve symptoms
809 traffics the f508 CFTR to the membrane and then the 770 can enhance the function and relieve symptoms
29
Give some more examples of combinations and the mutations that they have been designed to target
Tezacaftor and ivacaftor for F508 Triple Elexa, Teza and Iva for F508
30
Studies into the various combinations - Key points from the western blotting
Normalisied to Calnexin (intensity) Teza and elexa the most effective combination giving the greatest realtvie band C intensity
31
Studies into the various combinations - effect on chloride transport
Triple combination leads to a massive increase in the ammount of Cl transport (most effective)
32
Teza and Iva (f508 clinical trials) - lung function
Increase by around 3% Same as seen in luma/iva (orkambi)
33
Teza and Iva (f508 clinical trials) - Sweat cl
10 mM drop
34
Elexa, teza and iva (F508) triple therapy clinical trials - lung function
MAssive improvement (13/14%)
35
Elexa, teza and iva (F508) triple therapy clinical trials - sweat NaCl
Drop by 45mM (HUGE)