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BMS346 - Epithelial Physiology > L5 - CF and Small Molecules (Part 2) > Flashcards

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

A

1108

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
Q

Orkambi clinical trials - events leading to hospitalisation or requiring IV antibiotics

A

Reduced number of events in both treatment groups relative to the placebo

26
Q

What is the effect of 809 on F508

A

Can traffic it to the membrane and here it is fucntional

27
Q

In F508 is 809 alone enough to improve symptoms

A

No

28
Q

Describe how the 770, 809 combination can relieve symptoms

A

809 traffics the f508 CFTR to the membrane and then the 770 can enhance the function and relieve symptoms

29
Q

Give some more examples of combinations and the mutations that they have been designed to target

A

Tezacaftor and ivacaftor for F508

Triple Elexa, Teza and Iva for F508

30
Q

Studies into the various combinations - Key points from the western blotting

A

Normalisied to Calnexin (intensity)

Teza and elexa the most effective combination giving the greatest realtvie band C intensity

31
Q

Studies into the various combinations - effect on chloride transport

A

Triple combination leads to a massive increase in the ammount of Cl transport (most effective)

32
Q

Teza and Iva (f508 clinical trials) - lung function

A

Increase by around 3%

Same as seen in luma/iva (orkambi)

33
Q

Teza and Iva (f508 clinical trials) - Sweat cl

A

10 mM drop

34
Q

Elexa, teza and iva (F508) triple therapy clinical trials - lung function

A

MAssive improvement (13/14%)

35
Q

Elexa, teza and iva (F508) triple therapy clinical trials - sweat NaCl

A

Drop by 45mM (HUGE)

BMS346 - Epithelial Physiology (10 decks)

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