Lecture 6- Small molecules part 2

Question 1

VX-809

Answer 1

Pulse chase experiment showed increase in mature CFTR to the membrane
- does it function ?

Question 2

VX-809 is getting mature CFTR to the membrane but does it function ? Experiment?

Answer 2

Single channel patch clamp if NIH cells expressing Delta F508 CFTR

• PO shows f508 0.1
• VX-809 0.4 same as wt > F508 Cftr trafficked has normal Po
• Vx-770 + VX809 0.6 - sugeest combo treatment may be more affective
• ** VX-770 potentiated activity

Question 3

PO

Answer 3

Open probability

Question 4

VX-770

Answer 4

Ivakaftor

Question 5

VX-809 & F508 currents

Answer 5

HBE patients -/-

• add amiloride to block ENac
• expose cells to cAMP agonist
• activates channel if in membrane
• small response at lo conc
• highest response at 3 micromolar
• increasing conc of VX- 809 leads to an increase in current

Question 6

VX-809 & F508 clinical study

Answer 6

Randomised, double blind placebo 
-homozygous for delta F508 
- 28 days 
- tested different amounts 
- lung function 
- monitored FEV as a % of predicted 
- positive value closer to predicted 
- negative value = further from predicted 
**** No sign of functional pattern/ placebo improved 
VX-809 - no effect no improvement 
In vivo data 
- moderate improvement in sweat chloride

Question 7

Combination therapies

Answer 7

VX-770/VX-809

- Orkambi

Question 8

Orkambi

Answer 8

Some benefit but not massive

• sweat chloride drops
• monotherapy followed by combo then off
• improvement when combo - 12 mmol drop

Question 9

Orkambi - Change in FEV1 % of predicted

Answer 9

Orkambi vs just VX-809

• placebo slight worsening negative value
• Orkambi combo moderate improvement if VX-809 high concentration

Question 10

Phase 3 Trial - orkambi

Protocol

Answer 10

• 1108
• homozygous G508
• randomised/ double placebo
• -traffic and transport protocol
• 3 conditions > placebo
• 400 mg VX-809 / 250mg Ivacaftor
• VX-809 Vx-809/ 250mg Ivacaftor

Question 11

Orkambi Phase 3 Trial results -

Answer 11

• FEV1
  placebo - fall in lung function over time
• Lung function goes up
• improvement is moderate and much less than ivakaftor treatment
• proportion of patients showing improvement
• high proportion 5% improvement
• big impact in some patients- average of 3 % improvement
• Forrest plot- independent on what group it is there is some improvement but small overall

Question 12

issue with clinical trials

Answer 12

compliance

Question 13

Phase 3 trial - Orkambi

Answer 13

Time to first pulmonary exacerbation
- positive impact on at least some of the patients
Events leading to hospitalisation
- 45 in the placebo significantly lower in the combo treatments

Question 14

Overall conclusions of VX-770/VX-809

Answer 14

Vx- 809 can traffic delta F508 to the membrane and it is functional

• but in F508 patient Vx- 809 alone isn’t sufficient to improve symptoms
• BUT if VX-809 traffics F508 CFTr to the membrane the addition of potentiator VX-700 enhances function and relieves symptoms

Question 15

How much does it all cost ?

Answer 15

Ivacaftor - £189,000 per year per patient

Orkambi - £104,000 per year per patient

Question 16

Issue with Orkambi

Answer 16

benefit is quite small but cost is large

• still need all other treatments
• not licensed in the UK

Question 17

Big problem with gene therapy

Answer 17

• cells are constantly replaced
• repeat application required
• potential immune responses with adenoviruses

Question 18

First non-viral CFTR gene therapy 2015

Answer 18

Phase 2b clinical trial 
liposomes 
- had coding sequence for CFTR 
- 140 patients 
- 28 day intervals 9 doses 
- nebulised 
- control saline nebulised

Question 19

First non-viral CFTR gene therapy 2015- Results

Answer 19

• % change in % predicted value
• stabilise airway function - not improved or worse
• varied from patient to patient one patient 20% improvement to 17% fall in lung function on the other end of the spectrum

Forest plot

• FEv1 improvement significantly
• FVC improved significantly
• Gas trapping significantly reduced

Gene therapy patients - large shift in chloride secretion
- making CFTr

Question 20

Gene therapy overall conclusion

Answer 20

• Stabilisation of lung function
  -heterogenous population, some responded well others not
• could be due to liposome formulation
  control not great but ethically can use scrambled message fro CFTR