lecture 12

Question 1

What are the goals of treatment in CF?

Answer 1

• maintaining lung function:
• • treat infections
• • airway clearance
• adequate growth
• • diet
• • supplementation
• managing complications e.g.
• • CFRDM
• • Liver disease

Question 2

Who is in ‘The CF Team’?

Answer 2

• multidisciplinary care
• • physicians
• • nurses
• • physiotherapist
• • dietician
• • geneticist
• • psychologist
• centres of excellence: centres where they have a minimum of 50 patients with CF attending the centre, have access to multidisciplinary team, outcome for patients in terms of morbidity and mortality are significantly better

Question 3

What are some of the physiotherapeutic treatments of CF?

Answer 3

Techniques to improve airway clearing/mucus drainage.

In the first year or two of life the form of physiotherapy used are manual techniques i.e. techniques of percussion

• gravity assisted drainage and manual techniques
• • modified 5 position technique in infants
• active cycle of breathing techniques (ACBT)
• • introduced as blowing games
• autogenic drainage (AD)
• Assisted AD
• Positibe Expiratory Pressure (PEP)
• • mask
• • mouthpiece (MoPEP)
• • combination
• • bubble
• activity and exercise lead to bronchodilation and assist in airway clearance, e.g. trampolining

Question 4

How are antimicrobials used in the treatment of CF?

Answer 4

• prophylaxis

- exacerbations

Question 5

What are the routes by which an antibiotic can be taken?

Answer 5

• oral
• intravenous
• • home
• • hospital
• nebulised

Question 6

How do we chose what antibiotics to use? What are important things to take into consideration when choosing antibiotics?

Answer 6

• knowledge about what are the common pathogens involved in CF lung disease
• access to sputen, cough swabs, and bronchiolalveolar lavage samples (washing samples from lower airways taken via a brinchioscope - a camera with a suction channel passed down into the airways)
• based on the results of these sputen etc can determine what the pathogen is and test against a range of antibiotics to determine what is the most appropriate to deal with that infection
• in a person who is on antibiotics long term there is a risk of developing resistance: seen particularly in older CF patients; start to have airways infected by bacteria that are resistant to a wide range of antibiotics
• tend to give patients (particularly when they are there for a tune up) a minimum of two different antibiotics from different classes to minimise development of resistance
• also important to consider that patients with CF have different pharmacokinetics (i.e. clear the antibiotic differently): tend to require higher doses e.g. aminoglycosides significantly higher doses.

Question 7

Is there a general correlation between age of patient and pathogens they are most likely to acquire?

Answer 7

Yes

• staphylococcus aureaus is the most common organism in the younger age group
• Pseudomonas aeruginosa is unusual in the young childhood years but as the child moves through adolescence into adulthood it becomes much more common
• acquisition of pathogens occurs age-wise
• majority eventually acquire Pseudomonas

Question 8

What are some infections commonly spread from patient to patient in CF?

Answer 8

Patient to patient spread of infection

• pseudomonas aeruginosa
• Burkholderia cepacia
• MRSA (more of a problem in the US than australia)

Question 9

How can we prevent the spread of infection among CF patients?

Answer 9

Segregation of patients

• in-patient: don’t allow patients with CF to interact, have different rooms
• out-patient: when they come into clinic they go into a clinic room and the whole team rotates around them. Rooms are cleaned and disinfected between patients
• social activities: strongly recommend to families that they don’t mix CF children with other CF children. Means they lose peer support. Encourage parents to interact without the child present. Internet contact - link up young people with CF.

Question 10

What are mucolytics?

Answer 10

Therapies that work to think the mucus lining the lungs

• recombinant human deoxyribonuclease-1 (Pulmozyme)
• hypertonic saline
• mannitol (nebulise it, lines the lungs, is a sugar so draws water to itself)

Question 11

What some anti-inflammatory agents used in the treatment of CF?

Answer 11

• Azithromycin: initially developed as an antibiotic, but discovered to have anti-inflammatory properties, been shown to improve lung function and reduce exacerbations, particularly in those infected with Pseudomonas
• Prednisolone: corticosteroid, strong important anti-inflammatory agent, reduce inflammation and improve lung function but at a huge cost: all corticosteroids have very significant side-effects so have to limit their use in CF
• Inhaled steroids: lower dose, but not particularly effective in improving outcomes in patients with CF
• Ibuprofen: non-steroid, benefit in terms of improving lung function but with significant side effects especially in nephrotoxicity

Question 12

What is the role of nutrition in treating CF?

Answer 12

• close monitoring
• specialist dietician
• energy requirements 120-150% normal
• • wide variation
• • increased expenditure
• • increased losses
• • reduced intake/impaired appetite
• high fat (35-40%) high protein diet, high salt (i.e. maccas)
• supplemental feeds
• • oral
• • nasogastric
• • gastrostomy (PEG)
• improved growth improves lung function
• replacement of fat soluble vitamins: A, D, E and K
• • measure vitamin levels at least once a year and adjust supplements accordingly
• salt replacement

Question 13

How do we treat pancreatic insufficiency?

Answer 13

• enteric-coated pancreatic enzyme microspheres e.g. Creon
• quite big so hard to teach patient to swallow (that’s what he said)
• derived from porcine extract
• taken with all fat, protein and complex carbohydrate containing foods
• contain lipase, amylase, protease
• 500-2000 units lipase/kg/meal
• maximum 10,000 units lipase/kg/day

Question 14

What are some future therapies for CF?

Answer 14

• novel inhaled antibacterials
• anti-inflammatory agents
• correction of the underlying gene effect
• protein rescue therapy
  (high throughput screening and combinatorial chemistry has allowed for the development of some of these treatments)

Question 15

What are the different phases of clinical trials?

Answer 15

(usually animal testing prior to human testing)

Phase 1:

• safety and pharmocology
• start with low doses and increase
• healthy volunteers

Phase 2:
examine effectiveness 
- dose 
- delivery method 
- dosing interval 
confirm safety 
- 100-300 patients 

Phase 3 
Confirm previous findings
Demonstrate safety and efficacy 
Determine best dosage 
- 1000+ patients

Question 16

What are some of the novel antibacterials being considered for the treatment of CF?

Answer 16

More about the delivery of antibiotics than the antibiotics themselves
Inhaled can reduce side effects and increase bacterial killing

Dry-powder inhaler

• colistin
• tobramycin
• vancomycin

Nebulised

• Aztreonam
• Amikacin
• Levofloxacin

Question 17

What are some of the anti-inflammatory products being developed for the treatment of CF?

Answer 17

• Glutathione: antioxidant (CFTR acts as a glutathione transporter so reduced amounts in CF patients), trials haven’t being as promising as theories suggest
• Sildenafil: (aka viagra ) phosphodiesterase inhibitor
• KB001A: humanised monoclonal Fab fragment, targets Pseudomonas virulence factor and decreases local inflammation
• alpha 1 - antitrypsin: protease inhibitor, phase 2 study of inhaled alpha1-antitrypsin

Question 18

How could gene therapy help patients with CF?

Answer 18

• introduce a normal copy of the CFTR gene into the cells of the conducting airways
• likely to need repeated application
• lung efficient barrier to foreign material (very hard to get gene into cell)
• • avoid being cleared from lungs by mucociliary escalator
• penetrate mucus and then cell membrane
• cross cytoplasm and DNA must enter nucleus
• avoid host immune response
• more than 30 trials to date
• majority Phase I and II
• • safety only not clinical outcome
• many trials conducted to date have provided proof of principle for gene transfer to the airway epithelium
• gene expression lasts 1 to 4 weeks
• current phase 2 trial of monthly nebulised GL67A/pGM169

Question 19

What are vectors involved in gene therapy of CF?

Answer 19

• viral and non-viral options for gene transfer agent (GTA)
• majority of trials used delivery of GTA to nasal and maxillary sinus epithelia of CF patient volunteers as a surrogate tissue
• ran into a lot of problems because in a number of instances the virus killed the patients

Non-viral vectors

• cationic liposomes complexed with plasmid DNA
• • GL67A/pGM169 is the combination of cationic liposome (GL67A) and plasmid DNA expressing CFTR (pGM169)

Short duration of efficacy
- viral promoter exchanged for humanised promoter capable of sustaining prolonged gene exression

Mild flu-like symptoms
- presence of unmethylated CpG groups on bacterially derived DNA

Question 20

How can stem cells be used to treat CF?

Answer 20

• bone marrow-derived stem cells (BMSCs) have the capacity to change from one cell type to another (trans-differentiate)
• data on trans-differentiation in the lung are conflicting
• myelo-ablation and extensive damage of the lung with bleomycin or detergents is a prerequisite for engraftment
• frequency of engraftment in aways is reported to be very low (<1%)

(i.e. has caused serious damage to lung so far)

Question 21

How can protein rescue therapy be used to treat CF?

Answer 21

• overcome basic CFTR defect
• mutation (class) specific:
• • 6 classes

Question 22

What is Ivacaftor (Kalydeco)?

Answer 22

Class III protein rescue therapy durg:

• potentiator
• class III mutation
• Gly551Asp (G551D): impairs the ability of CFTR at the cell surface to open
• identified via high-throughput screening (HTS)
• significant improvement in lung function
• significant increase in weight
• longer time to exacerbation
• significant decrease symptoms
• significant reduction in sweat chloride values
• first therapy to target underlying defect
• 150mg tablet twice daily
• Ivacaftor approved by FDA on 31.01.2012
• Approved by European Medicines Agency
• Approved by National Institute for Health and Care Excellence (NICE) 2013
• FDA recently approved its use in other mutations
• G178R, G551S, G1244E, G1249D
• S549N, S549R, S1251N, S1255P
• very expensive: $294,000 per patient per year
• Gly551Asp (G551D) is in 4% of CF patients worldwide, 2800 patients worldwide
• $823.2 million per year
• $58.8M in australia
• has been approved for use in Australia
• Pharmaceutical Benefits Advisory Committee (PBAC) recommended inclusion in Pharmaceutical Benefit Scheme (PBS)
• Not yet listed: ongoing negotiations regarding cost

Ivacaftor also has other potential benefits:

• class IV mutation Arg117His (R117H)
• • phase 3 trial commenced June 2012
• Class V and VI
• • Ivacaftor improves chloride conductance even in wild-type CFTR
• • No clinical trials at present

Question 23

How could protein rescue therapy help Class II mutations?

Answer 23

• most common mutation is Phe508del (DF508)
• correctors increase cellular processing and delivery of CFTR proteins to cell surface
• VX-809 (Lumacaftor) and VX-661
• • small molecular compounds
• • shown in cell culture and early phase 2 studies to increase the amount of Phe508del-CFTR trafficked to cell surface
• once trafficked to cell surface, Phe508del-CFTR doesn’t function optimally
• combine with potentiator, ivacaftor
• in-vitro studies of lumacaftor-ivacaftor in Phe508del respiratory epithelia
• • lumacaftor alone increases CFTR-mediated chloride transport to roughly 15% of wild type
• • addition of Ivacaftor increases transp ort to nearly 30% of wild type (30% considered adequate to overcome the clinical features of CF)
• Phase 3 studies underway: VX809/770
• Phase 2 studies VX661/770

Question 24

How could protein rescue therapy help Class I mutations?

Answer 24

• nonsense (premature stop codon) mutations: 10% of subjects
• Ataluren (previously PTC124)
• • small molecule compound that promotes read-through of premature truncation codons
• 2012 phase three trial of ataluren in 238 patients did not reach primary endpoint of improvement in FEV1 at 48 weeks: except in a subset of individuals who were not simultaneously taking nebulised aminoglycoside antibiotics