Current and future therapies in CF

Question 1

There is no cure for CF

All symptomatic treatment

Goals of treatment:

• Maintaining lung function
  
  • Treat i____
  • A____ c____
• Adequate growth
  
  • D___
  • Su____
• Managing complications e.g.
  
  • CFRDM
  • L___ D___

Answer 1

• Maintaining lung function
  
  • Treat infections
  • Airway clearance
• Adequate growth
  
  • Diet
  • Supplementation
• Managing complications e.g.
  
  • CFRDM
  • Liver disease

Question 2

CF Team

PTs require multidisciplinary care

Define a CF “centre of excellence”

Answer 2

Centres which treat >50 CF PTs,

have access to a multidisciplinary team

>>Shown to have better outcomes when treated at centres of excellence

Question 3

Physiotherapy

Infants:

Gr___ A___ Dr____ and Ma___ Te____

• elaborate

Answer 3

Physiotherapy

Infants:

Gravity Assisted Drainage and Manual Techniques

• Techniques to try and move mucus from the airways
• Manual percussion techniques to try and loosen up mucus

Question 4

Physiotherapy Techniques - Self

• A___ C___ of B____ T___ (ACBT)
• A____ D___ (AD)
• A____ AD
• P___ E___ P____ (PEP)

Activity and exercise also very important

Answer 4

Physiotherapy Techniques - Self

• Active Cycle of Breathing Techniques (ACBT)
• Autogenic Drainage (AD)
• Assisted AD
• Positive Expiratory Pressure (PEP)

Activity and exercise also very important

Question 5

Antimicrobials

• Prophylaxis
  
  • Treatments to prevent infection
• Exacerbations
  
  • Treat

Want to prevent and treat infection, thus liberal use of antibiotics are important
BUT…

Answer 5

Remember that aminoglycosides e.g. gentamycin are nephrotoxic and ototoxic so be careful about dosage

Question 6

Antibiotics

Chosen through:…

• Route
• Susceptibility testing
  
  • how?
• Resistance
• Pharmacokinetics
  
  • **C____ in CF patients

Answer 6

Chosen through:…

• Route
• Susceptibility testing
  
  • Testing of PT sputum
• Resistance
• Pharmacokinetics
  
  • Changed for some drugs in CF patients so need to have different dose regimens

Question 7

Antimicrobials

Acquisition of pathogens occurs age-wise

Majority eventually acquire P______

Answer 7

S. Aureus is common in early years
Pseudomonas Aeruginosa (any sp.) rises over lifetime

Question 8

Infection control - Beyond cohorting

Control:

• Patient to patient spread of infection
  
  • such as?
• Segregation of patients
  
  • in what context?

Answer 8

Control:

• Patient to patient spread of infection
  
  • P. aeruginosa
  • MRSA
  • NTM (non-tuberculosis microbacteria
• Segregation of patients
  
  • In/out-patient
  • Social activities

Question 9

Other respiratory therapies

Mucolytics

• Act to t___ the mucus to make it easier to clear airways
  
  • R____ human d_____-1 (P____)
  • H____ saline
  • M_____ol
    
    • Explain MOA for all mucolytics:

Answer 9

Mucolytics

Act to thin the mucus to make it easier to clear airways

• Recombinant human deoxyribonuclease-1 (Pulmozyme)
  
  • Cleave dead neutrophils who die trying to fight the infection (neutrophil dna makes mucus thicker)
• Hypertonic saline
  
  • very salty saline, nebulised hypertonic saline draws water into lungs to hydrate mucus
• Mannitol
  
  • same MOA as hypertonic saline, draws water into mucus

Question 10

Other respiratory therapies

Anti-inflammatory agents

• Azi_____
  
  • explain
• Steroids not recommended because of:

Answer 10

Other respiratory techniques

Anti-inflammatory agents

• Azithromycin
  
  • Macralide antibiotic that also has some anti-inflammatory action
  • Shown to have improved outcomes in PTs with chronic P. aeruginosa infection
  • Only medication shown to be successful, used worldwide
• Steroids not recommended because of:
  
  • Immunosuppressive side effects

Question 11

Nutrition

Needs to be closely monitored and planned by a specialist dietician

• Energy requirements are ___ -___% normal
  
  • Wide v___
  • Increased e____
  • Increased l____
  • Reduced i____
    
    • why?

Answer 11

• Energy requirements are 120-150% normal
  
  • Wide variation
  • Increased expenditure
  • Increased losses
  • Reduced intake
    
    • Lung disease = nausea
    • Nasal polyps = cannot smell or taste food = reduced appetite

Question 12

Nutritional requirements

• High ___ (35-40%) high ___ diet
• Supplemental feeds
  
  • via?
• Improved growth improves l___ f___
  
  • Close association between g___ n___ and g___ l___ h___
  • M______ PTs
    
    • S____ life expectancy
    • Faster r___ in r____ f____

Answer 12

Nutritional requirements

• High fat (35-40%) high protein diet
• Supplemental feeds
  
  • oral
  • nasogastric
  • gastrostomy (PEG)
    ​
• Improved growth improves lung function
  
  • Close association between good nutrition and good lung health
  • Malnourished PTs
    
    • Shorter life expectancy
    • Faster reduction in respiratory force

Question 13

Vitamins and Electrolytes

• F__-s___ vitamins
  
  • Which 4?
• S___ replacement

Answer 13

Vitamins and Electrolytes

• Fat-soluble vitamins
  
  • A, D, E, K
• Salt replacement

Question 14

Pancreatic enzymes

• Enteric-coated pancreatic enzyme microspheres e.g. Creon
• Taken with all ___, ___, C___ c___ containing foods
  
  • Excluding water/fruit juice that has no c___ c___
• Contain l___, a___, p___
• 500-2000 units lipase/kg/meal
• Maximum ____ units lipase/kg/day

Answer 14

• 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 15

Future Therapies

• Novel symptomatic treatments
  
  • anti-infective
  • anti-inflammatory agents
  • Mucolytics
  • Nutritional
• G___ therapy
  
  • Looking for a ____ to CF
• P___ r____ therapy

Answer 15

Future Therapies

• Novel symptomatic treatments
  
  • anti-infective
  • anti-inflammatory agents
  • Mucolytics
  • Nutritional
• Gene therapy
  
  • Looking for a cure to CF
• Protein rescure therapy

Question 16

Novel Antibacterials

May look to target pseudomonas, noted to be associated with rapid decline in lung function

• V____cin i____ p____
• F____cin/t____cin i____ s____
• Inhaled n___ o___
• i.v. G____

Explain MOA of drugs

Answer 16

Novel Antibacterials

• Vancomycin inhalation powder
  
  • Treatment of MRSA
  • P2 study demonstrated significant decrease in MRSA density in sputum, P3 underway
• Fosfomycin/tobramycin inhalation solution
  
  • combination antibiotic: P2 study
• Inhaled Nitric Oxide: P2 study
  
  • known to have anti-microbial properties when inhaled
• i.e. Gallium
  
  • Similar to iron
  • Dirupts iron-dependent biological processes
  • in vitro kills antibiotic-resistant pseudomonas
  • P2 study in chronically infected adults
• Fosfomycin/tobramycin inhalation solution
• Inhaled nitric oxide
• i.v. Gallium

Question 17

Anti-inflammatory

• CTX-4430 (A_____)
  
  • Inhibit production of leukotriene B4
  • LTB4 is potent neutrophil chemoattractant that is increased in CF
• JBT-101 (L_______)
  
  • Synthetic oral endocannabinoid-mimetic
  • Binds CB2 receptor and trigers pathways that resolve inflammation
  • P2 study demonstrated reduced exacerbation rate in adults
  • P2 study in adolescents underway
• LAU-7b
  
  • Oral form of the retinoid fenretinide
  • Regulate epithelial growth

Answer 17

Anti-inflammatory

• CTX-4430 (Acebilustat)
  
  • Inhibit production of leukotriene B4
  • LTB4 is potent neutrophil chemoattractant that is increased in CF
• JBT-101 (Lenabasum)
  
  • Synthetic oral endocannabinoid-mimetic
  • Binds CB2 receptor and trigers pathways that resolve inflammation
  • P2 study demonstrated reduced exacerbation rate in adults
  • P2 study in adolescents underway
• LAU-7b
  
  • Oral form of the retinoid fenretinide
  • Regulate epithelial growth

Question 18

Gene Therapy

Ideal scenario = find a cure for CF

• Introduce a normal copy of CFTR gene into cells of the c___ a____
  
  • Elaborate
• Likely to need r____ a_____
  
  • why?
• Lung e____ b____ to foreign material
  
  • avoid being c_____ from lungs by m_____ e_____
  • penetrate mucus and then cell membrane
  • cross cytoplasm and DNA must enter nucleus
  • Avoid host i___ r___
  • so?

Answer 18

Gene Therapy

Ideal scenario = find a cure for CF

• Introduce a normal copy of CFTR gene into cells of the conducting airways
  
  • possible in lab in a relatively straightforward, repeatable way
• Likely to need repeated application
  
  • CF is a lifelong disease, epithelial cells in airways regular turnover
• Lung efficient barrier to foreign material
  
  • 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
  • ***Hard part is getting normal CFTR gene to PT airway epithelium cells and then into nucleus
  • ***although mucociliary clearance is impaired and lung defense is not as effective in CF, not completely ineffective

Question 19

Gene Therapy

More than 30 trials to date

• Majority Phase _ and _
  
  • S___ only, not c___ o____
• Many trials conducted to date have provided p___ of p___ for g___ t___ to the a___ e_____
• Gene expression lasts _____
  
  • Likely need repeated application

Answer 19

Gene Therapy

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
  
  • Likely repeated application

Question 20

Gene Therapy

• V___ and n__-v__ options for g__ t___ a___ (GTA)
• Majority of trials used delivery of GTA to n___ and m___ s___ e___ of CF patient volunteers as a s____ tissue

Answer 20

Gene Therapy

• 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

Question 21

Gene Therapy - Vectors

For use as GTA

• V___ vectors
  
  • A____
  • R____
  • A___-____ v___
• Multiple clinical trials in 1990s
• R___ a____ not efficacious

Answer 21

Gene Therapy - Vectors

For use as GTA

• Viral vectors
  
  • Adenovirus
  • Retrovirus
  • Adeno-associated virus
• Multiple clinical trials in 1990s
• Repeated administration not efficacious

Question 22

Gene Therapy - Vectors

• N__-v___ vectors
  
  • Cationic liposomes complexed with plasmic DNA
• S___ d___ of e___
• M__ f__-l__ s____

Answer 22

Gene Therapy - Vectors

• Non-viral vectors
  
  • Cationic liposomes complexed with plasmic DNA
• Short duration of efficacy
• Mild flu-like symptoms

Question 23

Example of non-viral vector for Gene Therapy

P2 trial of 140 PTs ≥ 12 years of age

• Randomised to non-viral vector (nebulised pGM169/GL67A) or 0.9% saline (placebo) every 28 days for 1 year

How did it turn out??

Answer 23

3.7% diff in FEV1 at 1 year = not clinically significant enough

Stable PFTs in treatment group

Decline in placebo group

Question 24

Gene Therapy - Back to Viral Vectors

• L____ vectors now being developed
  
  • Derived from h____ i____ virus
  • Other gene therapies can be used e.g. primary immunodeficiency
  • C__ T_-___ therapy
• L___p_______c____ (LPC)
  
  • Normal component of l___ s____
  • T_____ p______ airway t___ j____
  • I____ v____ a___ to airway cells
  • LPC c_____ enhances g___ e_____ in mouse studies

Answer 24

Gene Therapy - Back to Viral Vectors

• Lentiviral vectors now being developed
  
  • Derived from human immunodeficiency virus
  • Other gene therapies can be used e.g. primary immunodeficiency
  • CAR T-cell therapy
• Lysophosphatidylcholine (LPC)
  
  • Normal component of lung surfactant
  • Transiently permeabilizes airway tight junctions
  • Improve vector access to airway cells
  • LPC conditioning enhances gene expression in mouse studies

Question 25

A large focus of CF research is on protein rescue therapy PRT aims to: PRT is:

Answer 25

A large focus of CF research is on protein rescue therapy PRT aims to: * Overcome basic CFTR defect PRT is: * Mutation (class) specific

Question 26

Recap CFTR class mutations List them. F508del is a class what mutation G551D is a class what mutation

Answer 26

F508del = class II G551D = class III

Question 27

Protein Rescue Therapy - Ivacaftor Ivacaftor is a * P\_\_\_\_ * Class ___ mutation * Gly551Asp (G551D): Impairs ability of CFTR at the cell surface to \_\_\_\_ * Identified via high-throughput screening (HTS) Q) How does Ivacaftor work?

Answer 27

Protein Rescue Therapy - Ivacaftor Ivacaftor is a * Potentiator * Class III mutation * Gly551Asp (G551D): Impairs ability of CFTR at the cell surface to open * Identified via high-throughput screening (HTS) A) Ivacaftor activates CFTR protein, overcomes defective regulation of ATP binding/hydrolysis - also increases ion channel open probability - Like for class IV (abnormal ion channel conductance/gating) = use flavinoid compounds

Question 28

Ivacaftor - Good news * Significant improvement in l\_\_\_ f\_\_\_ * Significant increase in w\_\_\_ * Significant increase in time to e\_\_\_\_ * Significant decrease in s\_\_\_ * Significant reduction in s\_\_\_ c\_\_\_ v\_\_\_ * First therapy to target u\_\_\_ d\_\_\_ * First of its kind to improve ____ f\_\_\_\_

Answer 28

Ivacaftor - Good news * Significant improvement in lung function * Significant increase in weight * Significant increase in time to exacerbation * Significant decrease in symptoms * Significant reduction in sweat chloride values * First therapy to target underlying defect * First of its kind to improve CFTR function

Question 29

Ivacaftor (Kalydeco) * Approved by FDA in 2012 * Subsequently expanded to * PTs with 8 other class III mutations * PTs ≥ 6 yrs with R117H mutation * Younger PTs (2-5yrs)

Answer 29

Ivacaftor (Kalydeco) EXPANDED TO PTs with class IV mutation (R117H)

Question 30

Ivacaftor in Australia * Approved by TGA in July 2013 * PTs from 6 years * G551D * Additonal 9 class III mutations in 2014 * Listed on Pharmaceutical Benefits Scheme (PBS) Dec 2014 * 10 class III mutations

Answer 30

Ivacaftor in Australia G551D 10 class III mutations in total

Question 31

Sustained benefits of Ivacaftor 151 patients with G551D followed for 6 months Showed what kind of improvments?

Answer 31

Sustained improvements in sweat Cl, FEV1, BMI, MCC (mucociliary clearance)

Question 32

Ivacaftor (Kalydeco) Not so good news is:

Answer 32

Super expensive $294,000 per PT per year Many new potentiators in devlopment

Question 33

Protein rescue therapy: Class II mutations * Most common mutation = F508del * recap * Correctors * how do they work? * VX-809 (Lumacaftor) and VX-661 (Tezacaftor) * Small molecular compounds * shown in cell culture and early phase 2 studies to increase \_\_\_

Answer 33

Protein rescue therapy: Class II mutations * Most common mutation = F508del * abnormal protein, 97% stuck in ER and degraded * Correctors * increase cellular processing and delivery of CFTR protein to cell surface * VX-809 (Lumacaftor) and VX-661 (Tezacaftor) * Small molecular compounds * shown in cell culture and early phase 2 studies to increase amt of F508del-CFTR trafficked to cell surface

Question 34

Problem in treating Class II mutations Once trafficked to cell surface, F508del-CFTR doesnt f\_\_\_\_ o\_\_\_\_ * Combine with p\_\_\_\_, I\_\_\_\_\_\_ * How do p\_\_\_ work? * In-vitro studies of lumacaftor-ivacaftor (orkambi) in F508del respiratory epithelia * lumacaftor alone increase CFTR-mediated Cl- transport to roughly 15% of wild type * Addition of Ivacaftor increases transport to nearly 30% of WT

Answer 34

Problem in treating Class II mutations Once trafficked to cell surface, F508del-CFTR doesnt function optimally * Combine with potentiator, Ivacaftor * Potentiators activate protein, overcome defective regulation of ATP binding/hydrolysis, increase ion channel open probability * In-vitro studies of lumacaftor-ivacaftor (orkambi) in F508del respiratory epithelia * lumacaftor alone increase CFTR-mediated Cl- transport to roughly 15% of wild type * Addition of Ivacaftor increases transport to nearly 30% of WT

Question 35

Potentiators + Correctors Orkambi (ivacaftor + lumacaftor) * Approved for h\_\_\_\_ F508del * Mean change in FEV1 of 2.6% to 4% * Significantly decrease e\_\_\_\_\_\_ rate by 39% * Increase weight from 1.23 - 1.57kg Symdeko (ivacaftor + tezacaftor) * Approved for h\_\_\_\_ F508 del * Approvd for h\_\_\_\_\_\_ F508del + 26 other mutations * Mean change FEV1 = 4% * Exacerbation rate reduce by 35% * BMI no change

Answer 35

Potentiators + Correctors Orkambi (ivacaftor + lumacaftor) * Approved for homozygous F508del * Mean change in FEV1 of 2.6% to 4% * Significantly decrease exacerbation rate by 39% * this is why it got approved * Increase weight from 1.23 - 1.57kg Symdeko (ivacaftor + tezacaftor) * Approved for homozygous F508 del * Approvd for heterozygous F508del + 26 other mutations * Mean change FEV1 = 4% * Exacerbation rate reduce by 35% * again, why it got approved * BMI no change

Question 36

Triple combinations 1 __ + 2 \_\_\_ * Introduction of a 2nd ___ to try and \_\_\_\_ * P3 studies underway for * H\_\_\_\_ for F508del * additional m\_\_\_ f\_\_\_ m\_\_\_\_ (class I, II, V) * Interim results announced 6 March 2019 * Mean increase in ppFEV1 13.8% in F508del/minimal function * Mean increase ppFEV1 10% in homozygous F508del already receiving symdeko

Answer 36

Triple combinations 1 potentiator + 2 correctors * Introduction of a 2nd corrector to try and improve CFTR function * P3 studies underway * Homozygous for F508del * additional minimal function mutations (class I, II, V) * Interim results announced 6 March 2019 * Mean increase in ppFEV1 13.8% in F508del/minimal function * Mean increase ppFEV1 10% in homozygous F508del already receiving symdeko

Question 37

Minimal function mutations are * many currently eligible for\_\_\_\_ * classes \_\_, \_\_, \_\_\_

Answer 37

Minimal function mutations are * many currently eligible for current clincial p3 trials * Several classes, including I, II, V