Current and future therapies in CF Flashcards
The role of physiotherapy The role of antimicrobials Managing pancreatic insufficiency Future therapies: Pharmacological, gene therapy
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___
- Maintaining lung function
- Treat infections
- Airway clearance
- Adequate growth
- Diet
- Supplementation
- Managing complications e.g.
- CFRDM
- Liver disease
CF Team
PTs require multidisciplinary care
Define a CF “centre of excellence”
Centres which treat >50 CF PTs,
have access to a multidisciplinary team
>>Shown to have better outcomes when treated at centres of excellence
Physiotherapy
Infants:
Gr___ A___ Dr____ and Ma___ Te____
- elaborate
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
Physiotherapy Techniques - Self
- A___ C___ of B____ T___ (ACBT)
- A____ D___ (AD)
- A____ AD
- P___ E___ P____ (PEP)
Activity and exercise also very important
Physiotherapy Techniques - Self
- Active Cycle of Breathing Techniques (ACBT)
- Autogenic Drainage (AD)
- Assisted AD
- Positive Expiratory Pressure (PEP)
Activity and exercise also very important
Antimicrobials
- Prophylaxis
- Treatments to prevent infection
- Exacerbations
- Treat
Want to prevent and treat infection, thus liberal use of antibiotics are important
BUT…
Remember that aminoglycosides e.g. gentamycin are nephrotoxic and ototoxic so be careful about dosage
Antibiotics
Chosen through:…
- Route
- Susceptibility testing
- how?
- Resistance
- Pharmacokinetics
- **C____ in CF patients
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
Antimicrobials
Acquisition of pathogens occurs age-wise
Majority eventually acquire P______
S. Aureus is common in early years Pseudomonas Aeruginosa (any sp.) rises over lifetime
Infection control - Beyond cohorting
Control:
- Patient to patient spread of infection
- such as?
- Segregation of patients
- in what context?
Control:
- Patient to patient spread of infection
- P. aeruginosa
- MRSA
- NTM (non-tuberculosis microbacteria
- Segregation of patients
- In/out-patient
- Social activities
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:
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
Other respiratory therapies
Anti-inflammatory agents
- Azi_____
- explain
- Steroids not recommended because of:
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
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?
- 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
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____
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
Vitamins and Electrolytes
- F__-s___ vitamins
- Which 4?
- S___ replacement
Vitamins and Electrolytes
- Fat-soluble vitamins
- A, D, E, K
- Salt replacement
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
- 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
Future Therapies
- Novel symptomatic treatments
- anti-infective
- anti-inflammatory agents
- Mucolytics
- Nutritional
- G___ therapy
- Looking for a ____ to CF
- P___ r____ therapy
Future Therapies
- Novel symptomatic treatments
- anti-infective
- anti-inflammatory agents
- Mucolytics
- Nutritional
- Gene therapy
- Looking for a cure to CF
- Protein rescure therapy
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
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
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
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
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?
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
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
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
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
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
Gene Therapy - Vectors
For use as GTA
- V___ vectors
- A____
- R____
- A___-____ v___
- Multiple clinical trials in 1990s
- R___ a____ not efficacious
Gene Therapy - Vectors
For use as GTA
- Viral vectors
- Adenovirus
- Retrovirus
- Adeno-associated virus
- Multiple clinical trials in 1990s
- Repeated administration not efficacious
Gene Therapy - Vectors
- N__-v___ vectors
- Cationic liposomes complexed with plasmic DNA
- S___ d___ of e___
- M__ f__-l__ s____
Gene Therapy - Vectors
- Non-viral vectors
- Cationic liposomes complexed with plasmic DNA
- Short duration of efficacy
- Mild flu-like symptoms
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??
3.7% diff in FEV1 at 1 year = not clinically significant enough
Stable PFTs in treatment group
Decline in placebo group
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
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
A large focus of CF research is on protein rescue therapy
PRT aims to:
PRT is:
A large focus of CF research is on protein rescue therapy
PRT aims to:
- Overcome basic CFTR defect
PRT is:
- Mutation (class) specific
Recap
CFTR class mutations
List them.
F508del is a class what mutation
G551D is a class what mutation
F508del = class II
G551D = class III
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?
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
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____
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
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)
- Subsequently expanded to
Ivacaftor (Kalydeco)
EXPANDED TO PTs with class IV mutation (R117H)
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
Ivacaftor in Australia
G551D
10 class III mutations in total
Sustained benefits of Ivacaftor
151 patients with G551D followed for 6 months
Showed what kind of improvments?
Sustained improvements in sweat Cl, FEV1, BMI, MCC (mucociliary clearance)
Ivacaftor (Kalydeco)
Not so good news is:
Super expensive
$294,000 per PT per year
Many new potentiators in devlopment
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 ___
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
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
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
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
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
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
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
Minimal function mutations are
- many currently eligible for____
- classes __, __, ___
Minimal function mutations are
- many currently eligible for current clincial p3 trials
- Several classes, including I, II, V
