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BIOM30002 > Current and future therapies in CF > Flashcards

Current and future therapies in CF Flashcards

The role of physiotherapy The role of antimicrobials Managing pancreatic insufficiency Future therapies: Pharmacological, gene therapy

1
Q

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___
A
  • Maintaining lung function
    • Treat infections
    • Airway clearance
  • Adequate growth
    • Diet
    • Supplementation
  • Managing complications e.g.
    • CFRDM
    • Liver disease
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2
Q

CF Team

PTs require multidisciplinary care

Define a CF “centre of excellence”

A

Centres which treat >50 CF PTs,

have access to a multidisciplinary team

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

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3
Q

Physiotherapy

Infants:

Gr___ A___ Dr____ and Ma___ Te____

  • elaborate
A

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
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4
Q

Physiotherapy Techniques - Self

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

Activity and exercise also very important

A

Physiotherapy Techniques - Self

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

Activity and exercise also very important

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5
Q

Antimicrobials

  • Prophylaxis
    • Treatments to prevent infection
  • Exacerbations
    • Treat

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

A

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

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6
Q

Antibiotics

Chosen through:…

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

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
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7
Q

Antimicrobials

Acquisition of pathogens occurs age-wise

Majority eventually acquire P______

A 
S. Aureus is common in early years
Pseudomonas Aeruginosa (any sp.) rises over lifetime
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8
Q

Infection control - Beyond cohorting

Control:

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

Control:

  • Patient to patient spread of infection
    • P. aeruginosa
    • MRSA
    • NTM (non-tuberculosis microbacteria
  • Segregation of patients
    • In/out-patient
    • Social activities
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9
Q

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:
A

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
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10
Q

Other respiratory therapies

Anti-inflammatory agents

  • Azi_____
    • explain
  • Steroids not recommended because of:
A

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
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11
Q

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?
A
  • 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
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12
Q

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____
A

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
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13
Q

Vitamins and Electrolytes

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

Vitamins and Electrolytes

  • Fat-soluble vitamins
    • A, D, E, K
  • Salt replacement
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14
Q

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
A
  • 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
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15
Q

Future Therapies

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

Future Therapies

  • Novel symptomatic treatments
    • anti-infective
    • anti-inflammatory agents
    • Mucolytics
    • Nutritional
  • Gene therapy
    • Looking for a cure to CF
  • Protein rescure therapy
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16
Q

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

A

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
17
Q

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
A

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
18
Q

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?
A

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
19
Q

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
A

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
20
Q

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
A

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
21
Q

Gene Therapy - Vectors

For use as GTA

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

Gene Therapy - Vectors

For use as GTA

  • Viral vectors
    • Adenovirus
    • Retrovirus
    • Adeno-associated virus
  • Multiple clinical trials in 1990s
  • Repeated administration not efficacious
22
Q

Gene Therapy - Vectors

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

Gene Therapy - Vectors

  • Non-viral vectors
    • Cationic liposomes complexed with plasmic DNA
  • Short duration of efficacy
  • Mild flu-like symptoms
23
Q

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??

A

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

Stable PFTs in treatment group

Decline in placebo group

24
Q

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
A

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
25
Q

A large focus of CF research is on protein rescue therapy

PRT aims to:

PRT is:

A

A large focus of CF research is on protein rescue therapy

PRT aims to:

  • Overcome basic CFTR defect

PRT is:

  • Mutation (class) specific
26
Q

Recap

CFTR class mutations

List them.

F508del is a class what mutation

G551D is a class what mutation

A

F508del = class II

G551D = class III

27
Q

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?

A

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
28
Q

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____
A

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
29
Q

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)
A

Ivacaftor (Kalydeco)

EXPANDED TO PTs with class IV mutation (R117H)

30
Q

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
A

Ivacaftor in Australia

G551D

10 class III mutations in total

31
Q

Sustained benefits of Ivacaftor

151 patients with G551D followed for 6 months

Showed what kind of improvments?

A

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

32
Q

Ivacaftor (Kalydeco)

Not so good news is:

A

Super expensive

$294,000 per PT per year

Many new potentiators in devlopment

33
Q

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 ___
A

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
34
Q

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
A

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
35
Q

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
A

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
36
Q

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
A

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
37
Q

Minimal function mutations are

  • many currently eligible for____
  • classes __, __, ___
A

Minimal function mutations are

  • many currently eligible for current clincial p3 trials
  • Several classes, including I, II, V

BIOM30002 (20 decks)

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