Grant WatererMBBS PhD MBA FRACP FCCP MRCP
Professor of Medicine, University of Western AustraliaProfessor of Medicine, Northwestern University, Chicago
Year in review: Bronchiectasis
Disclosure
• I consult for Savara Pharmaceuticals– Inhaled GM-CSF, inhaled vancomycin, inhaled
amikacin-Fosfomycin
Bronchiectasis is finally getting the attention of drug companies and regulatory authorities
Weycker et al Chron Respir Dis 2017
US Healthcare Claims Data 2013
Diel et al ERJ 2019
38.5 million Euro per year in direct and indirect costs to the German Healthcare system
Treatment studies – the “good” the “bad” and the “ugly”
Question 1• Concerning bronchiectasis• A – Phase III randomised controlled trials have
shown that inhaled antibiotics improve outcomes• B – Phase III randomised controlled trials have
shown that oral macrolides improve outcomes• C – A and B are correct• D – Neither A and B are correct
Question 1• Concerning bronchiectasis• A – Phase III randomised controlled trials have
shown that inhaled antibiotics improve outcomes• B – Phase III randomised controlled trials have
shown that oral macrolides improve outcomes• C – A and B are correct• D – Neither A and B are correct
Failed phase III trials of inhaled antibiotics
• DPI cipfloxacin (RESPIRE 1 and RESPIRE 2)– Bayer
• Nebulised liposomal ciprofloxacin (ORBIT-3, ORBIT-4) – Aradigm
• Nebulized aztreonam (AIR-BX1, AIR-BX2)– Gilead
Study Design – ORBIT-3 and ORBIT-4Nebulized ARD-3150 or placebo were administered once daily for 6 cycles of 28 days on treatment, separated by 28 days off treatment, during the 48-week double-blind phase
Patients should be off anti-pseudomonal therapy
for at least 28 days prior
to Visit 1
Treatment Cycle 1 Treatment Cycle 2 Treatment Cycle 3
There were a total of 6 treatment cycles
Treatment Cycle 6
Screening Period 28 Days ON
Treatment
28 Days OFF
Treatment
28 Days ON
Treatment
28 Days OFF
Treatment
28 Days ON
Treatment
28 Days OFF
Treatment28 Days
ON Treatment28 Days
OFF Treatment
CFU
CFU
CFU
CFU
CFU
CFU
CFU
CFU
CFU
CFU
CFU
CFU
CFU
336 days ~ 48 weeks
ARD-3150QD
Placebo QD
Haworth et al, Am J Respir Crit Care Med 2017;195:A7604Haworth et al Respiratory Med 2019
Haworth et al Respiratory Med 2019
Haworth et al Respiratory Med 2019
Inhaled Cipro effectively cleared bacteria
-2.50
-2.00
-1.50
-1.00
-0.50
0.00
0 4 8 12 16 20 24 28 32 36 40 44 48
Ave
rage
Cha
nge
in L
og10
CFU
s (L
S M
ean)
Week
ORBIT-3 Linhaliq
Orbit-3 Placebo
ORBIT-4 Linhaliq
Orbit-4 Placebo
Haworth et al Respiratory Med 2019
Subgroup analyses based on prior exacerbation frequency
StudyExacerbation frequency Linhaliq, n Placebo, n RR 95% CI
ORBIT4 2-3 166 76 0.68 0.50-0.93
ORBIT4 4+ 40 21 0.52 0.31-0.87
ORBIT3 2-3 141 69 0.94 0.66-1.32
ORBIT3 4+ 42 25 0.68 0.44-1.04
Haworth et al Respiratory Med 2019
3 Macrolide RCT’s
0
0.5
1
1.5
2
2.5
BLESS BAT EMBRACE
DrugPlacebo
Exac
erba
tion
rate
/yea
r
Serisier et al JAMA 2013 Altenberg et al JAMA 2013 Wong et al Lancet 2012
Macrolides• BLESS
– Serisier et al JAMA 2013– Erythromycin 400mg bd in 117pts for 12/12
• BAT– Altenberg et al JAMA 2013– Azithromycin 250mg daily in 83 pts for 12/12
• EMBRACE– Wong et al Lancet 2012– Azithromycin 500mg 3x/week in 141 patients for 6/12
Question 2• Which of these macrolides inhibits cytochrome P450?• A – Clarithomycin• B – Azithromycin• C – Erythromcin• D – A and B but not C• E – A and C but not B• F – B and C but not A
Question 2• Which of these macrolides inhibits cytochrome P450?• A – Clarithomycin• B – Azithromycin• C – Erythromcin• D – A and B but not C• E – A and C but not B• F – B and C but not A
Macrolide imbalance at randomization
Trial Group
Macrolide use at
randomizationn (%)
ORBIT-3 Overall Population Ciprofloxacin DI (n=183 patients) 43 (23%)
Placebo (n=95 patients) 13 (14%)
ORBIT-4 Overall PopulationCiprofloxacin DI (n=206 patients) 34 (17%)
Placebo (n=98 patients) 24 (24%)
Macrolide use was not stratified at baseline in the ORBIT studies
Haworth et al Respiratory Med 2019
RESPIRE 1 and RESPIRE 2
De Soyza et al ERJ 2018Askamit et al ERJ 2018
Respire 1De Soyza et al ERJ 2018
14-days on-off
28-days on-off
Respire 2Askamit et al ERJ 2018
14-days on-off
28-days on-off
https://www.fda.gov/
https://www.fda.gov/
RESPIRE 1
RESPIRE 2
https://www.fda.gov/
https://www.fda.gov/
AIR-BX1 and AIR-BX2
Az 75mg TDS OR
PlaceboOFF
Az 75mg TDS OR
PlaceboOFF
4 weeks 4 weeks 4 weeks 4 weeks
Barker et al Lancet Respir Med 2014
Barker et al Lancet Respir Med 2014
Perc
enta
ges
(%) o
f res
pons
e
L ow
M od erate
H ig h
0
2 0
4 0
6 0
8 0AZLI
P lac ebo
Bacterial Load
p = 0.01
-1 0 -5 0 5 1 0 1 5 2 0
L o w
M o d e r a te
H ig h
Changes in QoL-B-RSS
Bact
eria
lloa
d
Favourplacebo
FavourAztreonam
% achieving QOL improvement above the MCID
Re-analysis of the pooled AIR-BX studies stratified for airway bacterial load at baseline
High = >107 cfu/g Sibila et al, AJRCCM 2019
What have we learned?
• If you enrole patients who have few exacerbations or low bacterial counts, you won’t have a positive trial
• No registered inhaled antibiotic for bronchiectasis at present
• Trials ongoing – tobramycin and colistin in current phase III
Anything else new?
Subtle Immune dysfunction
Bedi et al AJRCCM 2018
Neutrophils from patients with idiopathic bronchiectasis are reprogrammed for longer survival with resulting impaired function.Same not seen in patients with other active infections (e.g. pneumonia)
Drugs in preclinical and phase I
• Biofilm inhibitors• Quorum sensing inhibitors• Antimicrobial peptides• Iron sequestering agents• Efflux pump inhibitors• Nanoparticles of heavy metals (Ag, Au, Zn etc)
Conclusion
• Frustration at failed phase III studies due to poor design
• On going hope for inhaled antibiotics• Immunomodulators/biofilm inhibitors – watch
this [email protected]
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