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 space!grant.waterer@uwa.edu.au