ard-3150, linhaliq nda

CI-1

LINHALIQ (ciprofloxacin dispersion for inhalation)

NDA 210693

Antimicrobial Drugs Advisory Committee Meeting

January 11, 2018

Aradigm Corporation

CI-2

Introduction

Juergen Froehlich, MD, MBA, FCP

Chief Medical Officer

Aradigm Corporation

CI-3

Proposed Indication

Treatment of non-cystic fibrosis bronchiectasis

(NCFBE) patients with chronic lung infections with

Pseudomonas aeruginosa

CI-4

What You Will Hear Today

1. NCFBE with Pseudomonas aeruginosa

– Chronic, debilitating condition; no known cure

2. Linhaliq: first inhaled antibacterial well tolerated by NCFBE patients

– Reduces pulmonary exacerbations (PEs) and makes lives more tolerable

3. Evidence from one Phase 2 and two Phase 3 trials:

– 1202 (ORBIT-4): positive

– 1201 (ORBIT-3): did not meet primary endpoint

• Other PE endpoints show positive trends

• Additional PE frequency analyses narrow the difference

4. Increased MICs do not result in loss of efficacy, emergence of super

organisms or difficult-to-treat infections

CI-5

NCFBE: High Unmet Medical Need

Severe, rare disease

– Irreversible structural damage of bronchi

– Airway inflammation

– Recurrent respiratory infections

Chronic lung infections with Pseudomonas aeruginosa

– Higher morbidity and mortality

PEs are a serious irreversible morbidity

– Predict increased hospitalization, worse quality of life, and mortality

To date, no treatment has been approved for the prevention or

reduction of PEs

– Off-label, chronic use of anti-bacterial drugs

CI-6

Linhaliq − Quinolone with High Activity Against Pseudomonas aeruginosa

Dual formulation: liposome encapsulated

aqueous dispersion (CFI) and

unencapsulated aqueous solution of free

ciprofloxacin (FCI)

– Small liposomes with components similar

to lung surfactant

– Slow release from CFI with instant peak

from FCI

Delivery of ciprofloxacin not limited by

drug solubility

Administration with a jet nebulizer

and compressor

6 mL

FCI CFI

CI-7

Dosing and Administration

Recommended Dose

– 189 mg/6 mL once daily by oral inhalation

Dosing Regimen

– Chronic use

– Repeated cycles of 28 days on-treatment,

followed by 28 days off-treatment

CI-8

Regulatory Designations

Orphan Drug

Qualified Infectious Disease Product

Fast Track

Priority Review

CI-9

Clinical Development

Phase 1 and Phase 2a clinical trials with liposome encapsulated

ciprofloxacin and Linhaliq prototype in healthy volunteers and

NCFBE patients

Phase 2b and 3 trials in severe patients with NCFBE and chronic lung

infections with Pseudomonas aeruginosa

– 24 week double blind Phase 2b trial 0902 (ORBIT-2)

– Two 48 week double blind Phase 3 trials

• 1202 (ORBIT-4)

• 1201 (ORBIT-3)

CI-10

Evaluation of Totality of Evidence

NCFBE is a complex condition with evolving understanding

Time to first exacerbation traditionally used as primary endpoint in

clinical trials

Patients in Linhaliq trials are experiencing frequent PEs

– Frequency of PEs are most meaningful, especially those requiring

interventions with antibacterials

Are the data provided “adequate to support safety and efficacy of

ciprofloxacin DI for the treatment of non-cystic fibrosis bronchiectasis

adult patients (>18 years of age) with chronic lung infections with

Pseudomonas aeruginosa?”1

1. FDA Briefing Document, page 5.

CI-11

Summary

Linhaliq has demonstrated substantial evidence of safety and

effectiveness for the proposed indication with clinically meaningful

results from three studies

– 1202 (ORBIT-4) met all primary and secondary PE endpoints

– 1201 (ORBIT-3) results trend in the same direction

– 0902 (ORBIT-2) provides additional supportive evidence

Minimal safety and tolerability risks unlike many off-label

antibacterial therapies in this patient population

Urgent, unmet need; no approved products

Totality of evidence supports a favorable benefit/risk profile

CI-12

Today’s Agenda

IntroductionJuergen Froehlich, MD, MBA, FCP – CMOAradigm Corporation

Unmet Medical Need /

Disease BackgroundGregory Tino, MDUniversity of Pennsylvania – Perelman School of Medicine

Efficacy

Igor Gonda, PhD – CEO and PresidentAradigm Corporation

Janet Wittes, PhD – President

Statistics Collaborative, Inc.

SafetyJuergen Froehlich, MD, MBA, FCP – CMOAradigm Corporation

Benefit / Risk

Sanjay Sethi, MD, FACPUniversity at Buffalo, State University of New York

James Chalmers, MDNinewells Hospital and Medical School – Department of

Respiratory Medicine Dundee

CI-13

Additional Expert Advisors

Angela Davis, MDGlobal Medical Director, Pulmonary

Grifols

Donald VanDevanter, PhDAdjunct Professor, Pediatrics

Case Western Reserve University School of Medicine

Adam Wanner, MD

Professor of Medicine

University of Miami Health System –

Miller School of Medicine

CI-14

Today’s Agenda




Efficacy





Benefit / Risk




CM-1

Unmet Medical Need/Disease Background

Gregory Tino, MD

Associate Professor of Medicine

Perelman School of Medicine, University of Pennsylvania

Chief, Department of Medicine

Penn Presbyterian Medical Center

CM-2

What is Bronchiectasis?

Characterized pathologically by airway inflammation and permanent

bronchial dilatation, and clinically by productive cough and recurrent

respiratory infections

Etiologies include

– Post-infectious

– Congenital syndromes

– Immunodeficiency states

– Immune mediated diseases

– Idiopathic

Barker AF. N Engl J Med. 2002;346:1383-1393.

Mysliwiec V, Pina JS. Postgrad Med. 1999; 106:123-131.

Pasteur MC, et al. Am J Respir Crit Care Med. 2000; 162:1277-1284.

CM-3

Adapted from McShane PJ, et al. Am J Resp Crit Care Med. 2013.

Pathogenesis is a Vicious Cycle

Chronic

Bacterial

Infection

Abnormal

Mucus

Clearance

Neutrophil

Inflammation

(Proteases)

Airway

Destruction and

Distortion

Inciting

Events

Pulmonary

Exacerbations

CM-5

NCFBE Epidemiology

Estimated prevalence

– >110,000 patients in the United States1

– Increases with age1

– Increasing at a rate of ~9% annually2

Microbiology is complex

One-third have chronic lung infection with

Pseudomonas aeruginosa (PA)3

1. Weycker et al, Clin Pulm Med 2005; 12:205-209; Chron Resp Dis 2017; 14:377-384.

2. Seitz, Chest 2012; 142:432-439.

3. Aksamit, Chest 2017; 151:982-992.

CM-6

PA Results In More Hospitalizations and Higher Mortality Rates Than Other Infections

GNR=Gram negative rods

Chalmers, et al. AJRCCM. 2014; 189:576-585.

Finch, et al. Annals ATS. 2015; 12:1602-1611.

12.0

88.6

0 20 40 60 80 100

Not colonized

S. pneumoniae

H. influenzae

M. catarrhalis

S. aureus

Other GNR

P. aeruginosa

% hospitalization over 4 years

6

21.2

0 5 10 15 20 25

Not colonized

S. pneumoniae

H. influenzae

M. catarrhalis

S. aureus

Other GNR

P. aeruginosa

% mortality over 4 years

7× Higher Risk of Hospitalization 3× Higher Mortality

CM-7

BE with PA Results in Worse Quality of Life than Patients with Other Severe Respiratory Diseases

B E + P A B E I P F M o d e r a t e

C O P D

S e v e r e

C O P D

A d u l t

c y s t i c

f i b r o s i s

S e v e r e

a s t h m a

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

Wo

rse

nin

g Q

OL

SGRQ total score

1. Kreuter, et al. Respir Res. 2017. 2. Kerwin, et al. Intl J COPD. 2017. 3. Magnussen, et al. NEJM. (Oct) 2014.

4. Padilla, et al. Arch Bronconeumol. 2007. 5. Ortega, et al. NEJM. (Sept) 2014.

CM-8

Most Common Symptoms of Pulmonary Exacerbations

Increased cough

Change in sputum characteristics (consistency, color,

volume or hemoptysis)

Increased dyspnea and chest congestion

Malaise, fatigue, lethargy or decreased exercise tolerance

Increased wheezing

CM-9

Goals of Treatment - Prevent and Reduce PEs

PEs requiring intervention with antibacterials or hospitalization

adversely impact quality of life and result in irreversible morbidity

and mortality

– Median duration of symptoms is 16 days

– Symptoms can persist for weeks; 16% had not recovered by 35 days

Patients with history of PEs are more likely to have future events

Reducing PEs is the highest priority

Brill, et al. Resp Res. 2015; 16:1-9.

Chalmers, et al. AJRCCM. 2014; 189:576-585.

CM-10

Bacterial Load and Impact on Pulmonary Exacerbations

High bacterial load (CFUs) linked to:

– Risk of future exacerbations

– Future hospitalizations for PE’s

– Markers of lung inflammation

Chalmers, et al. Am J Respir Crit Care Med 2012; 186, 657-665.

CFUs

Outpatient Exacerbations

Exacerb

ati

on

s/y

ear

CM-11

Other Goals of Treatment

Pulmonary function - FEV1 does not improve with antibiotic therapy

- Aim is to stabilize lung function

Quality of life - No fully validated method of assessment

- Reducing PE’s expected to have major impact

Mortality - Difficult to study in short term trials

CM-12

“Met” Needs

CM-13

Case Study

77 year-old man:

– Diagnosed with bronchiectasis after a pneumonia

CM-14

Clinical Course

Managed for many years with rotating oral

antibiotics + chest physiotherapy

Chronic P. aeruginosa infection

Daily sputum production - 40 mL

2-3 acute infectious exacerbations per year sometimes

requiring hospitalization and/or IV antibiotics

Intolerant of macrolides

CM-15

Current Treatment Options have Significant Limitations

There are no approved treatments, including for PE reduction

There is extensive, but variable, off label use of antibacterials

in the US

– Use of antibiotics for exacerbation only - 41%

– Suppressive antibacterials - 39%

• 14% macrolides, 10% inhaled antibiotics, 7% rotating regimen

Unlike in CF, inhaled antibiotics are used without evidence of

efficacy and are often poorly tolerated

Aksamit, et al. Chest 2017:151.

CM-16

Poor Tolerability of Inhaled Antibiotics for NCFBE with PA

Safety Issues vs Placebo

Antibiotic Regimen Respiratory AEs Bronchospasm Drug Withdrawals

Aminoglycosides

Barker, et al. 2000 YES − No

Drobnic, et al. 2005 − YES YES

Bilton, et al. 2006 YES − YES

Murray, et al*. 2011 YES YES No

Aztreonam

AIR-BX1 YES − YES

AIR-BX2 YES − YES

– = Not studied.

*Single blind study (n=27, active; n=30, placebo).

Efficacy

Reduction of PEs

NO

NO

−

Yes

NO

NO

CM-17

Summary

Bronchiectasis is a disease with increasing prevalence resulting in

significant morbidity and mortality

PA is a particularly challenging pathogen

Prevention and reduction of acute exacerbations are key goals

All current treatments are off-label and have safety and efficacy

concerns

Safe and tolerable inhaled antibiotic that prevents and reduces

exacerbations is a critical unmet need

CM-18

Today’s Agenda




Efficacy





Benefit / Risk




CE-1

Efficacy Results

Igor Gonda

CE-2

Dosing Regimen / Dosing Rationale

Dose

– 3 mL liposomal + 3 mL aqueous

Dosing interval

– Long half life in the lung enables once daily dosing

– Promotes good adherence

Dosing regimen

– 28 day on/off cycles

– Based on inhaled antibiotics (Tobi, Cayston) in CF patients with chronic

P. aeruginosa lung infections

CE-3

Oral Ciprofloxacin PK and In Vitro Susceptibility BreakpointC

ipro

flo

xacin

(µ

g/m

L)

Oral / IV

Ciprofloxacin

Plasma Cmax

Oral / IV

Ciprofloxacin

Sputum Cmax

Resistant isolates

Oral / IV Ciprofloxacin Cmax – Plasma

Oral / IV Ciprofloxacin Cmax - Sputum

CE-4

0.001

0.01

0.1

1

10

100

1000

10000

0 5 10 15 20 25 30

Cip

rofl

ox

acin

(µ

g/m

L)

Time, hr

Ciprofloxacin Sputum and Plasma Exposure Consistent with Product Design

Oral/IV Ciprofloxacin Cmax - Sputum

Isolates resistant toOral/IV Ciprofloxacin

Linhaliq – Sputum concentrations

Oral/IV Ciprofloxacin Cmax - Plasma

Linhaliq – Plasma concentrations

New dose 24 hr

~1700 ×

~15 ×

~11250 ×Pre-dose

Pre-dose

CE-5

Consistent Reduction in Sputum Density of P. aeruginosa

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

0 4 8 12 16 20 24 28 32 36 40 44 48

Avera

ge C

han

ge i

n L

og

10

CF

Us (

LS

Mean

)

Weeks

ORBIT-3 Placebo

ORBIT-4 Placebo

ORBIT-3 Linhaliq

ORBIT-4 Linhaliq

CE-6

Phase 2 and Phase 3 studies

0902 = ORBIT-2

1201 = ORBIT-3

1202 = ORBIT-4

CE-7

Three Randomized Placebo-Controlled Trials in NCFBE Patients with Chronic Lung Infections with P. aeruginosa

Phase 2: 24 weeks double blind, 1:1 randomization

– ORBIT-2: 42 subjects

Phase 3: 48 weeks double blind plus 28 day open label with 30 day

follow-up, 2:1 randomization



≥2 PEs in the prior 12 months, chronic infections with P. aeruginosa

CE-8

ORBIT-2 Phase 2 Study

Inhalation once daily, 28 day on/off cycles for up to 24 weeks

– Trial medication discontinued once subject exacerbated

Adult NCFBE subjects

– Enrolled 20 Linhaliq and 22 placebo subjects

Primary endpoint met:

– Mean change in sputum P. aeruginosa log CFU from baseline to Day 28:

-4.20 Linhaliq vs. -0.08 placebo, p=0.002

CE-9

ORBIT-2: Linhaliq’s Impact on Time to First PE: Prespecified Secondary Endpoint

Pro

po

rtio

n o

f su

bje

cts

wit

ho

ut

PE

0.0

0.1

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Hazard Ratio = 0.53 (0.25, 1.16)

Log-rank p value = 0.057

Linhaliq

Placebo

0 50 100 150

Linhaliq 20 12 9 6Placebo 22 11 7 2

Time to First PE (Days)Patients at Risk

CE-10

Phase 3 Studies

1201 = ORBIT-3

1202 = ORBIT-4

CE-11

ORBIT-4 and ORBIT-3: Key Inclusion Criteria

Age 18 and older

CT-confirmed diagnosis of BE

Documented history of ≥2 PEs treated with antibiotics in prior

12 months

Chronic lung infection with P. aeruginosa and presence of

≥1 nonresistant P. aeruginosa isolate at screening visit (allowed

patients with resistant strains as long as one was nonresistant)

BE = Bronchiectasis; CT = computed tomography.

CE-12

ORBIT-4 and ORBIT-3: Key Exclusion Criteria

Clinical diagnosis of cystic fibrosis

Primary diagnosis of COPD related to smoking history of >10 cigarette

pack-years

NTM infection requiring treatment

Antipseudomonal therapy within 28 days prior to 1st dose of study

drug (patients on stable chronic macrolides at baseline were not

excluded)

COPD = chronic obstructive pulmonary disease; NTM = non-tuberculous mycobacteria.

CE-13

Pre-specified Primary and Secondary PE Endpoints

Primary

– Time to First PE (log-rank)

If met:

Secondary (negative binomial regression)

– Frequency, All PEs

– Frequency, Severe PEs

– Frequency of PEs requiring interventions with antibiotics*

(Moderate and Severe PEs)

Unless otherwise noted, all analyses were stratified by sex and prior PEs

* Pre-specified secondary endpoint for EMA

CE-14

ORBIT-4 and ORBIT-3: Protocol-Defined Criteria for PEs

Rigorously defined: minimum 4 of 9 concurrent signs and symptoms

– Change in sputum production (consistency, color, volume, or hemoptysis)

– Increased dyspnea (chest congestion or shortness of breath)

– Increased cough

– Decreased exercise tolerance, malaise, fatigue, or lethargy

– Increased wheezing

– Fever (≥38ºC)

– Forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC)

decreased 10% from a previously recorded value

– Radiographic changes indicative of a new pulmonary process

– Changes in chest sounds

A O’Donnell. 1998.

Symptoms documented in >85% of PEs are shown in blue. Symptoms observed in <40% are shown in italics

CE-15

ORBIT-4 and ORBIT-3: Protocol-Defined Severity of PEs

Mild

– Adjustment in treatment (excluding antibiotics) possible

Moderate

– Treatment with oral or inhaled antibiotics

– Increase in the dose of baseline macrolides

Severe

– Treatment with intravenous antibiotics or

– Hospitalization

CE-16

Definition of Duration of a PE

Onset date of a PE: first point at which ≥4 of the predefined signs or

symptoms occurred concurrently

End date of a mild PE: investigator's judgment of resolution of the PE

End of a moderate or severe PE: investigator's judgment of resolution of

the PE, or the conclusion of treatment with antibiotics, whichever occurred

later

– New PE defined if next course of antibiotics initiated ≥14 days after resolution

of prior PE

CE-17

Pulmonary Exacerbation Blinded Adjudication Committee (PEBAC)

PEBAC was set up to adjudicate potential discrepancies in a

blinded fashion:

– Differences between investigator assessed PE and protocol criteria

– Subjects receiving antibiotics for a respiratory reason, but not

reported as PE

The process was coordinated and documented by a Contract

Research Organization to avoid involvement of the Sponsor

PEBAC made decisions in accordance with the protocol defined

criteria for PEs, their severity and duration

CE-18

28 DaysON

LinhaliqQD

30-DayFollow-up

Period

28 DaysON

Treatment

28 DaysOFF

Treatment

28 DaysON

Treatment

28 DaysOFF

Treatment

28 DaysON

Treatment

28 DaysOFF

Treatment

ORBIT-4 and ORBIT-3: Study Design

Nebulized Linhaliq or placebo administered once daily

48-week double-blind phase, followed by a 28-day open label extension

OLE

2:1

randomization

N=255 / study

336 days ~ 48 weeks

LinhaliqQD

Placebo QD

Cycle 2Cycle 1

Screening

Randomization was stratified by sex, prior PE, and smoking status.

Cycle 6

CE-19

ORBIT-4 ORBIT-3

LinhaliqN=206

PlaceboN=98

LinhaliqN=183

PlaceboN=95

Age (yrs), mean ± SD 63 ± 13 64 ± 13 64 ± 14 67 ± 11

Sex, Female (%) 65 64 69 71

Race (%)WhiteAsianBlack or African AmericanOther / Not Reported

Ethnicity (%)Hispanic or Latino

825112

12

844111

9

88822

3

94411

3

Nonsmoker (%) 99 100 98 99

Number of PEs in prior year (%)

2-3 81 78 77 73

≥4 19 21 23 26

Chronic use of macrolides (%) 17 25 24 14

Baseline FEV1 % predicted, mean ± SD 63 ± 22 60 ± 21 57 ± 22 57 ± 20

ORBIT-4 and ORBIT-3: Baseline Characteristics

FA Population.

CE-20

ORBIT-4: Patient Disposition

LinhaliqN=207 Randomized (ITT)

N=206 Treated (FA)

Completed DB Phase orhad first PE

n=195 (95%)*

Completed DB study drug n=169 (82%)

Opted for Open Labeln=164 (97%)**

Completed Open Labeln=163 (99%)***

Placebo N=101 Randomized (ITT)

N=98 Treated (FA)

Completed DB Phase or had first PEn=91 (93%)*


Opted for Open Labeln=71 (92%)**

Completed Open Labeln=70 (99%)***

* Based on FA population; ** Based on subjects completing DB study drug; *** Based on subjects starting Open Label

CE-21

ORBIT-3: Patient Disposition

LinhaliqN=193 Randomized (ITT)

N=183 Treated (FA)

Completed DB Phase or had first PEn=162 (89%)


Opted for Open Labeln=127 (97%)

Completed Open Labeln=126 (99%)

Placebo N=97 Randomized (ITT)

N=95 Treated (FA)

Completed DB Phase or had first PEn=83 (87%)


Opted for Open Labeln=68 (96%)

Completed Open Labeln=61 (90%)

* Based on FA population; ** Based on subjects completing DB study drug; *** Based on subjects starting Open Label

CE-22

ORBIT-4 and ORBIT-3 Study Results

CE-23

0

0.2

0.4

0.6

0.8

1

0 50 100 150 200 250 300 350

Primary Endpoint: Time to First PE


HR = 0.72 (0.53, 0.97)

Median: Linhaliq: 230 days

Placebo: 158 days

Linhaliq

Placebo

Time to First PE (Days)

Pro

po

rtio

n w

ith

ou

t P

E

Time to First PE (Days)

ORBIT-4 ORBIT-3

Linhaliq 206 171 146 124 109 90 85 0

Placebo 98 66 54 48 39 34 28 0

0

0.2

0.4

0.6

0.8

1

0 50 100 150 200 250 300 350


HR = 0.99 (0.71, 1.38)

Median: Linhaliq: 214 days

Placebo: 136 days

183 136 104 93 82 72 64 0

95 72 47 40 39 35 31 0

Patients at Risk

CE-24

Secondary Endpoint:Frequency of All PEs

ORBIT-4 ORBIT-3

Linhaliq Placebo Linhaliq Placebo

All PEs*

Mean PEs/Subject 0.98 1.47 1.09 1.31

Risk ratio (95% CI) 0.63 (0.48, 0.82) 0.85 (0.65, 1.12)

p value p<0.001 p=0.26a

*Negative Binomial Regression; a Nominal

CE-25

Secondary Endpoints:Frequency of All PEs and Severe PEs

ORBIT-4 ORBIT-3


All PEs*

Mean PEs/Subject 0.98 1.47 1.09 1.31

Risk ratio (95% CI) 0.63 (0.48, 0.82) 0.85 (0.65, 1.12)

p value p<0.001 p=0.26a

Severe PEs*

Mean PEs/Subject 0.14 0.30 0.22 0.28

Risk ratio (95% CI) 0.40 (0.22, 0.74) 0.80 (0.42, 1.51)

p value p=0.003 p=0.48a

*Negative Binomial Regression; a Nominal

CE-26

Frequency of Moderate and Severe PEs (Those Requiring Intervention with Antibiotics)

ORBIT-4 ORBIT-3


Moderate and Severe PEs*

Mean PEs/Subject 0.78 1.27 0.86 1.13

Risk ratio (95% CI) 0.58 (0.44, 0.77) 0.78 (0.58, 1.05)

p value p<0.001 p=0.10

*Pre-specified endpoint for EMA; negative binomial regression

CE-27

Summary of Pre-Specified PE Efficacy Results

ORBIT-4

0 . 2 2 . 01

ORBIT-3

Hazard / Risk Ratio (95% CI)

All PEsTime to First PE

Negative Binomial, FA

Moderate

& Severe

PEs*

Negative Binomial, FA

Severe

PEsNegative Binomial, FA

0 . 2 2 . 01

* Requested by EMA

p=0.032

p<0.001

p<0.001

p=0.0031

p=0.97

p=0.26

p=0.10

p=0.48

CE-28

Ciprofloxacin MIC by Highest P. aeruginosa IsolatePooled Studies

100

10

1

Study Visit

BL 3 4 5 6 7 8 9 10 11 12 13 14

On Off On Off On Off On Off On Off On OffTreatment:

Cip

rofl

oxacin

MIC

(m

cg

/mL

)

Linhaliq

Placebo

Boxes represent 25th to 75th quartiles with median indicated by white line. Whiskers show lowest and highest values observed.

CE-29

Higher Ciprofloxacin MICs at Baseline and On Study Did Not Impact Relative Risk of All PEs

Highest Ciprofloxacin MIC at baseline

MIC <4 mcg/mL

MIC ≥4 mcg/ml

Highest Ciprofloxacin MIC at any visit

MIC <4 mcg/mL

MIC ≥4 mcg/mL

10 . 2 2 . 0

Relative Risk* (CI)

*Pooled ORBIT-4 and ORBIT-3; Post hoc analysis; Negative binomial regression

CE-30

Pre-randomization

– Demographics

– Baseline characteristics

Factors Explored for Differences Between ORBIT-3 and ORBIT-4

Post-randomization

– Microbiology

– Dosing compliance

– Pharmacokinetics

Sensitivity analyses

CE-31

Factors Explored for Differences Between ORBIT-3 and ORBIT-4

Important factors noted in blue

Pre-randomization

– Demographics

– Baseline characteristics

• Baseline macrolides

Post-randomization

– Dosing compliance

– Pharmacokinetics

– Microbiology

Sensitivity analyses

– Prior PEs

– Frequency of all respiratory events requiring

intervention with anti-bacterials

CE-32

Impact of Prior PEs on Frequency of PEsSubgroup Analysis

10 . 2 2 . 0

Risk Ratio (95% CI)

Pre-specified analysis; Negative binomial regression

Study Prior PEs RR 95% CI

ORBIT-4 2-3 0.68 0.50, 0.93

ORBIT-4 ≥4 0.52 0.31, 0.87

ORBIT-3 2-3 0.94 0.66, 1.32

ORBIT-3 ≥4 0.68 0.44, 1.04

Pooled 2-3 0.79 0.63, 0.99

Pooled ≥4 0.60 0.43, 0.84

CE-33

KMs for Pre-Specified Prior PE Categories by Study

Source:Aradigm\ORBIT-4\Post submission queries\Programsf_tt1pe_fa_nope.sas Run date: 21NOV17 13:26

Number of Prior PEs = 2-3

Time to First Pulmonary Exacerbation

166 142 125 110 99 87 80 0

77 56 49 41 35 31 27 0

Linhaliq

Placebo

0 50 100 150 200 250 300 350

Days to First PE

1.00

0.75

0.50

0.25

0.00

Pro

port

ion W

ithout

PE

PlaceboLinhaliqTreatment Group

0 50 100 150 200 250 300 350

Days to First PE

1.00

0.75

0.50

0.25

0.00

Pro

port

ion W

ithout

PE


+ Censored

Linhaliq

Placebo

+ Censored + Censored

ORBIT-4 2-3 prior PEs ORBIT-3 2-3 prior PEs

0 50 100 150 200 250 300 3500 50 100 150 200 250 300 350

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

Days to First PEDays to First PE

0 50 100 150 200 250 300 350

Days to First PE

1.00

0.75

0.50

0.25

0.00

Pr o

port

i on

Wit h

out

PE

0 50 100 150 200 250 300 350

Days to First PE

Pro

port

i on

Wit h

out

PE

+ Censored

ORBIT-3 ≥4 prior PEs

0 50 100 150 200 250 300 350

Days to First PE

0.00

0.25

0.50

0.75

1.00

Source:Aradigm\ORBIT-4\Post submission queries\Programsf_tt1pe_fa_nope.sas Run date: 21NOV17 13:26

Number of Prior PEs = >= 4

Time to First Pulmonary Exacerbation

40 35 31 25 23 18 16 0

21 15 13 10 7 6 3 0

Linhaliq

Placebo

0 50 100 150 200 250 300 350

Days to First PE

1.00

0.75

0.50

0.25

0.00

Pro

port

ion W

ithout

PE


0 50 100 150 200 250 300 350

Days to First PE

1.00

0.75

0.50

0.25

0.00

Pro

port

ion W

ithout

PE


+ Censored

Linhaliq

Placebo

+ Censored

ORBIT-4 ≥4 prior PEs

0 50 100 150 200 250 300 350

Days to First PE

0.00

0.25

0.50

0.75

1.00

Pro

po

rtio

n W

ith

ou

t P

E

CE-34

Interdependence of PEs

At the beginning of Phase 3: little known about natural course of PEs

in NCFBE

Recent clinical research: past PEs are strong predictors of future PEs

Frequency analysis methods should reflect this interdependence

CE-35

Additional Post Hoc Analyses

Janet Wittes

CE-36

Methods for Analyzing Frequency of PEs

Assumptions underlying the prespecified negative binomial model

– Each PE is independent of the previous ones – not plausible

– The hazard function is constant over time – not plausible

Counting Process

– A generalization of the method used for the primary analysis

– Not dependent on either assumption

CE-37

The Anderson-Gill Counting Process

The PEs are not necessarily independent

– The model “understands” that having one PE can predispose a patient to

having another

The hazard function is not necessarily constant over time

– The risk of having a PE can vary over the course of the disease

CE-38

300

Cu

mu

lative

pla

ce

bo

en

dp

oin

t e

ve

nts

ORBIT-4 and ORBIT-3: Cumulative PE Events over Time

Estimate(95% CI)

Nominalp value

Neg binomial (RR) 0.63 (0.48, 0.82) <0.001

Counting process (HR) 0.61 (0.49, 0.76) <0.001

Linhaliq

Placebo

Cu

mu

lativ

e L

inh

aliq

endpoin

t events

Study day

Estimate(95% CI)

Nominal p value

Neg binomial (RR) 0.85 (0.65, 1.12) 0.26

Counting process (HR) 0.84 (0.67, 1.06) 0.14

ORBIT-4 1201300

200

100

0

Study day Study day

Placebo

Linhaliq

Cu

mu

lativ

e L

inh

aliq

endpoin

t events

ORBIT-3 300

200

100

0

CE-39

Imbalance of Chronic Macrolide Use at BaselineORBIT-4 and ORBIT-3

17

2425

14

0

5

10

15

20

25

30

ORBIT-4 ORBIT-3

% o

f S

ub

jec

ts

Linhaliq Placebo

CE-40

Impact of Linhaliq on Reduction of PEs:With and Without Adjustment for Baseline Macrolides

ORBIT-4

0 . 2 2 . 01

ORBIT-3

Hazard Ratio (95% CI)

0 . 2 2 . 01

All PEs

Counting Process

Stratified for BL Macrolides

Moderate & Severe PEs

Counting Process


Severe PEs

Counting Process


0 . 2 2 . 01

BL=Baseline

Pooled

p<0.001

p=0.001

p<0.001

p<0.001

p=0.001

p=0.003

p=0.14

p=0.10

p=0.038

p=0.036

p=0.40

p=0.16

CE-41

Prespecified Quality of Life Endpoint

Secondary Endpoint

– QOL-B (comparing baseline to Week 48)

CE-42

Cycle 1

28 DaysON

Treatment

28 DaysOFF

Treatment

28 DaysON

Treatment

28 DaysOFF

Treatment

QOL-B Measured every 28 Days, with 7 Day Recall

28 DaysON

Treatment

28 DaysOFF

Treatment

~48 weeks

R

e

c

a

l

l

R

e

c

a

l

l

R

e

c

a

l

l

QOL-BQOL-BQOL-BQOL-BQOL-B

R

e

c

a

l

l

R

e

c

a

l

l

R

e

c

a

l

l

R

e

c

a

l

l

Cycle 2 Cycle 6

QOL-B QOL-B

CE-43

Placebo: Visit to Visit Changes in QOL-B Appear to Be Random

Minimal changes in CFUs during ON and OFF periods

OFF Periods just as likely as ON Periods to have positive changes in QOL-B

-5

-3

-1

1

3

5

7

9

-3 -2 -1 0 1 2 3

Q

OL

-B

Log 10 CFU

1202 Placebo ON

1201 Placebo ON

1202 Placebo OFF

1201 Placebo OFF

CE-44

Linhaliq: Visit to Visit Changes in QOL-B are Correlated with Visit to Visit Changes in CFUs

Each data point represents the mean delta QOL-B for all patients during that treatment cycle There are 6 on-treatment periods

and 6-off treatment periods per study

-10

-8

-6

-4

-2

0

2

4

6

8

10

-3 -2 -1 0 1 2 3

Q

OL

-B

Log 10 CFU

ORBIT-4 Linhaliq ON Treatment

ORBIT-3 Linhaliq ON Treatment

ORBIT-4 Linhaliq OFF Treatment

ORBIT-3 Linhaliq OFF Treatment

Reduction in QOL-B

during a PE

CE-45

QOL-B Measured every 28 Days, with 7 Day Recall

ON OFF ON OFFF ON OFF ON OFF ON OFF ON OFF

Visit 1 3 42 5 6 7 8 9 10 11 12 13 14

Baseline

QOL-BEOS

QOL-B

CE-46

Results of QOL Prespecified Endpoint

Change in QOL-B Respiratory Symptoms Scale Score from baseline

to the end of last Off-Treatment Period (Week 48)

– ORBIT-4: Linhaliq 7.28, placebo 6.51, p=0.70

– ORBIT-3: Linhaliq 1.97, placebo 3.61, p=0.45

CE-47

Linhaliq Reduced Hospitalizations and Use of IV Antibiotics Associated with PEs

Linhaliq Placebo

% Reduction

for Linhaliq

Subjects hospitalized for a PE 13% 18% 26%

Subjects receiving IV Antibiotics for a PE 11% 17% 32%

Frequency of PEs requiring hospitalization 16% 21% 23%

Frequency of PEs requiring use of IV antibiotics 16% 24% 32%

Pooled study data

CE-48

Use of Antibiotics for Respiratory Reason Recurrent Event Analysis with Counting Process

ORBIT-4 ORBIT-3 Pooled

Linhaliq Placebo Linhaliq Placebo Linhaliq Placebo

Mean Events/Subject 1.07 1.47 1.13 1.37 1.10 1.42

Risk ratio (95% CI) 0.67 (0.54, 0.83) 0.81 (0.65, 1.00) 0.73 (0.63, 0.85)

p valuea p<0.001 p=0.054

a Nominal

CE-49

Efficacy Conclusions

CE-50

Totality of Evidence

Hazard/risk Ratio (95% CI)

0 . 2 2 . 01 0 . 2 2 . 01

ORBIT-4 ORBIT-3

Time to first PE

Reduction of all PEs,

neg binomial

Reduction of all PEs,

counting process

Antibiotics for respiratory

reason

Reduction of moderate &

severe PEs, neg binomial

Reduction of moderate &

severe PEs, counting process

Reduction of severe PEs,

neg binomial

Reduction of severe PEs,

counting process0 . 2 2 . 01

Pooled

CE-51

Totality of Evidence

0 . 2 2 . 01

Number of PEs

Requiring hospitalization

Requiring IV antibiotics

Number of Subjects

Requiring hospitalization for a PE

Requiring IV antibiotics for a PE

Hazard/risk Ratio (95% CI)

Pooled

Pooled study data

CE-52

Efficacy Benefits of Linhaliq

Linhaliq demonstrated efficacy attributes important for NCFBE

patients — particularly those at risk of high morbidity and mortality

CE-53

Today’s Agenda




Efficacy





Benefit / Risk




CS-1

Safety

Juergen Froehlich, MD, MBA, FCP

CS-2

Background on Safety Database

Represents pooled data from ORBIT-3 and ORBIT-4

– 582 patients total: Linhaliq (n= 389) and Placebo (n=193)

Exposure/Compliance were high: ≥90% compliance achieved by

80-87% of subjects in both treatment arms

Supportive data from ORBIT-2 is consistent with Phase 3 Data

– 42 patients total: Linhaliq (n=20) and Placebo (n=22)

Placebo was selected for good tolerability

– Dilute liposomes mixed in isotonic saline

CS-3

Frequent Comorbidities at Baseline

Preferred Term

Linhaliq

N=389

%

Placebo

N=193

%

Hypertension 36.5 37.8

Gastro-esophageal reflux disease 23.7 26.4

Asthma 20.3 24.4

Chronic obstructive pulmonary disease 18.8 16.6

Osteoporosis 13.4 17.1

Osteoarthritis 12.3 18.7

Hypercholesterolemia 9.5 11.9

Occurring in ≥10% of patients in either group (Safety Population)

CS-4

Concomitant Anti-bacterial Drugs Introduced During Study

Linhaliq

N=389

%

Placebo

N=193

%

Fluoroquinolones 45.5 50.8

Penicillins, combinations (incl. beta-lactamase) 21.1 24.9

Macrolides 15.2 19.2

Cephalosporins, third generation 10.8 20.7

Aminoglycosides 9.3 10.4

Penicillins with extended spectrum 8.0 12.4

Tetracyclines 8.0 9.3

Combinations of sulfonamides and trimethoprim, incl. derivatives 5.7 5.2

Carbapenems 2.3 5.7

CS-5

Concomitant Pulmonary Medications During Study

Linhaliq

N=389

%

Placebo

N=193

%

Corticosteroids 36.2 43.0

Corticosteroids 11.1 10.4

Glucocorticoids 30.6 38.3

Bronchodilators 27.5 29.0

Adrenergics 25.7 26.9

Anticholinergics 12.3 15.5

Mucolytics 18.5 22.3

a. Includes all routes of administration.

CS-6

AE Overview

LinhaliqN=389

%

PlaceboN=193

%

AE 88.2 94.3SAE 23.4 26.9Fatal AE 1.5 2.6

Study drug discontinued due to AE 8.7 8.3Withdrawal from study due to AE 5.4 3.6

CS-7

Most Common Respiratory AEs in ≥5% Subjects

Preferred TermLinhaliq, %

N=389Placebo, %

N=193Cough 64.5 65.3

Dyspnea 54.2 53.4

Sputum increased 46.5 56.0

Wheezing 39.3 43.5

Forced expiratory volume decreased 33.9 26.9

Breath sounds abnormal 26.5 23.3

Sputum purulent 22.1 25.9

Forced vital capacity decreased 21.9 19.7

Increased viscosity of bronchial secretion 17.0 19.2

Hemoptysis 14.9 14.0

Sputum abnormal 11.8 14.0

Pulmonary function test decreased 5.1 6.2

Sputum discolored 3.3 5.7

CS-8

Other Most Common AEs in ≥5% Subjects

Preferred Term

LinhaliqN=389

%

PlaceboN=193

%

Patients who had an AE 88.2 94.3

Fatigue 36.5 46.1

Exercise tolerance decreased 25.2 28.5

Lethargy 22.6 19.7

Malaise 13.4 15.0

Headache 11.3 13.0

Dysgeusiaa 8.2 6.7

Nausea 7.7 5.7

Dizziness 7.2 4.7

a. "Taste (abnormal) during inhalation" events were coded to "Dysgeusia“.

Preferred Term

LinhaliqN=389

%

PlaceboN=193

%

Chest pain 5.9 4.7

Arthralgia 5.9 4.7

Diarrhea 5.4 9.8

Nasopharyngitis 5.4 5.7

Back pain 5.4 3.1

Pneumonia 5.1 3.6

Oropharyngeal pain 4.9 10.4

Chest discomfort 4.9 5.2

Rhinorrhea 3.6 7.8

CS-9

Pre-specified AEs of Special Interest (AESI) 1- 5%

Preferred Term

LinhaliqN=389

%

PlaceboN=193

%

Dysphonia 2.3 4.1

Pleuritic pain 2.3 0.5

Throat irritation 2.1 2.6

Pleurisy 1.5 1.6

Bronchospasm 1.3 1.0

Laryngitis 1.0 1.0

Pharyngitis 0.5 1.0

Upper-airway cough syndrome 0.5 1.0

Pharyngeal erythema 0.3 1.0

CS-10

Adverse Drug Reactions Reported in ≥2% of Subjects in Linhaliq and More Frequent than Placebo

Adverse Reaction

Linhaliq

N=389%

Placebo

N=193%

Dysgeusia (unpleasant or bitter taste) 8.2 6.2

Forced expiratory volume decreased 4.9 2.1

Pulmonary function test decreased 3.1 2.6

Hemoptysis 2.6 1.0

Chest discomfort 2.3 2.1

Dizziness 2.1 1.0

Increased viscosity of bronchial secretion 2.1 1.6

CS-11

SAEs in ≥2% of Subjects in Either Treatment Group

Preferred Term

Linhaliq

N=389

%

Placebo

N=193

%

Patients who had an SAE 23.4 26.9

Dyspnea 4.4 6.7

Pneumonia 3.6 3.1

Hemoptysis 2.3 1.0

Respiratory failure 2.1 2.1

Pyrexia 0.8 2.6

Sputum increased 0.5 3.1

Lower respiratory tract infection 0.5 3.1

CS-12

Deaths

Linhaliq

N=389

Placebo

N=193

Patients, n (%) 7 (1.8) 7 (3.6)

Cause of death as

reported

Bronchopneumonia

Respiratory failure

Pneumonia

Thalamus hemorrhage

Loss of consciousness

Cardiac arrest

Sudden death

Respiratory failure

Chronic respiratory failure

Pneumonia

Asphyxia

Respiratory insufficiency

“Disease for which subject

received study treatment”

Pancreatic carcinoma

All deaths were reported as unrelated to Linhaliq or placebo.

CS-13

Serial Spirometry: FEV1 % Predicted at Baseline and Week 24

No change in the whole study population

Baseline Week 24

LinhaliqN=389

Placebo N=193

LinhaliqN=389

Placebo N=193

Time Point Mean ± SD Mean ± SD

Pre-Dose 60.0 ± 22.1 58.5 ± 20.6 61.3 ± 22.4 59.4 ± 19.6

15 min 59.2 ± 22.6 58.0 ± 20.8 60.4 ± 22.2 59.3 ± 19.1

30 min 59.5 ± 22.8 58.1 ± 20.2 60.7 ± 22.4 58.7 ± 18.9

90 min 61.4 ± 23.2 60.3 ± 20.7 62.8 ± 23.3 61.1 ± 20.4

CS-14

Serial Spirometry: FEV1 % Predicted Decreased ≥15% at Baseline and Week 24

No subject discontinued study drug due to low spirometry values

1.1% of subjects in each group discontinued study drug due to bronchospasm

Baseline Week 24

Post-Dose

Linhaliq

N=389

Placebo

N=193

Linhaliq

N=389

Placebo

N=193

Time Point % %

15 min 5.5 2.2 2.3 0

30 min 5.2 3.3 3.6 0.7

90 min 3.7 2.2 2.4 2.7

Any time point 8.6 5.9 5.8 2.6

CS-15

Absolute Change from Baseline

-0.12

-0.10

-0.08

-0.06

-0.04

-0.02

0.00

0.02 Linhaliq

Placebo

Week 48Week 24Baseline

Ab

so

lute

Ch

an

ge f

rom

Baselin

e (

lite

rs)

Mean

±95%

CIs

-0.12

-0.10

-0.08

-0.06

-0.04

-0.02

0.00

0.02

n=285

n=265

n=127n=137

FEV1

FVC

n=285

n=265n=137n=127

CS-16

Carbon Monoxide Diffusion Capacity (DLCO):Mean % Change from Baseline

-40

-30

-20

-10

0

10

20

30

40%

Ch

an

ge

fro

m B

as

eli

ne

Me

an

±S

DLinhaliq

Placebo

Week 48

121

70

Week 24

131

74

Baseline*

158

90

* Pre-dose, Day 1

Linhaliq

Placebo

CS-17

Laboratory and Other Safety Parameters

No clinically meaningful differences between Linhaliq and Placebo

groups in

– Clinical chemical laboratories and hematology

– Shift tables

– Urinalysis

– Vital signs

– ECG

CS-18

Reported AEs Representing Fluoroquinolone Class Effects

System Organ Class (SOC) Linhaliq, % Placebo, %

AEs in nervous system disorders 39.3 37.3

AEs in psychiatric disorders 5.4 8.3

AEs in hepatobiliary disorders 1.0 1.6

AEs of photosensitivity 0.3 0

Preferred Term

Paresthesia 0 1.0

Muscular weakness 0.8 0

Tendonitis 0.8 0.5

Tendon rupture 0 0.5

Drug hypersensitivity 0.5 0

Diarrheaa 5.4 9.8

QTc change of >30ms from BL to Week 48 6.6 8.3

QTc change of >60ms from BL to Week 48 2.5 3.8

a. No event was reported as C. difficile-associated diarrhea.

Note: Subjects with myasthenia gravis excluded from clinical trials with Linhaliq; Myasthenia gravis was not reported as an AE.

CS-19

Resistance Development

During on-treatment periods constant reduction of ciprofloxacin

susceptibility in P. aeruginosa isolates with at least partial recovery

during subsequent off-period

No observations of ciprofloxacin resistant pathogen infections

Treatment courses and durations of systemic infections were

comparable

CS-20

No Change in Susceptibility of P. aeruginosa for Selected Antimicrobials, Pooled Studies

>2-fold MIC Increase

Antibacterial Drug

Linhaliq

N=191

n (%)

Placebo

N=97

n (%)

Amikacin 17 (8.9) 12 (12.4)

Aztreonam 32 (16.8) 21 (21.6)

Cefepime 44 (23.0) 17 (17.5)

Ceftazidime 32 (16.8) 19 (19.6)

Ciprofloxacin 62 (32.5) 17 (17.5)

Gentamicin 15 (7.9) 6 (6.2)

Meropenem 22 (11.5) 16 (16.5)

Piperacillin 27 (14.1) 17 (17.5)

Ticarcillin/Clav 24 (12.6) 14 (14.4)

Tobramycin 5 (2.6) 3 (3.1)

Odds Ratio (Linhaliq/Placebo) with 95%CI

0.1 1.0 10.0

CS-21

Safety Summary

Safety profile of Linhaliq similar to placebo

No increase in respiratory AEs

– Low rates of bronchospasm

No increase in fluoroquinolone class effects

Less use of antibacterial and other respiratory therapies

No observations of ciprofloxacin resistant pathogen infections

Other antipseudomonal antibiotics showed no trend of decreased

susceptibility in P. aeruginosa

Aradigm is committed to continued microbiological surveillance post

approval

CS-22

Today’s Agenda




Efficacy





Benefit / Risk




CR-1

Risk-Benefit of Linhaliq in NCFBE:A Focus on Antimicrobial Resistance

Sanjay Sethi, MD

Professor, Jacobs School of Medicine

Division Chief, Pulmonary Critical Care and Sleep Medicine

University at Buffalo, SUNY

CR-2

DSMB Chair Perspective

Clinical implications of resistance emergence with Linhaliq a major

focus for the DSMB

DSMB reviewed detailed microbiology data and infection related

serious adverse events

– Increase in PA MICs seen more often with Linhaliq over time

(as expected)

– No pulmonary or systemic infection related SAE determined to be related

by the Investigator or the DSMB to these higher MIC bacteria

– Superinfections with other antibiotic resistant bacteria (or other

microbes) not seen

CR-3

Cystic Fibrosis Experience with Inhaled Antibiotics Over 20 Weeks

Increased PA MIC is seen with inhaled tobramycin in CF

Burns, et al. JID. 1999.

0

10

20

30

40

50

60

70

80

Tobramycin Placebo

MIC increased MIC unchanged MIC decreased

Week 0 to 20

p=0.007

% o

f P

A I

so

late

s

CR-4

Cystic Fibrosis Experience with Inhaled AntibioticsOver 56 Weeks

Adapted from Mazurek, et al. Pediatr Pulmon. 2014.

Persistent reduction in P. aeruginosa is seen with inhaled tobramycin

-3

-2

-1

0

1

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

TNS4 - Safety Population (Extension, N=209)

“On” “On” “On” “On” “On” “On” “On”

Me

an

±9

5%

CI

CORE 48 WEEK EXTENSION

Study WeekNo assessments at Week 20, 36, and 44.

CR-5

Cystic Fibrosis Experience with Inhaled AntibioticsOver 92 Weeks

Benefits of inhaled tobramycin persist in the 2nd year

0

2

4

6

8

10

Winter Spring Summer Fall

% o

f S

tud

y D

ays H

osp

italized

Season

Placebo

1st Year Inhaled Tobramycin Solution

2nd Year Inhaled Tobramycin Solution

Adapted from Moss, et al. Chest. 2001.

CR-6

Other Lessons from Inhaled Antibiotics Use in Cystic Fibrosis

Antimicrobial susceptibility of sputum bacteria is not predictive of

antibiotic efficacy at CF exacerbation

Chronic inhaled use of an antibiotic does not preclude use of the

same antibiotic systemically for exacerbations

Hurley, et al. J Cyst Fibros. 2012.

Smith, et al. Chest. 2003.

CR-7

Use of Systemic Antibiotics in ORBIT -3 and -4

Linhaliq led to a reduction in systemic antibiotic use

– Antibiotic resistance is related to overall antibiotic exposure

Most frequent systemic antibiotic class was fluoroquinolones

– Most common reason was PE

– The mean (+/- SD) number of antibiotics per PE

• Placebo: 2.40 ± 1.70

• Linhaliq: 2.30 ± 1.60

– Mean number of antibiotics per PE were comparable for successive PEs

CR-8

Societal Implications of Linhaliq Use

NCFBE is an orphan disease; only a small number of patients

eligible for Linhaliq

– Contribution of Linhaliq to the overall fluoroquinolone use would be

minor (168k of 34 million prescriptions, 0.5%)

Patient to patient transmission of fluoroquinolone resistant strains

is extremely rare

Hilliam, et al. ERJ. 2017.

CR-9

Risk Benefit Ratio in Terms of Antimicrobial Resistance

For the NCFBE patient

– Safe, well tolerated, lung targeted treatment that reduces exacerbations

and systemic antibiotic use

– No increase in antibiotic resistant bacterial infections

– No superinfections with difficult to treat bacteria

– Fluoroquinolones still an option for PEs

For the Society at large

– Fluoroquinolone resistant strains that emerge due to Linhaliq are unlikely

to become a public health concern

CR-10

The Risk/Benefit Profile of Linhaliq for the Treatment of Bronchiectasis

Professor James D Chalmers, MD PhD

British Lung Foundation Chair of Respiratory Research

University of Dundee

CR-11

Reducing Frequency of PEs is the Key Objective of Bronchiectasis Therapy

Major role in disease progression and morbidity

“Irreversible morbidity”

Annual frequency and severity are major drivers of clinical decision making

– Time to first exacerbation is not used for clinical decision making

– Moderate/severe exacerbations are most clinically important

Chalmers, et al. AJRCCM. 2014;189(5) 576-85.

Brill, et al. Respir Res. 2015;16(1):16.

Polverino, et al. ERJ 2017;50(3) Pii1700629.

Critical unmet medical need to identify a safe therapy that can reduce

frequency of moderate and severe PEs

CR-12

0 . 2 2 . 01

Hazard / Risk Ratio (95% CI)

0 . 2 2 . 01 0 . 2 2 . 01

% PEReduction

27%

33%

42%

Clinically Meaningful Reductions in Prespecified Endpoints

ORBIT-4 ORBIT-3 Pooled

* Requested by EMA.

All PEs

Moderate

& Severe PEs*

Severe PEs

% PEReduction

15%

22%

20%

% PEReduction

37%

42%

60%

CR-13

0.001

0.01

0.1

1

10

100

1000

10000

0 5 10 15 20 25 30

Cip

rofl

ox

acin

(µ

g/m

L)

Time, hr

Linhaliq Provides High Sputum, Low Plasma Exposure

Oral/IV Ciprofloxacin Cmax - Sputum

Isolates resistant toOral/IV Ciprofloxacin

Linhaliq – Sputum concentrations

Oral/IV Ciprofloxacin Cmax - Plasma

Linhaliq – Plasma concentrations

New dose 24 hr

~1700 ×

~15 ×

~11250 ×Pre-dose

Pre-dose

CR-14

What are the alternatives to Linhaliq?

Most patients are treated with repeated courses of oral and IV

antibiotics

Off label inhaled antibiotic use is common

– 10% in the U.S. bronchiectasis registry

Major challenges in clinical practice

– Lack of proven efficacy

– Many patients cannot currently access therapy due to lack of approval

– Poor tolerability leading to drug discontinuation

McCullough, et al. BMC Pulm Med. 2014;14:107.

Barker, et al. Lancet Resp Med. 2014;2(9):738-49.

Barker, et al. AJRCCM. 2000;162(2pt1):481-5.

CR-15

Perspective on Potential Concerns

Potential Concern Perspective

1. ORBIT-3 failed to reach

its primary endpoint

Baseline imbalances between ORBIT-3 and -4 make pooled data

most clinically meaningful

Frequency of PEs is more clinically meaningful

Data much more consistent in those with >3 PEs

ORBIT-4 is robustly positive

2. Clinical meaningfulness

of the reduction in PEs

Substantially higher level of effect than prior therapies for NCFBE

Patients regard the reductions as highly meaningful

CR-16

Small Incremental Benefits have Resulted in Transformation of Cystic Fibrosis

Ag

e (

years

)

1930 1940 1950 1960 1970 1980 1990 2000 2010

40

35

30

25

20

15

10

5

0

CR-17

Perspective on Potential Concerns

Potential Concern Perspective

1. ORBIT-3 failed to reach

its primary endpoint

Baseline imbalances between ORBIT-3 and -4 make pooled data

most clinically meaningful

Frequency of PEs is more clinically meaningful

Data much more consistent in those with very frequent Pes

ORBIT-4 is a robustly positive study

2. Clinical meaningfulness

of the reduction in PEs

Substantially higher level of effect than prior therapies for NCFBE

Patients regard the reductions as highly meaningful

3. Impact on quality of life Tool used in this study only measures respiratory symptoms and

was not designed to measure drug response

Patients on Linhaliq felt better during treatment

4. Antibiotic resistance Linhaliq targeted at only the most severe patients; already have high

rates of antibiotic use

Decades of experience with inhaled antibiotics in cystic fibrosis

Reassuring efficacy data

Linhaliq will have no meaningful impact on AMR at population level

CR-18

Totality of Evidence Supporting Safety and Efficacy

Key safety endpoints

– No increase in respiratory AE’s

– Low bronchospasm rates

– No increase in known quinolone class

effects

Resistance

– As expected, MIC’s increase on

treatment

– No loss of efficacy with increasing MIC’s

– Quinolones remain an effective

treatment for PEs

– No evidence of treatment emergent or

difficult to treat infections

PE endpoints

– Reduction of all PE’s

– Reduction of severe PE’s

– Reduction of moderate and severe PE’s

Reduced healthcare utilization

– Reduction in all antibiotic use

– Reduced duration of hospitalization

– Reduced antibiotic days

Other benefits

– Improved respiratory symptoms by

QoLB when on treatment

– Consistent antipseudomonal activity

CR-19

Why are we here today?

Complex disease, severe population,

orphan indication

First therapy with clear efficacy in

reducing PEs

Clinically meaningful benefit to patients

Approval would have a transformative

effect on the field

Are the data provided adequate to support the safety and efficacy of

ciprofloxacin DI for the treatment of NCFBE adult patients (>18 years

of age) with chronic lung infections with Pseudomonas aeruginosa?

XX-1

Supporting Slidesfor Linhaliq

MR-68

Highest P. aeruginosa Ciprofloxacin MIC and Association with PE, Pooled Studies

Linhaliq Subject Samples

Stratified average, random effects

0%

5%

10%

15%

20%

25%

Proportion of micro samples associated with

PE (95%CI)

Highest P. aeruginosa Ciprofloxacin MIC (mcg/mL)

MC-1

Microbiologic Processing Sites

New York

Dublin

Singapore

MR-12

Ciprofloxacin MIC by Highest P. aeruginosa IsolatePooled Studies

100

10

1

Study Visit

BL 3 4 5 6 7 8 9 10 11 12 13 14

On Off On Off On Off On Off On Off On OffTreatment:

Cip

rofl

oxacin

MIC

(m

cg

/mL

)

Linhaliq

Placebo

Boxes represent 25th to 75th quartiles with median indicated by white line. Whiskers show lowest and highest values observed.

MR-24

Highest Ciprofloxacin MIC P. aeruginosa Isolate Ciprofloxacin MIC Distributions, Pooled Studies

Ends of 1st and 6th On-Cycles Ends of 1st and 6th Off-Cycles

ON ON ON ON ON ON

Visit 1 3 42 5 6 7 8 9 10 11 12 13 14

0%

10%

20%

30%

40%

Proportion ofHighest MIC

P. aeruginosa Isolates

Ciprofloxacin MIC (mcg/mL)

HI Visits 3 and 13

Linhaliq Visit 3

Linhaliq Visit 13

Placebo Visit 3

Placebo Visit 13

0%

10%

20%

30%

40%

Proportion ofHighest MIC

P. aeruginosa Isolates

Ciprofloxacin MIC (mcg/mL)

HI Visits 4 and 14

Linhaliq Visit 4

Placebo Visit 4

Linhaliq Visit 14

Placebo Visit 14

ON-39

Concomitant Anti-bacterial Drugs Introduced During Study: ORBIT-3 and ORBIT-4

ORBIT-3 ORBIT-4

LinhaliqN=193

%

PlaceboN=97

%

LinhaliqN=207

%

PlaceboN=101

%

Fluoroquinolones 47.7 48.5 41.1 50.5

Penicillins, combinations (incl. beta-lactamase) 22.3 26.8 18.8 21.8

Macrolides 11.4 18.6 17.9 18.8

Cephalosporins, third generation 12.4 17.5 8.7 22.8

Aminoglycosides 14.5 11.3 3.9 8.9

Penicillins with extended spectrum 6.2 9.3 9.2 14.9

Tetracyclines 6.7 10.3 8.7 7.9

Combinations of sulfonamides and trimethoprim, incl. derivatives

6.2 4.1 4.8 5.9

Carbapenems 1.6 4.1 2.9 6.9

EF-82

ORBIT-4 Serial KMs0

0.2

0.4

0.6

0.8

10 100 200 300 400

Pro

po

rtio

n w

ith

ou

t P

E E

ven

t

Linhaliq 206 171 146 124 109 90 84 2Placebo 98 66 54 48 39 34 28 0

0

0.2

0.4

0.6

0.8

10 100 200 300 400


0

0.2

0.4

0.6

0.8

10 100 200 300 400


0

0.2

0.4

0.6

0.8

10 100 200 300 400


SecondEvent

FourthEvent

FirstEvent

ThirdEvent

LinhaliqPlaceboCensored

Subjects at Risk

Subjects at Risk

Subjects at Risk

Subjects at Risk

EF-83

ORBIT-3 Serial KMs0

0.2

0.4

0.6

0.8

10 100 200 300 400


0

0.2

0.4

0.6

0.8

10 100 200 300 400


0

0.2

0.4

0.6

0.8

10 100 200 300 400


0

0.2

0.4

0.6

0.8

10 100 200 300 400


SecondEvent

FourthEvent

FirstEvent

ThirdEvent

LinhaliqPlaceboCensored

Pro

po

rtio

n w

ith

ou

t P

E E

ven

t

Subjects at Risk

Subjects at Risk

Subjects at Risk

Subjects at Risk

EF-16

Comparison of the FA vs per Protocol Population Analyses Using the Counting Process

ORBIT-4 ORBIT-3

Hazard Ratio (95% CI)

All PEs

Counting Process – FA

Counting Process – PP

Stratified baseline macrolide use

Moderate & Severe PEs Counting Process – FA



Severe PEs

Counting Process – FA



Pooled

p<0.001

p<0.001

p=0.004

p<0.001

p<0.001

p<0.001

p=0.001

p=0.004

p=0.011

p=0.14

p=0.046

p=0.035

p=0.038

p=0.015

p=0.017

p=0.40

p=0.26

p=0.12

EF-95

ORBIT-4: K-M: Time to First Moderate or Severe Exacerbation

Pro

po

rtio

n w

ith

ou

t M

od

era

te/S

evere

PE

HR = 0.66 (0.48, 0.91)p=0.0097

LinhaliqPlacebo

Log Rank Test

Post hoc analysis, nominal p values

Subjects at Risk

Linhaliq 206 177 156 135 122 105 96 0

Placebo 98 71 62 51 42 37 30 78

Time to First Moderate or Severe PE

EF-97

ORBIT-3: K-M: Time to First Moderate or Severe Exacerbation

LinhaliqPlacebo

Log Rank Test

Post hoc analysis, nominal p values

HR = 0.88 (0.62, 1.24)p=0.46

Subjects at Risk

Linhaliq 183 143 116 105 95 84 76 0

Placebo 95 73 51 42 41 39 34 0

Pro

po

rtio

n w

ith

ou

t M

od

era

te/S

evere

PE

EF-221

Why do we see lower frequency of exacerbations during the trial than at baseline?

Registry data shows high variability in annual exacerbation frequency in real life clinical practice

Placebo effect, with enhanced compliance with existing interventions like airway clearance

Regression to the mean

Robust definition of exacerbations: higher threshold for defining exacerbations vs usual clinical practice

EF-56

ORBIT-2: Linhaliq Met the Primary Endpoint

Significant reduction of P. aeruginosa load at Day 28 for Linhaliq compared to placebo

P. aeruginosa log CFUsMean ± SD

Linhaliq Placebo p-value

Baseline 6.4 ± 2.4 6.0 ± 2.6

Day 28 2.1 ± 3.4 5.9 ± 3.8

Change from Baseline to Day 28 -4.2 ± 3.7 -0.1 ± 3.8 0.002

ANCOVA

BD-61

T26, pg95. Average P. aeruginosa log10 CFU Density Change by Highest Ciprofloxacin MIC Category (Pooled)

MC-78Probability of >0.5 or >1.0 log10 CFU P. aeruginosa Reduction among Linhaliq Subjects as a Function of Starting Density and Ciprofloxacin MIC, Pooled Data

Logistic Regression

MC-56

Subjects with Density Measurements by Visit, PrespecifiedOrganisms, Pooled Studies

MC-55

Sputum Densities by Study VisitPooled Studies

MC-4

Species Isolated By Selective CulturePooled Studies

Citrobacter amalonaticus Hafnia alvei Rahnella aquatilis

Citrobacter braakii Klebsiella oxytoca Ralstonia pickettii

Citrobacter freundii Klebsiella ozaenae Raoultella ornithinolytica

Citrobacter koseri Klebsiella pneumoniae Raoultella planticola

Citrobacter species Kluyvera ascorbata Raoultella terrigena

Citrobacter youngae Kluyvera cryocrescens Serratia fonticola

Enterobacter aerogenes Kluyvera intermedia Serratia liquefaciens

Enterobacter amnigenus 1 Kluyvera species Serratia marcescens

Enterobacter amnigenus 2 Leclercia adecarboxylata Serratia odorifera

Enterobacter asburiae Moraxella catarrhalis Serratia plymuthica

Enterobacter cancerogenus Morganella morganii Serratia proteamaculans

Enterobacter cloacae Pantoea species Serratia rubidaea

Enterobacter gergoviae Proteus mirabilis Serratia species

Escherichia coli and other coliform species Proteus vulgaris Staphylococcus aureus

Ewingella americana Providencia alcalifaciens Streptococcus pneumoniae

Haemophilus influenzae Providencia rettgeri Yersinia enterocolitica

Haemophilus parainfluenzae Pseudomonas aeruginosa

(50 categories)6,755 respiratory specimens (Linhaliq = 4580, Placebo = 2175)

MC-5

Prevalence of Bacterial Species >0.5%, Pooled Studies

0

2

4

6

8

10

12

14

16

18

0.01% 0.10% 1.00% 10.00% 100.00%

Species Prevalence with 95% CI

Linhaliq

Placebo

Pseudomonas aeruginosaStaphylococcus aureus

Escherichia coli and other coliform speciesHaemophilus influenzae

Klebsiella pneumoniaeKlebsiella oxytoca

Serratia marcescensStreptococcus pneumoniae

Enterobacter cloacaeCitrobacter koseri

Citrobacter freundiiRaoultella planticola

Proteus mirabilisSerratia liquefaciens

Citrobacter braakiiPantoea species

Enterobacter gergoviae

Stratified averages, random effects

SA-114

Incidence of Systemic Infections

UTIs were the only category of systemic infections that were higher in Linhaliqthan in Placebo

– Course and treatment of UTIs were similar: 12.6 days for Linhaliq, 12.7 days for Placebo

Category

LinhaliqN=389n (%)

PlaceboN=193n (%)

Sinusitis 21 (5.4%) 11 (5.7%)UTI 22 (5.7%) 6 (3.1%)Upper Respiratory Tract Infections 63 (16.2%) 34 (17.6%)Lower Respiratory Tract Infections 46 (11.8%) 23 (11.9%)

Total 152 (39.1%) 74 (38.3%)

EF-28

Impact of Adding a Stratification for Study to Pooled Analyses

Pooled (Stratified by Study)

HR or RR (95% CI) p-value

Frequency of All PEs

Negative Binomial 0.73 (0.60, 0.88) 0.0011

Frequency of Moderate and Severe PEs


Frequency of Severe PEs


Time to First PE

Log-Rank 0.82 (0.66, 1.03) 0.097

Time to Moderate and Severe PE

Log-Rank 0.75 (0.59, 0.94) 0.018

MR-90

Higher Ciprofloxacin MICs at Baseline and On Study Did Not Impact Relative Risk of All PEs

10.2 2.0

Relative Risk* (CI)

*Pooled ORBIT-4 and ORBIT-3; Post hoc analysis; Negative binomial regression

Highest Ciprofloxacin MIC at baseline

MIC <2 mcg/mL

MIC 2-8 mcg/mL

MIC >8 mcg/mL

Highest Ciprofloxacin MIC at any visit

MIC <2 mcg/mL

MIC 2-8 mcg/mL

MIC >8 mcg/mL

EF-159

Reasons for Dropouts

ORBIT-4 ORBIT-3Linhaliq Placebo Linhaliq PlaceboN=206 N=98 N=183 N=95

n % n % n % n %Reason for Dropouts 26 12.6 17 17.3 41 22.4% 18 18.9%

Adverse event 5 2.4 4 4.1 16 8.7 3 3.2Protocol-defined PE 0 0 0 0 1 0.5 0 0Lack of efficacy 1 0.5 0 0 2 1.1 0 0Protocol deviation 1 0.5 1 1.0 2 1.1 1 1.1Investigator Decision 3 1.5 1 1.0 3 1.6 1 1.1Lost to Follow-up 3 1.5 0 0 3 1.6 1 1.1Withdrawal by subject 13 6.3 11 11.2 14 7.7 11 11.6Other 2 1.0 0 0 0 0 1 1.1

ard-3150, linhaliq nda

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