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Mechanisms of Action & Nuvaira™ Lung Denervation System

Pallav L Shah

Royal Brompton Hospital

Chelsea & Westminster Hospital

Imperial College

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Conflict of interest disclosure

• PneumRx reimbursed the Royal Brompton Hospital and Chelsea & Westminster Hospital

for clinical trial expenses (RENEW trial, RENEW Xover, RESET coil randomised trial)

• CSA Medical reimbursed the Royal Brompton Hospital and Chelsea & Westminster

Hospital for clinical trial expenses (RejuvenAir trial)

• Nuvaira reimbursed the Royal Brompton Hospital and Chelsea & Westminster Hospital for

clinical trial expenses (Airflow trial)

• Uptake medical reimbursed the Royal Brompton Hospital for clinical trial expenses (Step

Up trial)

• Pulmonx reimbursed the Royal Brompton Hospital for clinical trial expenses (Liberate trial)

• Boston Scientific, Erbe, Olympus/Keymed, Cook Medical, PneumRx, Medtronic,

Immotech, Pulmonx sponsorship to Imperial College for an annual interventional

bronchoscopy course

• Consultancy activity for Olympus/Keymed, PneumRx, Medtronic, Nuvaira, Broncus, CSA

Medical & Pulmonx sponsorship

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By the end of this presentation you should be able to

• Define Targeted Lung Denervation

• Describe the function of the dual-cooled catheter

• List two effects TLD has in the sheep model

• Explain why there is the potential for greater effect

in future human studies

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Targeted Lung Denervation (TLD): concept and defintion

Denervation

• Disrupt parasympathetic nerves to

decrease release of acetylcholine

Lung

• Decrease smooth muscle tone

• Decrease mucus production

Targeted

• Anatomically to only the lung

• To a depth where the nerves are

locatedFetal pig lung stained to show

airway nerves

Treatment

site

Nerves

TLD Concept TLD Definition

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TLD designed to decrease airway smooth muscle tone

COPD Before TLD

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TLD designed to decrease airway smooth muscle tone

COPD After TLD

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Vagus nerve disruption improves lung function

Nadel J. J Physiol 1962; 163: 305-16.

Karczewski W. J Physiol 1969; 201: 293-304.

Jammes Y. J Physiol 1979; 291: 305-16.

Wagner EM. J Appl Physiol 1995; 78: 403-9.

Wagner EM. J Appl Physiol 1999; 86: 294-7.

Dimitrov-Szokodi D. J Thoracic Surg 1957; 33:166-84.

Animal Intervention Change

Dog (1962)

Bilateral cervical vagus

cooling- 22% (Rlung)

Cat

(1979)

Unilateral cervical sensory

vagotomy- 30% (Rlung)

Cat

(1979)

Bilateral total cervical

vagotomy- 34% (Rlung)

Sheep

(1995)Bilateral vagotomy - 29% (Rlung)

Sheep

(1999)

Bilateral total cervical

vagotomy- 54% (Rlung)

Human

(1957)

Bilateral hilar nerve

transection+ 18% MVV

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Evolution of the NuvairaTM Lung Denervation System

GEN1 GEN2

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dNervaTM Dual Cooled Catheter

Catheter Shaft

Electrode

Balloon

99999

Effect is targeted to depth with surface cooling

Tissue Mimicking Gel

Balloon

1010101010

Four step TLD procedure

Position

Inflate

Confirm

Activate

1

2

3

4

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TLD procedure animation

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Extensive animal testing prior to human use

Major Findings

• TLD can be performed safely in sheep

• Demonstration of physiologic effect

• Safety profile supports evaluation in human studies

• Decrease in motor innervation durable to two years

• Higher dose produces deeper effect and potential for better efficacy

Studies: 17

Animals: 151

Airways: 295

Activations: 1755

Follow-up: 0, 7, 30, 90, 180, 365, 640 days

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Treatment assessment

Figure 21. Normal bronchus distal to treatment site, H&E. Note normal appearance

of right mainstem bronchus, approximately 2 cm distal to treatment area. Note normal

appearance of airway and surrounding tissue of this level, including pulmonary artery to

left of image, pulmonary vein to right of image, and multiple small nerve branches and

bronchial vessels. In particular, note thinness and delicate nature of submucosa and

peribronchiolar tissues (compare with treatment induced fibrosis in Figure 1 and 2).

Client Name: Innovative Pulmonary Solutions

Study ID: IP092810 VDx Accession #:NIP092810-040 – ANIMAL #040 - 30 days FINAL PATHOLOGY REPORT

Page 24 of 28

Client Name: Innovative Pulmonary Solutions Study ID: D0008 VDx Accession #:NIP011411 IP#D0008 “Dosing Study” FINAL PATHOLOGY REPORT

Page 14 of 42

Figure 1. Animal #155, LMB, 4.8 KiloJoules Total Treatment Energy (8 Watts x 5

treatments x 120 seconds), 1 day post-treatment.

Gross Inspection

H&E and/or Trichrome Axon Immuno StainingBronchoscopy

100

μm

Unpublished Data

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Sustained motor denervation

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0D 30D 90D 180D 365D 365D 22W 640D

Moto

r A

xon

s

(ChA

T S

core

)

1515151515

Sustained improvement in dynamic airway resistance at 1-yr

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

0 Days 30 Days 90 Days 365 Days

Rdyn;

% C

ha

nge f

rom

0 d

ay 32W 365Day (n = 4)

0W 365 Day (n= 4)

Treatment @ 365 days (n=4)

Sham @ 365 days (n=4)

Unpublished Data

1616161616

Client Name: Holaira Study ID: IPS-D0030 VDx Accession #:NIP092011 FINAL PATHOLOGY REPORT

Page 8 of 25

Figure 1. Animal 478, 30 days, Left bronchus, H&E. Note the circumferential treatment effect

extending through the full thickness of the bronchial wall. This was typical of all treatment sites at both

time points.

Figure 2. Animal 479, 640 days, Left bronchus, H&E. Note the circumferential treatment effect

extending through the full thickness of the bronchial wall. This was typical of all treatment sites at both

time points.

0

1

2

3

4

5

6

15W 20W 22W

Dep

th o

f T

rea

tment E

ffe

ct

Only these 2 tested in

early clinical work

Depth of TLD effect can be controlled

She

ep B

ron

chu

sH

um

an B

ron

chu

s

Unpublished Data

1717171717

Conclusions for Targeted Lung Denervation

• Dual-cooled catheter targets tissue heating at depth while

protecting the airway surface

• TLD in the healthy sheep model

• Is safe

• Produces sustained motor denervation

• Decreases airway resistance

• Higher energy can produce a deeper effect

• Supports human studies