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Mechanisms of Action & Nuvaira™ Lung Denervation System
Pallav L Shah
Royal Brompton Hospital
Chelsea & Westminster Hospital
Imperial College
11111
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
33333
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
44444
TLD designed to decrease airway smooth muscle tone
COPD Before TLD
55555
TLD designed to decrease airway smooth muscle tone
COPD After TLD
66666
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
77777
Evolution of the NuvairaTM Lung Denervation System
GEN1 GEN2
88888
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
1111111111
TLD procedure animation
1212121212
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
1313131313
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
1414141414
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