Breathing New Life Into Treatment Approaches for COPD: The Latest Insights Into the Role of Type 2 Inflammation and Targeted Biologic Therapy

Chair, Dave Singh, discusses COPD in this EBAC/CME/MOC/AAPA activity titled “Breathing New Life Into Treatment Approaches for COPD: The Latest Insights Into the Role of Type 2 Inflammation and Targeted Biologic Therapy.” For the full presentation, complete EBAC/CME/MOC/AAPA information, and to apply for credit, please visit us at https://bit.ly/4bx8k1Q. EBAC/CME/MOC/AAPA credit will be available until October 6, 2025.

1. Breathing New Life Into Treatment
Approaches for COPD

The Latest Insights Into the Role of Type 2
Inflammation and Targeted Biologic Therapy

Dave Singh
Professor of Respiratory Medicine & Clinical Pharmacology
University of Manchester

Manchester, United Kingdom

Go online to access full EBAC/CME/MOC/AAPA information, including faculty disclosures.

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2. Our Goals for Today

Expand your knowledge of recent clinical data on
emerging targeted biologic therapy for the
treatment of COPD

Equip you with strategies for applying the latest
clinical evidence regarding novel approaches to
the treatment of COPD

Copyright © 2000-2024, PeerView

3. WHO estimates that, by 2060, more than 5.4 million deaths per year
will be attributable to COPD and related co-existing conditions

Exacerbations of COPD, regardless of severity, lead to poorer QOL,
increased hospitalizations, and increased risk of death
Despite currently available management strategies,
disease burden remains high for many patients

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4. aths Increases With Increasing Frequency and
Severity of Exacerbations!

Patients most at risk of dying are those with 21 severe exacerbation
Number of acute exacerbations of COPD

— 0 moderate (n = 51,568) — 1 moderate (n= 19,418) — 2moderate (n= 10,333) — 3 moderate (n = 5,654)
— 4 moderate (n= 3,125) — 5+ moderate (n = 5,065) — 1+ severe (n= 4,411)

Proportion Dead

o 2 4 6 8
Analysis Time, y

1. Adapled from Rothe Ky eta. Am J Respir Cit Care Med. 2018:198-464-471.

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5. Phenotype and Endotyp

Precision medi

O ©
Biological information Clinical features

detected using biomarkers

Use phenotype and
endotype information

1. Singh D. New Drugs for Away Diseases. In: Janes SM, es. Encycopedaof Respratoy Mene. 2nd ed. Elsevier, Academie Press 2021; volume 2. PeerView

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6. Inflammation in COPD

1 Paterno F Sn DD. Eur Resp. 2024:93:2400150. PeerView

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7. physiology of COPD

Evidence of type 2 inflammation is present in 20%-40% of patients
with COPD and is associated with an increased risk of exacerbations

See Eurocard 2072000680 PeerView

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8. Blood Eosinophils and COPD
N
T2 airway Inflammation ee)
Microbiome
scientist dans
El Pe D en |
ICS response?

+ 400 cime
À par win een ostuctve pumenan disease who have increases exacerbation rk .
1. Singh Det al Am Res Ct Coe Med. 2022208.1724 PeerView

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9. s à
2
= à

=
“an

a

= *

a

1. Higham A etal,Alergy2021.76:1861-1864.

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Degen
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10. Central Drivers of Type 2 Inflammation Have Unique and

Overlapping Functions!

IL4 1L-13 ILS
Th2 cell differentiation Goblet cell hyperplasia Eosinophil differentiation and survival,
Mucociliary dysfunction

Excess mucus production
Collagen deposition
‘Smooth muscle proliferation
Increased contractility
Hyperresponsiveness
Neuroimmune dysfunction

B-cell isotype switching and IgE production
Mast cell and basophil degranulation

Mast cell activation and trafficking to tissue
Fibrosis and airway remodeling
Epithelial barrier dysfunction and microbiome imbalance
TARC-induced migration of Th2 cells
Activation of macrophages to M2 type
Eosinophil recruitment and trafficking to tissue

1 Masper tal. ERY Open os. 2228008762021. PeerView

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11. logy of COPD"

Smoke! oxidative Viruses.
Microbiome Pollutants “stage.

Cytokines and immune cells
most commonly elevated in
patients with type 2
inflammation include

+ ILS

+ IL-4

l (mepotzs err
+ 11-13 A ES
Sora

+ Type 2 innate lymphoid cells mn

Engage

tronos Rn
+ Th2 cells Gant == = en
+

We Infame
prodion Wafching tothe lo.

41. Rabo KF ot al. A
3 Brghting CE
5. Ganudade Set

Resp Cot Car nd 2023208295405. 2. Pin ta. Am J Rasp Cet Cr Med, 199:150:511:4517,
ance 100058 1400408: 4, va Ret a Eur Respir. 200729906 919. R
Am Am Tnorc Soc. 2018: Saut 4} SZM-SZUG © Barnes PJ, Alergy. 201074 1249-1256, PeerView

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12. Approaches?"

A proportion of patients with moderate to very severe airflow limitation continue to
have exacerbations despite receiving optimized therapy

Some patients with COPD and high eosinophil counts continue to have COPD
exacerbations, despite triple therapy with LABA/LAMA/ICS

Current maintenance therapies do not specifically target key
type 2 inflammatory mediators
Roflumilast reduces EOS counts in tissue and sputum, but not circulating EOS, and has been
shown to be most effective in those with elevated blood EOS at baseline

1.Rabe KF etl Am J Resp Gt Care Med, 2028 208-295-405, PeerView

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13. Data From ERS 2024 and
Other Recent Congresses

Copyright © 2000-20;

14. NOTUS Clinical Trial Design!

A randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 study to
evaluate the efficacy and safety of dupilumab administered every 2 weeks in patients with
moderate or severe COPD with type 2 inflammation

— — — —

Screening Randomization Treatment Period Follow-up
Dupilumab 4
@ & N PL sc 300 maazw | n=470

n=465

Prespecified statistical analysis plan: The primary analysis was performed following a positive interim analysis and included all
available data for the 935 randomized participants, 721 of whom had the opportunity to reach week 52.

1. Bhalt SP eta. Engl Med. 2028390 2274-2283 PeerView

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15. NOTUS: Annualized Rate and Cumulative Mean Number of

Moderate or Severe Exacerbations'

-34% 10
P<.001

&

— Placebo

dé 0.9 À — Dupilumab 300 mg Q2W

14
12
10
08
06

‘Cumulative Mean No. of Events

04
02

Annualized Rate of Moderate or Severe
COPD Exacerbations + 95% Cl

0 4 8 12 16 20 24 28 32 36 40 44 48 52
No. at isk irene we

Placebo Dupilumab Placebo 465 464 458 453 453 448 430 415 403 394 384 368 351 303
70 n=465 Dupilumabi30OMPOZW 469 464 464 464 460 455 438 424 408 305 385 370 354 344

€ Dupilumab has been approved for treatment of COPD with type 2 inflammation since July

2024 in Europe and since September 2024 in the United States and China

1. Bhatt SP e a. W Engl J Med, 2028390227426, PeerView

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16. antly Reduced Exacerbation Rates in

COPD and Type 2 Inflammation Over 52 Weeks!

Results From Pooled Analysis of Phase 3 BOREAS and NOTUS

= Placebo mDupilumab 300 mg Q2W

14
35 512 ES 31%
285 10
BES
Sig 0.794
SU Sos
sas
30 E
EOS 06
zo
ou
Beg
Ba?
230% 02
se
3
à 0
Pooled ITT Population
Tena sta ERS 2008 PeerView

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17. Dupilumab Si ntly Improves Lung Function in Patients

With COPD and Type 2 Inflammation Over 52 Weeks!

Results From Pooled Analysis of Phase 3 BOREAS and NOTUS

in Prebronchodilator
3

lean (SE), L

Dupilumab 300 mg Q2W

Time, wk

as etai ERS 2008 PeerView

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18. Dupilumab Improves QOL
pe 2 Inflammation’

Post-hoc
subgroup

patients without
a moderate or
severe
exacerbation
during the

week trial p

1. Rabe K etl, ERS 2024,

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Non-Exacerbators Wi

COPD

Results From Phase 3 BOREAS
MM Placevoazw PB Dupiumab 300 mg azw
Nonexacerbator Population q es
Baseine 2258 sa
Sgn ital sco 413000) ds
$
4
fg 3200
238,
HE 230
2 0039
Ls mean dterance vet
o er esta
ITT Population
Basa nea; sos
Sond Wal score win aan más
A i
a
€
E 2000
fi .. :
fp A E 2700)
$ P= 0017
Lsmeanaiterence vs 34
placebo (95% CI}: (5510-13)

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19. Dupilumab Improves Respiratory Symptoms in Patients Wi
COPD and Type 2 Inflammation’

Results From Phase 3 BOREAS
, use een
ie
BE: e er
BES Depiad 200 mg 02
Bes ire
TE E = Kern EJ EJ
En ha
A
M
A == ll
EH Be E
file
ER
eT ee E E a [2
=
1. Papi A etal. ERS 2024. PeerView

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20. Mepolizumab May Be of Clinical Benefit for Patients With COPD Wii

Elevated Eosinophils Wi hout Chronic Bronchitis!

Improvement in CAT Score Change Was Seen With Mepolizumab vs
Placebo in Patients With Inflammation and With Symptoms of CB

= emer sa GB 19) ao G (07)
Tepes 100 mg se “acero Totana 100 m9 SS 4 À, a ue,
E =a Fo 3 =a Ze SS
AR EE pact PAR RES vs Rues ETS

Improvement In SGRO Score Change was Seen With Mepolizumab
vs Placebo In Patents With inflammation and Was Moro Preneunced.
In Patients With Symptoms of CB

wa = 189) DT)

LE
5

Vor cn ae)

+ Analys' performed using a negate binomial regression model estmates based on weighting applied 10 each level of dass varie determine from observed
proporions. + Resuls were numorcay ere betwoon mepolzumab and placebo groups, ut dáferenco was not slastealy dilrant Analysis performed using mixed

HORS PeerView

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21. Benralizumab Increases Time to Recurrent Exacerbations in Pts With COPD on

Triple Therapy With Frequent Exacerba

ns and Eosinophi

Phenotype’

+ Apooled post-hoc analysis of the benralizumab GALATHEA and TERRANOVA trials in COPD compared
the probability of experiencing a moderate or severe recurrent exacerbation in patients with

— 2300 blood EOS/mcL, on triple therapy, 23 exacerbations in prior year, and 21 exacerbation after
randomization following benralizumab 100 mg or placebo
+ 145 patients were included (73 benralizumab, 72 placebo)

Exacerbation Events

6

6

7

Crude Rate

Placebo — Senralizumab

167

Placebo

1. Singh Det al. nt J Chron Obstruct Palmen Dis. 2029:18:1595-1598

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— —
—

—
——

|

05 10 15
Favors benralizumad 100 mg 4— — Favors placebo

Rate Ratio (95% CD P
04002072) 0022
04624001) 0247
0334008130) 1188
OSB men) 0017
0.60(041087) or
0.48(0.16-143) 1862

20 25 30

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22. Itepekimab Shows Benefit With Regard to COPD Exacerbation in

Former Smokers Regardless of Exacerbation History!
Results From {tent rome bers Rega of Bases Naty "one Satara parie o Encerenios tay
a Phase 2a = bis “2 COPD Era nthe Yor toro Sereno
Study meat 3 5%
ae gh.
ÿ sl FE 20
8% Ms 1m
A = i ul en
ll: N:
u Placebo ‘hopkimab 300 mg Q2W
A 230000 Escritos ni Yu Ber Seine
Er Eso 20
Phase 3 HE sl p ib
study is $ sl FH =
ongoing ue 1, EN
i E a _ ay oie
too. =e 41”
nae He
O nm FT ne menu
{Rabe Ket, ERS 2024. PeerView

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23. Tozorakimab Had a Positive Effect on Lung Functi
Reduced Risk of COPD CompEx Events!
+ Patients (aged 40-80 y) Results From Phase 2a FRONTIER-4
were randomized 1:1
to receive tozorakimab Although the FRONTIER-4 study did not meet the primary endpoint for pre-BD
FEV;, tozorakimab showed rical benefit: lacebo for pre-BD FEV, in the
800 ma or placebo SC PT population aná In prespecfied and posthoc subgroups
interventional period to ee eer cn
R$ m
assess the effect on nz e Pr m 2180060
lung function in exacerbation | H
patients with COPD o E . CE vu 8968010430)
and chronic bronchitis tans" = E sou 100)
receiving dual or triple rose min se 2 AS
inhaled maintenance posa maus u = es
therapy inte proteus 12 mo rana
rs sn Ge simon
+ Primary endpoint: Pair ben . 8 Base mo)
change in pre-BD ae a 8 pe] rer
FEV, from baseline mes © mm
to week 12 eg
1. Singh Det aL ERS 2024. PeerView

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24. Tozorakimab Had a Positive Effect on Lung Function a
Reduced Risk of COPD CompEx Events? (Cont'd)

Results From Phase 2a FRONTIER-4

Tozorakimab treatment resulted in a reduced risk of COPDCompEx events vs.
placebo in the ITT population and in prespecified and post hoc subgroups

Fron Faves ere)
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Tea ae

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4 mun mean ess

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somme mos) meo enomım

Er en HE

Enr 0 mon emo

£ FRET

1. Singh Det al ERS 2024.

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o7 os Y

Ditferance va placebo in coracempex
Event

Phase 3 COPD LUNA program ongoii

‘at Week 28, HR (80% Ci),

Change in Mucus Plugging From Baseline
to Week 28 Assessed by CT Imaging

E]

agas Bug In 3 say
[Game GT mages om FRONTIER-£

PA

oc

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25. Tezepelumab: Reduction in Overall Rate of Moderate or Severe

COPD Exacerbations'

Annualized Rate of Moderate or Severe COPD Exacerbations Over 52 Weeks and Change From Baseline

Results From to Week 52 in Pre-BD FEV! and SGRQ Total Score
Phase 2a COURSE EE Rate Ratio (95%)
a i Hodes or ca COPD vo A
333 patients with wet 109175 160011 —+H oran
moderate to very severe sec<rsoaruma mau win ns 110075100
COPD randomized 1:1 secatsoctum Pre ——i os 049.09)
; BEC 230 etme. um mom —— 05025119
to receive tezepelumab —— somorenotar sonst masa —— 078050113)
420 mg or placebo Cart eh wen ss —+ ram
Severe COPD exacerbations H
Get ns rca rom
e Rate rate osc)
Favors eropoumab rép pacte
— —
Toxicon” néon Suge
FT
Ar garer va ai: mon 100000 2085,001 0056
ii cta drone mano SEC sue man ses costanera
O Que ae 2150 sm cs Boca (2000014
ÉD onaorpaton was def ae an DEC 230 cam 24016 0.48 0044190245)
‘exacerbation hat requred hosptalzaton (Sefned SCRA eta seo
‘Ss an patent admin of 224 hin to hospal, Overt 107408 29816230080)
inan observation area, the ED, or our equivalent "eo <tg0cetsnet. cos 1161 6610347
hoakhearefecity depending on Mo county and ec etsoetamat. are 2395110000)
Peer system) 803560 cana zuen ass, ann.
1. Singh Det Am I Resp On Caro Mad. 2028:20882782 PeerView

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26. Tezepelumab Delayed Time to First M
Exacerbation vs Placebo!

Results From Phase 2a
Tezepelumab Numerically Delayed the Time to

lerate or Severe COPD

COURSE
First Moderate or Severe COPD Exacerbation vs Placebo

+ 333 pis with pg 10
moderate to 3% 09 | tema oe e COREG)
very severe + aug | Patents witht exacerbation, 6) 709 23005 Piacabo (n= 168)
COPD dos
randomized ¿a Teure 420 mg 80 O4W (0 19)
1:1 to 25”
E
és 0
end y © Seo a ER En a a à «© à à à
bene ‚umal Time to First Moderate or Severe COPD Exacerbation, wk
placate > Tezepelumab Numerically Delayed the Time to First Severe COPD Exacerbation vs Placebo
2810
33 Hazard ratio (95% Ci) 0.70 036-132)
08 À wean. Ne
ln
z
eos
2 5 a Tompotama £20 mg Sc aa acabo m
as, u
e TE TORE TORE TE TORE à À à à +
Time to First Severe COPD Exacerbation, wk A
1 Singh Det ERS 2024 dos ió PeerView

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27. Other Ongoing Trials

Astegolimab

Phase 3 ongoing: NCT05878769, NCT05595642

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28. Asignificant unmet need exists in COPD management, including the need for targeted
therapies to address the underlying pathophysiology leading to disease progression,
such as type 2 inflammation

A need for biomarkers to help select patients who would most likely benefit from
these therapies is also needed

Dupilumab has been approved for treatment of COPD with type 2 inflammation since
July 2024 in Europe and since September 2024 in the United States and China
Several other biologic agents are currently under study

ew

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