Cross-Talk Between Lung and Liver in Alpha-1 Antitrypsin Deficiency: A Call for Integrated Care
PeerVoice
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Oct 20, 2025
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About This Presentation
Alice M. Turner, MBChB, PhD, Mattias Mandorfer, MD, PhD, and Franziska Trudzinski, MD, PhD, discuss alpha-1 antitrypsin deficiency in this IME activity titled "Cross-Talk Between Lung and Liver in Alpha-1 Antitrypsin Deficiency: A Call for Integrated Care." For the full presentation, pleas...
Slide Content
PeerVoice
Cross-Talk Between Lung and Liver in Alpha-1 Antitrypsin Deficiency:
A Call for Integrated Care
Learning Objectives
* Apply current guideline recommendations for timely testing and screening for
alpha-1 antitrypsin deficiency (AATD) to facilitate early diagnosis and
interventions
Identify best practices and practical strategies for the collaborative monitoring
and management of patients with AATD
Assess the phase 3 landscape of investigational therapies for the treatment of
liver disease associated with AATD
Supported by an educational grant from Takeda Pharmaceuticals USA, Inc.
www.peervoice.com/XSX870 Copyright © 2010-2026. Peer
Cross-Talk Between Lung and Liver in Alpha-1 Antitrypsin Deficiency:
A Call for Integrated Care
Learning Objectives
* Apply current guideline recommendations for timely testing and screening for
alpha-1 antitrypsin deficiency (AATD) to facilitate early diagnosis and
interventions
Identify best practices and practical strategies for the collaborative monitoring
and management of patients with AATD
Assess the phase 3 landscape of investigational therapies for the treatment of
liver disease associated with AATD
Supported by an educational grant from Takeda Pharmaceuticals USA, Inc.
www.peervoice.com/XSX870 Copyright © 2010-2026. Peer
PeerVoice
Part 1 of 5: Siloed vs Unite
The Case for Cross-Specialty Collaboration in AATD
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD, PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
Part 1 of 5: Siloed vs Unite
The Case for Cross-Specialty Collaboration in AATD
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD, PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Patient Case 1: 75-Year-Old Man With Pi*ZZ AATD and COPD
Under follow-up for lung FEV 115 L (35% predicted)
disease for >20 years FVC: 3.13 L (70% predicted)
+ PI*ZZ AATD with severe COPD - FEV/FVC ratio: 36%
+ TLCO:17% predicted
* KCO: 25% predicted
+ Left lower lobe endobronchial
al fblietion valve insertion in 2019
+ HF with reduced EF (LVEF: 40%) * Ambulatory oxygen
+ Prostate cancer
No additional risk factors for + Alcohol intake: + BMI: 22-25 kg/m?
AATD-associated liver disease O units/week + No metabolic disease
Comorbidities
‘AATD: alpha-1 antitrypsin deficiency; BMI: body mass index; COPD: chronic obstructive pulmonary disease; FEV: forced expiratory volume in | second; FVC: forced
vital capacity; HF: heart faro; KCO: carbon monoxide transfer coefficient; LVEF: lat ventricular ejection fraction; Pi*ZZ: protease inhibitor ZZ; TLCO: transfer factor
for carbon monoxide.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Patient Case 1: 75-Year-Old Man With Pi*ZZ AATD and COPD
Under follow-up for lung FEV 115 L (35% predicted)
disease for >20 years FVC: 3.13 L (70% predicted)
+ PI*ZZ AATD with severe COPD - FEV/FVC ratio: 36%
+ TLCO:17% predicted
* KCO: 25% predicted
+ Left lower lobe endobronchial
al fblietion valve insertion in 2019
+ HF with reduced EF (LVEF: 40%) * Ambulatory oxygen
+ Prostate cancer
No additional risk factors for + Alcohol intake: + BMI: 22-25 kg/m?
AATD-associated liver disease O units/week + No metabolic disease
Comorbidities
‘AATD: alpha-1 antitrypsin deficiency; BMI: body mass index; COPD: chronic obstructive pulmonary disease; FEV: forced expiratory volume in | second; FVC: forced
vital capacity; HF: heart faro; KCO: carbon monoxide transfer coefficient; LVEF: lat ventricular ejection fraction; Pi*ZZ: protease inhibitor ZZ; TLCO: transfer factor
for carbon monoxide.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Patient Case 1: 75-Year-Old Man With Pi*ZZ AATD and COPD
(Cont'd)
2018
Transient Elastography
| screening in pulmonary clinic
Liver stiffness: 99kPa_ + Bilirubin: 13 pmol/L. * Hb:162 g/L
AST: 41 U/L * ALP:81U/L + Plt: 135 x 10%/L
ALT: 38 U/L + GGT: 105 U/L + INR12
ELF score: 101
Referred to joint lung/liver clinic
Annual follow-up
US of liver > coarse echotexture
No features of decompensation
More recent overall decline, some weight loss, admissions with HF symptoms and
increase in exacerbations
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ELF: enhanced liver fibrosis; GGT: gamma-glutamyl transferase:
Hb: haemoglobin: INR: international normalised ratio; Pt: platelet count; US: ultrasound,
PeerVoice Activity; Alice M. Turner, MBChB, PhO; September 2025.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
Patient Case 1: 75-Year-Old Man With Pi*ZZ AATD and COPD
(Cont'd)
2018
Transient Elastography
| screening in pulmonary clinic
Liver stiffness: 99kPa_ + Bilirubin: 13 pmol/L. * Hb:162 g/L
AST: 41 U/L * ALP:81U/L + Plt: 135 x 10%/L
ALT: 38 U/L + GGT: 105 U/L + INR12
ELF score: 101
Referred to joint lung/liver clinic
Annual follow-up
US of liver > coarse echotexture
No features of decompensation
More recent overall decline, some weight loss, admissions with HF symptoms and
increase in exacerbations
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ELF: enhanced liver fibrosis; GGT: gamma-glutamyl transferase:
Hb: haemoglobin: INR: international normalised ratio; Pt: platelet count; US: ultrasound,
PeerVoice Activity; Alice M. Turner, MBChB, PhO; September 2025.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
PeerVoice
Patient Case 1: Other Analyses and Characteristics
Measurement [rosie [moana [ovoans [ronons [aura Jronuzz [ons panorzaasrovae beroaasJarcars
BM, kg/m? pass | 25m [2664 | - | 2ası | 2460 | 2472 | 2898 | 2248
[AST UL ala [a | |. a [a x [se [so [ao [ss [o [7 | «
AU x | ss [er | as [38 wz [2 || ss | a |s | a | « | 2s | 2 | 0
Bit), ymol/L. 0 [peda rn Ir sf[efsf[s fe lal fale fe |»
‘aL, U/L es ||» | a | 9 a |» |» |» [us | wo | wo | ve [ue | wos [m2
‘ear. uit 53 | so [os | eo | 100 nos | 98 wa we | ws | we | 14 | m4 | 101 | 202
‘ALB, g/t a | as [a | | TOESENESEHEBEIEHEIESE:
Hb, g/t 100 | wo | 168 | 101 12 wo | wr [wo | wr [wo [es | 152 | 102 | 105
Hb, rat 159
Pit, x10%7/L ve | we | me | we ns wo | sr | mo | ws | 107 [19 [us | 166 | 109
ine 12 v4 [u ve [iu [as lu
[AFP, U/mL 2 2 2 | 2
ALB: albumin; AFP: alpha-fetoprotein; BILE bilirubin.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Patient Case 1: Other Analyses and Characteristics
Measurement [rosie [moana [ovoans [ronons [aura Jronuzz [ons panorzaasrovae beroaasJarcars
BM, kg/m? pass | 25m [2664 | - | 2ası | 2460 | 2472 | 2898 | 2248
[AST UL ala [a | |. a [a x [se [so [ao [ss [o [7 | «
AU x | ss [er | as [38 wz [2 || ss | a |s | a | « | 2s | 2 | 0
Bit), ymol/L. 0 [peda rn Ir sf[efsf[s fe lal fale fe |»
‘aL, U/L es ||» | a | 9 a |» |» |» [us | wo | wo | ve [ue | wos [m2
‘ear. uit 53 | so [os | eo | 100 nos | 98 wa we | ws | we | 14 | m4 | 101 | 202
‘ALB, g/t a | as [a | | TOESENESEHEBEIEHEIESE:
Hb, g/t 100 | wo | 168 | 101 12 wo | wr [wo | wr [wo [es | 152 | 102 | 105
Hb, rat 159
Pit, x10%7/L ve | we | me | we ns wo | sr | mo | ws | 107 [19 [us | 166 | 109
ine 12 v4 [u ve [iu [as lu
[AFP, U/mL 2 2 2 | 2
ALB: albumin; AFP: alpha-fetoprotein; BILE bilirubin.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Patient Case 1: Transient Elastography Results
N T
auosne os/osne |owoshe Mons) 2110/21 | TO/ti/22)) 27/07/23 || 26/10/23 SION) [04/04/24] 13/02/25
|
Median
pr 92 - - ns na 10 - 167 - - 26
CAP, dB/m 274 - - 332 258 276 - 335 - - 239
CAP: controlled attenuation parameter.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Patient Case 1: Transient Elastography Results
N T
auosne os/osne |owoshe Mons) 2110/21 | TO/ti/22)) 27/07/23 || 26/10/23 SION) [04/04/24] 13/02/25
|
Median
pr 92 - - ns na 10 - 167 - - 26
CAP, dB/m 274 - - 332 258 276 - 335 - - 239
CAP: controlled attenuation parameter.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Pa
Proactive liver Lifestyle advice
assessment (zero alcohol, BMI)
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVaice
Pa
Proactive liver Lifestyle advice
assessment (zero alcohol, BMI)
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVaice
PeerVoice
Case complexities
What is causing his symptoms:
Heart, lung, or liver?
PeerVoice Activity; Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Case complexities
What is causing his symptoms:
Heart, lung, or liver?
PeerVoice Activity; Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Patient Case 1: Discussion (Cont'd)
Does multispecialty
Case complexities management really add to
his care?
Yes, addresses cirrhotic
decompensation as cause of
What is causing hi toms:
at is causing his symptoms: dyspnoea
Heart, lung, or liver?
X Unlikely to receive active
liver disease management
because of comorbidity
(cannot enter trials or have
therapy)
PeerVoice Activity; Alice M. Turner, MBChB, PhD; September 2028.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Patient Case 1: Discussion (Cont'd)
Does multispecialty
Case complexities management really add to
his care?
Yes, addresses cirrhotic
decompensation as cause of
What is causing hi toms:
at is causing his symptoms: dyspnoea
Heart, lung, or liver?
X Unlikely to receive active
liver disease management
because of comorbidity
(cannot enter trials or have
therapy)
PeerVoice Activity; Alice M. Turner, MBChB, PhD; September 2028.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Pa
nt Case
Id Man With COPD
Me
al History
+ Under long-term follow-up in the respiratory clinic for moderate-to-
severe COPD (FEV;: previously 60% predicted, now 45% predicted)
Alcohol intake: High (228 units/week)
(3 Transient Elasto;
phy
First transient elastography: 8 years into respiratory follow-up
» Median liver stiffness: 16 kPa
+ Prolonged period without referral to the hepatology clinic
At referral, transient elastography in the cirrhotic range > liver US
arranged > suspicious for HCC
HCC: hepatocellular carcinoma.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Pa
nt Case
Id Man With COPD
Me
al History
+ Under long-term follow-up in the respiratory clinic for moderate-to-
severe COPD (FEV;: previously 60% predicted, now 45% predicted)
Alcohol intake: High (228 units/week)
(3 Transient Elasto;
phy
First transient elastography: 8 years into respiratory follow-up
» Median liver stiffness: 16 kPa
+ Prolonged period without referral to the hepatology clinic
At referral, transient elastography in the cirrhotic range > liver US
arranged > suspicious for HCC
HCC: hepatocellular carcinoma.
PeerVoice Activity: Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
t Case
Missed opportunities
+ Lifestyle advice, more
aggressive/earlier
interventions for the liver
+ Transient elastography
screening to detect fibrosis
progression
+ US screening to detect HCC
PeerVoice Activity Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
t Case
Missed opportunities
+ Lifestyle advice, more
aggressive/earlier
interventions for the liver
+ Transient elastography
screening to detect fibrosis
progression
+ US screening to detect HCC
PeerVoice Activity Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
PeerVoice
Patient Case iscussion (Cont'd
Missed opportunities
Back to the case
+ Lifestyle advice, more
aggressive/earlier
interventions for the liver
+ Transient elastography
screening to detect fibrosis
progression
+ US screening to detect HCC
MRI used to characterise the
liver lesion
Patient returned for follow-
up > less than 10
units/week
Result: Fortunately showed
that it was not cancer
PeerVoice Activity Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
Patient Case iscussion (Cont'd
Missed opportunities
Back to the case
+ Lifestyle advice, more
aggressive/earlier
interventions for the liver
+ Transient elastography
screening to detect fibrosis
progression
+ US screening to detect HCC
MRI used to characterise the
liver lesion
Patient returned for follow-
up > less than 10
units/week
Result: Fortunately showed
that it was not cancer
PeerVoice Activity Alice M. Turner, MBChB, PhD; September 2025.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
PeerVoice
Part 2 of 5: Shifting the Paradigm to Proactive Screening of AAT!
Amplifying the Impact of Every AATD Diagnosis
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
Part 2 of 5: Shifting the Paradigm to Proactive Screening of AAT!
Amplifying the Impact of Every AATD Diagnosis
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Who Should Be Tested for AATD?
oy) Alpha-1 Foundation: Summary of Recommendations
Should be tested:
with polyangiitis, or unexplained bronchiectasis
Parents, siblings, and children, as well as extended family of individuals identified with an
abnormal gene for AAT, should be provided genetic counselling and offered testing for AATD
‘AAT: alpha-lantitrypsin,
Sandhaus RA ot al. Chronic Obstr Pulm Dis. 2016;3:668-682.
om/XSX870 Copyright © 2010-2025, PeerVoice
Who Should Be Tested for AATD?
oy) Alpha-1 Foundation: Summary of Recommendations
Should be tested:
with polyangiitis, or unexplained bronchiectasis
Parents, siblings, and children, as well as extended family of individuals identified with an
abnormal gene for AAT, should be provided genetic counselling and offered testing for AATD
‘AAT: alpha-lantitrypsin,
Sandhaus RA ot al. Chronic Obstr Pulm Dis. 2016;3:668-682.
om/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Allergies
Emphysema
Cazzola M et al. Eur Respir Rev. 2020;20(155):190079.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
Allergies
Emphysema
Cazzola M et al. Eur Respir Rev. 2020;20(155):190079.
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
PeerVoice
Impact of Diagnostic Delay
Multivariable Analysis of Overall Survival (Austrian Alpha-1 Lung Registry)
Variable HR (65% CI P
iagnostic delay, y; continuous 161(109-2:38) 016
[BMI kg/m?; continuous 086 (073-100) 049
Age, y; continuous 107 (102-112) 008
‘Active smoking at time of inclusion in registry
No 100 006
Yes 1184 (202-6583)
FEV, in % of expected value
>50 100 2a
«50 3.23 (083-1538)
Long-term oxygen therapy at inclusion in registry
No 100 107
Yes 2.33 (083-650)
A longer diagnostic delay was significantly associated with worse survival
Meischi T et al Respir Res. 2023:24(1):34,
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Impact of Diagnostic Delay
Multivariable Analysis of Overall Survival (Austrian Alpha-1 Lung Registry)
Variable HR (65% CI P
iagnostic delay, y; continuous 161(109-2:38) 016
[BMI kg/m?; continuous 086 (073-100) 049
Age, y; continuous 107 (102-112) 008
‘Active smoking at time of inclusion in registry
No 100 006
Yes 1184 (202-6583)
FEV, in % of expected value
>50 100 2a
«50 3.23 (083-1538)
Long-term oxygen therapy at inclusion in registry
No 100 107
Yes 2.33 (083-650)
A longer diagnostic delay was significantly associated with worse survival
Meischi T et al Respir Res. 2023:24(1):34,
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Benefit of Screening: Survival in Persons With Severe Pi*ZZ
(Swedish National AATD Registry)
Screened cases
3
Never smokers
zos Fos
a Nonrespiratory 2
2 06 cases 8 06
E E
3 04 Respiratory cases 3 04
3 2 Opportunity for
a 02 a 02 i lifestyle
interventions
00 00
0 2 4 6 8 10 12 4 6 18 0 2 4 6 8 10 1 4 16 18
Follow-Up Time, y Follow-Up Time, y
Tanash HA et al Respir Res. 2010:1(1):44,
www.peervoice.com/XSX870 Copyright © 2010-2025,
Benefit of Screening: Survival in Persons With Severe Pi*ZZ
(Swedish National AATD Registry)
Screened cases
3
Never smokers
zos Fos
a Nonrespiratory 2
2 06 cases 8 06
E E
3 04 Respiratory cases 3 04
3 2 Opportunity for
a 02 a 02 i lifestyle
interventions
00 00
0 2 4 6 8 10 12 4 6 18 0 2 4 6 8 10 1 4 16 18
Follow-Up Time, y Follow-Up Time, y
Tanash HA et al Respir Res. 2010:1(1):44,
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PeerVoice
Benefits of Diagnosis
Consider
initiation of
augmentation
therapy for
pulmonary
disease
Referrals to
hepatology
‘Adapted from Cazzola M et al Eur Respir Rev. 2020:29(155):190073.
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Benefits of Diagnosis
Consider
initiation of
augmentation
therapy for
pulmonary
disease
Referrals to
hepatology
‘Adapted from Cazzola M et al Eur Respir Rev. 2020:29(155):190073.
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PeerVoice
Monitoring Approach for AATD-Associated Liver Disease:
Expert Delphi Panel
Referral rom general practitioners, Known family history or geno/phenotype
Pulmonologists, or other specialists testing results indicating AATD
Hepatologist/gastroenterologist for hepatological evaluation® to.
establish diagnosis of AATD-LD, patient and family education,
‘and to stage disease and plan monitoring,
Re-evaluation in 2 VCTE 213 kPa or clear biochemical or
onda... VOTE <okPa + VOTE 28-18 kPa a ee
‘advanced liver disease
Consider additional
INTs (MRE, ELF) or liver Increased vigilance and
biopsy if discordant a Ko __ frequency of monitoring and
results from 2 or moro. MELD score >16 or management of cirhosis
Nits End core
are perra oy any ic prior o patos er or experi: es Consider ver transplant
AATD-LO: AATD-associated liver disease; MELO: model for end-stage liver disease; MRE: magnetic resonance elastography; NIT: non-interventional test;
CTE: vibration-controlled transient elastography.
Clark VC et al. United European Gastroenterol J, 2025 Mar 12 [Epub ahead of print] DO 10:1002/u2g2 70008.
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Monitoring Approach for AATD-Associated Liver Disease:
Expert Delphi Panel
Referral rom general practitioners, Known family history or geno/phenotype
Pulmonologists, or other specialists testing results indicating AATD
Hepatologist/gastroenterologist for hepatological evaluation® to.
establish diagnosis of AATD-LD, patient and family education,
‘and to stage disease and plan monitoring,
Re-evaluation in 2 VCTE 213 kPa or clear biochemical or
onda... VOTE <okPa + VOTE 28-18 kPa a ee
‘advanced liver disease
Consider additional
INTs (MRE, ELF) or liver Increased vigilance and
biopsy if discordant a Ko __ frequency of monitoring and
results from 2 or moro. MELD score >16 or management of cirhosis
Nits End core
are perra oy any ic prior o patos er or experi: es Consider ver transplant
AATD-LO: AATD-associated liver disease; MELO: model for end-stage liver disease; MRE: magnetic resonance elastography; NIT: non-interventional test;
CTE: vibration-controlled transient elastography.
Clark VC et al. United European Gastroenterol J, 2025 Mar 12 [Epub ahead of print] DO 10:1002/u2g2 70008.
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PeerVoice
Assessment and Monitoring of Lung Disease in
Patients With AATD: Expert Delphi Panel
Agreement Weighted
Category Statement love aerea
Liver tests — All patients with AATD should undergo liver functions tests annually Agreement 58
Al patents should be referred t aliverspeciat folowing a legnosis | Agreement 50
‘Other All patients with AATD should be asked about:
monitoring Antibiotics and/or systemic corticosteroids used for an exacerbation Consensus 68
Meere An occurrence of pneumonia since last visit/during last 12 months Consensus 69
and amoking An emergency room visit/hospitalisation for any respiratory disease
states ing exacerbation (COPD, asthma, bronchiectasis, etc) since last visit/during last Consensus 69
12 months
‘Change in smoking status Consensus 68
Exposure to environmental tobacco smoke Consensus 686
Exposure to environmental factors requiring treatment (eg at work, indoor
pee Consensus 66
COPD recommendations, eg, GOLD strategy, should always be followedin all Agreement 5.8
patients with AATO in relation to use of LABA/LAMAJICS
Weighted average score 0.0-2.0- consensus in negative; 21-3.0: agreement in negative; 3-4.
50-59: agreement; 26.0: consensus.
‘consensus or agreement;
GOLD: Global Initiative for Chronic Obstructive Lung Disease; ICS: inhaled corticosteroids; LABA: long-acting beta agonist; LAMA: long-acting musc:
antagonist
Miravitles M et al Respir Res. 2024:25(1:318.
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Assessment and Monitoring of Lung Disease in
Patients With AATD: Expert Delphi Panel
Agreement Weighted
Category Statement love aerea
Liver tests — All patients with AATD should undergo liver functions tests annually Agreement 58
Al patents should be referred t aliverspeciat folowing a legnosis | Agreement 50
‘Other All patients with AATD should be asked about:
monitoring Antibiotics and/or systemic corticosteroids used for an exacerbation Consensus 68
Meere An occurrence of pneumonia since last visit/during last 12 months Consensus 69
and amoking An emergency room visit/hospitalisation for any respiratory disease
states ing exacerbation (COPD, asthma, bronchiectasis, etc) since last visit/during last Consensus 69
12 months
‘Change in smoking status Consensus 68
Exposure to environmental tobacco smoke Consensus 686
Exposure to environmental factors requiring treatment (eg at work, indoor
pee Consensus 66
COPD recommendations, eg, GOLD strategy, should always be followedin all Agreement 5.8
patients with AATO in relation to use of LABA/LAMAJICS
Weighted average score 0.0-2.0- consensus in negative; 21-3.0: agreement in negative; 3-4.
50-59: agreement; 26.0: consensus.
‘consensus or agreement;
GOLD: Global Initiative for Chronic Obstructive Lung Disease; ICS: inhaled corticosteroids; LABA: long-acting beta agonist; LAMA: long-acting musc:
antagonist
Miravitles M et al Respir Res. 2024:25(1:318.
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PeerVoice
Who S$! Id Be Tested for AATD?
Alpha-1 Foundation: Summary of Recommendations
"TI
For family testing after a proband is identified, AAT level testing alone is not
recommended because it does not fully characterise disease risk from AATD
Sandhaus RA ot al. Chronic Obstr Pulm Dis. 2016:3:668-682.
Copyright © 2010-2025, PeerVoice
Who S$! Id Be Tested for AATD?
Alpha-1 Foundation: Summary of Recommendations
"TI
For family testing after a proband is identified, AAT level testing alone is not
recommended because it does not fully characterise disease risk from AATD
Sandhaus RA ot al. Chronic Obstr Pulm Dis. 2016:3:668-682.
Copyright © 2010-2025, PeerVoice
PeerVoice
Algorithm for Familial Testing for AATD: ERS
Check partner « » Check siblings
| Monitor | As for index Check partner
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Check children
*Test parents (if available) if a null gene is suspected.
ERS: European Respiratory Society.
Miravitles M et al Eur Respir J. 2017:50(5)1700610.
Algorithm for Familial Testing for AATD: ERS
Check partner « » Check siblings
| Monitor | As for index Check partner
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Check children
*Test parents (if available) if a null gene is suspected.
ERS: European Respiratory Society.
Miravitles M et al Eur Respir J. 2017:50(5)1700610.
PeerVoice
Association of the Pi*Z Variant With Clinical
Liver-Related Outcomes
Cumulative Incidence Estimate of Liver-Related Outcomes
m10 years m20 years
PiMZ carriers Noncarriers
Analysis of Finnish population cohorts (FINRISK 1992-2012 and Health 2000) with registry follow-up through 2015. The cohort
included 1198 heterozygous Pi»Z carriers and 32,564 noncarriers (mean age 49.6 years; 53.5% women). Over a median follow-
up of 129 years, 281 liver-related events (hospitalisation, cancer, or death) and 3,457 non-liver-related deaths were observed.
Luukkonen PK et al. Gastroenterology. 2021160874-1875,
Incidence, %
= » PB
55065
oo
oa
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Association of the Pi*Z Variant With Clinical
Liver-Related Outcomes
Cumulative Incidence Estimate of Liver-Related Outcomes
m10 years m20 years
PiMZ carriers Noncarriers
Analysis of Finnish population cohorts (FINRISK 1992-2012 and Health 2000) with registry follow-up through 2015. The cohort
included 1198 heterozygous Pi»Z carriers and 32,564 noncarriers (mean age 49.6 years; 53.5% women). Over a median follow-
up of 129 years, 281 liver-related events (hospitalisation, cancer, or death) and 3,457 non-liver-related deaths were observed.
Luukkonen PK et al. Gastroenterology. 2021160874-1875,
Incidence, %
= » PB
55065
oo
oa
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PeerVoice
Family Members Could Be at Risk for COPD
Family-based study to determine the risk of COPD in Pi*MZ individuals
Genotype
Pi*MM (n = 99) *MZ (n = 89)
FEV,/FVC, median (IQR)
Never smoker 081 (0.75-0.85) 077 (073-083) NS
Ever smoker 077 (072-081) 071(0.58-0.77) 0013
FEV, % predicted, median (IQR)
Never smoker 1013 (887-106) 102.2 (88.3-108.4) NS
Ever smoker 94.8 (821-102.4) 82.3 (631-94.4) 0009
FEF 254-75, Predicted, median (IQR)
Never smoker 841(707-100.8) 76.1 (63.6-99.4) Ns
Ever smoker 64.8 (52.2-90.2) 477 (227-668) 0002
FEF. rox forced expiratory low at 25~75% of FVC; NS: not significant, IQR: interquartile range.
MeElvaney NG. Eur Respir Rev. 2015:24:52-57. Molloy K et al Am J Respir Crit Care Med, 2014 189-419-427.
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Family Members Could Be at Risk for COPD
Family-based study to determine the risk of COPD in Pi*MZ individuals
Genotype
Pi*MM (n = 99) *MZ (n = 89)
FEV,/FVC, median (IQR)
Never smoker 081 (0.75-0.85) 077 (073-083) NS
Ever smoker 077 (072-081) 071(0.58-0.77) 0013
FEV, % predicted, median (IQR)
Never smoker 1013 (887-106) 102.2 (88.3-108.4) NS
Ever smoker 94.8 (821-102.4) 82.3 (631-94.4) 0009
FEF 254-75, Predicted, median (IQR)
Never smoker 841(707-100.8) 76.1 (63.6-99.4) Ns
Ever smoker 64.8 (52.2-90.2) 477 (227-668) 0002
FEF. rox forced expiratory low at 25~75% of FVC; NS: not significant, IQR: interquartile range.
MeElvaney NG. Eur Respir Rev. 2015:24:52-57. Molloy K et al Am J Respir Crit Care Med, 2014 189-419-427.
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PeerVoice
Part 3 of insuring No Liver Disease Goes Unnoticed:
Tangible Tips From Our Hepatology Colleagues
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
Part 3 of insuring No Liver Disease Goes Unnoticed:
Tangible Tips From Our Hepatology Colleagues
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Individuals With the Pi*ZZ Genotype Are Susceptible to Lung
and Liver Damage
Pi*MM genotype Pi*ZZ genotype
+ Z-AAT misfolds and
polymerises in the liver
+ Z-AAT polymers are
Blood also present in the
vessel :
\ serum and in the lungs
1
aww 1 e _ Z-AKT monomer
ART
1 a Z-AAT polymer
Foil KE. Ther Adv Chronic Dis. 20212(Suppl}33-48. Saltini C, Krotova K. In: Strnad P et al, eds. af-Antitrypsin Deficiency (ERS Monograph). Sheffield, European
Respiratory Society. 2019;82-63. Stinad P et al N Engl J Med. 2020;382:1443-1455, Teckman JH. COPD. 2013;10(Suppl 35-43.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Individuals With the Pi*ZZ Genotype Are Susceptible to Lung
and Liver Damage
Pi*MM genotype Pi*ZZ genotype
+ Z-AAT misfolds and
polymerises in the liver
+ Z-AAT polymers are
Blood also present in the
vessel :
\ serum and in the lungs
1
aww 1 e _ Z-AKT monomer
ART
1 a Z-AAT polymer
Foil KE. Ther Adv Chronic Dis. 20212(Suppl}33-48. Saltini C, Krotova K. In: Strnad P et al, eds. af-Antitrypsin Deficiency (ERS Monograph). Sheffield, European
Respiratory Society. 2019;82-63. Stinad P et al N Engl J Med. 2020;382:1443-1455, Teckman JH. COPD. 2013;10(Suppl 35-43.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Individuals With the Pi*ZZ Genotype Are Susceptible to Lung
and Liver Damage (Cont'd)
Pi*MM genotype H Pi*ZZ genotype
—6%
Z-AAT polymers accumulate
in the liver and may cause
liver damage such as fibrosis,
cirrhosis, or HCC
we
Foil KE. Ther Adv Chronic Dis. 202112(Suppi} 33-48. Strnad P et al N Eng! J Med. 2020;382:1443-1486, Teckman JH. COPD. 2013:10(Suppl1) 35-43.
Z-AAT monomer
© viie-typ0 Saw EMT polymer
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Individuals With the Pi*ZZ Genotype Are Susceptible to Lung
and Liver Damage (Cont'd)
Pi*MM genotype H Pi*ZZ genotype
—6%
Z-AAT polymers accumulate
in the liver and may cause
liver damage such as fibrosis,
cirrhosis, or HCC
we
Foil KE. Ther Adv Chronic Dis. 202112(Suppi} 33-48. Strnad P et al N Eng! J Med. 2020;382:1443-1486, Teckman JH. COPD. 2013:10(Suppl1) 35-43.
Z-AAT monomer
© viie-typ0 Saw EMT polymer
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Impact of the Pi*Z Genotype on Serum Levels of AAT
60 + --- Lower limit of normal: 90 mg/dL (-17 LM) | 300 $
a 7: i — Protective threshold: 11 uM (~50 mg/dl) 5
AN Potymerisation | Aggregetion in § 50 250 >
… Propensity Hepatocytes: 3 >
Wil Noni qe =
type © 2 8
Maar | No Eso wo À
Misfoldea 2 | En En:
Yes E A lisis re oes
@ =” | qn &
Misfolded S- Moderate, | 3
err fel. |b A
MM MZ ss sz zz NullNull E
Risk of emphysema No Verylow Verylow Low High Veryhigh
Risk of liver disease No Possibly No Possibly High No
Brode Sk et al. CMAJ. 2012184:1365-1371 Lomas DA et al In: Strnad P et al, eds. af-Antitrypsin Deficiency (ERS Monograph), Sheffield. European Respiratory
Society. 2019:6-26. Strnad P et al. N Eng! J Med. 2020;382:1443-1455,
www.peervoice.com/XSX870 Copyright © 2010-2025, Peer
Impact of the Pi*Z Genotype on Serum Levels of AAT
60 + --- Lower limit of normal: 90 mg/dL (-17 LM) | 300 $
a 7: i — Protective threshold: 11 uM (~50 mg/dl) 5
AN Potymerisation | Aggregetion in § 50 250 >
… Propensity Hepatocytes: 3 >
Wil Noni qe =
type © 2 8
Maar | No Eso wo À
Misfoldea 2 | En En:
Yes E A lisis re oes
@ =” | qn &
Misfolded S- Moderate, | 3
err fel. |b A
MM MZ ss sz zz NullNull E
Risk of emphysema No Verylow Verylow Low High Veryhigh
Risk of liver disease No Possibly No Possibly High No
Brode Sk et al. CMAJ. 2012184:1365-1371 Lomas DA et al In: Strnad P et al, eds. af-Antitrypsin Deficiency (ERS Monograph), Sheffield. European Respiratory
Society. 2019:6-26. Strnad P et al. N Eng! J Med. 2020;382:1443-1455,
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PeerVoice
Interpreting Liver Enzymes (GGT, AST, ALT), FIB-4, and APRI
GGT, ALT, and AST can be elevated in individuals with Pi
eee oe
In population studies, elevations were only found in 11% to 24% of t 1 t t t
participants, although liver fibrosis was reported in up to 30% of
participants
Repeated elevated liver enzymes are associated with an increased risk of
developing liver disease in individuals with Pi*ZZ (7.6x increase in risk)
AAPRE AST to platelet ratio index: FIB-4:fibrosis-4 index; LFT: liver function test.
Clark VC etal. J Hepatol 2018;681357-1364, Fromme Met al Gut. 2022.71415-429. Homesch Ket al Gastroenterology. 2019157705-T9:1.
Tanash HA et al Gastroenterol, 2019:54:541-548, Personal Communication; Mattias Mandorter, MD, PhD: September 2025,
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
Interpreting Liver Enzymes (GGT, AST, ALT), FIB-4, and APRI
GGT, ALT, and AST can be elevated in individuals with Pi
eee oe
In population studies, elevations were only found in 11% to 24% of t 1 t t t
participants, although liver fibrosis was reported in up to 30% of
participants
Repeated elevated liver enzymes are associated with an increased risk of
developing liver disease in individuals with Pi*ZZ (7.6x increase in risk)
AAPRE AST to platelet ratio index: FIB-4:fibrosis-4 index; LFT: liver function test.
Clark VC etal. J Hepatol 2018;681357-1364, Fromme Met al Gut. 2022.71415-429. Homesch Ket al Gastroenterology. 2019157705-T9:1.
Tanash HA et al Gastroenterol, 2019:54:541-548, Personal Communication; Mattias Mandorter, MD, PhD: September 2025,
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
PeerVoice
sociated Liver Disease
No
-Invasive Monitoring of AAT!
II
+ VCTE is the most used non- + Traditional ultrasound can be
invasive technique for first time used in monitoring a patient
evaluation with AATD-associated liver
+ MRE is highly sensitive and disease but it has limited
specific for detection of sensitivity for fibrosis
advanced fibrosis, but limited + Main imaging tool used for HCC
due to cost and availability monitoring and evaluation
Clark VC et al. United European Gastroenterol . 2025 Mar 12. [Epub ahead of print] DOI: 10:1002/u08270008,
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sociated Liver Disease
No
-Invasive Monitoring of AAT!
II
+ VCTE is the most used non- + Traditional ultrasound can be
invasive technique for first time used in monitoring a patient
evaluation with AATD-associated liver
+ MRE is highly sensitive and disease but it has limited
specific for detection of sensitivity for fibrosis
advanced fibrosis, but limited + Main imaging tool used for HCC
due to cost and availability monitoring and evaluation
Clark VC et al. United European Gastroenterol . 2025 Mar 12. [Epub ahead of print] DOI: 10:1002/u08270008,
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PeerVoice
NITs for Risk Stratification and Staging
Fibrosis Stage
rom [rom] F2 | rs | Fa Fafeirhosis
to
sian] 2 | Fa | Fa | Fe NA
ress) Probable cACLD EACLD
NA SPH unlikely | Probable GSP [CSP
A
22
58
22
25
=o
CE
26
28
E
Ed
se © 5 25
LSM by VCTE (kPa)
Image provided courtesy of Mattias Mandorfer, MD, PhD; September 2025,
CAGLD: compensated advanced chronic liver disease: CSPH: chronically significant portal hypertension; LSM: iver stiffness measurement.
European Association for the Study of the Liver. J Hepatol. 202175:659-689. Papatheodoridi M et al J Hepatol. 2021:74:109-1M6, de Franchis R et al. J Hepatol
2022:76:959-974, Strnad P et alin: Strnad P et al eds. aT-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society. 2019:14-126. Hamesch
K Stenad P. Chronic Obstr Pulm Dis. 2020;7.260-271
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Copyright © 2010-2025, Peer
NITs for Risk Stratification and Staging
Fibrosis Stage
rom [rom] F2 | rs | Fa Fafeirhosis
to
sian] 2 | Fa | Fa | Fe NA
ress) Probable cACLD EACLD
NA SPH unlikely | Probable GSP [CSP
A
22
58
22
25
=o
CE
26
28
E
Ed
se © 5 25
LSM by VCTE (kPa)
Image provided courtesy of Mattias Mandorfer, MD, PhD; September 2025,
CAGLD: compensated advanced chronic liver disease: CSPH: chronically significant portal hypertension; LSM: iver stiffness measurement.
European Association for the Study of the Liver. J Hepatol. 202175:659-689. Papatheodoridi M et al J Hepatol. 2021:74:109-1M6, de Franchis R et al. J Hepatol
2022:76:959-974, Strnad P et alin: Strnad P et al eds. aT-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society. 2019:14-126. Hamesch
K Stenad P. Chronic Obstr Pulm Dis. 2020;7.260-271
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PeerVoice
How Often Should Monitoring Be Done?
Initial Evaluation
Referral to a hepatologist and use of
laboratory measures, LSM, and
ultrasound
Frequency of Liver Monitoring
Frequency of evaluation of patients
with AATD-associated liver disease is
based on LSM:
+ Lower LSM: Every 2-3 years
+ Higher LSM: Every 6-12 months
Description
Fibrosis
Level
Severity of
Fibrosis
No fibrosis/no scarring,
Portal tract fibrosis.
without septa formation/
minimal scarring
Porta tract brosis with
introquent/raro sopta
formation (searing
around vessels within
the liver)
Numerous septa, but no
cirrhosis (bridging
fibrosis)
Girrhosis/advanced
scarring
FO
A
F2
F3
Fa
Mild to moderate
fibrosis,
Significant
fibrosis
Severe/
‘advanced
fibrosis
Clark VC et al. United European Gastroenterol J. 2026 Mar 12. [Epub ahead of print] DOI: 10:1002/ueg2.70009. Chowdhury AB, Mehta Ki. Clin Exp Med. 2023:28:273-
285,
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How Often Should Monitoring Be Done?
Initial Evaluation
Referral to a hepatologist and use of
laboratory measures, LSM, and
ultrasound
Frequency of Liver Monitoring
Frequency of evaluation of patients
with AATD-associated liver disease is
based on LSM:
+ Lower LSM: Every 2-3 years
+ Higher LSM: Every 6-12 months
Description
Fibrosis
Level
Severity of
Fibrosis
No fibrosis/no scarring,
Portal tract fibrosis.
without septa formation/
minimal scarring
Porta tract brosis with
introquent/raro sopta
formation (searing
around vessels within
the liver)
Numerous septa, but no
cirrhosis (bridging
fibrosis)
Girrhosis/advanced
scarring
FO
A
F2
F3
Fa
Mild to moderate
fibrosis,
Significant
fibrosis
Severe/
‘advanced
fibrosis
Clark VC et al. United European Gastroenterol J. 2026 Mar 12. [Epub ahead of print] DOI: 10:1002/ueg2.70009. Chowdhury AB, Mehta Ki. Clin Exp Med. 2023:28:273-
285,
www.peervoice.com/XSX870
Copyright © 2010-2025, PeerVoice
PeerVoice
When to Refer?
“Recommendations
include starting with a
referral to a
gastroenterologist or
hepatologist for
evaluation of
underlying liver
disease and fibrosis
staging with VCTE”
pr
‘ade om perl pescar. ono nero gehen
Peach nung A
Peer er te
ons a pa ten na
Rome | voran mr Fine veri
= cnn
Cerca sons
= in, RARE
= Bee Face y
y Lee, Melb co ier
Clark VC et al. United European Gastroenterol J, 2025 Mar 1. [Epub ahead of print] DOI: 10:1002/u0g2.70008.
www.peervoice.com/XSX870
Copyright © 2010-2025,
When to Refer?
“Recommendations
include starting with a
referral to a
gastroenterologist or
hepatologist for
evaluation of
underlying liver
disease and fibrosis
staging with VCTE”
pr
‘ade om perl pescar. ono nero gehen
Peach nung A
Peer er te
ons a pa ten na
Rome | voran mr Fine veri
= cnn
Cerca sons
= in, RARE
= Bee Face y
y Lee, Melb co ier
Clark VC et al. United European Gastroenterol J, 2025 Mar 1. [Epub ahead of print] DOI: 10:1002/u0g2.70008.
www.peervoice.com/XSX870
Copyright © 2010-2025,
PeerVoice
Part 4 of ooking Beyond the Lung:
Surveying the Investigational Landscape for AATD-Associated
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
Part 4 of ooking Beyond the Lung:
Surveying the Investigational Landscape for AATD-Associated
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Ongoing Trials in AATD
Organ Agent Mechanism of Action test Trial PI
Fazirsiran ‘Small interfering RNA Phase 3 (NCTO5677971)
Liver
smn-349 | Smallmoleculo chaperone for | phase y (NCTO6738017)
BEAM-302 | DNA editing (lipid nanoparticle) | Phase 1/2 (NCT06389877)
Lung and 7 7 Phase 1b/2a
bey WVE-006 | RNA editing oligonucleotide ER
KRRO-10 | RNA editing oligonucleotide | Phase 1/28 (NCT06677307)
inhaled AAT | _AAT protein replacement Phase 3 (NCT04204252)
INBRX=101/ a
SO) | AAT protein replacement Phase 2 (NCTO5897424)
Lung Alvelestat | Neutrophil elastase inhibitor | Phase 2 (NCTO3679598)
Gene therapy (non-integrating
KB-408 herpes simplex virus type! | Phase 1 (NCTO6049082)
vector)
See clinicaltrials gov for more information.
www.peervoice.com/XSX870
Scan the QR code
to access
clinicaltrials.gov
for more
information
Copyright © 2010-2025, PeerVoice
Ongoing Trials in AATD
Organ Agent Mechanism of Action test Trial PI
Fazirsiran ‘Small interfering RNA Phase 3 (NCTO5677971)
Liver
smn-349 | Smallmoleculo chaperone for | phase y (NCTO6738017)
BEAM-302 | DNA editing (lipid nanoparticle) | Phase 1/2 (NCT06389877)
Lung and 7 7 Phase 1b/2a
bey WVE-006 | RNA editing oligonucleotide ER
KRRO-10 | RNA editing oligonucleotide | Phase 1/28 (NCT06677307)
inhaled AAT | _AAT protein replacement Phase 3 (NCT04204252)
INBRX=101/ a
SO) | AAT protein replacement Phase 2 (NCTO5897424)
Lung Alvelestat | Neutrophil elastase inhibitor | Phase 2 (NCTO3679598)
Gene therapy (non-integrating
KB-408 herpes simplex virus type! | Phase 1 (NCTO6049082)
vector)
See clinicaltrials gov for more information.
www.peervoice.com/XSX870
Scan the QR code
to access
clinicaltrials.gov
for more
information
Copyright © 2010-2025, PeerVoice
PeerVoice
SEQUOIA Phase 2 Trial: Fazirsiran vs Placebo
Placebo (n = 14) Open-label
Fazirsiran 25 mg (n = 9) extension
Fazirsiran 100 mg (n = 8) de
Fazirsiran 200 mg (n = 9) QI2W
has ee à à 4
Paired biopsies cut-off
(hovesis ony) 2 +
FE
| Fibrosis
{No fibrosis °°
‘ Patients with fibrosi
QHW every 12 weeks.
Clark VC et al. Gastroenterology. 2024:1671008-1018.05.
www.peervoice.com/XSX870 Copyright © 2010-2025,
SEQUOIA Phase 2 Trial: Fazirsiran vs Placebo
Placebo (n = 14) Open-label
Fazirsiran 25 mg (n = 9) extension
Fazirsiran 100 mg (n = 8) de
Fazirsiran 200 mg (n = 9) QI2W
has ee à à 4
Paired biopsies cut-off
(hovesis ony) 2 +
FE
| Fibrosis
{No fibrosis °°
‘ Patients with fibrosi
QHW every 12 weeks.
Clark VC et al. Gastroenterology. 2024:1671008-1018.05.
www.peervoice.com/XSX870 Copyright © 2010-2025,
PeerVoice
SEQUOIA Phase 2 Trial: Primary Endpoint
—- Fazirsiran 25 mg -0- Fazirsiran 100 mg -®-Fazirsiran 200 mg -@- Placebo
40 Primary endpoint: Week 16 Week 48
(n= 40) (n= 25)
in Serum Z-AAT pg/mL, %
8
-40
-60 74%
a es
-90%
Mean (SD) Percentage Change
0.4 8 2 16 20 24 28 32 36 40 44 48 52
FE # # # 1
Bio
“P < 0001 (refer to publication for more detail). Study Visit, wk Be
SD: standard deviation; Z-AAT: mutant AAT.
Clark VC et al. Gastroenterology. 2024:1671008-1018.05.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
SEQUOIA Phase 2 Trial: Primary Endpoint
—- Fazirsiran 25 mg -0- Fazirsiran 100 mg -®-Fazirsiran 200 mg -@- Placebo
40 Primary endpoint: Week 16 Week 48
(n= 40) (n= 25)
in Serum Z-AAT pg/mL, %
8
-40
-60 74%
a es
-90%
Mean (SD) Percentage Change
0.4 8 2 16 20 24 28 32 36 40 44 48 52
FE # # # 1
Bio
“P < 0001 (refer to publication for more detail). Study Visit, wk Be
SD: standard deviation; Z-AAT: mutant AAT.
Clark VC et al. Gastroenterology. 2024:1671008-1018.05.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
SEQUOIA Phase 2 Trial: Secondary Endpoint
Change From Baseline in Total Liver Z-AAT Concentra
240
220
200
180
160
140
120
100
80
60
40
20
o
-20
-40
-60
-80
-100
Percentage Change From Baseline, %
Clark VC et al. Gastroenterology. 2024;1671008-1018.05.
www.peervoice.com/XSX870
Median (0103)
n at Post-Dose Biopsy
Medien (1.05) ve 587 247 En
ae (288,1152) | (413.1694) | (68.0040) (087-332)
LS mean & dtference 29% ry wae
(95% Ci) vs placebo = | te2osmro-s3x) | (-202% 10-46%) | (-208% 19-76%)
atpost-doce biopsy P=.0021 P= 0085 92.0002
Copyright © 2010-2025, PeerVoice
SEQUOIA Phase 2 Trial: Secondary Endpoint
Change From Baseline in Total Liver Z-AAT Concentra
240
220
200
180
160
140
120
100
80
60
40
20
o
-20
-40
-60
-80
-100
Percentage Change From Baseline, %
Clark VC et al. Gastroenterology. 2024;1671008-1018.05.
www.peervoice.com/XSX870
Median (0103)
n at Post-Dose Biopsy
Medien (1.05) ve 587 247 En
ae (288,1152) | (413.1694) | (68.0040) (087-332)
LS mean & dtference 29% ry wae
(95% Ci) vs placebo = | te2osmro-s3x) | (-202% 10-46%) | (-208% 19-76%)
atpost-doce biopsy P=.0021 P= 0085 92.0002
Copyright © 2010-2025, PeerVoice
PeerVoice
EQUOIA Phase 2 Trial: Additional Findings
Im Baseline mm Post-dose biopsy
$0176 so213 60
sol224
x 50
¢ 40
30
soj224 6
10
o
Placebo Fazirsiran Portal inflammation Interface hepatitis
improved” improved
BO ©
Patient:
Mean (SD) PAS+D
Globule Burden Score
o
Fazirsiran was associated with a more favourable improvement' 21-point improvement in 50% of patients
in fibrosis score compared with placebo with fazirsiran vs 38% with placebo.
+ Patients with adjudicated fibrosis of at least Flat baseline.» Patients with a baseline score of more than O.
PAS+D: periodic acid-Schiff staining with diostase digestion
Clark VC et al. Gastroenterology. 2024;1671008-1018.65.
www.peervoice.com/XSX870 Copyright © 2010-2025,
erVeice
EQUOIA Phase 2 Trial: Additional Findings
Im Baseline mm Post-dose biopsy
$0176 so213 60
sol224
x 50
¢ 40
30
soj224 6
10
o
Placebo Fazirsiran Portal inflammation Interface hepatitis
improved” improved
BO ©
Patient:
Mean (SD) PAS+D
Globule Burden Score
o
Fazirsiran was associated with a more favourable improvement' 21-point improvement in 50% of patients
in fibrosis score compared with placebo with fazirsiran vs 38% with placebo.
+ Patients with adjudicated fibrosis of at least Flat baseline.» Patients with a baseline score of more than O.
PAS+D: periodic acid-Schiff staining with diostase digestion
Clark VC et al. Gastroenterology. 2024;1671008-1018.65.
www.peervoice.com/XSX870 Copyright © 2010-2025,
erVeice
PeerVoice
AROAAT2002 Phase 20
Liver and serum Z-AAT reduced following fazirsiran administration
All patients had reductions in
Nadir achieved at Week 6 in serum
Facepiece sisal Z'ANT concentration
La 8 8 Fazirsiran 200 mg: -90% + 5%
Week 24/48 Fazirsiran 100 mg: -87% + 6%
-83.3% (95% Cl, -89.7 to -76.4) P u
Liver health biomarkers improved following fazirsiran administration
+ Mean serum ALT levels were reduced in fazirsiran-treated patients from Week 16
through Week 52 vs baseline
+ Eight patients had GGT levels above ULN at baseline, of whom 4 had GGT levels
within the normal range at Week 52
ULN: upper limit of normal
Stmad P et al. N Engl J Med. 2022:387:514-524,
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
AROAAT2002 Phase 20
Liver and serum Z-AAT reduced following fazirsiran administration
All patients had reductions in
Nadir achieved at Week 6 in serum
Facepiece sisal Z'ANT concentration
La 8 8 Fazirsiran 200 mg: -90% + 5%
Week 24/48 Fazirsiran 100 mg: -87% + 6%
-83.3% (95% Cl, -89.7 to -76.4) P u
Liver health biomarkers improved following fazirsiran administration
+ Mean serum ALT levels were reduced in fazirsiran-treated patients from Week 16
through Week 52 vs baseline
+ Eight patients had GGT levels above ULN at baseline, of whom 4 had GGT levels
within the normal range at Week 52
ULN: upper limit of normal
Stmad P et al. N Engl J Med. 2022:387:514-524,
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
SEQUOIA Phase 2 Trial: Safety
Patient Fazirsiran 25 mg Fazirsiran 100 mg WE
Incidence (n=9) (n=8)
TEAES, n(%) 13 (93) 9 (100) 8 (100) 9 (100) 26 (100)
Frequently reported TEAEs
COVID-19 2(14) 00) 2 (25) 6 (67) 8 (81)
Headache 3 (2) 4(44) 13) 2(22) 7(27)
Proceduralpain 3(21) 1) 00) 4(44) 5 (19)
Arthralgia 3(2) 2(22) 2(25) o(0) 4 (15)
Diarrhoea 2(14) 2(22) 1013) 00) 3.02)
Nausea 32) 1) 00) 1), 2(8)
Back pain 00) 1m) 113) 2(22) 415)
Fatigue 2(14) 1) 1013) 00) 2(8)
‘Across both SEQUOIA and AROAAT2002, pulmonary function tests sho indent effects, and DLCO,,
ble through Week 52. In SEQUOIA, FEV, was stable across treatment groups, whereas in AROAAT2002, the
median FEV, was stable but the mean FEV, declined gradually over ti
DLCO ree: diffusing capacity of the lungs for carbon monoxide adjusted for haemoglobin concentration; TEAE: treatment
Clark VC et al. Gastroenterology. 2024:167:1008-1018.e5. Strnad P et al. N Engl J Med. 2022.387:514-624.
'ergent adverse event.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
SEQUOIA Phase 2 Trial: Safety
Patient Fazirsiran 25 mg Fazirsiran 100 mg WE
Incidence (n=9) (n=8)
TEAES, n(%) 13 (93) 9 (100) 8 (100) 9 (100) 26 (100)
Frequently reported TEAEs
COVID-19 2(14) 00) 2 (25) 6 (67) 8 (81)
Headache 3 (2) 4(44) 13) 2(22) 7(27)
Proceduralpain 3(21) 1) 00) 4(44) 5 (19)
Arthralgia 3(2) 2(22) 2(25) o(0) 4 (15)
Diarrhoea 2(14) 2(22) 1013) 00) 3.02)
Nausea 32) 1) 00) 1), 2(8)
Back pain 00) 1m) 113) 2(22) 415)
Fatigue 2(14) 1) 1013) 00) 2(8)
‘Across both SEQUOIA and AROAAT2002, pulmonary function tests sho indent effects, and DLCO,,
ble through Week 52. In SEQUOIA, FEV, was stable across treatment groups, whereas in AROAAT2002, the
median FEV, was stable but the mean FEV, declined gradually over ti
DLCO ree: diffusing capacity of the lungs for carbon monoxide adjusted for haemoglobin concentration; TEAE: treatment
Clark VC et al. Gastroenterology. 2024:167:1008-1018.e5. Strnad P et al. N Engl J Med. 2022.387:514-624.
'ergent adverse event.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
The Redwood Study Phase 3 Trial
Select Inclusion Criteria Intervention/Treatment
+ Men and women from 18 to 75 years old Placebo
+ Must have the Pi*ZZ genotype and already have liver
disease
+ Liver biopsy must show stage F2, F3, or F4 fibrosis Fazirsiran 200 mg
Lung (pulmonary) function or condition must meet
some predefined criteria (FEV, 250%) Q2W
Day1 ——> Week 4 Week 196
Select Exclusion Criteria 7 7 7 =
Have a history of liver decompensating events { Primary Outcome
* Han lof Schr forms: of: Chwriic iver Reduction from baseline of at least 1 stage of
+ Dior typee:6l Shronle Wer sense histologic fibrosis METAVIR staging in the
centrally read liver biopsy at Week 106 in
AATD-associated liver disease with METAVIR
stage F2 and F3 fibrosis will be assessed
Clinicialtrialgov: NCT05677971. Last update posted 12 September 2025; Accessed 12 September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
The Redwood Study Phase 3 Trial
Select Inclusion Criteria Intervention/Treatment
+ Men and women from 18 to 75 years old Placebo
+ Must have the Pi*ZZ genotype and already have liver
disease
+ Liver biopsy must show stage F2, F3, or F4 fibrosis Fazirsiran 200 mg
Lung (pulmonary) function or condition must meet
some predefined criteria (FEV, 250%) Q2W
Day1 ——> Week 4 Week 196
Select Exclusion Criteria 7 7 7 =
Have a history of liver decompensating events { Primary Outcome
* Han lof Schr forms: of: Chwriic iver Reduction from baseline of at least 1 stage of
+ Dior typee:6l Shronle Wer sense histologic fibrosis METAVIR staging in the
centrally read liver biopsy at Week 106 in
AATD-associated liver disease with METAVIR
stage F2 and F3 fibrosis will be assessed
Clinicialtrialgov: NCT05677971. Last update posted 12 September 2025; Accessed 12 September 2025.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Phase 2 Trial of Inhalable AAT vs Placebo: Primary Endpoi
Antineutrophil Elastase Capacity
Levels of Antigenic AAT in the Epithelial Lining Fluid
P= 002
P=.004
en
75 P=.002 2 F à
| Placebo Aa .
= 70L|0% 80mg aat = 20
= 307] m 160 mg AAT =
E mg E
S 25 =
8 20 210
$ El
Ss 5
2 3
zo < 5
5
0 o
on on on on
Time, wk Time, wk
Brantly Met al. ERJ Open Res. 2025:1(1}00537-2024.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Phase 2 Trial of Inhalable AAT vs Placebo: Primary Endpoi
Antineutrophil Elastase Capacity
Levels of Antigenic AAT in the Epithelial Lining Fluid
P= 002
P=.004
en
75 P=.002 2 F à
| Placebo Aa .
= 70L|0% 80mg aat = 20
= 307] m 160 mg AAT =
E mg E
S 25 =
8 20 210
$ El
Ss 5
2 3
zo < 5
5
0 o
on on on on
Time, wk Time, wk
Brantly Met al. ERJ Open Res. 2025:1(1}00537-2024.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Phase 2 Trial of Inhalable A
vs Placebo: Secondary
poi
NE in the Epithelial Lining Fluid
P=.0020 P=.0122
2500 — — Placebo site 1
Placebo site 2
2000
© 80mgAAT
= 1500 m 160 mg AAT
€
w e =
Z 1000
sof 8 — Hu
Fes E E
o 2 o 12 o 12 o 2
Time in Study, wk
Brantly Met ol. ERJ Open Res. 2025;1K1}00837-2024.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Phase 2 Trial of Inhalable A
vs Placebo: Secondary
poi
NE in the Epithelial Lining Fluid
P=.0020 P=.0122
2500 — — Placebo site 1
Placebo site 2
2000
© 80mgAAT
= 1500 m 160 mg AAT
€
w e =
Z 1000
sof 8 — Hu
Fes E E
o 2 o 12 o 12 o 2
Time in Study, wk
Brantly Met ol. ERJ Open Res. 2025;1K1}00837-2024.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Phase 2 Trial of Inhalable AAT vs Placebo: Safety
ADA did not impact safety or AAT concentrations
in the epithelial lining fluid or plasma
Cough was the most commonly z 5000
reported drug-related TEAE Eo
+ 33.3% with 80 mg AAT 3
+ 8.3% with 160 mg AAT 2
+ 250% with placebo 5
E
<
Week O Week 12
© ADA(+) 80 mg AAT e ADA(+) 160 mg AAT
= ADA(-) 80 mg AAT m ADA(-) 160 mg AAT
ADA: anticrug antibod:
Brant Metal. ER Open Res. 2025:K1.00597-2024.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Phase 2 Trial of Inhalable AAT vs Placebo: Safety
ADA did not impact safety or AAT concentrations
in the epithelial lining fluid or plasma
Cough was the most commonly z 5000
reported drug-related TEAE Eo
+ 33.3% with 80 mg AAT 3
+ 8.3% with 160 mg AAT 2
+ 250% with placebo 5
E
<
Week O Week 12
© ADA(+) 80 mg AAT e ADA(+) 160 mg AAT
= ADA(-) 80 mg AAT m ADA(-) 160 mg AAT
ADA: anticrug antibod:
Brant Metal. ER Open Res. 2025:K1.00597-2024.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
AATD: A New Era
Encouraging safety and efficacy signals are emerging across
studies
Broad momentum: Patients may see real change in standards of
care
iting moment for clinicians as the field is accelerating rapidly
PeerVoice Activity: Alice M. Turner, MBCHB, PhO; September 2025.
com/XSX870 Copyright © 2010-2025, PeerVoice
AATD: A New Era
Encouraging safety and efficacy signals are emerging across
studies
Broad momentum: Patients may see real change in standards of
care
iting moment for clinicians as the field is accelerating rapidly
PeerVoice Activity: Alice M. Turner, MBCHB, PhO; September 2025.
com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
Part 5 of 5: “Ask the Faculty” and Take-Home Messages
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
Part 5 of 5: “Ask the Faculty” and Take-Home Messages
Alice M. Turner, MBChB, PhD Mattias Mandorfer, MD,PhD Franziska Trudzinski, MD, PhD
University of Birmingham Medical University of Vienna Thoraxklinik Heidelberg
University Hospitals Birmingham Vienna, Austria Heidelberg University
NHS Foundation Trust Heidelberg, Germany
Birmingham, West Midlands,
United Kingdom
Copyright © 2010-2025, PeerVoice
PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
Alice M. Turner, MBChB, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AiRNA; AstraZeneca; and Takeda Pharmaceutical Company Limited.
Grant/Research Support from CSL Behring; Grifols S.A; Takeda Pharmaceutical Company Limited; and
Vertex Pharmaceuticals Incorporated.
Honoraria from AiRNA; Beam; GSK plo.; Korro Bio Inc; and Tessera Therapeutics.
Mattias Mandorfer, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc; AstraZeneca; Echosens SA; Gilead Sciences, Inc. |psen Biopharmaceuticals,
\ Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Grant/Research Support from Echosens SA.
Speakers Bureau participant with AbbVie Inc.; AstraZeneca; Echosens SA; Gilead Sciences, Inc; Ipsen
Biopharmaceuticals, Inc Takeda Pharmaceutical Company Limited; and W. L. Gore & Associates Inc.
Honoraria from AbbVie Inc.; AstraZeneca; Collective Acumen; Echosens SA; Gilead Sciences, Inc. Ipsen
Biopharmaceuticals, Inc; Takeda Pharmaceutical Company Limited; and W. L. Gore 8: Associates Inc.
Franziska Trudzinski, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing, or Educational
Events from Boehringer Ingelheim International GmbH; Chiesi Pharmaceuticals BV; CSL Behring: Grifols
S.A.; GSK plo.; Novartis AG; RG Gesellschaft für Information und Organisation mbH; and STREAMED UP.
Participation on a Data Safety Monitoring Board or Advisory Board for Chiesi Pharmaceuticals BW. CSL
Behring; and GSK ple.
www.peervoice.com/XSX870 Copyright © 2010-2025, PeerVoice
PeerVoice
“Ask the Faculty” and Take-Home Messages
Alice M. Turner, MBChB, PhD
University of Birmingham
University Hospitals Birmingham NHS Foundation Trust
Birmingham, West Midlands,
United Kingdom
Mattias Mandorfer, MD, PhD
Medical University of Vienna
Vienna, Austria
Franziska Trudzinski, MD, PhD
Thoraxklinik Heidelberg
Heidelberg University
Heidelberg, Germany
PeerVoice
www.peervoice.com/XSX870 Copyright © 2010-2026, Pe
“Ask the Faculty” and Take-Home Messages
Alice M. Turner, MBChB, PhD
University of Birmingham
University Hospitals Birmingham NHS Foundation Trust
Birmingham, West Midlands,
United Kingdom
Mattias Mandorfer, MD, PhD
Medical University of Vienna
Vienna, Austria
Franziska Trudzinski, MD, PhD
Thoraxklinik Heidelberg
Heidelberg University
Heidelberg, Germany
PeerVoice
www.peervoice.com/XSX870 Copyright © 2010-2026, Pe
Tags
alpha-1 antitrypsin deficiency
aatd
pi*zz genotype
protease inhibitor zz variant
screening
chronic obstructive pulmonary disease
copd
familial testing
genetic counseling
augmentation therapy
aatd-associated liver disease
aatd-ld
liver fibrosis
hepatocellular carcinoma
hcc
forced expiratory volume in 1 second
fev1
forced vital capacity
fvc
carbon monoxide transfer coefficient
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