2020 SID Annual Meeting Virtual Conference

Prof. Dr. Matthias Goebeler

Department of Dermatology, Venereology and AllergologyUniversity Hospital Würzburg,Würzburg, Germany

13-16th

May2020

Efgartigimod in Pemphigus

Interim Phase 2 Results

Disclosure

Prof. Dr. Matthias Goebeler serves as a consultant for argenx and receives compensation for these services. The terms of the agreement have been reviewed and approved by the University Hospital Würzburg.

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2

Pemphigus: Autoimmune Blistering Disease

Pemphigus is characterized by painful blisters and erosions on mucous membranes and/or skin surfaces

• Pemphigus vulgaris is the most common type

• Often accompanied by difficulties in swallowing and weight loss

• Erosions may cause severe pain, itching and burning and can sometimes lead to life-threatening fluid loss or infection

• Estimated ~44K Pemphigus patients in the U.S. and EU5; typical onset is 45-65 years

Pemphigus foliaceus

Pemphigus vulgaris

Pemphigus vulgarisPemphigus vulgaris

Schmidt et al. 2019, Lancet; International Pemphigus & Pemphigoid Foundation; argenx proprietary research 3

In Pemphigus, IgG antibodies target adhesion molecules desmoglein 1 and/or 3 (Dsg-1, Dsg-3) causing keratinocytes to separate resulting in suprabasal or subcorneal blistering of the skin and/or erosions at mucous membranes

Pathogenic IgG Antibodies Play Central Role in Pemphigus

Basement membrane

Skin and mucous membrane*

• Steric hindrance • Depletion of desmogleins• Acantholysis: loss of intercellular connections

Specifically, anti-Dsg IgG antibodies cause:

Spindler&Waschke 2018, Front Immunol; *The figure is a reproduction based on Figure 4 from Kasperkiewicz et al. 2017, Nat Rev Dis Primers 4

Goals Of New Potential Pemphigus Therapies

Patients and physicians report the need for new therapies that address key unmet needs

Achieve fast disease control (DC) and complete remission (CR)1

• Rituximab has a relatively slow onset of therapeutic effect

• Relapse rates remain high, between 30-80% particularly without maintenance infusions and increased follow-up

Minimize corticosteroid use to improve side effect profile2

• Steroids and broad immunosuppressants come with side effects that can significantly impair patient quality of life

Kasperkiewicz et al. 2017, Nat Rev Dis Primers; Joly et al. 2017, Lancet; Schmidt et al. 2019, Lancet 5

Efgartigimod Reduces IgG Antibodies By Blocking FcRn

IgG Antibody

FcRn

IgG Antibody

FcRn

Efgartigimod

Roopenian et al. 2007, Nat Rev Immunol; Vaccaro et al. 2005, Nat Biotech; Ulrichts et al. 2018, J Clin Invest

IgG Recycling in Vascular Endothelium Efgartigimod Mechanism of Action

6

Adaptive Phase 2 Proof-Of-Concept Trial

Cohort 415

Efgartigimod dose (mg/kg) 10 25

Induction 4 Weekly infusions Weekly infusions until EoC

Maintenance period (weeks) 6 8 12 Up to 34

Maintenance Dosing 2 doses at weeks 2 and 6 Every other week

SOC No steroids or stable dose of prednisone (patients relapsing on therapy)Discretion of investigator

(monotherapy or 20 mg/d)20 mg/d (patients off therapy) orstable dose (patients on therapy)

Cohort 16

Cohort 25

Cohort 38

IgG/PDAI correlation Maintenance control CRs emerge CRs and ability to taper

Optimized maintenance dosing

IDMC Assessment & Recommendation

Recognized prednisone association

Extended and standardizedtreatment regimen

EoC: End of Consolidation – PDAI: Pemphigus Disease Area Index – SOC: Standard of Care – IDMC: Independent Data Monitoring Committee – CR: Complete Remission – CS: Corticosteroids 7

Patient Demographics And Baseline Characteristics

Safety Analysis Set (N=34) Efficacy Analysis Set* (N=31)

Age (mean ± SD) 51.5 ± 15.3 52.4 ± 15.5

Sex (N (%))• Male• Female

12 (35%)22 (65%)

10 (32%)21 (68%)

Pemphigus vulgaris type• Mucosal-dominant• Mucocutaneous• Cutaneous

25 (74%)9 (36%)

14 (56%)2 (8.0%)

23 (74%)9 (39%)

12 (52%)2 (8.7%)

Pemphigus foliaceus 9 (26%) 8 (26%)

Disease History• Newly diagnosed• Relapsing

14 (41%)20 (59%)

12 (39%)19 (61%)

Baseline PDAI severity• Mild (PDAI <15)• Moderate (PDAI 15-44)

12 (35%)22 (65%)

12 (39%)19 (61%)

Baseline PDAI score (mean ± SD) (min, median, max score)• Overall 17.9 ± 10.6 (1.0, 18.9, 39.9) 20.1 ± 11.7 (2.0, 19.0, 39.9)

Treatment initiated at Baseline (N (%))• Efgartigimod monotherapy• Efgartigimod + low-dose CS

11 (32%)23 (68%)

8 (26%)23 (74%)

*3 patients excluded from efficacy analysis by IDMC (exclusion criterion violation; pre-existing wound infection; insufficient exposure)

Data Cut Off 25 Mar 2020

8

Safety And Tolerability Summary

Treatment Emergent Adverse Events (TEAEs)Reported in ≥ 2 patients per dose group

Efgartigimod 10 mg/kg(N=19)

Efgartigimod 25 mg/kg(N=15)

TEAEs (Total) 16 (84%) 12 (80%)

Bronchitis 2 (11%) –

Rhinitis – 2 (13%)

Nasopharyngitis – 2 (13%)

Influenza-like illness 1 (5.3%) 2 (13%)

Abdominal pain 1 (5.3%) 2 (13%)

Diarrhoea 2 (11%) 2 (13%)

Vomiting 2 (11%) 1 (6.7%)

Headache 1 (5.3%) 3 (20%)

Dizziness 2 (11%) –

Anaemia 1 (5.3%) 2 (13%)

Alanine aminotransferase increased – 2 (13%)

Efgartigimod deemed related TEAEs 5 (26%) 6 (40%)

Influenza-like illness 1 (5.3%) 2 (13%)

Headache – 2 (13%)

Alanine aminotransferase increased – 2 (13%)

• Favorable tolerability profile consistent with previous studies

• Most TEAEs were mild; no related SAEs§

• No deaths and no TEAEs leading to study discontinuation

Mild and moderate infections common in Pemphigus (Schmidt et al. 2019, Lancet; Kasperkiewicz et al. 2017, Nat Rev Dis Primers§ 2 SAEs occurred deemed unrelated to efgartigimod (pneumonia and tibia fracture)

Data Cut Off 25 Mar 2020

9

IgG Reductions Drive Fast and Deep PDAI Improvements

Data show efgartigimod treatment phases with at least biweekly dosing; excludes IgG4 for one patient (outlier)Data cut off 25 Mar 2020 / 7 Nov 2019 for IgG4Excludes mild pemphigus according to Shimizu definition

IgG Reduction and PDAI Score Improvements in Responders

Weekly or biweekly maintenance dosing at variable frequency

Shimizu et al. 2014, J Dermatol; Murrell et al. 2020, J Am Acad Dermatol 10

W4 W8 W12 W16 W20 W24 W28 W32

0

50

100

Pe

rce

nta

ge

of

Ba

se

lin

e (

%)

IgG4

Dsg-1

Dsg-3

PDAI activity

0 14 28 42 56 70 84 98 112

126

140

154

168

182

196

210

224

238

252

266

280

294

0

10

20

30

40

50

Time (Days)

PD

AI

ac

tiv

ity

weekly/every other week

0 14 28 42 56 70 84 98 112 126 140 154 168

0

10

20

30

Time (Days)

PD

AI

ac

tiv

ity

0 14 28 42 56 70 84 98 112 126 140

0

10

20

30

40

50

Time (Days)

PD

AI

ac

tiv

ity

0 14 28 42 56 70 84 98 112

0

10

20

30

Time (Days)

PD

AI

ac

tiv

ity

Adaptive Design Yields Optimal Dosing Schedule

CRs and ability to taper

Cohort 1 (N = 4)*

DC 4

Cohort 4 (N = 15)

DC 14

EoC 11

CR 7

Cohort 3 (N = 7)

DC 7

CR 3

Cohort 2 (N = 5)*

DC 3

IgG/PDAI correlation Maintenance control

CRs emerge

*CR not evaluated in Cohorts 1-2 : Represents drug administration

0 14 28 42 56 70 84 98 112

0

10

20

30

Time (Days)

PD

AI

ac

tiv

ity

11

Patient Anecdote 1: Significant PDAI Improvement On Monotherapy; Low-dose Steroids Drive To CR

Efgartigimod monotherapy followed by low-dose corticosteroids (CS) combination

• Disease control (DC) within 1 week on efgartigimod monotherapy (after first infusion)• PDAI score down by 78%

• Complete remission (CR) within 5 weeks on efgartigimod/low-dose corticosteroids combo

• Ongoing, durable CR on low-dose CS therapy

Key Findings

Newly Diagnosed Mucocutaneous PV | 65-year old female PDAI activity score: 23 | Anti-Dsg-3: > 800 RU/mL | Anti-Dsg-1: 129 RU/mL

Efgart (10 mg/kg) 4 x weekly + 6 x every other week

Prednisolone 20 mg/d

DC CRCohort 3

12DC: Disease Control – CR: Complete Remission – CS: Corticosteroids – PDAI: Pemphigus Disease Area Index

efgartigimod treatment

0 14 28 42 56 70 84 98 112 126 140 154 168

0

25

50

75

100

Time (Days)

Pe

rce

nta

ge

of

Ba

se

lin

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%)

IgG

Anti-Dsg-1

Anti-Dsg-3

PDAI activityfollow-up

Patient Anecdote 2: Long-term, Durable CR On Minimal Therapy

Efgartigimod/low-dose corticosteroids combination

• Disease control (DC) within 2 weeks – despite initial flare• PDAI score down by 75% in 5 weeks

• End of consolidation (EoC) within 9 weeks

• Complete response (CR) within 10 weeks

• Ongoing, durable CR on minimal therapy

Key Findings

Newly diagnosed mucosal dominant PV | 47-year old male PDAI activity score: 10.3 | Anti-Dsg-3: > 800 RU/mL | Anti-Dsg-1: 69 RU/mL

Efgart (25 mg/kg) 9 x weekly + 13 x every other week

Prednisolone 20 mg/d

DC CRCohort 4

10 mg/d

EoC CR CRmin

Day 1

Day 14

Chest blister

13DC: Disease Control – EoC: End of Consolidation – CR: Complete Remission - PDAI: Pemphigus Disease Area Index

efgartigimod treatment

0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 224 238 252 266 280 294

0

25

50

75

100

125

150

Time (Days)

Pe

rce

nta

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Ba

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%)

IgG

Anti-Dsg-1

PDAI activity

Anti-Dsg-3

follow-up

Patient Anecdote 3: Ability To Taper Steroids Upon Achieving EoC

Efgartigimod/low-dose corticosteroids combination

• Disease control (DC) within 4 weeks • PDAI score down by >90% in 5 weeks

• End of consolidation (EoC) within 5 weeks

• Patient preferred strong prednisolone taper to achieving CR

• Patient treatment history• 90 mg/day prednisolone (2007-2013)• 90 mg/day of prednisolone plus 100 mg/day azathioprine

(2015-2016)• 150 mg/day of prednisolone plus 2 g/day mycophenolate

mofetil (2017)

Key Findings

Relapsing PF (diagnosed in 2007) | 57-year old male PDAI activity score: 20.3 | Anti-Dsg-1: 252 RU/mL

Efgart (25 mg/kg) 5 x weekly + 14 x every other week

20

Cohort 4

7.5 mg/d prednisolone

Day 1 Day 29

15 10

Day 43

14DC: Disease Control – EoC: End of Consolidation – R: Relapse – PDAI: Pemphigus Disease Area Index

efgartigimod treatment

0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 224 238 252

0

25

50

75

100

Time (Days)

Pe

rce

nta

ge

of

Ba

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%)

IgG

Anti-Dsg-1

PDAI activityFU

DC EoC R

Phase 2 Proof-Of-Concept Data Support Advancement To Phase 3

90% disease control (28/31 patients) – majority after 1-2 infusions

Median time to DC: 15 to 22 days (mono/combo therapy)

Fast onset of action

70% complete clinical remission (7/10 patients) on optimized dosing*

Time to CR: 2-13 weeks

Deep responses

11/15 patients in Cohort 4 achieved EoC

Steroid sparing potential demonstrated

Durable responses observed and 11 patients still on study

Determined by independent monitoring committeeFavorable tolerability

Efgartigimod clears a-Dsg antibodies/Steroids stimulate Dsg synthesisPotential synergy

* At least biweekly efgartigimod + corticosteroids @ 0.25-0.5mg/kg 15

Acknowledgements to the teams of:

Bata-Csörgő Zsuzsanna, University of Szeged,Szeged, Hungary

Baum Sharon, Chaim Sheba Medical Center,Ramat Gan, Israel

Caproni Marzia, USL Toscana Centro, Florence, Italy

De Simone Clara, Catholic University Policlinic A. Gemelli, Rome, Italy

Didona Biagio, Dermatopathic Institute of the Immaculate, Rome, Italy

Goebeler Matthias, University Hospital of Würzburg, Würzburg, Germany

Gyulai Rolland, University of Pécs, Pécs, Hungary

Hahn Matthias, University Hospital of Tübingen, Tübingen, Germany

Parodi Aurora, University Hospital San Martino of Genova, Genova, Italy

Remenyik Eva, University of Debrecen, Debrecen, Hungary

Reznichenko Nataliya, Zaporizhzhya State Medical University, Zaporizhzhya, Ukraine

Schmidt Enno, University of Lübeck, Lübeck, Germany

Stepanenko Roman, Bogomolets National Medical University, Kiev, Ukraine

Zeeli Tal, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

Ziv Michael, Ha'Emek Medical Center, Afula, Israel

Thank you to the patients & their families16