prof. dr. matthias goebeler venereology and allergology ... · 2 (8.0%) 23 (74%) 9 (39%) 12 (52%) 2...
TRANSCRIPT
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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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
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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
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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
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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
e (
%)
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
ge
of
Ba
se
lin
e (
%)
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
se
lin
e (
%)
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