Thema: Biologika Teil 2: IL-17 und IL-23 Blockade

Thema:

Biologika Teil 2: IL-17 und IL-23 Blockade

Univ.-Prof. Dr. Matthias AugustinDirektor, Institut für Versorgungsforschung in der

Dermatologie und bei Pflegeberufen und

Hamburg Center for Health Economics

Universitäres Psoriasis-Zentrum des UKE

DDA-Zertifizierungsworkshop 06.09.2019

Scoring und Therapieziele bei Psoriasis

Systemtherapien

am 06.09.2019

Augustin M, Kirsten N: PsoNet Magazin 1/2019

Scoring und Therapieziele bei Psoriasis

Systemtherapien

am 06.09.2019

Augustin M, Kirsten N: PsoNet Magazin 1/2019

PLUS 11

biosimilars

Psoriasis: Aktuelle und neue Wirkstoffe

Hawkes JE, Chan TC, Krueger JG. J Allergy Clin Immunol 2017;140:645–53; modified by Reich K, 2017

Feed forward response Feed backward response

Wirkstoff Hersteller/ Vertrieb

Zielmolekül PASI-90 (%) in Wo. 12

Entwicklungs-phase

Pso 1°

Pso 2°

PsA

Adalimumab u.a. Abbvie TNF-alpha 26 – 47** zugelassen + +

Etanercept u.a. Pfizer TNF-alpha 17 – 22** zugelassen + +

Infliximab u.a. MSD TNF-alpha 46 – 53** zugelassen + +

Certolizumab UCB TNF-alpha 50 – 68*** zugelassen +

Golimumab MSD TNF-alpha 18 – 36*** zugelassen +

Secukinumab Novartis IL-17A 69 – 72 zugelassen + +

Ixekizumab Lilly IL-17A 68 – 71 zugelassen + +

Brodalumab LEO IL-17-Rez. 69 – 70 zugelassen +

Bimekizumab UCB IL-17A/F 79# Phase III

CJM-112 Novartis IL-17A - Phase I / II Ustekinumab Janssen IL-12/23 35 – 47** zugelassen + +

Guselkumab Janssen IL-23p19 73* zugelassen +

Tildrakizumab Sun/Almirall IL-23p19 36 zugelassen +

Risankizumab Abbvie IL-23p19 81 (Ph. II) zugelassen +

LY3074828 Lilly IL-23p19 Phase III

*Wo. 16; **pooled efficacy data, Puig, JEADV 2014; 28,1633-53 #nur Phase 2-Daten; *** single study data


Biologika bei Psoriasis mit aktuellen Studiendaten

CVderm 2017



Entwicklungs-phase

Pso 1°

Pso 2°

PsA


















CVderm 2017

PLUS 13

Biosimilars

Wirkstoff Hersteller/

Vertrieb

Handels-name PASI-90 (%)

in Wo. 12

Entwickl.-

phase

Pso

1°

Pso

2°

PsA

Acitretin generisch generisch n.A. zugelassen +

Apremilast Celgene Otezla 20 – 26# zugelassen + +

Ciclosporin generisch generisch n.A. zugelassen + DMF, MEF Biogen Fumaderm 18 – 22* zugelassen +

DMF Almirall Skilarence 18 – 22* zugelassen +

MTX generisch generisch 22 – 38## zugelassen + +

Apo805K1 ApoPharma Phase II/III

Baricitinib Lilly JAK1/2 inh. Phase II/III

FP187 Forward DMF Phase II/III

KD025 Kadmon ROCK2 Inh. Phase II/III

Prurisol Cellceutix IL-20 + PRINS inh. Phase II/III

VTP-43742 Vitae ROR-gamma T inh. Phase II/III

XP23829 Dr. Reddy’s DMF Phase II/III

ZPL-389 Ziarco H4 receptor-antag. Phase II/III

*Woche 16; **pooled efficacy data, Puig et al., JEADV 2014; 28,1633-53 #incl. Registerdaten ##Wo.24


Systemtherapeutika bei Psoriasis mit aktuellen Studiendaten

CVderm 2017

Was heißt das für die Arzneimittelwahl in der Praxis?Erster Blick: Klinische Wirksamkeit

PsA

PsO

+

+

10 20 30 40 50 60 70 80 90 100

PsA

PsO

Leflunomide

Sulfasalazin

FAE

Apremilast

MTX

+

+

Anti-IL17:

Secu, Ixe,

Broda

Infliximab

Etanercept

Adalimumab

Ustekinu-

mab

Ciclosporine

Retinoids

Anti-IL23:

Gusel-, Tildra-,

Risankizumab

10 20 30 40 50 60 70 80 90 100

IL-17 inhibition Secukinumab

Ixekizumab

Brodalumab

The IL-17 Cytokine Family

Current concepts of psoriasis treatment

IL-17A

Secukinumab

Ixekizumab

IL-17RA

Brodalumab

Modified from Patel DD, et al. ARD 2013;72(Suppl. 2):ii116

Current concepts of psoriasis treatment

1. Rich P, et al. Br J Dermatol. 2013 168, pp 402-411; 2. Papp KA et al., NEJM 2012 366:1181–9;3. Leonardi C et al., NEJM 2012 366:1190–9; 4 Fachinformation Ixekizumab 04/2016

Secukinumab1 Ixekizumab3,4 Brodalumab2

Spezies voll human humanisiert voll human

Isotyp IgG1κ IgG4κ IgG2κ

Spezifität IL-17A, IL-17A/F IL-17A, IL-17A/F IL-17 Receptor A-chain

blocking IL-17A/C/E/F

Dosierung 2x 150 mg

Woche 0 bis 4 q1w

Ab Woche 5 q4w

2x 80 mg Woche 0

80 mg q2w bis Woche 10

80 mg q4w bis Woche12




Ixekizumab

Brodalumab

Leitfragen:

Wie sehen die Langzeitdaten aus?

Welche Differenzierung?

Immunogenität?

Secukinumab bei Psoriasis

SecukinumabFully human mAb

IgG1 bound to IL-17A

IL-17A

16

Placebo (n = 324)Secukinumab 150 mg (n = 327)Secukinumab 300 mg (n = 323) Etanercept (n = 323)

FIXTURE: secukinumab versus etanercept

(versus placebo) through 52 weeks

*P <0.0001 for comparisons of secukinumab vs. etanercept; †P <0.0001 for comparisons of secukinumab vs. placebo;‡P <0.001 for comparisons of secukinumab vs. etanercept; §P <0.001 for comparisons of secukinumab vs. placebo; primary endpoint at Week 12

No comparison with placebo was performed for PASI 100 because there were no patients with a response in the placebo group

Each piece of missing data is replaced with multiple values representing an overall distribution of the possible data (multiple imputation)

Adapted from Langley RG, et al. Poster presented at: International Congress of Psoriasis: From Gene to Clinic, London, UK, 2014. Poster #P99.

74.6%

70.6%

Res

po

nd

ers

(%

)

87.3%

72.8%

63.0%

66.2%

*†

*†

Week Week

49.3%

39.0%

34.0%

‡§

56.0%

‡§

PASI 90 ResponsePASI 75 Response PASI 100 Response

17

**

*

*

** * * *

* * * * * *

** p=0,0001, * p<0,0001 vs. Ustekinumab; multiple imputation

PA

SI 9

0-R

esp

on

der

(%)

Woche

PASI 90 response rates (up to week 52)

----

----

----

----

----

----

----

----

----

----

----

-

76,2%

59,5%

80,1%

60,6%

----

----

----

----

----

----

----

----

----

----

----

17

Clinical efficacy CLEAR –Secukinumab versus ustekinumab

Blauvelt A et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque

psoriasis up to 1 year: Results from the CLEAR study J Am Acad Dermatol 2017; 76: 60-69

Secukinumab vs. FAEs (PRIME)

Sticherling, Br J Dermatol 2017, doi:10.1111/bjd.15707

PE:

PASI 75 response at

week 24

Pa

tie

nts

wit

h P

AS

I 7

5 r

es

po

ns

e (

%)

Week

p < 0,001

90%

34%

Secukinumab (n = 105) Fumarsäureester (n = 95)

Secukinumab vs. FAEs (PRIME)

Sticherling, Br J Dermatol 2017, doi:10.1111/bjd.15707

PE:

PASI 75 response at

week 24

Pa

tie

nts

wit

h P

AS

I 7

5 r

es

po

ns

e (

%)

Week

p < 0,001

90%

34%

Secukinumab (n = 105) Fumarsäureester (n = 95)

Secukinumab:

Fumarsäureestern

hochgradig überlegen

20

Secukinumab efficacy data over two years

Randomized extension of ERASURE and FIXTURE

• Percentage of patients in continuous-treatment groups who reached Week 104 without relapse* was

87.1% (secukinumab 300 mg) and 72.8% (secukinumab 150 mg)

• In the treatment-withdrawal groups, 16.0% (secukinumab 300 mg–placebo) and

12.7% (secukinumab 150 mg–placebo) did not relapse on placebo

Multiple imputation used to handle missing data in groups that continued secukinumab q4w;

In the treatment-withdrawal groups NRI was used

*A loss of >50% of the maximum PASI gain compared to the baseline of the core studies

Secukinumab 300 mg (n = 363)

Secukinumab 150 mg (n = 297)

Secukinumab 300 mg / treatment withdrawal (n = 180)

Secukinumab 150 mg / treatment withdrawal (n = 150)

Week

0

20

40

60

80

100

52 60 68 76 84 92 100

PASI 90

0

20

40

60

80

100

52 60 68 76 84 92 100

Week

PASI 100

20

40

Week

Resp

on

ders

(%

)

0

60

80

100

52 60 68 76 84 92 100

PASI 75

Blauvelt A, et al. AAD 2015, Late breaker

Sponsored by Novartis Pharma AG

Secukinumab – clinical responses in psoriasis over 5 years (SCULPTURE)

Bissonnette R et al. Secukinumab demonstrates sustained efficacy and a favorable safety profile through 5 years of treatment in moderate to

severe psoriasis. P2223, EADV 2017, Geneva

PASI75

PASI90

PASI100




P2223

Secukinumab Demonstrates High Sustained Efficacy and a Favorable Safety Profile Through

5 Years of Treatment in Moderate to Severe Psoriasis R Bissonnette,1 T Luger,2 D Thaçi,3 D Toth,4 A Lacombe,5 S Xia,6 R Mazur,5 M Patekar,5 P Charef,5 M Milutinovic,5 and C Leonardi7 1Innovaderm Research, Montreal, Canada;

2Department of Dermatology, University of Münster, Albert-Schweitzer-Campus, Münster, Germany;

3Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein,

Lübeck, Germany; 4Probity Medical Research and XLR8 Medical Research, Windsor, Canada;

5Novartis Pharma AG, Basel, Switzerland;

6Beijing Novartis Pharma Co. Ltd., Shanghai, China;

7Department of Dermatology, Saint Louis

University Health Science Center, St Louis, USA

INTRODUCTION

• Psoriasis is a chronic immune-mediated skin disease usually requiring

long term management

• Secukinumab, a fully human monoclonal antibody that neutralizes IL-17A,

has been shown to have significant efficacy in the treatment of moderate

to severe psoriasis and psoriatic arthritis, demonstrating sustained and

long lasting high levels of efficacy with a favorable safety profile1-5

• This secukinumab analysis is the first phase 3 study of an IL-17A inhibitor

evaluating efficacy and safety up to 5 years of treatment at the approved

dose

METHODS

• In the core SCULPTURE study, patients that were Psoriasis Area and

Severity Index (PASI) 75 responders at Week (Wk) 12 continued receiving

subcutaneous secukinumab 300 mg every 4 Wks until Year 1 (n=168 at

Wk 52) (Figure 1)

• Patients subsequently entered the extension phase (NCT01640951)

and continued the same double-blinded treatment regimen to Year 3,

and thereafter un-blinded to Year 5 (n=126 at Wk 260)

• No additional therapies (topicals) were permitted in the extension study

• Here we report final PASI 75/90/100 and absolute PASI ≤1/≤2/≤3

responses, dermatology life quality index (DLQI) 0/1 response (no impact

of skin disease on subject’s quality of life), and safety/tolerability through

5 years of treatment for the secukinumab 300 mg fixed interval arm only,

which is the recommended labelled dose regimen

• Efficacy data are reported as observed unless otherwise stated; multiple

imputation (MI) and last observation carried forward (LOCF) data are

reported for PASI responses as additional supportive analyses. Safety

events are analyzed per year using exposure adjusted incidence rates

(per 100 patient-years)

Double - blind Open-label

(Mostly home drug administration)

BL(Weeks) 52

Secukinumab 300 mg Fixed-interval

104 15612 208 260

N=168 N=155 N=141 N=134 N=126

Secukinumab

300 mg

Secukinumab 300 mg Retreatment-as-needed

Secukinumab 150 mg Fixed-interval Secukinumab

150 mg


Secukinumab 300 mg Retreatment-as- eeded

Secukinumab 150 mg Fixed-inter alSecukinumab

150 mg


99.5% treatment compliance*

RESULTS

Baseline characteristics and subject disposition

• On completion of the 1-year core study, 168 subjects in the 300 mg cohort

entered the extension study

• Baseline demographics and clinical characteristics of extension study

subjects are presented in Table 1

• The mean PASI score of 23.5, percentage BSA involvement of 33.1% and

mean DLQI of 13.1, indicated a high disease severity at baseline

• At the end of Year 5, 126 subjects had completed the treatment phase of

the study and 42 had discontinued treatment (Table 2)

Efficacy

• PASI 75, 90 and 100 response rates sustained from Year 1 (88.9%, 68.5%

and 43.8%, respectively) to Year 5 (88.5%, 66.4% and 41%) (Figure 2)

– Similarly, PASI 75, 90 and 100 response rates sustained to Year 5

in the MI (80.1%, 58.6% and 35.6%) and LOCF (79.2%, 59.5% and

37.5%) analyses (Figure 2)

– PASI responses were consistent across the different analyses

undertaken (Figure 2)

• Secukinumab on average improved psoriasis by 90% through 5 years; the

mean improvement in mean absolute PASI from baseline to Year 1 was

91.1%, and from baseline to Year 5 was 90.1%

• Absolute PASI ≤1/≤2/≤3 responses sustained from Year 1 (58.6%, 67.9%

and 74.1%, respectively) to Year 5 (53.3%, 66.4% and 75.4%) (Figure 3)

– Similarly, PASI ≤1/≤2/≤3 responses sustained to Year 5 in the MI (47%,

58.4% and 66.9%) and LOCF (48.2%, 60.1%, 69%) analyses

Figure 3. Secukinumab Delivers Sustained Improvements in Psoriasis

Through 5 Years

0

20

% R

es

po

nd

ers

40

60

80

100

Year 1n = 162

Year 2n = 152

Year 3n = 139

Year 4n = 132

Year 5n = 122

PASI ≤3 PASI ≤2 PASI ≤1

74.1%

58.6%

67.9%75.4%

66.4%

53.3%

As observed analysis; n, number of evaluable patients; PASI, Psoriasis Area and Severity Index score

• Two thirds of patients reported no impact of skin disease on their lives

through 5 years of treatment; DLQI 0/1 responses were 72.7% at Year 1

and 65.5% at Year 5 (Figure 4)

0

20

DL

QI 0

/1 %

Res

po

nd

ers

40

60

80

100

Year 1n = 165

Year 2n = 153

Year 3n = 138

Year 4n = 132

Year 5n = 119

65.5%72.7%

Safety

• The safety profile of secukinumab remained favorable through 5 years of

treatment with no increase in yearly adverse event (AE) rates from Year 1

(Table 3)

• No new safety signals were identified and the safety profile was consistent

with that established in a large phase 3 program6

CONCLUSIONS

• Secukinumab treatment sustained high levels of skin clearance and

improvement in quality of life with a favorable safety profile through

5 years

– Average PASI improvement through 5 years was ~90%

– Patients experienced long lasting relief from the burden of psoriasis

– The safety profile was favorable with no increase of events over time

REFERENCES1. Hueber W et al. Sci Transl Med. 2010;2:52ra72.

2. Langley RG et al. N Engl J Med. 2014;371:326–338.

3. Thaci D et al. JAAD. 2015;73:400.

4. Blauvelt et al. JAAD. 2017;76:60–69.

5. Mease et al. N Engl J Med. 2015;373:1329–39.

6. van de Kerkhof et al. J Am Acad Dermatol. 2016;75(1):83–98.

ACKNOWLEDGMENTSAll authors participated in the development of the poster for presentation. The authors thank Brendan Marshall, PhD (Novartis Ireland Ltd.) for editorial and medical writing support, which was funded by Novartis Pharma AG, Switzerland in accordance with the Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

ePoster presented: at 26th European Academy of Dermatology and Venereology Congress, September 13–17, 2017, Geneva, Switzerland

0

20

% R

es

po

nd

ers

40

60

80

100

Year 1n = 162As observed

Year 2n = 152

Year 3n = 139

Year 4n = 132

Year 5n = 122

As observedPASI 75 MI LOCF As observedPASI 90 MI LOCF As observedPASI 100 MI LOCF

Δ=~5%

Δ=~7%

Δ=~8%




P2223

Secukinumab Demonstrates High Sustained Efficacy and a Favorable Safety Profile Through

5 Years of Treatment in Moderate to Severe Psoriasis R Bissonnette,1 T Luger,2 D Thaçi,3 D Toth,4 A Lacombe,5 S Xia,6 R Mazur,5 M Patekar,5 P Charef,5 M Milutinovic,5 and C Leonardi7 1Innovaderm Research, Montreal, Canada;

2Department of Dermatology, University of Münster, Albert-Schweitzer-Campus, Münster, Germany;

3Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein,

Lübeck, Germany; 4Probity Medical Research and XLR8 Medical Research, Windsor, Canada;

5Novartis Pharma AG, Basel, Switzerland;

6Beijing Novartis Pharma Co. Ltd., Shanghai, China;

7Department of Dermatology, Saint Louis

University Health Science Center, St Louis, USA

INTRODUCTION

• Psoriasis is a chronic immune-mediated skin disease usually requiring

long term management

• Secukinumab, a fully human monoclonal antibody that neutralizes IL-17A,

has been shown to have significant efficacy in the treatment of moderate

to severe psoriasis and psoriatic arthritis, demonstrating sustained and

long lasting high levels of efficacy with a favorable safety profile1-5

• This secukinumab analysis is the first phase 3 study of an IL-17A inhibitor

evaluating efficacy and safety up to 5 years of treatment at the approved

dose

METHODS

• In the core SCULPTURE study, patients that were Psoriasis Area and

Severity Index (PASI) 75 responders at Week (Wk) 12 continued receiving

subcutaneous secukinumab 300 mg every 4 Wks until Year 1 (n=168 at

Wk 52) (Figure 1)

• Patients subsequently entered the extension phase (NCT01640951)

and continued the same double-blinded treatment regimen to Year 3,

and thereafter un-blinded to Year 5 (n=126 at Wk 260)

• No additional therapies (topicals) were permitted in the extension study

• Here we report final PASI 75/90/100 and absolute PASI ≤1/≤2/≤3

responses, dermatology life quality index (DLQI) 0/1 response (no impact

of skin disease on subject’s quality of life), and safety/tolerability through

5 years of treatment for the secukinumab 300 mg fixed interval arm only,

which is the recommended labelled dose regimen

• Efficacy data are reported as observed unless otherwise stated; multiple

imputation (MI) and last observation carried forward (LOCF) data are

reported for PASI responses as additional supportive analyses. Safety

events are analyzed per year using exposure adjusted incidence rates

(per 100 patient-years)

Double - blind Open-label

(Mostly home drug administration)

BL(Weeks) 52

Secukinumab 300 mg Fixed-interval

104 15612 208 260

N=168 N=155 N=141 N=134 N=126

Secukinumab

300 mg


Secukinumab 150 mg Fixed-interval Secukinumab

150 mg



Secukinumab 150 mg Fixed-inter alSecukinumab

150 mg


99.5% treatment compliance*

RESULTS

Baseline characteristics and subject disposition

• On completion of the 1-year core study, 168 subjects in the 300 mg cohort

entered the extension study

• Baseline demographics and clinical characteristics of extension study

subjects are presented in Table 1

• The mean PASI score of 23.5, percentage BSA involvement of 33.1% and

mean DLQI of 13.1, indicated a high disease severity at baseline

• At the end of Year 5, 126 subjects had completed the treatment phase of

the study and 42 had discontinued treatment (Table 2)

Efficacy

• PASI 75, 90 and 100 response rates sustained from Year 1 (88.9%, 68.5%

and 43.8%, respectively) to Year 5 (88.5%, 66.4% and 41%) (Figure 2)

– Similarly, PASI 75, 90 and 100 response rates sustained to Year 5

in the MI (80.1%, 58.6% and 35.6%) and LOCF (79.2%, 59.5% and

37.5%) analyses (Figure 2)

– PASI responses were consistent across the different analyses

undertaken (Figure 2)

• Secukinumab on average improved psoriasis by 90% through 5 years; the

mean improvement in mean absolute PASI from baseline to Year 1 was

91.1%, and from baseline to Year 5 was 90.1%

• Absolute PASI ≤1/≤2/≤3 responses sustained from Year 1 (58.6%, 67.9%

and 74.1%, respectively) to Year 5 (53.3%, 66.4% and 75.4%) (Figure 3)

– Similarly, PASI ≤1/≤2/≤3 responses sustained to Year 5 in the MI (47%,

58.4% and 66.9%) and LOCF (48.2%, 60.1%, 69%) analyses

Figure 3. Secukinumab Delivers Sustained Improvements in Psoriasis

Through 5 Years

0

20

% R

es

po

nd

ers

40

60

80

100

Year 1n = 162

Year 2n = 152

Year 3n = 139

Year 4n = 132

Year 5n = 122

PASI ≤3 PASI ≤2 PASI ≤1

74.1%

58.6%

67.9%75.4%

66.4%

53.3%

As observed analysis; n, number of evaluable patients; PASI, Psoriasis Area and Severity Index score

• Two thirds of patients reported no impact of skin disease on their lives

through 5 years of treatment; DLQI 0/1 responses were 72.7% at Year 1

and 65.5% at Year 5 (Figure 4)

0

20

DL

QI 0

/1 %

Res

po

nd

ers

40

60

80

100

Year 1n = 165

Year 2n = 153

Year 3n = 138

Year 4n = 132

Year 5n = 119

65.5%72.7%

Safety

• The safety profile of secukinumab remained favorable through 5 years of

treatment with no increase in yearly adverse event (AE) rates from Year 1

(Table 3)

• No new safety signals were identified and the safety profile was consistent

with that established in a large phase 3 program6

CONCLUSIONS

• Secukinumab treatment sustained high levels of skin clearance and

improvement in quality of life with a favorable safety profile through

5 years

– Average PASI improvement through 5 years was ~90%

– Patients experienced long lasting relief from the burden of psoriasis

– The safety profile was favorable with no increase of events over time

REFERENCES1. Hueber W et al. Sci Transl Med. 2010;2:52ra72.

2. Langley RG et al. N Engl J Med. 2014;371:326–338.

3. Thaci D et al. JAAD. 2015;73:400.

4. Blauvelt et al. JAAD. 2017;76:60–69.

5. Mease et al. N Engl J Med. 2015;373:1329–39.

6. van de Kerkhof et al. J Am Acad Dermatol. 2016;75(1):83–98.

ACKNOWLEDGMENTSAll authors participated in the development of the poster for presentation. The authors thank Brendan Marshall, PhD (Novartis Ireland Ltd.) for editorial and medical writing support, which was funded by Novartis Pharma AG, Switzerland in accordance with the Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

ePoster presented: at 26th European Academy of Dermatology and Venereology Congress, September 13–17, 2017, Geneva, Switzerland

0

20

% R

es

po

nd

ers

40

60

80

100

Year 1n = 162As observed

Year 2n = 152

Year 3n = 139

Year 4n = 132

Year 5n = 122

As observedPASI 75 MI LOCF As observedPASI 90 MI LOCF As observedPASI 100 MI LOCF

Δ=~5%

Δ=~7%

Δ=~8%

Fazit Secukinumab:

a) Gute Langzeitdaten

b) Vielseitige Wirksamkeit

c) Immunogenität kein Problem

d) Prediktorenstudie zu CV

outcomes

24

Secukinumab in der Leitlinie2017

25

Secukinumab in der Leitlinie2017


Ixekizumab

Brodalumab

Leitfragen:


Welche Differenzierung zu Secukinumab?

Immunogenität?

Ixekizumab bei Psoriasis

Data on file, Eli Lilly and Company and/or one of its subsidiaries.

ETN: Etanercept; IXE Q2W: 80 mg Ixekizumab alle 2 Wochen nach einer Initialdosis von 160 mg; *p < 0,001 vs. PBO; †p < 0,001 vs. ETN; +p < 0,05 vs. PBO; PASI bei Baseline: 20;

LOCF: Last Observation Carried Forward; PASI: Psoriasis Area and Severity Index; PBO: Placebo. Anmerkung: Es wurde auch eine Q4W Dosierung in der Induktionsphase

untersucht, die allerdings nicht Bestandteil der Zulassung geworden ist.

0

20

40

60

80

100

0 1 2 4 8 12

Mit

tle

re V

erb

es

se

run

g vo

m

Au

sg

an

gs

we

rt (

PA

SI,

%)

Wochen

PBO (N=168) ETN (N=358) IXE 2QW (N=351)

36+

51+

70*†

85*† 91*†

52*†

30*†

9+

20+

59+

4 8 10 12 7

Ixekizumab: Mittlere Verbesserung des PASI Induktionsphase – Woche 12 (UNCOVER-2)

Nach 2 Wochen 50% mittlere Verbesserung im PASI

In both studies, both IXE dose had higher PASI 90 by Week 2 compared to etanercept (p<0.001) and by Week 4 compared to placebo (p<0.001). In both

studies, both IXE dose groups had higher PASI 100 by Week 4 compared to etanercept (p<0.001) and placebo [p<0.01 (UNCOVER-2) and p<0.001

(UNCOVER-3)]; ITT-NRI

UNCOVER-2 and -3 Ixekizumab vs etanercept first 12 weeks

Griffiths C, Reich K, et al. Lancet 2015;386:541–51.

*p<.05, **p<.01, ***p<.001 by Fisher‘s exact test

IXE=Ixekizumab; NRI=Non-Responder Imputation; PASI=Psoriasis Area and Severity Index; UST=Ustekinumab

PASI 90 DLQI 0/1

IXORA-S Efficacy outcomes comparison ixekizumab vs. ustekinumab week 24, NRI

Reich et al. Br J Dermatol. 2017 May 19. doi: 10.1111/bjd.15666. [Epub ahead of print]; Supplement.

*P<0.05 vs IXE vs FAE; †P<0.05 IXE vs MTX; ‡P<0.05 MTX vs FAE

Nx, number of dropouts

Reich K, et al. EADV 2017; P1938

24-week, randomized open-label study: ixekizumab, fumaric acid esters, and methotrexate

in psoriasis patients naïve to systemic therapy

Primary endpoint: PASI 75 response over 24 weeks

FAE (n=54)

MTX (n=54)

IXE q2w/IXE q4w (n=54)

20

02

40

60

100

80

Pa

tie

nts

(%

)

4 6 8 10 12 140

Weeks

16 18 20 22 24

22.2

70.4

90.7*†‡

FAE (N=54, Nx=23)

MTX (N=54, Nx=49)

IXE q2w/IXE q4w (N=54, Nx=50)

20

02

40

60

100

80

Pa

tie

nts

(%

)

4 6 8 10 12 140

Weeks

16 18 20 22 24

52.2

77.6

98.0

NRI As observed

• Discontinued study before Week 24: FAE n=29; MTX n=3; IXE n=5

IXORA-S Ixekizumab vs. Ustekinumab

Results at EADV: nails and scalp

Comparison of ixekizumab and ustekinumab efficacy in

the treatment of nail lesions of patients with moderate

to severe plaque psoriasis: 24-week data of IXORA-S

trial1

Comparison of ixekizumab and ustekinumab in the treatment of

scalp psoriasis in patients with moderate-to-severe psoriasis:

24-week data from the IXORA-S trial2

1Dutronc et al. EADV 2017 OP03.01. 2Plummer et al. EADV 2017 P1928

Nagelpsoriasis (NAPSI) Kopfhautpsoriasis (PSSI)

IXORA-S Ixekizumab vs. Ustekinumab

Results at EADV: nails and scalp

Comparison of ixekizumab and ustekinumab efficacy in

the treatment of nail lesions of patients with moderate

to severe plaque psoriasis: 24-week data of IXORA-S

trial1

Comparison of ixekizumab and ustekinumab in the treatment of

scalp psoriasis in patients with moderate-to-severe psoriasis:

24-week data from the IXORA-S trial2

1Dutronc et al. EADV 2017 OP03.01. 2Plummer et al. EADV 2017 P1928

Nagelpsoriasis (NAPSI) Kopfhautpsoriasis (PSSI)

Fazit Ixekizumab:

a) Gute Langzeitdaten 2 J.

b) Breite klinische

Effektivität incl. Itch, Pain,

Nails, Scalp

• Taltz® is available as an autonjector or a prefilled syringe

• With each at a dosage of 80 mg Ixekizumab

• Easy for dosing:

Starting dose 2 Injections (2 x 80 mg)

1 Injection (80 mg) every 2 weeks during the induction phase (week 2-12)

1 Injection (80 mg) every 4 weeks during the maintenance period (starting at week 16)

Induction phase Maintenance

week

Dosierung Ixekizumab


Ixekizumab

Brodalumab

Leitfragen:


Welche Differenzierung zu Secukinumab und

Ixekizumab?

Depression, Suizidalität?

PsA?

Brodalumab bei Psoriasis

*MACE: myocardial infarction (MI), stroke or CV death **ISR: injection site reactionsa 1 prostate cancer and 1 invasive papillary breast carcinoma

Russell CB, Rand H, Bigler J et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol 2014;192:382836.Papp KA, Leonardi C, Menter A et al. Brodalumab, an antiinterleukin-17-receptor antibody for psoriasis. N Engl J Med 2012;366:1181-9.

PASI75 PASI100 85% 37%nach 12 Wochen

Brodalumab: Wirksamkeit nach 12 Wochen

AMAGINE-2: Efficacy outcomes (NRI)

P values were calculated by Bonferroni-based recycling testing, which includes all primary and key secondary endpoint comparisons with placebo and ustekinumab, at a significance level of 0.05.

Non-responder imputation was used to impute missing data. Weight-based brodalumab group: a subset in which patients ≤100 kg at baseline received 140 mg Q2W and patients >100 kg at

baseline received 210 mg Q2W.

PASI, Psoriasis Area Severity Index; Q2W, every 2 weeks; sPGA, static Physician’s Global Assessment

Lebwohl M et al. N Engl J Med 2015;373:1318–28 and Supplementary Appendix

81 4 1

70

22

61

22

67

26

58

26

86

44

79

45

77

34

69

34

0

20

40

60

80

100

PASI 75 PASI 100 sPGA 0/1 sPGA 0

Pa

tie

nts

ach

ievin

g P

AS

I 7

5,

PA

SI

10

0, sP

GA

0/1

or

sP

GA

0

(%

)

Placebo (n=309)

Ustekinumab (n=300)

Brodalumab 140 mg Q2W(n=610)


Weight-based brodalumab(n=610)

*

*

*

*

*

*

*

*

p=0.0

8

p<0.001

p<0.001

p<0.001

p<0.001

p=0.013

p<0.001

p=0.078

PASI 75 or 100, and sPGA 0/1 or 0 response rates at Week 12

*p<0.001 vs placebo

AMAGINE-3: Efficacy outcomes (NRI)

P values were calculated by Bonferroni-based recycling testing, which includes all primary and key secondary endpoint comparisons with placebo and ustekinumab, at a significance level of

0.05. Non-responder imputation was used to impute missing data. Weight-based brodalumab group: a subset in which patients ≤100 kg at baseline received 140 mg Q2W and patients >100 kg

at baseline received 210 mg Q2W.

PASI, Psoriasis Area Severity Index; Q2W, every 2 weeks; sPGA, static Physician’s Global Assessment

Lebwohl M et al. N Engl J Med 2015;373:1318–28 and Supplementary Appendix

60,3 4 0,3

69

19

57

19

69

27

60

27

85

37

80

37

77

30

69

30

0

20

40

60

80

100

PASI 75 PASI 100 sPGA 0/1 sPGA 0

Pa

tie

nts

ach

ievin

g P

AS

I 7

5,

PA

SI

10

0, sP

GA

0/1

or

sP

GA

0 (

%)

Placebo (n=315)

Ustekinumab (n=313)



Weight-based brodalumab(n=628)

*

*

*

*

*

*

*

*

p=0.007

p<0.001

p<0.001

p<0.001

p=0.007

p<0.001

p<0.001

p<0.001

*p<0.001 vs placebo

PASI 75 or 100, and sPGA 0/1 or 0 response rates at Week 12

AMAGINE-1, -2 and -3: Efficacy of brodalumab in nail and scalp psoriasis

NAPSI score at Week 121

(multiple imputation)

Brodalumab

Placebo

n=261

140 mg

Q2W

n=466

210 mg

Q2W

n=472

NAPSI, mean (SE) 8.5 (0.3) 6.0 (0.2) 5.2 (0.2)

Tx difference vs placebo, least

squares mean (95% CI)-

2.5

(2.0–3.0)

3.3

(2.8–3.8)

p value vs placebo <0.001 <0.001

Nail psoriasis data are a pooled analysis of AMAGINE-1, -2 and -3.1 Scalp psoriasis data is analysis of AMAGINE-1; non-responder imputation was used to impute missing data.2 PSSI only summarised in subjects with baseline PSSI ≥15 and

SSA ≥30%.2 *p<0.001, †p=0.007 for comparisons between brodalumab and placebo groups.2

NAPSI, Nail Psoriasis Severity Index; PSSI, Psoriasis Scalp Severity Index; Q2W, every 2 weeks; SE, standard error1Lebwohl MG et al. P5296 Presented at 75th Annual Meeting of the American Academy of Dermatology, March 3-7, 2017, Orlando, FL;

2Yamauchi P et al. P5247 Presented at 75th Annual Meeting of the American Academy of Dermatology, March 3–7, 2017, Orlando, FL

11,6

37,546,3

0

10

20

30

40

50

Placebon=261

Brodalumab140 mg Q2W…

Brodalumab210 mg Q2W…

NA

PS

I sco

re

imp

rove

me

nt fr

om

b

ase

line

(%

)

Improvement in NAPSI score at Week 121

AMAGINE-1, -2 and -3 (as observed)

0

10

20

30

40

50

60

70

-3 2 7 12Pa

tie

nts

ach

ievin

g P

SS

I 1

00

(%

)

WeekPlacebo

63.4%

41.0%

3.2%

*

*

*

*

**

*

†

PSSI 100 response rates through Week 122

AMAGINE-1 (NRI)

1) Nails 2) Scalp

AMAGINE-1, -2 and -3: Impact of brodalumab on HRQoL through Wk 52

Pooled analysis of AMAGINE-1, -2 and -3. *At baseline, patients were required to have DLQI ≥5AE, adverse events; DLQI, Dermatology Life Quality Index; QoL, quality-of-life

Puig L et al. P1793 Presented at 26th EADV Congress, Geneva, Switzerland, September 13–17, 2017

94,2

78

0

20

40

60

80

100

12 16 20 24 28 32 36 40 44 48 52

Pro

po

rtio

n o

f p

atie

nts

(%

)

Week

DLQI improvement ≥5*

DLQI 0 or 1

Proportion of patients achieving

DLQI ≥5 or 0/1 through Week 52 (as observed)

Brodalumab Provides Robust and Sustained Levels of

Efficacy in Moderate-to-severe Psoriasis: 120 Weeks of

Treatment in the AMAGINE 2 Study

PASI Responses with BRO 210mg q2w Treatment Through Week 120 of AMAGINE-2

100%=all patients entering OLE;

as observed

Lebwohl et al. EADV 2017 P1790.

PASI75

PASI90

PASI100

Brodalumab Provides Robust and Sustained Levels of

Efficacy in Moderate-to-severe Psoriasis: 120 Weeks of

Treatment in the AMAGINE 2 Study

PASI Responses with BRO 210mg q2w Treatment Through Week 120 of AMAGINE-2

100%=all patients entering OLE;

as observed

Lebwohl et al. EADV 2017 P1790.

PASI75

PASI90

PASI100

Fazit Brodalumab:

a) Hohe PASI-Response

b) Stabile Langzeitdaten >2 J.

c) Keine Sicherheitssignale

• Kyntheum® is available as an autionjector or a prefilled syringe

• With each at a dosage of 210 mg Brodalumab

• Easy for dosing:

Starting dose 1 Injection (210 mg)

Followed by a 1 injection at week 2 and 3

Maintenance: 1 injection every other week

Dosierungsschema von Brodalumab

IL-17 inhibition Immunogenität?

Overview of subjects with TE-AD-Ab in SKB Phase 3 studies in moderate to severe psoriasis

Subject/studySKB dose

(mg)Prior

biologic

Week of positive signal

AD-Ab (titer)

Neutralizing antibodies

Efficacy lossAE

possibly 1g related

PK

1/ERASURE 150 None 12 No titer* Yes No None Normal

2/ERASURE PBO 150 None 24No titer*

No No NoneNot

available

3/FIXTURE 150 None 24 6.41 No No None Normal

4/FIXTURE150

None 12 No titer* No No None Normal

5/SCULPTURE150

FlNone

2452

2.842.69

YesNo None Normal

6/SCULPTURE150

RANNone 52 1.05 Yes

Regained response on retreatment

NoneNot

available

7/SCULPTURE150

FlETN 12 No titer* Not available

Partial responder

None Normal


9/FIXTURE 300 None 24 No titer* No No None Normal

10/SCULPTURE300FI

None 24 No titer* Not available No None Normal

FI, fixed interval; RAN, retreatment as needed. *Titer could not be determined

Reich K, et al. Br J Dermatol. 2017; 176:752-758

Immunogenicity of Secukinumab

Overview of subjects with TE-AD-Ab in SKB Phase 3 studies in moderate to severe psoriasis

Subject/studySKB dose

(mg)Prior

biologic

Week of positive signal

AD-Ab (titer)

Neutralizing antibodies

Efficacy lossAE

possibly 1g related

PK

1/ERASURE 150 None 12 No titer* Yes No None Normal

2/ERASURE PBO 150 None 24No titer*

No No NoneNot

available


4/FIXTURE150

None 12 No titer* No No None Normal

5/SCULPTURE150

FlNone

2452

2.842.69

YesNo None Normal

6/SCULPTURE150

RANNone 52 1.05 Yes

Regained response on retreatment

NoneNot

available

7/SCULPTURE150

FlETN 12 No titer* Not available

Partial responder

None Normal


9/FIXTURE 300 None 24 No titer* No No None Normal

10/SCULPTURE300FI

None 24 No titer* Not available No None Normal

FI, fixed interval; RAN, retreatment as needed. *Titer could not be determined

Reich K, et al. Br J Dermatol. 2017; 176:752-758

Immunogenicity of Secukinumab

Fazit Immunogenität bei

anti-IL-17-Ak:

a) Funktionell nicht

bedeutend

b) beste Daten für

Secukinumab

Zusammenfassung: Status IL-17 inhibition

• EMA label: Secukinumab, Ixekizumab, Brodalumab

• Schnelle und hohe Response (PASI 90/100)– SEC>ETN, SEC>UST, IXE>ETN, IXE>UST, SEC>FAEs, IXE>FAEs, MTX

• Effektiv bei vielen Pso-Manifestationen (SEC; scalp, nails,

palmoplantar, PsA)

• Langzeit-Response bei allen 3 Präparaten

• Diskussion über “controlled disease/disease modification“ in

Subgruppe von Patienten

• Unterschiede in der klinisch relevanten Immunogenität?

• Erste Evidenz für potentiell kardioprotektiven Effekt (SEC)

SEC=Secukinumab; IXE=Ixekizumab; BRO=Brodalumab

ETN=Etanercept; FAE=Fumarsäureester; MTX=Metothrexat; UST=Ustekinumab

IL-23 inhibition Guselkumab

Tildrakizumab

Risankizumab



Entwicklungs-phase

Pso 1°

Pso 2°

PsA


















CVderm 2019

Leitfragen:

Wie sehen die PASI-Raten aus?

Welche Differenzierung zu TNF-Antagonisten

und zu anti-IL-17?

Safety?

Guselkumab bei Psoriasis

VOYAGE 1

Guselkumab versus Adalimumab – PASI

PASI 75

Perc

en

tag

e o

f P

ati

en

ts (

%)

PASI 90 PASI 100

Weeks WeeksWeeks

Placebo

(n=174)

Guselkumab

(n=329)

Adalimumab

(n=334)

Placebo → Guselkumab

(n=165)

1

†P<0.001 Gus vs. ADA*P<0.001 Gus vs. placebo

*

††

*

††

*

† †

Blauvelt, A, et al. Am Acad Dermatol. 2017;76(3):405-417.

ADA, Adalimumab; Gus, Guselkumab; PASI, Psoriasis Area and Severity Index.

Guselkumab: Voyage 124 / 48 Wochen

70,075,2

2,4

48,5

46,854,8

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Wochen

VOYAGE 2

Guselkumab (n=496)

Placebo→Guselkumab (n=248)

Adalimumab (n=248)

73,380,2

2,9

46,1

49,7 53

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Pa

tie

nte

n(%

)

Wochen

VOYAGE 1

Guselkumab (n=329)

Placebo→Guselkumab (n=174)

Adalimumab (n=334)

*p<0.001 vs. ADA

***

*

Blauvelt A et al. J Am Acad Dermatol. 2017 Mar;76(3):405-417 VOYAGE-IReich K et al. Am Acad Dermatol. 2017 Mar;76(3):418-431 VOYAGE II

Wirkstoff Guselkumab in Studienphase IIIWirkstoff Guselkumab noch nicht zugelassen

Guselkumab: PASI 9024 / 28 Wochen

73,380,2

76,3

2,9

46,1

81,8

49,7 5347,9

0

20

40

60

80

100

0 8 16 24 32 40 48

Pa

tie

nte

n(%

)

Weeks

Guselkumab (n=329) Placebo→Guselkumab (n=174) Adalimumab (n=334)

*

*

*

*p<0.001 vs. ADA

Blauvelt A et al. J Am Acad Dermatol. 2017 Mar;76(3):405-417 VOYAGE-IWirkstoff Guselkumab in Studienphase III

Wirkstoff Guselkumab nicht zugelassen

Guselkumab: PASI 9048 Wochen

VOYAGE 1 – Psoriasis Distribution of PASI Responsesat Week 48

Blauvelt, A, et al. Am Acad Dermatol. 2017;76(3):405-417.

PASI, Psoriasis Area and Severity Index.

VOYAGE 1: Prespecified endpoints of PASI 90 and PASI 100 response with guselkumab through 2

years

Griffiths CEM, et al. EADV 2017; D3T01.I Sponsored by Janssen Clinical Research and Development LLC

PASI 90 PASI 100

GUS Placebo→GUS ADA →GUS

n= 329 329 307 290

n= 174 165 161 158

n= 334 334 279 158

n= 329 329 307 290

n= 174 165 161 158

n= 334 334 279 158

0

20

012

Weeks

100

40

80

60

4 20 443628 52 60 847668 92 100

Pa

tie

nts

(%

)

24.0

46.6

50.555.1

51.6

49.0

0

20

012

Weeks

100

40

80

60

4 20 443628 52 60 847668 92 100

Pa

tie

nts

(%

)

50.5

78.9

80.1

82.382.1

81.1

NRI=72.3

NRI=43.2

VOYAGE 2 – Clinical Efficacy in Guselkumab Maintenance and Withdrawal from Weeks 28 to 48

Reich K, et al. J Am Acad Dermatol. 2017;76(3):418-431. & Janssen data on file.

†Through week 48, a small number of patients (n=16) were retreated with guselkumab.

PASI, Psoriasis Area and Severity Index.

Guselkumab

(n=193)

Withdrawal†

(n=182)

*P<0.001

PASI 75 PASI 100PASI 90

Weeks WeeksWeeks

88.6

36.8

‡Estimated median time to loss of PASI 90

response was 8.6 weeks for subjects in the

adalimumab group.

Estimated median time to loss of

PASI 90 response was 15.2 weeks

from Week 28‡

p<0.001

p=0.023 (post hoc)p=0.002

Primary Endpoint

Deodhar A, et al. ACR 2016. LB Abstract #4L.

ACR, American College of Rheumatology

Guselkumab PsA Phase II

ACR 20/50/70 Responses at Week 24

Percent of Patients with Complete Resolution of Enthesitisand Dactylitis at Week 24

p=0.012

in Patients with Enthesitis at Baseline

p=0.001

in Patients with Dactylitis at Baseline

Enthesitis Dactylitis



Percent of Patients with Complete Resolution of Enthesitisand Dactylitis at Week 24

p=0.012

in Patients with Enthesitis at Baseline

p=0.001

in Patients with Dactylitis at Baseline

Enthesitis Dactylitis

Fazit Guselkumab:

a) Hohe Ansprechquoten

b) Äußerst nachhaltige

Langzeitdaten

c) Wirksamkeit bei PsA



• Tremfya® ist als Autoinjektor oder Fertigspritze verfügbar

• Jede enthält 100 mg Guselkumab

• Dosierung:

Startdosis 1 Injektion (100 mg) s.c.

1 Injektion (100 mg) nach 4 Wochen

1 Injektion (100 mg) alle 8 Wochen während der Erhaltungsphase (beginnendnach 4 Wochen)

Tremfya®: Administration und Dosierung


Tildrakizumab

Risankizumab

Leitfragen:


Welche Differenzierung zu Guselkumab?

Safety?

Tildrakizumab bei Psoriasis

reSURFACE 1 and 2:Overall efficacy after 12 and 28 weeks

Association Between Psoriasis Area and Severity Index and

Physician’s Global Assessment Responses in Moderate-to-

Severe Chronic Plaque Psoriasis Studies of Tildrakizumab

Kristian Reich1; Kim A. Papp2; Andrew Blauvelt3; Stephen K. Tyring4;

Rodney Sinclair5; Diamant Thaci6; Qing Li7; Nicole Cichanowitz7;

Stuart Green7; Carmen La Rosa7

1 SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany; 2K. Papp Clinical Research and

Probity Medical Research, Waterloo, Ontario, Canada; 3Oregon Medical Research Center, Portland, OR, USA; 4Department of Dermatology, University of Texas, Houston, TX, USA; 5University of Melbourne, Melbourne, VIC, Australia; 6University of Lübeck, Lübeck, Germany; 7Merck & Co., Inc., Kenilworth, NJ, USA

sain_195865-0001-EADV_ePoster_PASI_V2.00 08/15/2017

European Academy of Dermatology and Venereology, Output Size: 47.81” x 33.11” Scale: 200%

INTRODUCTION

• Tildrakizumab (TIL) is a high-affinity, humanized, IgG1/κ, anti-IL-23p19 monoclonal antibody under development for the treatment of moderate-to-severe chronic plaque psoriasis

• TIL has been shown to result in significantly higher Psoriasis Area and Severity Index (PASI) 75, 90, and 100 and Physician’s Global Assessment (PGA) response rates compared with placebo1,2

• PASI and PGA are the most commonly used measures of psoriasis severity

• The association between PASI improvement and PGA response has not been investigated for treatment with TIL

OBJECTIVE

• To assess whether there was an association between PASI and PGA responses using data from two Phase 3 studies of TIL

MATERIALS & METHODS

• Two randomized controlled studies of TIL for chronic plaque psoriasis, reSURFACE 1 (Phase 3; NCT01722331) and reSURFACE 2 (Phase 3; NCT01729754), have been previously described2

• Patients in the studies were adults with moderate to severe plaque psoriasis, defined as ≥10% body surface area, ≥3 PGA, and PASI ≥12

• In Part 1 (weeks 1–12) of the studies, patients were randomized to subcutaneous TIL 200 mg, 100 mg, or placebo, and treatment was administered at weeks 0 and 4

– In reSURFACE 2, etanercept (ETN) 50 mg administered 2x/week was an additional treatment arm

• In Part 2 (weeks 12–28) of the studies, all patients receiving placebo in Part 1 were re-randomized to TIL 200 mg or 100 mg and received TIL at weeks 12, 16, and 28

– Patients receiving TIL in Part 1 continued their originally randomized treatment and received a dose of TIL at week 16

– Patients receiving ETN in Part 1 of reSURFACE 2 continued ETN, but administered 1x/week

• Co-primary endpoints in both studies were the proportion of patients achieving at least PASI 75 and the proportion achieving a PGA score of “clear” or “minimal,” with at least a 2-grade reduction from baseline (PGA response) at week 12

– The proportion achieving PASI 90 and 100 at week 12 were key secondary endpoints

– The proportion achieving PASI 75 and PGA score of ‘clear’ or ‘minimal’ with at least a 2-grade reduction from baseline (PGA response), at weeks 12 and 28 vs ETN were key secondary endpoints in reSURFACE 2

CONCLUSIONS

• There was a high and significant association between PASI 75, PASI 90, or PASI 100 responses and achieving PGA 0/1 in tildrakizumab studies at weeks 12 and 28 in patients with moderate-to-severe chronic plaque psoriasis

• PASI 100 is more strongly associated with PGA response than PASI 75 or PASI 90 in trials of TIL

References

1. Papp K, et al. Br J Dermatol. 2015;173(4):930-939.

2. Reich K, et al. Lancet. 2017;390(10091):276-288.

Disclosures

K. Reich has served as consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Amgen, Biogen Idec, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck & Co., Inc., Novartis, Pfizer, Vertex, and Takeda. K.A. Papp has provided professional services to AbbVie, Amgen, Anacor, Active Biotech, Allergan, Astellas, AstraZeneca, Basilea, Bayer, Biogen Idec, BMS, Boehringer Ingelheim, CanFite, Celgene, Coherus, Dermira, Eli Lilly, Forward Pharma, Genentech, GSK, Janssen, Kyowa Hako Kirin, Kythera, Leo Pharma, Merck Sharp & Dohme Corp., Merck-Serono, Novartis, Pfizer, Regeneron, Rigel, Roche, Sanofi-Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. A. Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Aclaris, Allergan, Almirall, Amgen, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly and Company, Genentech/Roche, GlaxoSmithKline, Janssen, Leo, Merck & Co., Inc., Novartis, Pfizer, Purdue Pharma, Regeneron, Sandoz, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma, UCB, Valeant, and Vidac and as a paid speaker for Eli Lilly and Company, Janssen, Regeneron, and Sanofi Genzyme. S. Tyring has participated in trials supported by grants from Merck & Co., Inc., Kenilworth, NJ, USA. R. Sinclair has provided professional services to Leo Pharma, Amgen, Novartis, Merck & Co., Inc., Celgene, Coherus Biosciences, Janssen, Regeneron, MedImmune, GlaxoSmithKline, Cutanea, Samson Clinical, Boehringer Ingelheim, Pfizer, MSD, Oncobiologics, Roche, Eli Lilly and Company, and Bayer. D. Thaci has served as consultant, advisory board member, and/or investigator for AbbVie, Almiral, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Dignity, Galderma, GlaxoSmithKline, Janssen-Cilag, Leo Pharma, Lilly, Maruho, Medac, MedImmune, MSD, Novartis, Regeneron, Sandoz, Sanofi-Aventis, Sun Pharma, Takeda, and Pfizer. Q. Li, N. Cichanowitz, S. Green, and C. La Rosa are employees of Merck & Co., Inc., Kenilworth, NJ, USA.

• The proportion of response was analyzed using the Cochran-Mantel-Haenszel test stratified by weight (≤90 kg, >90 kg) and prior exposure to biologics for psoriasis

• At week 12, analysis using nonresponder imputation was prespecified

• At week 28, analysis using nonresponder imputation was prespecified for PASI 75 and PGA response in reSURFACE 2; analysis of observed data was prespecified for PASI 75, 90, 100, and PGA response in reSURFACE 1 and for PASI 90 and 100 in reSURFACE 2

• Chi-square test was used on the odds ratio for the association between the proportion of PASI 75, PASI 90, or PASI 100 and PGA responders using pooled data from patients in all treatment groups who had both PASI and PGA assessments at baseline and weeks 12 or 28

• P-values were not adjusted for multiplicity

RESULTS

• In all, 772 patients were included in reSURFACE 1 and 1,090 patients were included in reSURFACE 2

• For reSURFACE 1/reSURFACE 2, PASI 75, 90, and 100 and PGA 0/1 response rates at week 12 with TIL 200 mg and 100 mg are shown in Figure 1

– Response rates at week 28 are shown in Figure 2

• Statistically significant associations between PASI 75, 90, and 100 responses and PGA 0/1 responses were observed at both weeks 12 and 28 (Table 1; P<0.001 for all associations)

• Interpretation of the odds ratios indicates that, for example, with an odds ratio of 47.0 for PASI 75 and PGA response at week 12, for a PASI 75 responder, the odds of getting a PGA response are ~47 times larger than the odds for a PASI 75 nonresponder

• Thus, based on the odds ratios, the association between PASI 100 and PGA response is higher than that of PASI 75 or PASI 90 and PGA response

• Although only 17.1% -23.7% of patients at week 12 were both PASI 100 and PGA responders, 76.3% -82.9% of patients were still PGA responders (Table 1)

• At week 28, 32.8%-40.8% were both PASI 100 and PGA responders; 59.2% -67.2% of patients were still PGA responders (Table 1)

Table 1. Association Between the Proportion of Patients With PASI and PGA Response at Weeks 12 and 28

PASI Response

reSURFACE 1 reSURFACE 2

PGA Response,% No

PGA Response,% Yes

Odds Ratio (95% CI) P-valuea

PGA Response,% No

PGA Response,% Yes


Week 12 n=374 n=372 n=512 n=510

PASI 75 response

No 83.4 9.7 81.4 11.0

Yes 16.6 90.3 47.0 (30.3, 72.8)

<0.001 18.6 89.0 35.6 (24.9, 50.8)

<0.001

PASI 90 response

No 97.9 43.0 96.5 44.7

Yes 2.1 57.0 60.6 (29.2, 125.8)

<0.001 3.5 55.3 33.9 (20.6, 56.1)

<0.001

PASI 100 response

No 100 76.3 100 82.9

Yes 0 23.7 233.0 (14.4, 3770.3)

<0.001 0 17.1 211.8 (13.1, 3422.8)

<0.001

Week 28 n=186 n=387 n=326 n=528

PASI 75 response

No 51.1 3.4 69.0 8.3

Yes 48.9 96.6 30.0 (16.1, 56.0)

<0.001 31.0 91.7 24.5 (16.6, 36.1)

<0.001

PASI 90 response

No 86.0 24.8 93.3 26.1

Yes 14.0 75.2 18.7 (11.6, 30.0)

<0.001 6.7 73.9 39.1 (24.3, 62.8)

<0.001

PASI 100 response

No 100 59.2 100 67.2

Yes 0 40.8 257.6

(15.9, 4164.4)

<0.001 0 32.8 318.7

(19.8, 5136.3)

<0.001

PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment.aP-values not adjusted for multiplicity.

Figure 1. PASI 75, 90, and 100 and PGA 0/1 Response

Rates With TIL in reSURFACE 1 and 2 at Week 12.

Nonresponder imputation was prespecified.

0

10

20

30

40

50

60

70

80

90

100

PASI 75 PASI 90 PASI 100 PGA 0/1

Resp

on

se R

ate

, %

reSURFACE 1: Week 12 TIL 200 mg

TIL 100 mg

0

10

20

30

40

50

60

70

80

90

100


Re

spo

nse R

ate

, %

reSURFACE 2: Week 12

62

35

14

5964

35

14

58

66

37

12

5961

39

12

55

PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment; TIL, tildrakizumab.



Nonresponder imputation was prespecified for PASI

75 and PGA in reSURFACE 2; analysis of observed

data was prespecified for all other endpoints shown.

82

59

32

69

80

52

24

66

0

10

20

30

40

50

60

70

80

90

100


Resp

onse

Rate

, %


TIL 100 mg

73

58

27

6974

56

23

65

0

10

20

30

40

50

60

70

80

90

100


Resp

on

se R

ate

, %



Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.Presented at the 26th EADV Congress; Geneva, Switzerland; 13-17 September 2017.

P1726

Reich K, EADV poster 2017

Association Between Psoriasis Area and Severity Index and

Physician’s Global Assessment Responses in Moderate-to-

Severe Chronic Plaque Psoriasis Studies of Tildrakizumab

Kristian Reich1; Kim A. Papp2; Andrew Blauvelt3; Stephen K. Tyring4;

Rodney Sinclair5; Diamant Thaci6; Qing Li7; Nicole Cichanowitz7;

Stuart Green7; Carmen La Rosa7

1 SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany; 2K. Papp Clinical Research and

Probity Medical Research, Waterloo, Ontario, Canada; 3Oregon Medical Research Center, Portland, OR, USA; 4Department of Dermatology, University of Texas, Houston, TX, USA; 5University of Melbourne, Melbourne, VIC, Australia; 6University of Lübeck, Lübeck, Germany; 7Merck & Co., Inc., Kenilworth, NJ, USA

sain_195865-0001-EADV_ePoster_PASI_V2.00 08/15/2017

European Academy of Dermatology and Venereology, Output Size: 47.81” x 33.11” Scale: 200%

INTRODUCTION

• Tildrakizumab (TIL) is a high-affinity, humanized, IgG1/κ, anti-IL-23p19 monoclonal antibody under development for the treatment of moderate-to-severe chronic plaque psoriasis

• TIL has been shown to result in significantly higher Psoriasis Area and Severity Index (PASI) 75, 90, and 100 and Physician’s Global Assessment (PGA) response rates compared with placebo1,2

• PASI and PGA are the most commonly used measures of psoriasis severity

• The association between PASI improvement and PGA response has not been investigated for treatment with TIL

OBJECTIVE

• To assess whether there was an association between PASI and PGA responses using data from two Phase 3 studies of TIL

MATERIALS & METHODS

• Two randomized controlled studies of TIL for chronic plaque psoriasis, reSURFACE 1 (Phase 3; NCT01722331) and reSURFACE 2 (Phase 3; NCT01729754), have been previously described2

• Patients in the studies were adults with moderate to severe plaque psoriasis, defined as ≥10% body surface area, ≥3 PGA, and PASI ≥12

• In Part 1 (weeks 1–12) of the studies, patients were randomized to subcutaneous TIL 200 mg, 100 mg, or placebo, and treatment was administered at weeks 0 and 4

– In reSURFACE 2, etanercept (ETN) 50 mg administered 2x/week was an additional treatment arm

• In Part 2 (weeks 12–28) of the studies, all patients receiving placebo in Part 1 were re-randomized to TIL 200 mg or 100 mg and received TIL at weeks 12, 16, and 28

– Patients receiving TIL in Part 1 continued their originally randomized treatment and received a dose of TIL at week 16

– Patients receiving ETN in Part 1 of reSURFACE 2 continued ETN, but administered 1x/week

• Co-primary endpoints in both studies were the proportion of patients achieving at least PASI 75 and the proportion achieving a PGA score of “clear” or “minimal,” with at least a 2-grade reduction from baseline (PGA response) at week 12

– The proportion achieving PASI 90 and 100 at week 12 were key secondary endpoints

– The proportion achieving PASI 75 and PGA score of ‘clear’ or ‘minimal’ with at least a 2-grade reduction from baseline (PGA response), at weeks 12 and 28 vs ETN were key secondary endpoints in reSURFACE 2

CONCLUSIONS

• There was a high and significant association between PASI 75, PASI 90, or PASI 100 responses and achieving PGA 0/1 in tildrakizumab studies at weeks 12 and 28 in patients with moderate-to-severe chronic plaque psoriasis

• PASI 100 is more strongly associated with PGA response than PASI 75 or PASI 90 in trials of TIL

References

1. Papp K, et al. Br J Dermatol. 2015;173(4):930-939.

2. Reich K, et al. Lancet. 2017;390(10091):276-288.

Disclosures

K. Reich has served as consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Amgen, Biogen Idec, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck & Co., Inc., Novartis, Pfizer, Vertex, and Takeda. K.A. Papp has provided professional services to AbbVie, Amgen, Anacor, Active Biotech, Allergan, Astellas, AstraZeneca, Basilea, Bayer, Biogen Idec, BMS, Boehringer Ingelheim, CanFite, Celgene, Coherus, Dermira, Eli Lilly, Forward Pharma, Genentech, GSK, Janssen, Kyowa Hako Kirin, Kythera, Leo Pharma, Merck Sharp & Dohme Corp., Merck-Serono, Novartis, Pfizer, Regeneron, Rigel, Roche, Sanofi-Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. A. Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Aclaris, Allergan, Almirall, Amgen, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly and Company, Genentech/Roche, GlaxoSmithKline, Janssen, Leo, Merck & Co., Inc., Novartis, Pfizer, Purdue Pharma, Regeneron, Sandoz, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma, UCB, Valeant, and Vidac and as a paid speaker for Eli Lilly and Company, Janssen, Regeneron, and Sanofi Genzyme. S. Tyring has participated in trials supported by grants from Merck & Co., Inc., Kenilworth, NJ, USA. R. Sinclair has provided professional services to Leo Pharma, Amgen, Novartis, Merck & Co., Inc., Celgene, Coherus Biosciences, Janssen, Regeneron, MedImmune, GlaxoSmithKline, Cutanea, Samson Clinical, Boehringer Ingelheim, Pfizer, MSD, Oncobiologics, Roche, Eli Lilly and Company, and Bayer. D. Thaci has served as consultant, advisory board member, and/or investigator for AbbVie, Almiral, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Dignity, Galderma, GlaxoSmithKline, Janssen-Cilag, Leo Pharma, Lilly, Maruho, Medac, MedImmune, MSD, Novartis, Regeneron, Sandoz, Sanofi-Aventis, Sun Pharma, Takeda, and Pfizer. Q. Li, N. Cichanowitz, S. Green, and C. La Rosa are employees of Merck & Co., Inc., Kenilworth, NJ, USA.

• The proportion of response was analyzed using the Cochran-Mantel-Haenszel test stratified by weight (≤90 kg, >90 kg) and prior exposure to biologics for psoriasis

• At week 12, analysis using nonresponder imputation was prespecified

• At week 28, analysis using nonresponder imputation was prespecified for PASI 75 and PGA response in reSURFACE 2; analysis of observed data was prespecified for PASI 75, 90, 100, and PGA response in reSURFACE 1 and for PASI 90 and 100 in reSURFACE 2

• Chi-square test was used on the odds ratio for the association between the proportion of PASI 75, PASI 90, or PASI 100 and PGA responders using pooled data from patients in all treatment groups who had both PASI and PGA assessments at baseline and weeks 12 or 28

• P-values were not adjusted for multiplicity

RESULTS

• In all, 772 patients were included in reSURFACE 1 and 1,090 patients were included in reSURFACE 2

• For reSURFACE 1/reSURFACE 2, PASI 75, 90, and 100 and PGA 0/1 response rates at week 12 with TIL 200 mg and 100 mg are shown in Figure 1

– Response rates at week 28 are shown in Figure 2

• Statistically significant associations between PASI 75, 90, and 100 responses and PGA 0/1 responses were observed at both weeks 12 and 28 (Table 1; P<0.001 for all associations)

• Interpretation of the odds ratios indicates that, for example, with an odds ratio of 47.0 for PASI 75 and PGA response at week 12, for a PASI 75 responder, the odds of getting a PGA response are ~47 times larger than the odds for a PASI 75 nonresponder

• Thus, based on the odds ratios, the association between PASI 100 and PGA response is higher than that of PASI 75 or PASI 90 and PGA response

• Although only 17.1% -23.7% of patients at week 12 were both PASI 100 and PGA responders, 76.3% -82.9% of patients were still PGA responders (Table 1)

• At week 28, 32.8%-40.8% were both PASI 100 and PGA responders; 59.2% -67.2% of patients were still PGA responders (Table 1)

Table 1. Association Between the Proportion of Patients With PASI and PGA Response at Weeks 12 and 28

PASI Response


PGA Response,% No

PGA Response,% Yes


PGA Response,% No

PGA Response,% Yes


Week 12 n=374 n=372 n=512 n=510

PASI 75 response

No 83.4 9.7 81.4 11.0

Yes 16.6 90.3 47.0 (30.3, 72.8)

<0.001 18.6 89.0 35.6 (24.9, 50.8)

<0.001

PASI 90 response

No 97.9 43.0 96.5 44.7

Yes 2.1 57.0 60.6 (29.2, 125.8)

<0.001 3.5 55.3 33.9 (20.6, 56.1)

<0.001

PASI 100 response

No 100 76.3 100 82.9

Yes 0 23.7 233.0 (14.4, 3770.3)

<0.001 0 17.1 211.8 (13.1, 3422.8)

<0.001

Week 28 n=186 n=387 n=326 n=528

PASI 75 response

No 51.1 3.4 69.0 8.3

Yes 48.9 96.6 30.0 (16.1, 56.0)

<0.001 31.0 91.7 24.5 (16.6, 36.1)

<0.001

PASI 90 response

No 86.0 24.8 93.3 26.1

Yes 14.0 75.2 18.7 (11.6, 30.0)

<0.001 6.7 73.9 39.1 (24.3, 62.8)

<0.001

PASI 100 response

No 100 59.2 100 67.2

Yes 0 40.8 257.6

(15.9, 4164.4)

<0.001 0 32.8 318.7

(19.8, 5136.3)

<0.001

PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment.aP-values not adjusted for multiplicity.



Nonresponder imputation was prespecified.

0

10

20

30

40

50

60

70

80

90

100


Re

spo

nse R

ate

, %


TIL 100 mg

0

10

20

30

40

50

60

70

80

90

100


Respo

nse

Rate

, %


62

35

14

5964

35

14

58

66

37

12

5961

39

12

55




Nonresponder imputation was prespecified for PASI

75 and PGA in reSURFACE 2; analysis of observed

data was prespecified for all other endpoints shown.

82

59

32

69

80

52

24

66

0

10

20

30

40

50

60

70

80

90

100


Resp

on

se R

ate

, %


TIL 100 mg

73

58

27

6974

56

23

65

0

10

20

30

40

50

60

70

80

90

100


Re

spo

nse

Rate

, %



Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.Presented at the 26th EADV Congress; Geneva, Switzerland; 13-17 September 2017.

P1726

Tildrakizumab in moderate-to-severe chronic plaque psoriasis: Pooled analysis from 3 RCTs

reSURFACE 1/2 PASI and P05495

• 1⁰ endpoints: reSURFACE 1 and 2, PASI 75 and PGA 0/1 at Week 16; Study P05495, PASI 75 at Week 16

W0-28: patients who received drug from W0 to W28; as observed

Scott E, et al. EADV 2017, P1724 Sponsored by Sun Pharmaceutical Industries Ltd

TIL 200 mg TIL 100 mg ETN

20

04

40

60

100

80

PASI 75

Re

sp

on

se

ra

te (

%)

8 12 16 20 24 28

TIL 200 mg N 611 599 602 593 581

TIL 100 mg, N 610 603 598 583 575

ETN, N 306 298 288 283 277

20

04

40

60

100

80

PASI 100

8 12 16 20 24 28

611 599 602 593 581

610 603 598 583 575

306 298 288 283 277

20

04

40

60

100

80

PASI 90

8 12 16 20 24 28

611 599 602 593 581

610 603 598 583 575

306 298 288 283 277

Weeks

reSURFACE 1 and 2:Overall efficacy after 2 years of treatment

FAS population; observed data. Patients entering OLE after 64 or 52 weeks (reSURFACE 1 and reSURFACE 2) were

at least partial responders (PASI ≥50)

Papp K, et al. EADV 2017, D3T01.1H Sponsored by Merck & Co., Inc.


reSURFACE 1 and 2:Overall efficacy after 2 years of treatment

FAS population; observed data. Patients entering OLE after 64 or 52 weeks (reSURFACE 1 and reSURFACE 2) were

at least partial responders (PASI ≥50)

Papp K, et al. EADV 2017, D3T01.1H Sponsored by Merck & Co., Inc.


Fazit Tildrakizumab:

a) Schlechtere Outcomes als

Guselkumab

b) Keine Dosisabhängigkeit in

den Studien


Tildrakizumab

Risankizumab

Leitfragen:


Vergleich mit Ustekinumab?

Welche Differenzierung zu Guselkumab und

Tildrakizumab?

Safety?

Risankizumab bei Psoriasis

aPlacebo only at Weeks 4 and 16; bDosed per label (45 mg in patients with body weight ≤100 kg; 90 mg with body

weight >100 kg at randomization);cpatients completing Week 48 of the “parent” study (NCT02054481) were eligible to enroll in the OLE (NCT02203851);

patients with <PASI 50 during follow-up were eligible to enter the OLE without completing the “parent” study; dpatients

who failed to achieve PASI 90 in the OLE could increase their dose to 180 mg starting at Week 12, however, all

patients received RZK 90 mg for study period reported here

Venkitaramani D, et al. EADV 2017, P1812, P1816 Sponsored by AbbVie and Sponsored by Boehringer Ingelheim

Phase 2 trial of risankizumab in psoriasis: Study design of double-blind study and open-

label extension

Follow-upc

RKZ 18 mg sca

Ra

nd

om

ize

d 1

:1:1

:1

n=43

n=41

n=42

Dose

RKZ 90 mg sc

RKZ 180 mg sc

n=40UST 45/90 mg scb

Week 0 12 484 16 24

Double-blind (n=166) Open-label extension (n=110)

n=22

n=28

n=33

n=27

RKZ 90 mg sc

Week 0 12 16 24

OLE Week 24: Efficacy and safetyPrimary endpoint: PASI 90 at Week 12

71

Risankizumab Phase 2 PsO

Efficacy data (primary EP: PASI 90, Week 12)

*

**

mITT-NRI; *p = 0.0013 vs.

UST; **p < 0.0001 vs. UST

Papp KA, Blauvelt A, et al. N Engl J Med. 2017 Apr 20;376(16):1551-1560.

Dose Lastdose

Dose*

PASI90 - Ansprechen

EP, endpoint; mITT, modified intention-to-treat; NRI, non-responder imputation; PASI, Psoriasis Area and Severity Index; Risa, risankizumab; sPGA, Static Physicians Global Assessment; UST, ustekinumab.


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Risankizumab

(Plaque-Psoriasis) –

Nutzenbewertung gemäß § 35a SGB V

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Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - 10 -

Fragestellung B: erwachsene Patientinnen und Patienten, bei denen eine systemische

Therapie unzureichend angesprochen hat oder die diese nicht vertragen haben

In der Gesamtschau ergeben sich ausschließlich positive Effekte – teilweise nur in Subgrup-

pen – mit unterschiedlicher Ergebnissicherheit (Beleg oder Hinweis) für Risankizumab im

Vergleich zu Ustekinumab in den Endpunktkategorien Morbidität und gesundheitsbezogene

Lebensqualität. Das Ausmaß reicht dabei von beträchtlich bis gering bzw. nicht quantifizierbar.

Für die Remission (PASI 100) ergibt sich ein Beleg für einen beträchtlichen Zusatznutzen.

Zusammenfassend ergibt sich daher für erwachsene Patientinnen und Patienten mit mittel-

schwerer bis schwerer Plaque-Psoriasis, die auf eine systemische Therapie unzureichend

angesprochen oder diese nicht vertragen haben ein Beleg für einen beträchtlichen Zusatznutzen

von Risankizumab gegenüber Ustekinumab.

Tabelle 3 zeigt eine Zusammenfassung von Wahrscheinlichkeit und Ausmaß des Zusatznutzens

von Risankizumab.

Tabelle 3: Risankizumab – Wahrscheinlichkeit und Ausmaß des Zusatznutzens

Frage-stellung

Indikation Zweckmäßige Vergleichstherapiea

Wahrscheinlichkeit und Ausmaß des Zusatznutzens

A erwachsene Patientinnen und

Patienten mit mittelschwerer bis

schwerer Plaque-Psoriasis, die

im Rahmen einer erstmaligen

systemischen Therapie nicht für

eine konventionelle Therapie

infrage kommen

Adalimumab oder Guselkumab

oder Ixekizumab oder

Secukinumab

Zusatznutzen nicht belegt

B erwachsene Patientinnen und



auf eine systemische Therapie

unzureichend angesprochen

oder diese nicht vertragen

haben


oder Infliximab oder

Ixekizumab oder Secukinumab

oder Ustekinumab

Beleg für einen beträchtlichen

Zusatznutzen

a: Dargestellt ist jeweils die vom G-BA festgelegte zweckmäßige Vergleichstherapie. In den Fällen, in denen

der pU aufgrund der Festlegung der zweckmäßigen Vergleichstherapie durch den G-BA aus mehreren

Alternativen eine Vergleichstherapie auswählen kann, ist die entsprechende Auswahl des pU fett markiert.

G-BA: Gemeinsamer Bundesausschuss; pU: pharmazeutischer Unternehmer

Das Vorgehen zur Ableitung einer Gesamtaussage zum Zusatznutzen stellt einen Vorschlag des

IQWiG dar. Über den Zusatznutzen beschließt der G-BA.


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Risankizumab






Fragestellung B: erwachsene Patientinnen und Patienten, bei denen eine systemische

Therapie unzureichend angesprochen hat oder die diese nicht vertragen haben

In der Gesamtschau ergeben sich ausschließlich positive Effekte – teilweise nur in Subgrup-

pen – mit unterschiedlicher Ergebnissicherheit (Beleg oder Hinweis) für Risankizumab im

Vergleich zu Ustekinumab in den Endpunktkategorien Morbidität und gesundheitsbezogene

Lebensqualität. Das Ausmaß reicht dabei von beträchtlich bis gering bzw. nicht quantifizierbar.

Für die Remission (PASI 100) ergibt sich ein Beleg für einen beträchtlichen Zusatznutzen.

Zusammenfassend ergibt sich daher für erwachsene Patientinnen und Patienten mit mittel-

schwerer bis schwerer Plaque-Psoriasis, die auf eine systemische Therapie unzureichend

angesprochen oder diese nicht vertragen haben ein Beleg für einen beträchtlichen Zusatznutzen

von Risankizumab gegenüber Ustekinumab.

Tabelle 3 zeigt eine Zusammenfassung von Wahrscheinlichkeit und Ausmaß des Zusatznutzens

von Risankizumab.

Tabelle 3: Risankizumab – Wahrscheinlichkeit und Ausmaß des Zusatznutzens

Frage-stellung

Indikation Zweckmäßige Vergleichstherapiea

Wahrscheinlichkeit und Ausmaß des Zusatznutzens

A erwachsene Patientinnen und



im Rahmen einer erstmaligen

systemischen Therapie nicht für

eine konventionelle Therapie

infrage kommen


oder Ixekizumab oder

Secukinumab

Zusatznutzen nicht belegt

B erwachsene Patientinnen und



auf eine systemische Therapie

unzureichend angesprochen

oder diese nicht vertragen

haben


oder Infliximab oder

Ixekizumab oder Secukinumab

oder Ustekinumab

Beleg für einen beträchtlichen

Zusatznutzen

a: Dargestellt ist jeweils die vom G-BA festgelegte zweckmäßige Vergleichstherapie. In den Fällen, in denen

der pU aufgrund der Festlegung der zweckmäßigen Vergleichstherapie durch den G-BA aus mehreren

Alternativen eine Vergleichstherapie auswählen kann, ist die entsprechende Auswahl des pU fett markiert.

G-BA: Gemeinsamer Bundesausschuss; pU: pharmazeutischer Unternehmer

Das Vorgehen zur Ableitung einer Gesamtaussage zum Zusatznutzen stellt einen Vorschlag des

IQWiG dar. Über den Zusatznutzen beschließt der G-BA.


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Risankizumab






Tabelle 8: Charakterisierung der Studienpopulationen – RCT, direkter Vergleich:

Risankizumab vs. Ustekinumab (Fragestellung B)

Studie

Charakteristika

Kategorie

UltIMMa-1 UltIMMa-2

Risankizumab Ustekinumab Risankizumab Ustekinumab

Na = 100 Na = 34 Na = 90 Na = 36

Alter [Jahre], MW (SD) 50 (12) 47 (14) 45 (12) 47 (14)

Geschlecht [w / m], % 28 / 72 26 / 74 36 / 64 31 / 69

Gewicht, n (%)

≤ 100 kg 81 (81,0) 28 (82,4) 67 (74,4) 27 (75,0)

> 100 kg 19 (19,0) 6 (17,6) 23 (25,6) 9 (25,0)

Ethnie, n (%)

weiß 62 (62,0) 21 (61,8) 83 (92,2) 35 (97,2)

nicht weiß 38 (38,0) 13 (38,2) 7 (7,8) 1 (2,8)

geografische Region, n (%)

USA 26 (26,0) 7 (20,6) 19 (21,1) 9 (25,0)

Asien 31 (31,0) 10 (29,4) – –

andere 43 (43,0) 17 (50,0) 71 (78,9) 27 (75,0)

Dauer der Erkrankung [Jahre], MW (SD) 19,2 (12,2) 16,6 (9,5) 20,6 (11,2) 21,7 (12,6)

bekannte PsA (diagnostiziert oder im

Verdacht), n (%)

35 (35,0) 7 (20,6) 24 (26,7) 8 (22,2)

Nagelpsoriasis (NAPSI > 0), n (%) 68 (68,0) 25 (73,5) 50 (55,6) 22 (61,1)

Palmoplantare Psoriasis (PPASI > 0),

n (%)

36 (36,0) 11 (32,4) 32 (35,6) 13 (36,1)

Kopfhautpsoriasis (PSSI > 0), n (%) 91 (91,0) 29 (85,3) 80 (88,9) 28 (77,8)

Gesicht- und Halspsoriasis, n (%) k. A. k. A. k. A. k. A.

Genitalpsoriasis, n (%) k. A. k. A. k. A. k. A.

sPGA, n (%)

moderat (3) 80 (80,0) 27 (79,4) 69 (76,7) 32 (88,9)

schwer (4) 20 (20,0) 7 (20,6) 21 (23,3) 4 (11,1)

PASI, MW (SD) 22,5 (9,1) 21,9 (8,1) 21,5 (7,8) 18,4 (6,9)

PASI ≤ 20, n (%) k. A.b k. A.b k. A.b k. A.b

DLQI, MW (SD) 12,2 (6,6) 12,6 (7,0) 13,7 (7,7) 11,5 (6,3)

DLQI > 10, n (%) 58 (58,0) 20 (58,8) 56 (62,2) 19 (52,8)

Vorbehandlung, n (%)c

topische Therapie 30 (30,0) 12 (35,3) 8 (8,9) 3 (8,3)

Fototherapie / Fotochemotherapie 55 (55,0) 17 (50,0) 41 (45,6) 20 (55,6)

nicht biologische systemischer Therapie 63 (63,0) 20 (58,8) 63 (70,0) 26 (72,2)

Biologikatherapie 51 (51,0) 15 (44,1) 47 (52,2) 16 (44,4)

TNF-Antagonist 39 (39,0) 15 (44,1) 36 (40,0) 11 (30,6)

naiv zu systemischer Therapie, n (%) 10 (10,0) 5 (14,7) 11 (12,2) 2 (5,6)

(Fortsetzung)


Dossierbewertung

Auftrag:

Version:

Stand:

A19-41

1.0

29.08.2019


Risankizumab






Tabelle 12: Ergebnisse (Mortalität, Morbidität, gesundheitsbezogene Lebensqualität,

Nebenwirkungen, dichotom) – RCT, direkter Vergleich: Risankizumab vs. Ustekinumab,

(Fragestellung B)

Endpunktkategorie

Endpunkt

Zeitpunkt

Studie

Risankizumab Ustekinumab Risankizumab vs. Ustekinumab

N Patientinnen und Patienten mit Ereignis

n (%)


n (%)

RR [95 %-KI]a; p-Wert

Woche 52

Mortalität

Gesamtmortalität

UltIMMa-1 100 0 (0) 34 0 (0) n. b.

UltIMMa-2 90 0 (0) 36 0 (0) n. b.

Gesamt n. b.

Morbidität

Hautsymptomatik

Remission (PASI 100)b

UltIMMa-1 100 64 (64,0) 34 5 (14,7) 4,47 [1,97; 10,14];

< 0,001

UltIMMa-2 90 56 (62,2) 36 11 (30,6) 2,07 [1,24; 3,47];

0,006

Gesamtc 2,80 [1,80; 4,36];

< 0,001

Remission (PASI 100) –

Sensitivitätsanalyse (LOCF), ergänzend dargestelltd

UltIMMa-1 100 64 (64,0) 34 6 (17,6) 3,71 [1,78; 7,76] ; < 0,001

UltIMMa-2 90 58 (64,4) 35 12 (34,3) 1,92 [1,19; 3,10] ; 0,007

Gesamtc 2,49 [1,66; 3,75] ; < 0,001

Remission (PASI 100) –

Sensitivitätsanalyse (MI), ergänzend dargestellte

UltIMMa-1 100 64 (64,0) 34 5 (14,7) 4,46 [1,97; 10,12] ; < 0,001

UltIMMa-2 90 56,2 (62,4) 36 11 (30,6) 2,08 [1,24; 3,48] ; 0,005

Gesamtc 2,81 [1,80; 4,36] ; < 0,001

(Fortsetzung)


Dossierbewertung

Auftrag:

Version:

Stand:

A19-41

1.0

29.08.2019


Risankizumab






Tabelle 12: Ergebnisse (Mortalität, Morbidität, gesundheitsbezogene Lebensqualität,

Nebenwirkungen, dichotom) – RCT, direkter Vergleich: Risankizumab vs. Ustekinumab,

(Fragestellung B) (Fortsetzung)

Endpunktkategorie

Endpunkt

Zeitpunkt

Studie

Risankizumab Ustekinumab Risankizumab vs. Ustekinumab


n (%)


n (%)

RR [95 %-KI]a; p-Wert

PASI 90 (ergänzend dargestellt)b

UltIMMa-1 100 86 (86,0) 34 13 (38,2) 2,27 [1,47; 3,50] ; < 0,001

UltIMMa-2 90 74 (82,2) 36 17 (47,2) 1,74 [1,21; 2,48] ; 0,003

Gesamtc 1,97 [1,49; 2,60] ; < 0,001

PASI 75 (ergänzend dargestellt)b

UltIMMa-1 100 92 (92,0) 34 25 (73,5) 1,25 [1,01; 1,54] 0,036f

UltIMMa-2 90 85 (94,4) 36 28 (77,8) 1,21 [0,96; 1,53] ; 0,110

Gesamtc 1,24 [1,08; 1,43] ; 0,002

patientenberichtete Symptomfreiheit

PSS-Juckreiz 0b

UltIMMa-1 100 69 (69,0) 34 13 (38,2) 1,76 [1,13; 2,75];

0,013

UltIMMa-2 90 67 (74,4) 36 14 (38,9) 1,90 [1,25; 2,90];

0,003

Gesamt 1,85 [1,36; 2,51];

< 0,001

PSS-Schmerz 0b

UltIMMa-1 100 82 (82,0) 34 17 (50,0) 1,59 [1,13; 2,25];

0,008

UltIMMa-2 90 75 (83,3) 36 21 (58,3) 1,41 [1,06; 1,88];

0,018

Gesamt 1,49 [1,20; 1,86];

< 0,001

PSS-Rötung 0b

UltIMMa-1 100 68 (68,0) 34 12 (35,3) 1,97 [1,23; 3,16];

0,005

UltIMMa-2 90 68 (75,6) 36 15 (41,7) 1,82 [1,22; 2,71]

0,003

Gesamt 1,85 [1,37; 2,52];

< 0,001

(Fortsetzung)

• Interessante neue Therapieoptionen mit stabilen Langzeit-

Responses (“longevity") und patientenfreundlichen

Injektionsintervallen

• Hohe Ansprechraten (PASI 90/100)– Guselkumab >> Adalimumab (Phase III)

– Risankizumab >> Ustekinumab (Phase II) und >> Fumarsäureester

– Tildrakizumab >> Etanercept (Phase III)

• Guselkumab effektiv bei Kopfhaut- und Nagelpsoriasis

• Guselkumab zeigt als erstes anti-IL-23 Biologikum

Wirksamkeit bei PsA, dies auf Gelenksymptome, Enthesitis

und Daktylitis (phase II)

• Insgesamt günstige Nutzen-Risiko-Profile

Zusammenfassung: Status IL-23 inhibition

GUS=Guselkumab; TIL=Tildrakizumab; RIS=Risankizumab

Differenzierung im Langzeitverlauf

Wie können wir die System-

therapeutika ausdifferenzieren?

Comparative Effectiveness Research (CER) and

Network meta-analyses (NMA) in psoriasis

Original Paper

Efficacy of Systemic Treatments for Moderate to Severe Plaque Psoriasis: Systematic Review and Meta-Analysis

Introduction Key Words

Abstract

Aims:

Methods:

Results:

Conclusions:

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• A total of 60 trials meeting all inclusion criteria were included in the NMA

• Risankizumab, ixekizumab, brodalumab, and guselkumab had the highest PASI 90/100 rates at weeks 10-16 among assessed treatments; there were no statistically significant differences among these four treatments

• Risankizumab, ixekizumab, brodalumab, and guselkumab had significantly higher PASI 90/100 rates compared to etanercept, adalimumab, ustekinumab, certolizumab pegol, tildrakizumab, dimethyl fumarate, and apremilast; risankizumab, ixekizumab and brodalumab also had significantly higher rates than secukinumab and infliximab (p-value < 0.05)

Abbreviations: PBO: placebo, DF: dimethyl fumarate, APR: apremilast, ADA: adalimumab, ETA: etanercept, INF: infliximab, CZP: certolizumab pegol, UST: ustekinumab, SEC: secukinumab, IXE: ixekizumab, BRO: brodalumab, RIS: risankizumab, GUS: guselkumab, TIL: tildrakizumab, PASI: psoriasis area severity index Note: Error bars “ “denotes a 95% credible interval. Difference between treatments was tested at a significant level of 0.05.

Meta-Analysis Results at Weeks 12-16

April W. Armstrong,1 Luis Puig,2 Avani Joshi,3 Martha Skup,3 Svetlana Kalabina,4 David Williams,3 Junlong Li,5 Viviana Garcia-Horton,6 Keith A. Betts,7 Matthias

Augustin8 The Comparative Efficacy for Novel Treatments of Moderate to Severe Plaque Psoriasis Oral presentation and ePoster (#10006) AAD, Washington 2019.



Meta-Analysis Results at Weeks 44-60• A total of 23 trials on 10 treatments meeting all inclusion criteria were included in the meta-analysis. Long-term data were only

reported for the 50mg BIW dose for etanercept; PASI 100 were not reported for apremilast, etanercept, and infliximab

• Risankizumab, brodalumab, ixekizumab, guselkumab, and secukinumab had the highest estimated PASI 90/100 response rates at weeks 44-60, whose rates were significantly higher than etanercept, infliximab, adalimumab, ustekinumab and apremilast

• Among those five biologics, risankizumab had a significantly higher PASI 90 rate than ixekizumab and secukinumab; in addition, risankizumab, brodalumab, and ixekizumab had significantly higher PASI 100 rates than secukinumab, while risankizumab and ixekizumab also had significantly higher PASI 100 rates than guselkumab (p-value < 0.05)

• A sensitivity analysis including only trials that reported non-response imputed (NRI) data had similar results

Abbreviations: APR: apremilast, ADA: adalimumab, ETA: etanercept, INF: infliximab, UST: ustekinumab, SEC: secukinumab, IXE: ixekizumab, BRO: brodalumab, RIS: risankizumab, GUS: guselkumab, PASI: psoriasis area severity index, BIW: twice weeklyNote: Error bar “ “ denotes a 95% confidence interval. Difference between treatments was tested at a significant level of 0.05.

April W. Armstrong,1 Luis Puig,2 Avani Joshi,3 Martha Skup,3 Svetlana Kalabina,4 David Williams,3 Junlong Li,5 Viviana Garcia-Horton,6 Keith A. Betts,7 Matthias

Augustin8 The Comparative Efficacy for Novel Treatments of Moderate to Severe Plaque Psoriasis Oral presentation and ePoster (#10006) AAD, Washington 2019.

Fazit für die Praxis

Biologika bei PSoriasis

Fazit Biologics:

Fazit: Schnelles und langfristiges Ansprechen

Schnelles Ansprechen

Fazit: Vollständiges Ansprechen


Vollständiges Ansprechen

Fazit Biologics:

Fazit: Sichere Therapie ohne Nebenwirkungen Nebenwirkungen



Sichere Therapien

Weniger Nebenwirkungen

Fazit Biologics:

Fazit: Weniger Zeitaufwand



Sichere Therapien

Weniger Nebenwirkungen

Weniger Zeitaufwand

Fazit Biologics:

Herzlichen Dank für die

Aufmerksamkeit!

BEFORE 2004 2004 2008 2015

PASI 90Near-complete

resolution4

PASI 50Clinically

meaningfulresponsea1,2

PASI 100Complete

resolution5

2017 & BEYOND

PASI 75Significant response3

aMinimal response=PASI 25;1. Carlin CS, et al. J Am Acad Dermatol. 2004;50:859-866. 2. Leonardi CL, et al. N Engl J Med. 2003;349:2014-2022. 3. Papp KA, et al. Lancet. 2008;371:1675-1684. 4. Leonardi CL, et al. N Engl J Med. 2012;366:1190-1199. 5. Heydendael VMR, et al. N Engl J Med. 2003;349:658-665.

Entwicklung von Therapiezielen

?

Checkliste: Indikationsstellung zur Systemtherapie

Documents

Thema: Biologika Teil 2: IL-17 und IL-23 Blockade