Biologics in Psoriasis: 2018 and Beyond. Jeffrey M. Sobell MD Tufts University School of Medicine SkinCare Physicians Ora Clinical Research

Transcription

1 Biologics in Psoriasis: 218 and Beyond Jeffrey M. Sobell MD Tufts University School of Medicine SkinCare Physicians Ora Clinical Research

2 Biologics in Psoriasis FDA approved TNF inhibitors Etanercept Adalimumab Infliximab P4 inhibitors Ustekinumab IL-17 inhibitors Secukinumab Ixekizumab Brodalumab IL-23 inhibitors Guselkumab Investigational IL-23 inhibitors Tildrakizumab Risankizumab Mirikizumab TNF inhibitors Certolizumab pegol

3 Key immune cells and mediators in Initiation psoriasis Perpetuation Natural killer T cell Plasmacytoid dendritic cell Keratinocyte TNF-α IFN-γ IFN-α Macrophage TNF-α IL-1β IL-6 TNF-α Activation Myeloid dendritic cell IL-12 IL-23 Th1 cell Th17 cell TNF-α IFN-γ Keratinocyte IL-17A IL-17F IL-22 Hypothetical model based in part on non-clinical data Antimicrobial peptides IL-1β IL-6 TNF-α S1 CXCL8 CXCL9 CXCL1 CXCL11 CCL2 Modified from: Nestle FO, et al. N Engl J Med 29;361:

4 Properties of TNF-α Inhibitors Property TNF-α Inhibitor Adalimumab Etanercept Infliximab Structure Contains C human H 3 C H 2 Human CDR Fc region of Human p75 Human (IgG1) (IgG1) regions Human IgG1 TNF receptor EC Half-life 1 2 days 4 5 days domain days Administration Self-administered subcutaneous injection S S S S S S Self-administered subcutaneous injection Mouse (Binding site for TNF) IV infusion over 1 to 2 hours Lyophilized powder reconstituted with sterile H 2 O Dosage 8 mg day 1, 4 mg days 8 and 22, then 4 mg eow thereafter 5 mg BIW for 3 months; 5 mg weekly thereafter 5 mg/kg via infusion at weeks, 2, 6, then every 8 weeks IgG1 = immunoglobulin G subclass 1; EC = extracellular; CDR = complementarity-determining region; IV = intravenous; eow = every other week; biw = twice weekly. Sources: Humira package insert. AbbVie; Enbrel package insert. Amgen; Remicade package insert. Janssen.

5 Etanercept Step-Down Therapy: PASI Response Through Week 48 % of Patients % 49% 21% 79% 54% 21% 77% 48% 23% Etanercept 5 mg BIW Week Etanercept 25 mg BIW PASI 5 PASI 75 PASI 9 mitt=modified intent to treat; LOCF=last observation carried forward P <.1 vs placebo. 74% 45% 23% n = 194 mitt LOCF analysis mitt (n = 194) differs from ITT (n = 23) because mitt includes patients who received at least 1 dose of drug, while ITT includes all patients randomized to this study arm. Papp KA et al. Br J Dermatol. 25;152:

6 Adalimumab: PASI improvement at Week 16 (REVEAL) Menter et al. JAAD 28;58(1):16-15.

7 1 Infliximab: PASI 75 Response Through Week 5 61% of randomized patients (including those who withdrew for any reason) maintained PASI 75 for the long term (n=281 at Week 5) Percent of Patients % Patients who stayed on therap as scheduled (n=286) (n=286) (n=26) (n=234) Weeks Ability to maintain detectable serum levels of infliximab is one of the factors associated with maintenance of response over time Reich K, et al. Lancet. 25;366: Pre-specified analysis; Per protocol analysis

8 Psoriatic Arthritis: ACR 2 Week Placebo Adalimumab n=162 n=151 Placebo Etanercept n=14 n=11 Placebo Infliximab n=1 n=1 Mease PJ, et al. Arthritis Rheum. 24;5: ; Gladman DD, et al. Arthritis Rheum. 27;56(2): Antoni C, et al. Ann Rheum DIs. 25;64:

9 TNF-α Inhibitor Safety Warnings Serious infections Malignancies Demyelinating disease Congestive heart failure Hepatitis B Hematologic Autoimmunity Live vaccines Rubbert-Roth A. Rheumatology. 212;51:v38-47.

10 Leonardi CL, et al. Lancet. 28;371: Papp KA, et al. Lancet. 28;371: PASI 75 Response at Week 12 (After 2 Doses of Ustekinumab) 1 PHOENIX 1 1 PHOENIX 2 Percent of Patients Placebo 45 mg 9 mg n=255 n=255 n=256 Placebo 45 mg 9 mg n=41 n=49 n=411 P<.1 vs placebo for each dose comparison

11 Ustekinumab: Psoriatic Arthritis ACR 2 Responses Placebo Ustekinumab 45 mg 1 Ustekinumab 9 mg 9 Week 12 Week 24 8 P<.1 P< % 4% 4 5% 42% 3 2 2% 23% 1 Percentage of Patients Nonresponder imputation (NRI) analysis. n=26 n=25 n=24 n=26 n=25 n=24 McInnes I, et al. Lancet. 213;382:

12 Papp K, et al. Br J Dermatol. 213;168(4): Papp K, et al. J Am Acad Dermatol. 213;68(4 suppl): AB25. Abstract P6924. Events per 1 PY Follow-up 2 1 Safety of ustekinumab through up to 5 years Serious Infections NMSC Other Malignancies MACE Year 1 Year 2 Year 3 Year 4 Year 5 Adjudicated MACE included cardiovascular death, myocardial infarction and stroke

13 Secukinumab: ERASURE Study 738 Subjects Design Week -4 to -1 R Induction BL Wk 8 Wk 12 Secukinumab 3 mg Secukinumab 15 mg Placebo R Maintenance Treatment Q4W Treatment Q4W Secukinumab 3 mg Secukinumab 15 mg Q4W Q4W Placebo (responders only) Follow-up Wk 52 Wk 6 Langley RG, et al. Br J Dermatol 213;169:

14 ERASURE: Results through 52 weeks SEK 3 mg (n=245) SEK 15 mg (n=245) Placebo (n=247) b Patients (%) % PASI 75 Response 71.6% 4.5% PASI 9 Response Weeks p<.1 vs placebo at Wk 12. a IGA score of (clear) or 1 (almost clear) and an improvement of at least 2 points on the IGA scale compared with baseline; b One subject did not sign informed consent before starting study procedures and was excluded from analyses Langley RG, et al. Br J Dermatol 213;169:

15 ERASURE: 52 Week Safety Data AEs During entire treatment period (52 weeks) Any secukinumab 15 mg (n=353) Any secukinumab 3 mg (n=349) Placebo (n=247) Summary of Crude Incidence of AEs, n (%) Subjects with any AE(s) 287 (81.3) 286 (81.9) 124 (5.2) Death Serious AEs 19 (5.4) 19 (5.4) 5 (2.) Discontinuations due to AEs 18 (5.1) 12 (3.4) 5 (2.) Exposure-Adjusted Incidence of Most Common AEs, n (IR) Subjects with any AE(s) 287 (269.4) 286 (245.5) 124 (323.) Nasopharyngitis 69 (26.2) 57 (2.9) 2 (3.8) URTI 36 (12.7) 32 (11.1) 2 (3.) Headache 24 (8.4) 31 (1.9) 1 (15.1) Arthralgia 13 (4.4) 14 (4.7) 8 (12.) Psoriasis worsening 9 (3.) 8 (2.6) 1 (15.1) Nausea 8 (2.7) 3 (1.) 8 (12.) For the entire treatment period Mean exposure: 313. (15 mg) and 32.7 (3 mg) days for secukinumab vs days for placebo No MACEs during the induction period. During the maintenance period, 4 adjudicated MACEs occurred in 3 subjects: ischemic stroke in one subject on secukinumab 15 mg; CVA in one subject (originally on placebo; re-randomized to secukinumab 3 mg at Wk 12) and 2 incidences of MI in one subject on secukinumab 3 mg No definitive conclusions regarding secukinumab and MACE risk can be drawn due to the rarity of events and small exposure to placebo Treatment-emergent anti-drug antibodies were detected in 1 (.14%) subject, who was receiving 15 mg secukinumab, among 738 subjects tested, and were transient (detected only at Wk 12) Langley RG, et al. Br J Dermatol 213;169:

16 Secukinumab: FIXTURE study design Induction Maintenance Follow-up Baseline Week 8 Week 12 Week 52 Week 6 R Secukinumab 3 mg (n=327) Secukinumab 15 mg (n=327) Placebo (n=326) Etanercept 5 mg BIW (n=326) R Treatment Q4W Treatment Q4W Secukinumab 3 mg Secukinumab 15 mg Placebo 5 mg QW Q4W Q4W Langley RG, et al. Br J Dermatol 213;169:

17 FIXTURE: Response through 52 Weeks SEK 3 mg (n=323 a ) SEK 15 mg (n=327 a ) ETN (n=323 a ) PBO (n=324 a ) PASI 75 response PASI 9 response Responders (%) % 44% 4.9% Primary endpoint a Number of evaluable subjects Langley RG, et al. Br J Dermatol 213;169:

18 Safety through Week 52 Incidences of total and serious AEs similar with SEK and ETN 3 mg (n=467) Secukinumab 15 mg (n=469) Entire Treatment Etanercept (n=323) Placebo (n=327) Mean exposure, days Any AEs, % Death, % Non-fatal serious AEs, % Discontinuations due to AEs, % Most common AEs, exposure-adjusted incidence rate Nasopharyngitis Headache Back pain Diarrhea Arthralgia Upper respiratory tract infection Injection site erythema 6.1 Adverse events (AEs) shown are those that occurred at an incidence rate >6. per 1 subject-years in combined secukinumab group or etanercept group Langley RG, et al. Br J Dermatol 213;169:

19 Rare adverse events of special interest Serious AEs of special interest, n (%) a 3 mg (n=467) Secukinumab 15 mg (n=469) Etanercept (n=323) Placebo (n=327) Serious infections 5 (1.1) 3 (.6) 4 (1.2) 1 (.3) Malignant or unspecified tumors 3 (.6) 2 (.4) 2 (.6) 1 (.3) MACE () 2 (.4) 1 (.3) () Candida infections 12 (2.6%) subjects in secukinumab 15 mg group and 22 patients (4.7%) in 3 mg group; all mild or moderate 4 (1.2%) subjects in etanercept group; 3 out of 7 candida infections reported by the 4 patients were severe Treatment-emergent antidrug antibodies Detected in 4 (.4%) out of 98 patients tested: 2 on 15 mg and 2 on 3 mg MACE, major adverse cardiac event. a Not exposure adjusted Langley RG, et al. Br J Dermatol 213;169:

20 Secukinumab safety in moderate-to-severe plaque psoriasis: Pooled subanalysis of 1 studies evaluating exacerbation of Crohn s disease Entire treatment (randomization to Week 52) after induction, subjects in Phase 3 studies (>8% all subjects) received SKB q4w or RAN from Weeks 12 to 48 a, or ETN weekly from Weeks 12 to 51 Exposure-adjusted incidence of IBD during the entire treatment period Duration of exposure, days (mean ± SD) Ward N, et al. AAD 214, P8233 SKB 3 mg a (n=141) SKB 15 mg a SKB any dose b PBO ETN c (n=1395) (n=343) (n=793) (n=323) 35. ± ± ± ± ± 89.7 Incidence overall, n (%) IBD 3 (.26) 4 (.35) 9 (.33) 1 (.34) Crohn s disease 2 (.18) 3 (.11) Ulcerative colitis 2 (.17) 2 (.18) 4 (.15) 1 (.34) Anal fistula d 1 (.8) 1 (.4) Sclerosing cholangitis d 1 (.4) Incidence in the subgroup with prior history of IBD, n (%) [95% CI] Subjects with prior IBD history, n IBD overall () 2 (18.76) 3 (1.53) () [. 3.9] [ ] [ ] [ ] Crohn s disease () [. 3.9] 1 (9.28) [ ] 2 (6.99) [ ] () [ ] Ulcerative colitis () 1 (9.23) 1 (3.47) () [. 3.9] [ ] [ ] [ ] a Includes subjects from Phase 3 studies only who received the specified SKB dose (3 or 15 mg) regardless of dosing interval (ie, q4w, RAN); PBO subjects who were re-randomized to SKB at Week 12 are also included, and had an induction period with weekly SKB doses from Weeks 12 to 16; b Includes subjects from Phase 2 and 3 studies who received any dose of SKB; c ETN data are from one pivotal Phase 3 trial, FIXTURE; d Anal fistula and Sclerosing cholangitis are not true IBD, they were retrieved because of the broader search criteria applied RAN, retreatment-as-needed

21 Secukinumab for psoriatic arthritis: Percentage of Patients Nonresponder imputation (NRI) analysis. ACR 2 Responses Placebo Secukinumab Week 12 Week 24 P<.1 P<.1 25% ACR 2 56% 54% 15% n=1 n=1 n=1 n=1. McInnes. et al, Lancet. 215;386:

22 Ixekizumab: UNCOVER 1-3 study design Screening Induction dosing IXK 8 mg q2w (n=433) IXK 8 mg q4w (n=432) PBO q2w (n=431) UNCOVER-1 UNCOVER-2 and 3 spga (,1) Responders at Week 12 Re-randomization R Maintenance dosing IXK q4w IXK q12w PBO q4w IXK q4w IXK q4w IXK q4w Week 12 Nonresponders: IXK q4w spga (,1) at Week 12: PBO q4w IXK q4w Week Week 12 Week 6 Screening Double-blind induction dosing IXK q2w (n=351) IXK q4w (n=347) ETN 5 mg biw (n=358) PBO q2w (n=168) Week Week 12 (followed by a maintenance period for a total of 6 weeks) NRI, nonresponder imputation; spga, static PGA Gordon K, et al. WCD 215; Leonardi C, et al. WCD 215; Griffiths C, et al. WCD 215

23 Patients (%) Patients (%) Ixekizumab: Efficacy (UNCOVER-1) PASI 75, NRI Co-primary endpoints Gated secondary endpoints Weeks PBO (N=431) IXK q4w (N=432) IXK q2w (N=433) P<.1 vs PBO based on logistic regression (Fisher s exact test when PBO response %) NRI, nonresponder imputation; spga, static PGA Gordon K, et al. WCD PASI 9, NRI Weeks Patients (%) Patients (%) 1 spga (,1) NRI PASI 1, NRI Weeks Weeks

24 Ixekizumab: Efficacy Week 6 UNCOVER-1 spga (,1) through Week 6 among IXK-treated patients with spga (,1) at Week 12 (NRI) Patients (%) IXK q4w IXK q4w (n=11) IXK q2w IXK q4w (n=119) IXK q4w IXK q12w (n=11) IXK q2w IXK q12w (n=117) IXK q4w PBO (n=19) IXK q2w PBO (n=117) Week Patients with spga >2 at any timepoint between Weeks 12 and 6 were considered nonresponders at all subsequent visits Leonardi C, et al. WCD 215 NRI, nonresponder imputation; spga, static PGA

25 UNCOVER-3: Continuous ixekizumab for 6 weeks Response rate (%) Response rate (%) Blinded Weeks NRI based on treatment groups at Week a N=386 for induction period; b N=385 for induction period Griffiths C et al. Lancet 215;386: PASI 75 PASI Weeks PASI 1 Blinded OLE OLE Response rate (%) Blinded Weeks IXE q4w/ixe q4w a IXE q2w/ixe q4w b OLE

26 Ixekizumab: Safety through Week 6 n% Safety Weeks 1 12 PBO N=431 IXK q4w N=432 IXK q2w N=433 TEAE 21 (48.7) 264 (61.1) 257 (59.4) Death SAE 5 (1.2) 12 (2.8) 6 (1.4) Selection of AEs of special interest UNCOVER-1 Exposure adjusted event rates, n (IR) a Safety Weeks 12 6 a PBO N= 226, pt-y=12.9 IXK q12w N=227, pt-y = IXK q4w N=229, pt-y=187 TEAE 123 (119.5) 168 (18.2) 182 (97.1) Death 2 (1.1) SAE 7 (6.8) 9 (5.8) 15 (8.) Selection of AEs of special interest Infection-related SAE 1 (.2) 3 (.7) 3 (.7) Any candida 2 (.5) 3 (.6) 4 (.9) Malignancy 2 (.5) 3 (.7) MACE 1 (.2) Crohn s disease 1 (.2) Ulcerative colitis 1 (.2) Infection-related SAE 1 (1.) 1 (.6) 3 (1.6) Any candida 2 (1.9) 4 (2.6) 8 (4.3) MACE 3 (1.6) b Malignancy 2 (1.3) Crohn s disease 1 (1.) Ulcerative colitis P.5 vs PBO a Among patients with an static PGA (,1) at Week 12 b 1 death from unknown cause presumed to be cardiovascular death due to lack of other information IR, incidence rate; MACE, major cardiovascular adverse event; pt-y, patient-years Leonardi C, et al. WCD 215

27 SPIRIT-P1: ACR responders at Week 24 Responders (%) Placebo (n=16) ADA 4 mg q2w (n=11) IXE 8 mg q4w (n=17) IXE 8 mg q2w (n=13) ACR2 ACR5 ACR7 34 P.1, P.1 vs placebo Nonresponder imputation; ADA was active control Mease P, et al. AAD 216, P

28 Brodalumab: AMAGINE-2 and 3 study design R 2:2:1:1N 21 mg q2w BRO 14 mg q2w BRO R 2:2:2: mg q2w mg q2w BRO BRO (n=624) 14 mg q2w BRO 14 mg q4w BRO 14 mg q8w BRO Screening 7 days, 3 days UST a PBO Induction UST a 21 mg q2w Maintenance a 45 mg if 1 kg, 9 mg if >1 kg Day 1 Week 12 Week 52 Lebwohl M, et al. N Eng J Med. 215;373(14): Week 16 rescue PGA 3 or persistent spga 2 x 4 week

29 AMAGINE-2 and 3: PASI 75 Week 12 PASI 75 response rates (NRI) by week in the induction phase Responders (%) PBO UST BRO 14 mg q2w BRO 21 mg q2w AMAGINE-2 1 AMAGINE-3 86% 8 7% 67% 6 8% Week Adjusted P<.1 for BRO groups vs PBO at Week 12 Adjusted P=.78 for BRO 21 mg vs UST at Week 12 Responders (%) % 69.3% 69.2% 2 6% Week Coprimary endpoint: PASI 75 at Week 12 BRO vs PBO adjusted P<.1 for both dosages Secondary endpoint: BRO 21 mg q2w vs UST adjusted P=.7; weightbased BRO subgroup vs UST adjusted P=.7 Lebwohl M, et al. N Eng J Med. 215;373(14):

30 Responders (%) AMAGINE-2 and 3: PASI Responses for 21 mg q2w PASI response rates (NRI after treatment change) by week for constant BRO 21 mg through the maintenance phase PASI 75 PASI 9 PASI 1 AMAGINE-2 AMAGINE Week 8% 75% 56% Constant 21 mg q2w defined as patients randomized to BRO 21 mg q2w for both induction and maintenance phases Patients with inadequate response are not imputed further and observed data were used Lebwohl M, et al. N Eng J Med. 215;373(14): Responders (%) Week PASI responses increased during the induction period through Week 12 and stabilized from Week 16 through Week % 72.5% 52.6%

31 Brodalumab: Suicidal Ideation and behavior AEs n (follow-up time-adjusted incidence rate) [95% Cl] Ustekinumab (n=613; pt-y=53.6) 52-week pool a Brodalumab (n=419; pt-y=3545.7) Long-term pool b Brodalumab (n=4464; pt-y=9161.8) Suicidal ideation 1 (.2) [ ] 3 (.8) [.2.25] 22 (.24) [.15.36] Suicidal behavior 1 (.2) [ ] 4 (.11) [.3.29] 15 (.16) [.9.27] Completed suicide c (.) [..73] 2 (.6) [.1.2] 4 (.4) [.1.11] Intentional self-injury (.) [..73] 1 (.3) [<.1.16] 1 (.1) [..6] Suicide attempt Suicidal behavior Overall suicidal ideation and behavior 1 (.2) [ ] (.) [..73] 1 (.3) [<.1.16] (.) [..1] 6 (.7) [.2.14] 4 (.4) [.1.11] 2 (.4) [ ] 7 (.2) [.8.41] 34 (.37) [.26.52] a Cumulative events through 52-week, controlled treatment period b Includes events in the 52-week treatment period and uncontrolled OLE c Includes fatal event reported as intentional overdose that was adjudicated as indeterminate Lebwohl M, et al. AAD 217, P498 31

32 Guselkumab: VOYAGE 1 study design Screening Placebo-controlled Blinded active treatment Open label Group 1 (n=3) GUS 1 mg Week, 4, q8w Group 2 (n=15) R Placebo GUS 1 mg Week 16, 2, q8w Group 3 (n=3) ADA q2w Week GUS injection EP vs PBO 24 2 EP vs ADA 48 DBL 2 EP vs ADA Placebo à GUS injection ADA injection Blauvelt A, et al. EADV 216, D3T1.1D

33 VOYAGE 1: IGA /1 and PASI 9 Patients (%) IGA /1 at Week 16 (P<.1 vs placebo) Placebo (n=174) Guselkumab (n=329) Patients (%) Placebo (n=174) PASI 9 at Week 16 (P<.1 vs placebo) 73.3 Guselkumab (n=329) Blauvelt A, et al. EADV 216, D3T1.1D

34 VOYAGE 1: PASI response Patients (%) Patients (%) PASI 75 at Week Weeks PASI 1 at Week Weeks Week 16, 24 and 48 P<.1 vs ADA; Week 24 and 48 P<.1 vs ADA Blauvelt A, et al. EADV 216, D3T1.1D Patients (%) PASI 9 at Week Weeks GUS (n=329) Placebo à GUS (n=174) ADA (n=334)

35 VOYAGE 1: AEs of interest through Week 16 n (%) Placebo (n=174) Guselkumab (n=329) Adalimumab (n=333) 1 AE 86 (49.4) 17 (51.7) 17 (51.1) 1 SAE 3 (1.7) 8 (2.4) 6 (1.8) Discontinued due to 1 AE 2 (1.1) 4 (1.2) 3 (.9) Infections Infections treated with antibiotics Serious infections 44 (25.3) 13 (7.5) 85 (25.8) 2 (6.1) 85 (25.5) 24 (7.2) 2 (.6) MACE 1 (.3) 1 (.3) Malignancies NMSC Malignancy other than NMSC 1 (.3) 1 injection site reaction (ISR) 8 (2.4) 25 (7.5) Total number of injections Injections with ISR (1.1) (1.6) Blauvelt A, et al. EADV 216, D3T1.1D 35

36 Tildrakizumab: resurface 1 & 2 study design resurface 1 resurface 2 Screening BL End Part 1 1 o endpoint End Part 2 Day 28 Day 1 Week 12 Week 28 Visit 1 Visit 2 Visit 6 Visit 9 TIL 2 mg sc 2:2:1:2 R TIL 1 mg sc Placebo 1:1 R TIL 2 mg sc TIL 1 mg sc ETN 5 mg sc Reich K, et al. EADV 216, D3T1.1I

37 resurface 1 and 2: PASI 75 and PGA /1 PASI 75 PGA /1 a Responders (%) a PGA score of clear or minimal with 2-grade reduction from baseline P<.1 vs placebo; P<.5, P<.1 vs ETN; P-values unadjusted for multiplicity; calculated using the Cochran-Mantel-Haenszel test stratified by body weight ( 9kg, >9kg) and prior biologic exposure for psoriasis. Data as observed; NRI at Week 12 Reich K, et al. EADV 216, D3T1.1I resurface Weeks resurface Weeks TIL 1 mg TIL 2 mg Placebo àtil 1 mg Placebo àtil 2 mg ETN 5 mg

38 resurface 1 and 2: PASI 9 and 1 PASI 9 PASI 1 Responders (%) resurface 1 1 resurface Weeks Weeks TIL 1 mg TIL 2 mg Placebo àtil 1 mg Placebo àtil 2 mg ETN 5 mg P<.1 vs placebo Data as observed; NRI at Week 12 Reich K, et al. EADV 216, D3T1.1I

39 resurface 2: Safety n (%) Part 1 (Weeks 12) Part 2 (Weeks 12 28) TIL 2 mg (n=314) TIL 1 mg (n=37) Placebo (n=156) ETN 5 mg (n=313) TIL 2 mg/ TIL 2 mg (n=299) TIL 1 mg/ TIL 1 mg (n=294) ETN/ETN 5 mg (n=289) Placebo/ TIL 2 mg (n=72) Placebo/ TIL 1 mg (n=69) 1 AEs a 155 (49.4) 136 (44.3) 86 (55.1) 169 (54.) 135 (45.2) 135 (45.9) 164 (56.7) 31 (43.1) 37 (53.6) Serious AEs 6 (1.9) 4 (1.3) 4 (2.6) 7 (2.2) 6 (2.) 9 (3.1) 14 (4.8) 2 (2.8) 1 (1.4) Deaths 1 (.3) Discontinued b due to AEs 3 (1.) 3 (1.) 2 (1.3) 6 (1.9) 1 (.3) 1 (.3) 3 (1.) 1 (1.4) Most common AEs Injection site erythema 2 (.6) 2 (.7) 1 (.6) 27 (8.6) Nasopharyngitis 34 (1.8) 41 (13.4) 12 (7.7) 36 (11.5) 42 (14.) 23 (7.8) 34 (11.8) 3 (4.2) 8 (11.6) URTI 6 (2.) 5 (1.7) 7 (2.4) a Patients who took 1 dose of Part 1 study medication based on the treatment actually received b Patient on TIL 1 mg died: had alcoholic cardiomyopathy and hepatic steatosis, although adjudication was unable to determine cause of death Reich K, et al. EADV 216, D3T1.1I

40 Risankizumab Phase II Study Treatment arms RKZ18 mg at Week (PBO at Weeks 4 and 16) RKZ 9 mg at Weeks, 4 and 16 RKZ18 mg at Weeks, 4 and 16 UST (45 or 9 mg) at Weeks, 4 and 16 Prespecified primary analysis: PASI 9 at Week 12, comparing RZK (9 mg + 18 mg pooled) with UST Papp K, et al. AAD 215, Late breaker

41 Risankizumab Primary Endpoint:PASI 9 RKZ 18 mg RKZ 9 mg RKZ 18 mg RKZ 9 mg + 18 mg n PASI 9 (LOCF) Responders, n (%) 14 (32.6) 3 (73.2) 34 (81.) 64 (77.1) 16 (4.) Difference from UST 8.1% 33.% 39.5% 36.4% N/A P-value <.1 <.1 N/A PASI 9 (NRI) Week 12 analysis Responders, n (%) 13 (3.2) 3 (73.2) 33 (78.6) 63 (75.9) 16 (4.) Difference from UST 1.4% 33.% 37.2% 35.2% N/A P-value <.1 N/A UST Papp K, et al. AAD 215, Late breaker

42 Risankizumab: Adverse Events Through Week 12 n (%) RZK 18 mg (n=43) RZK 9 mg (n=41) RZK 18 mg (n=42) UST (n=4) Any AE a 31 (72.1) 27 (65.9) 24 (57.1) 24 (6.) Severe AE 2 (4.7) 1 (2.4) 1 (2.4) 2 (5.) AE considered drug related by investigator 6 (14.) 8 (19.5) 6 (14.3) 7 (17.5) AE leading to D/C 1 (2.3) 1 (2.4) () 1 (2.5) Serious AE b 2 (4.7) 2 (4.9) () 1 (2.5) a Most common AEs were nasopharyngitis and headache. b BI 18 mg: allergy to arthropod bite and erythema multiforme prolonging hospitalization; pelvic/rib fracture. BI 9 mg: GI bleed and resulting iron deficient anemia; cerebrovascular accident (stroke); patient had pre-existing cerebral aneurysm that required clipping and had a stroke in the immediate postop period. UST: diverticulitis unrelated to study medication. MedDRA v17.1 Papp K, et al. AAD 215,

43 Risankizumab: ultimma-1&2 Treatment arms Risankizumab 15 mg (n=34, 294) Ustekinumab 45/9 mg (n=1, 99) Placebo (n=12, 98) Regimen Week, 4 then every 12 weeks Primary endpoint Week 16: PASI 9 and PGA /1

44 Rizankizumab ultimma-1&2 results: Week 16 ultimma-1 ultimma-2 PASI 9 RKZ UST Placebo 5 2 PGA,1 RKZ UST Placebo 8 5 PASI 1 RKZ UST 12 24

45 Certolizumab pegol: CAMPASI 1&2 study design Screening Initial treatment period (double-blind) Maintenance period Open-label treatment Safety follow-up Week Placebo q2w <PASI 5 LD a PASI 5 <PASI 75 <PASI 5: withdrawn R LD a CZP 2 mg q2w CZP 2 mg q2w 1:2:2 <PASI 5 <PASI 5: withdrawn CZP 4 mg q2w Open-label dose switching <PASI 5 <PASI 5: withdrawn Escape CZP 4 mg q2w Coprimary endpoints PASI 75 and PGA b <PASI 5: withdrawn ᵃLD, loading dose of CZP 4 mg q2w at Weeks, 2, and 4 or Weeks 16, 18, and 2 ᵇPGA responder defined as PGA /1 with 2 category improvement I Gottlieb AB, et al. AAD 217, Late-breaking Research: Clinical Trials, 577

46 CIMPASI 1& 2: PASI 75 and PGA responder rates Gottlieb AB, et al. AAD 217, Late-breaking Research: Clinical Trials, 577 PASI 75 responder rate a Patients (%) CIMPASI P< P< CIMPASI P<.1 P< PGA responder rate a,b 1 CIMPASI-1 1 CIMPASI-2 P<.1 P<.1 P< P< Placebo CZP 2 mg CZP 4 mg Placebo CZP 2 mg CZP 4 mg (n=49) (n=91) (n=87) a Based on logistic regression model with factors for treatment, region, and prior biologic exposure (yes/no) using multiple imputation b Defined as PGA /1 with 2-category improvement Patients (%)

47 CIMPASI-1&2: Adverse events of interest reported through Week 16 n (%) CIMPASI-1 CIMPASI-2 Infections and infestations Tuberculosis Candida infections Oral fungal infection Fungal skin infection Herpes zoster Herpes dermatitis Epstein-Barr viral infection Placebo (n=51) 16 (31.4) CZP 2 mg (n=95) 3 (31.6) CZP 4 mg (n=88) 39 (44.3) 1 (1.1) Placebo (n=49) 15 (3.6) 1 (2.) CZP 2 mg (n=91) 26 (28.9) 1 (1.1) a 1 (1.1) 1 (1.1) CZP 4 mg (n=87) 34 (39.1) 1 (1.1) 1 (1.1) Serious infections 1 (1.1) b Malignancy 1 (1.1)ᶜ Depression 1 (1.1) 1 (1.1) 1 (1.1) ᵃVulvovaginal candidiasis; ᵇAbdominal abscess and hematoma infection; ᶜBasal cell carcinoma Gottlieb AB, et al. AAD 217, Late-breaking Research: Clinical Trials, 577

48 Conclusions Currently 8 FDA approved biologics for psoriasis New targets in development in response to advancements in basic science Therapies targeting IL-17 and IL-23 exhibit promising potential thus far Further study is necessary to eludate the long term efficacy and safety characteristics of these categories of drugs