10/28/2013. Disclosure. Ustekinumab. IL-12, IL-23 and Ustekinumab. IL-23 in Facet Joints in Patients with AS

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for the Treatment of Patients with Active Ankylosing Spondylitis: Results of a 28-Week, Prospective, Open-Label,

Callhoff, Joachim Listing, Joachim Sieper ACR 213 San Diego, CA October 28, 213 is a monoclonal antibody against

IL-12, IL-23 and is approved in the EU and in the US for the treatment of adult patients with 1) moderate to

In patients weighting > 1 kg: in the same regimen. Benson JM, et al. Nat Biotechnol 211;29:615-24.

with AS Entheseal inflammation at day 6 after administration of 3 μg IL- 23mc (bottom row) as compared to control

1 for the Treatment of Patients with Active Ankylosing Spondylitis: Results of a 28-Week, Prospective, Open-Label, Proof-of-Concept Study (TOPAS) Disclosure The study was supported by an unrestricted research grant from Janssen-Cilag. Rheumatology Campus Benjamin Franklin Charité Medical University, Berlin, Germany Denis Poddubnyy, Johanna Callhoff, Joachim Listing, Joachim Sieper ACR 213 San Diego, CA October 28, 213 is a monoclonal antibody against interleukins 12 and 23. IL-12, IL-23 and is approved in the EU and in the US for the treatment of adult patients with 1) moderate to severe plaque psoriasis and 2) active psoriatic arthritis. Approved dose: 45 mg s.c. at week, 4, and every 12 weeks thereafter. In patients weighting > 1 kg: in the same regimen. Benson JM, et al. Nat Biotechnol 211;29: Systemic IL-23 Expression in vivo Induces Highly Specific Entheseal Inflammation IL-23 in Facet Joints in Patients with AS Entheseal inflammation at day 6 after administration of 3 μg IL- 23mc (bottom row) as compared to control treatment with human α1 anti-trypsin minicircle (haatmc, top row) in B1.RIII mice. Entheseal tendon-bone interface. Histology of periosteal disease and osteoblast expansion at day 18 after treatment in B1.RIII mice. Adapted from: Sherlock JP et al. Nat Med 212;18: (with permission) Appel H, et al. Arthritis Rheum. 213;65:

HLA-B27 Misfolding & the IL-23/IL-17 Axis Possible Consequences of HLA-B27 Misfolding TOPAS Study: Patients Main inclusion criteria: Definite diagnosis of AS according to the modified New York

2 HLA-B27 Misfolding & the IL-23/IL-17 Axis Possible Consequences of HLA-B27 Misfolding TOPAS Study: Patients Main inclusion criteria: Definite diagnosis of AS according to the modified New York criteria. History of an inadequate response to 2 NSAIDs taken for at least 2 weeks each or NSAIDs intolerance/contraindication. Active disease as defined by a BASDAI value of 4 at screening despite concomitant treatment with an NSAID or without NSAIDs in case of intolerance/contraindication. Main exclusion criteria: History of inadequate response to previous anti-tnf α therapy. Previous treatment with biologics other than TNF α blockers. Layh-Schmitt G and Colbert RA. Curr Opin Rheum 28; 2: (with permission) TOPAS Study: Design TOPAS Study: Outcomes Primary endpoint: The Assessment of Spondyloarthritis International Society (ASAS)4 response at week 24 Screening period, up to 5 weeks Follow-up period, 12 weeks Weeks: Baseline Treatment period, 16 weeks Primary outcome assessment Secondary endpoints: ASAS2 response at week 24 ASAS partial remission at week 24 BASDAI % improvement at week 24 Improvement of the Ankylosing Spondylitis Disease Activity Score () Patient and physician acceptable symptom state Improvement of function (BASFI) Improvement of axial mobility (BASMI) Improvement in acute phase reactants (CRP, ESR) Improvement of active inflammation as assessed by MRI at week 24 TOPAS Study TOPAS Study: Patients (n = 2) Screening Baseline Week 24 N = 22 n = 2, Screening Failures N = 2 n = 3, Non-Responders N = 17 Parameter Value Age, years (mean ± SD) 37.5 ± 1.8 Duration of symptoms, years (mean ± SD) 13.3 ± 1.5 Male gender, n (%) 15 (75) HLA-B27 (+), n (%) 18 (9) Peripheral arthritis, n (%) 1 (5) Enthesitis, n (%) 8 (4) Elevated (>5 mg/l) CRP, n (%) 8 (4) Concomitant treatment with NSAIDs, n (%) 17 (85) Concomitant treatment with DMARDs, n (%) () Concomitant treatment with systemic steroids, n (%) 1 (5) Past treatment with a TNF α blocker, n (%) 1(5) 2

3 ASAS NSAIDs intake score % of patients 1/28/213 TOPAS: Results (Week 24) TOPAS: Results (Baseline - Week 24) Parameter Baseline Week 24 p-value 1 (mean ± SD) 3. ±.6 2. ± BASDAI, points NRS (mean ± SD) 5.3 ± ± 1.8 < BASFI, points NRS (mean ± SD) 5.3 ± ± 2.3 <.1 BASMI (mean ± SD) 1.6 ± ± Chest expansion, cm 3.7 ± ± Patient global, points NRS (mean ± SD) 6.3 ± ± 2.3 <.1 Physician global, points NRS (mean ± SD) 5.9 ± ± 1.9 <.1 General pain, points NRS (mean ± SD) 6.5 ± ± 2.4 <.1 EQ-5D.6 ±.2.8 ±.1 <.1 ASAS 4 ASAS 2 ASAS PR BASDAI n = 2, ITT analysis, LOCF CII (>=1.1) MI (>=2) inactive disease (<1.3) PASS PhASS ASQoL 9.4 ± ± 4. <.1 MASES (mean ± SD) 3.1 ± ± SPARCC (mean ± SD) 2.9 ± ± CRP, mg/l 5.9 ± ± ESR, mm/h 2. ± ± n = 2 CRP-Response: a Clear Correlation with the Clinical Response Reduction of the NSAIDs Intake under ASAS NSAIDs Intake Score All patients (n = 2) p = Baseline Week 24 n = 2 Dynamics of the Clinical Response to Impact of on Active Inflammation Detected by MRI 2 1 Baseline Week 2 Week 4 Week 8 Week 12 Week 16 Week 24 BASDAI BASFI p <.5 vs. Baseline n = 2 3

Patient 15, ASAS 4 and BASDAI responder Patient 21, ASAS 4, PR, BASDAI responder BASDAI: 8. 2.6; BASFI: 6.8 2.2; CRP 3.

2.8 Baseline Week 24 Baseline Woche 24 Patient 21 Baseline Woche 24 TOPAS-Study: Safety A total of 92 adverse events (AE)

rhinitis in 7 cases (8%), - abdominal pain/discomfort in 7 cases (8%), - headache in 7 cases (8%), - diarrhoea in 4 cases

Conclusion There is a signal that ustekinumab might be effective in the treatment of active ankylosing spondylitis There

safety signals were received Study management: - Beate Buss and Renate Lies Acknowledgments Data management support: -

4 Patient 15, ASAS 4 and BASDAI responder Patient 21, ASAS 4, PR, BASDAI responder BASDAI: ; BASFI: ; CRP 3.4 mg/l 1.1 mg/l; : BASDAI: ; BASFI: 1.1.4; CRP 1. mg/l 1. mg/l; : Baseline Week 24 Baseline Woche 24 Patient 21 Baseline Woche 24 TOPAS-Study: Safety A total of 92 adverse events (AE) were observed in the study (all of mild or moderate severity): - upper respiratory tract infections in 14 cases (15%), - rhinitis in 7 cases (8%), - abdominal pain/discomfort in 7 cases (8%), - headache in 7 cases (8%), - diarrhoea in 4 cases (4%). No study discontinuation because of AEs. One serious adverse event (SAE) occurred: worsening of AS-related back pain. No injection site reactions. No serious infections, opportunistic infections, cases of tuberculosis, cases of malignancies, or deaths were observed. Conclusion There is a signal that ustekinumab might be effective in the treatment of active ankylosing spondylitis There might be an effect of ustekinumab on systemic and local inflammation in ankylosing spondylitis was well tolerated, no new safety signals were received Study management: - Beate Buss and Renate Lies Acknowledgments Data management support: - Esther Apt, Sebastian Leidig, and Sabine Achtelstetter Biometry: - Johanna Callhoff and Joachim Listing Patient recruitment support: - Henning Brandt, Hildrun Haibel, Sandra Hermann, In-Ho Song, Inge Spiller, Uta Syrbe Safety database management: - Cristoph Thomann 4

5 Thank you for your attention! 5

BRIEF REPORT. Denis Poddubnyy, 1 Hildrun Haibel, 1 J urgen Braun, 2 Martin Rudwaleit, 3 and Joachim Sieper 1

BRIEF REPORT. Denis Poddubnyy, 1 Hildrun Haibel, 1 J urgen Braun, 2 Martin Rudwaleit, 3 and Joachim Sieper 1 ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 9, September 2015, pp 2369 2375 DOI 10.1002/art.39225 VC 2015, American College of Rheumatology BRIEF REPORT Clinical Course Over Two Years in Patients With Early