The New and Emerging Agents: Dermatology

Transcription

1 Psoriasis Treatment 2013: What is New and on the Horizon? Neil J Korman, MD, PhD Professor of Dermatology University Hospitals Case Medical Center Clinical Director Murdough Family Center for Psoriasis Cleveland, Ohio The New and Emerging Agents: Dermatology Neil J Korman, MD, PhD Professor of Dermatology University Hospitals Case Medical Center Clinical Director Murdough Family Center for Psoriasis Cleveland, Ohio 1

2 Neil J Korman Conflicts Of Interest Abbott Amgen Celgene Eli Lilly Janssen Novartis Pfizer Learning Objectives To identify new oral and biologic therapies for the treatment of moderate to severe psoriasis To discuss the role of the IL-17 pathway in the pathogenesis and treatment of psoriasis. Describe the safety and efficacy of the newest agents in the treatment of moderate to severe psoriasis 2

3 Psoriasis Requiring a Systemic Approach (Moderate to Severe Disease) CD80 CD28 IL-17 APC (Antigen Presenting Cell) CD80 ICAM1 CTLA4 LFA1 Infliximab T-cell TNF a Keratinocyte IL-12/23 Ustekinumab LFA3 CD2 IL-8 MHC Antigen TCR 3

4 Choosing Systemic Therapy Ustekinumab Advantages Very high efficacy Infrequent dosing Not contraindicated in MS Disadvantages Newest therapy Not approved for psor arthritis Ustekinumab Dosing 45 mg or 90 mg at wk 0, 4, 16 and then every 12 wks Wt < 100 kg 45 mg, Wt > 100 kg 90 mg Short term 67% PASI 75 at wk 12 Long term 71% PASI 75 at wk 28 4

5 Ustekinumab and Etanercept Comparator Trial Griffiths CE et al. N Engl J Med. 2010;362:118. Serious Infections, NMSC, Malignancies, and MACE in UST-treated Patients (Events/100 PY) 5

6 Role of IL-17 in Psoriasis Evolving evidence suggests that Th17 cells, a subset of CD4+ T cells, play an important pathologic role in psoriasis Th17 cells secrete many proinflammatory cytokines including several members of the IL- 17 family IL-17 levels are elevated in blood and lesional skin of pts with psoriasis and correlate with disease activity APC (Antigen Presenting Cell) CD80 CD80 ICAM1 CD28 CTLA4 LFA1 Infliximab T-cell IL-17 TNF a IL-12/23 Ixekizumab Secukinumab Brodalumab Keratinocyte LFA3 CD2 IL-8 MHC Antigen TCR 6

7 % of Patients IL-17 Inhibitors Ixekizumab is a humanized IgG4 monoclonal antibody that neutralizes IL-17A Secukinumab is a fully human IgG1 monoclonal antibody that neutralizes IL-17A Brodalumab is a fully human IgG2 monoclonal antibody that blocks the IL-17A receptor Ixekizumab Phase 2 PASI 75 Response Weeks p<.05 compared to placebo 7

8 % of Patients Ixekixumab Phase 2 PASI 100 Response Weeks p<.05 compared to placebo Ixekizumab Phase 2 Adverse Events Ixekizumab Adverse events b, n (%) Placebo (N = 27) 10 mg (N = 28) 25 mg (N = 30) 75 mg (N = 29) 150 mg (N = 28) Infections and infestations 7 (26) 12 (43) 9 (30) 9 (31) 8 (29) Nasopharyngitis c 5 (19) 3 (11) 3 (10) 3 (10) 4 (14) Upper respiratory infection c 1 (4) 1 (4) 3 (10) 1 (3) 1 (4) Injection site reaction (10) 1 (3) 2 (7) Headache 1 (4) 4 (14) 4 (13) 1 (3) 1 (4) Allergy/hypersensitivity d 2 (7) 1 (4) 1 (3) 2 (7) 1 (4) a Defined as those that first occurred or worsened after randomization, b Adverse events occurring in at least 5% of patients receiving Ixekizumab, c Most common infections, d Term consistent with reference to MedDRA (Medical Dictionary for Regulatory Activities) 8

9 Response Rate (%) Secukinumab Phase 2 PASI 75 and PASI 90 Response Week 12 of Treatment P<0.001 vs. placebo P=0.002 vs. placebo (n=27) (n=21) (n=26) (n=29) (n=22) Secukinumab Phase 2 Adverse Events 1 x 25 mg n = 29 Secukinumab 3 x 25 mg n = 26 3 x 75 mg n = 21 3 x 150 mg n = 27 Placebo n = 22 Adverse Events 14 (48.3) 14 (53.8) 7 (33.3) 18 (66.7) 11 (50.0) Gastrointestinal disorders 2 (6.9) 3 (11.5) 1 (4.8) 2 (7.4) 1 (4.5) General disorders and admin site conditions (18.5) 2 (9.1) Infections and infestations 3 (10.3) 3 (11.5) 5 (23.8) 7 (25.9) 2 (9.1) Injury, poisoning 1 (3.4) 1 (3.8) - 2 (7.4) 2 (9.1) Musculoskeletal and connective tissue dis 4 (13.8) 2 (7.7) 2 (9.5) 3 (11.1) 2 (9.1) Nervous system disorders - 4 (15.4) 2 (9.5) 1 (3.7) - Respiratory, thoracic, and mediastinal dis 1 (3.4) 2 (7.7) Skin and subcutaneous tissue disorders 6 (20.7) 3 (11.5) 2 (9.5) 3 (11.1) 3 (13.6) Vascular disorders 1 (3.4) 2 (7.7) - 2 (7.4) - Serious Adverse Events - 1 (3.8) Infections and infestations - 1 (3.8) Nervous system disorders - 1 (3.8) Death due to MI (4.5) 9

10 Percentage of Subjects Percentage of Subjects Brodalumab Phase 2 PASI 90 and PASI 75 Response at Week 12 Brodalumab Phase 2 PASI 100 Response at Week 12 10

11 Brodalumab Phase 2 Adverse Events AEs, n (%) PBO (n = 37) 70 mg Q2W (n = 38) Brodalumab Groups 140 mg Q2W (n = 39) 210 mg Q2W (n = 40) 280 mg Q4W (n = 41) Any 23 (62) 26 (68) 27 (69) 33 (82) 30 (73) Serious 0 0 Any grade 3, 4, or 5 event 2 (5) 1 (3) 1 (3) 3 (8) 2 (5) Common AEs (events that occurred in 4 subjects) Nasopharyngitis 3 (8) 6 (16) 1 (3) 4 (10) 2 (5) URI 2 (5) 3 (8) 3 (8) 2 (5) 5 (12) Arthralgia 1 (3) 1 (3) 2 (5) 0 4 (10) Injection-site erythema 1 (3) 1 (3) 1 (3) 3 (8) 4 (10) Pain in extremity 0 1 (3) 0 3 (8) 4 (10) Nausea. 1 (3) 4 (11) 1 (3) 1 (2) 0 New Oral Therapies On The Horizon Apremilast - PDE Inhibitor Tofacitanib - JAK Inhibitor 11

12 Apremilast: Mechanism of Action Apremilast is an oral pluri-potent immunomodulator: Apremilast inhibits the activity of PDE4 which modulates the production of several mediators, including TNF-α, IL-2, IL-10, IL-17, and IL-23. This MOA differentiates apremilast because it is not: Mono-potent like TNF-α inhibitors Immunosuppresive like methotrexate and the other orals 12

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14 The Janus Kinase (JAK) Family Janus kinases are intracellular signaling molecules. JAK3 is restricted to the immune system and is involved in signal transduction of cytokines JAK3 became a target for immunosuppression when a mutation in the receptor was associated with a form of severe combined immunodeficiency disease Tofacitinib, is a highly selective JAK3 inhibitor and is effective in the signaling of JAK1 and, to a much lesser extent, of JAK2. Tofacitinib Phase 2 PASI 75 Response 14

15 Tofacitinib Phase 2 Adverse Events Tofacitinib 2 mg BID (49) 5 mg BID (49) 15 mg BID (49) Placebo (50) Total patients 49 (100) 49 (100) 49 (100) 50 (100) Patients w/ any AE 27 (55.1) 28 (57.1) 30 (61.2) 30 (60) Patients w/ serious AE 2 (4.1) 1 (2) 0 0 Diarrhea (2) 3 (6) Nasopharyngitis 2 (4.1) 1 (2) 3 (6.1) 5 (10) Sinusitis 0 1 (2) 5 (10 2) 0 URI 4 (8.2) 4 (8.2) 2 (4.1) 5 (10) Back pain 1 (2) 1 (2) 3 (6.1) 1 (2) Headache 4 (8.2) 3 (6.1) 3 (6.1) 0 Psoriasis 0 2 (4.1) 0 4 (8) Treatment of Psoriasis 2013: Conclusions Many new oral and biologic therapies are being developed for patients with moderate to severe psoriasis These therapies will continue to improve the treatment paradigm for patients with psoriasis 15