Victoria P. Werth, M.D. University of Pennsylvania. Nithin Reddy, Majid Zeidi, Barbara White, Kristen Chen, Mohammad Bashir

Transcription

1 , a Cannabinoid Type 2 Receptor Agonist, Reduces T-Cell Population and Downregulates Type 1 and 2 Interferon Activities in Lesional Dermatomyositis Skin Victoria P. Werth, M.D. University of Pennsylvania Nithin Reddy, Majid Zeidi, Barbara White, Kristen Chen, Mohammad Bashir 1

2 DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY Victoria P. Werth, MD Grants: Corbus Consult: Corbus Developed and validated an outcome measure for cutaneous dermatomyositis (CDASI) 2

3 Treatment of Dermatomyositis Poor QoL associated with amyopathic DM Treatment of skin - Antimalarials (30% response rate) - Immunosuppressive medications - IVIG Many patients have refractory skin disease Large unmet therapeutic need 3

4 Interferon Signature in Skin of DM Patients Wong D al, PLOSONE 7:e29161,

5 Potential New Treatment for Dermatomyositis:, a synthetic, selective cannabinoid receptor type 2 (CB2) agonist that activates resolution of innate immune responses CB2 expressed on pdcs, T cells and other activated immune cells, keratinocytes, myocytes and fibroblasts Suppressed the secretion of TNFα IFN-α, and IFN-b from stimulated PBMCs of dermatomyositis patients in vitro Robinson E, J Invest Dermatol 77: ,

6 Reduces IFNα and TNFα Production by PBMC from DM Patients concentration (µm) concentration (µm) Robinson E and Werth VP, J Invest Dermatol 77: ,

7 Reduces IFNβ Production by PBMC from DM Patients concentration (µm) Robinson E and Werth VP, J Invest Dermatol 77: ,

8 Phase 2 Trial JBT101-DM-001 NIH funded, placebo-controlled, randomized trial First for skin-predominant dermatomyositis 22 patients with skin-predominant dermatomyositis - 1 month lenabasum 20 mg QD, 2 months 20 mg BID, one month safety and efficacy assessments off study drug No serious or severe AEs or changes in lab safety tests related to lenabasum Positive primary outcome (change in CDASI activity score), p = 0.04 for lenabasum 20 mg BID vs placebo at 16 weeks Many patient reported outcomes tracked improvement of disease activity Continued improvement in CDASI and multiple other efficacy outcomes at 12 months in open-label extension Werth et al, Arthritis Rheum (late-breaking abstract), 2017 Werth et al, ACR poster #2284,

9 Improves CDASI Activity Score Mean change from Day 1 Werth VP et al, Arthr Rheumatol (abstract),

10 Clinical Response to Baseline Week 12 10

11 Δ Patient Skin Activity VAS, mean SE Δ SkinDex Symptoms, mean SE Improves Patient-Reported Outcomes p = p = p = Weeks p = p = p = Weeks Δ PROMIS-29 Pain Interference, mean SE p = p = p = Weeks Patient Activity VAS SkinDEX Symptoms PROMIS-29 pain interference 11

12 CD4 Cells Week 0 Week 12 Week 0 Week 12 12

13 IFN-b Week 0 Week 12 Week 0 Week 12 13

14 IFN-g Week 0 Week 12 Week 0 Week 12 14

15 IL-4 Week 0 Week 12 Week 0 Week 12 15

16 IL-13 Area (%) IL-13 Area (%) IL-13 Area (%) IL-13 Area (%) IL-13 Week 0 Week 12 Week 0 Week ns ns ns ns Week Week 0 Week Week 16

17 IL-31 in Dermatomyositis Kim HJ and Werth VP, Br J Dermatol 179:559,

18 IL-31 Week 0 Week 12 Week 0 Week 12 18

19 IL-31RA Week 0 Week 12 Week 0 Week 12 19

20 mrna Expression Levels in Skin Tissue Relative to Healthy Controls 20

21 mrna Expression Levels in PBMCs Relative to Healthy Controls 21

22 Summary and Conclusions reduces type 1 (IFNβ) and type 2 IFN (IFNγ) protein and mrna in the skin in lenabasum-treated patients CD4 cells decreased in lenabasum-treated subjects IL-31 protein was reduced and correlated with the change in itch These effects have the potential to inhibit underlying disease pathways in DM and thus contribute to any clinical benefit of lenabasum in the treatment of DM 22