Small Molecule Inhibitor of the Wnt Pathway (SM755) as a Potential Topical Scleroderma Treatment Vishal Deshmukh, PhD, Allison Hood, Yusuf Yazici, MD
Disclosures Vishal Deshmukh, Ph.D. o Financial disclosure: Samumed, LLC; salary and equity Allison Hood o Financial disclosure: Former employee of Samumed, LLC Yusuf Yazici, M.D. o Financial disclosure: Samumed, LLC; salary and equity
Disclaimer This presentation is not intended to provide a comprehensive overview of all studies using SM755. SM755 is an investigational compound currently in clinical trials; SM755 has not been approved by the US Food and Drug Administration (FDA) or any other pharmaceutical regulatory authority, and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidate. While the complete mechanism of action (MOA) for SM755 is unknown, further investigation is being conducted. All of the MOA information is based on non-clinical data and the relationship to clinical benefit is unknown. This presentation is intended as a scientific exchange of medical information, is provided for educational purposes only, and is not intended for any promotional purpose or to offer medical advice; the information contained in this presentation is confidential and proprietary and is not available for further distribution in any form whatsoever.
Scleroderma/Systemic Sclerosis need for therapies Heterogeneous disease characterized by fibroblast dysfunction (fibrosis), small vessel vasculopathy and production of autoantibodies 1 Can be classified based on degree of skin involvement Limited cutaneous, diffuse cutaneous and without skin involvement No FDA approved therapies exist Treatment recommendations focused on immunosuppression and symptom management,3 Majority of patients experience skin sclerosis 1, 1. Van Den Hoogen, F., et al. (13) Arth. & Rheum;. Volkmann, E. R., & Furst, D. E. (15). Rheum. Dis. Clin. N. Am; 3. Kowal-Bielecka, O., (9). Ann. Rheum. Dis.,
Skin pathobiology of Scleroderma Clinical Pathology: 1 Dermal thickening, hardening of the skin, vascular changes Progression may lead to painful ulcerations and reactive hyperkeratosis Histopathology: Early - endothelial cell apoptosis, perivascular inflammation Late - excess extra-cellular matrix (ECM) deposition and vasculopathy Fibroblasts produce smooth muscle actin and release collagen, fibronectin and glycosaminoglycans Fibroblast activity becomes independent; mediated by TGFβ, PDGF, IL, IL13 and MCP-1 and other pathways (Notch, Hedgehog and Wnt) 1. Stern, EP. & Denton, CP (15). Rheumatic Disease Clinics of North America. Dees, C. & Distler, J.H.W. (13). Exp. Derm
The Wnt/β-Catenin pathway Wnt signaling is present in many cells, particularly in high turn-over tissues Wnt signaling is often implicated in development, tissue repair and regeneration Normal Wnt signaling is crucial for organ development and tissue homeostasis including skin Various human diseases are associated with abnormal Wnt signaling including SCL Mouse plantar epidermis Axin (Wnt target gene) DKK-1 (Wnt antagonist) Image from Lim, et al. (13) Science. 1. Nusse et al. 13. Wnt Signaling. Cold Spring Harbor Lab Press.. Clevers et al. 1. Science.
Wnt in Scleroderma Increased Wnt signaling leads to nuclear β-catenin in scleroderma fibroblasts 1 TGFβ cross-talk with Wnt signaling promotes transdifferentiation of fibroblasts into myofibroblasts, increased collagen accumulation and dermal thickening 1, Wnt activation drives upregulation of VEGF leading to angiogenesis 3 Healthy Scleroderma chromatin (blue) β-catenin (green) 1. Beyer, C., et al. (1). Ann. Rheum. Dis.. Akhmetshina, A., et al. (1) Nat. Comm. 3. Dejana, E. (1). Circ. Res.. Image Adapted from Yamamoto, T. (1). Exp.Rev. Derm.
Samumed has identified a candidate molecule from preclinical studies - SM755 Topical small molecule Potent inhibitor of Wnt pathway Sustained local and minimal systemic exposure Anti-fibrotic Potentially inhibits angiogenesis
F o ld C h a n g e o v e r D M S O R e la tiv e E x p re s s io n SM755 is a potent inhibitor of Wnt activity In vitro screening in a luciferase based Wnt reporter assay Wnt pathway inhibition confirmed by qpcr for Wnt target genes. R e la tiv e W n t in h ib itio n Wnt Target Genes 1.5. DMSO SM755 (3nM) 1. EC5=156.8nM 1.5.5. - 1 1 3 5 C o n c. S M 7 5 5 ( L o g n M ) 1..5. * * * * * * * * A xin T C F L E F 1 T C F 7
F o l d C h a n g e o v e r u n t r e a t e d F o l d C h a n g e o v e r u n t r e a t e d F o l d C h a n g e o v e r u n t r e a t e d F o l d C h a n g e o v e r u n t r e a t e d SM755 inhibited fibrotic gene expression in dermal fibroblasts in vitro Human dermal fibroblasts treated with TGFb1 to induce fibrosis. SM755 significantly inhibited TGFb1- induced ColA1, ACTA, PAI- 1 and CTGF gene expression compared to vehicle. 5. 1. 5 1.. 5. 8 6 Cola1 * * V e h i c l e T G F + T G F + V e h i c l e S M 7 5 5 ( 1 M ) * PAI-1 * 1 8 6 6 V e h i c l e T G F + T G F + V e h i c l e S M 7 5 5 ( 1 M ) ACTA CTGF V e h i c l e T G F 1 + T G F 1 + V e h i c l e T G F 1 + T G F 1 + V e h i c l e S M 7 5 5 ( 1 M ) V e h i c l e S M 7 5 5 ( 1 M ) Mean ± SEM, p<.1, *p<.1, ANOVA
% S M A p o s itiv e c e lls SM755 reversed fibrosis in human dermal fibroblasts in vitro Human dermal fibroblasts treated with TGFb1 to induce fibrosis Treated with SM755 after 8hrs 1 1 8 6 EC 5 = 15nM N o T G F - 1 T G F - 1 T G F - 1 + S M 7 5 5 SM755 decreased TGFb1-induced smooth muscle actin -3 - -1 1 L o g C o n c. (u M ) TGF-β1 Stimulated Control DMSO SM755 (.3 µm) SM755 (.1 µm) αsma / DAPI αsma / DAPI αsma / DAPI αsma / DAPI
SM755 Concentrations (ng/g or ng/ml) SM755 sustained local & minimal systemic exposure In vivo PK following QD x 7 day topical dosing (1mg/ml) of SM755 in healthy rat skin Minimal plasma concentrations with rapid clearance C max < ng/ml in plasma Sustained local exposure and penetration into healthy skin Up to µm concentration in deeper layers (>8x expected Tx dose) High levels of compound retained in the skin beyond days No systemic toxicity observed 1 1 1 1 1 1 1 1 7 1 1 8 35 Time After Last Dose (Days) Plasma Tendon Muscle 1 Muscle Bone Skin
Bleomycin model for Scleroderma Bleomycin (5µg) injected sub-cutaneous, every other day for 3 days induced scleroderma like symptoms in mice Thickening of the dermis, hardening of the skin and vascular changes in ~ weeks Bleomycin (q.a.d.) Day Day 3 Day 1 SM755 (q.d., topical.5mg/ml &.5mg/ml) SM755 (.5mg/ml and.5mg/ml) topical treatment (µl/cm ) started day 1 Skin sections stained with H&E/MT and thickness of each layer measured at areas/section, and > sections/mouse Skin Biopsy and Histology Quantification Example 1 1 1 3 3 3 Dermis Adipose Tissue Deep Fascia
M e a n D e rm a l T h ic k n e s s (p ix e ls S E M ) M e a n D e e p F a s c ia T h ic k n e s s (p ix e ls S E M ) M e a n A d ip o s e T h ic k n e s s (p ix e ls S E M ) SM755 attenuated fibrosis in a mouse model of Scleroderma SM755 (.5mg/ml and.5mg/ml) topical treatment (µl/cm ), started day 1 Significantly reduced dermal and deep fascia thickness and increased adipose thickness on day 3 compared to vehicle treatment (p<.1) Naïve SM755 [.5] Vehicle SM755 [.5] 5 D e rm is 3 D e e p F a s c ia 3 A d ip o s e L a y e r 3 1 1 1 N a ïv e V e h ic le S M 7 5 5 (. 5 m g /m l) S M 7 5 5 (.5 m g /m l) N a ïv e V e h ic le S M 7 5 5 (. 5 m g /m l) S M 7 5 5 (.5 m g /m l) N a ïv e V e h ic le S M 7 5 5 (. 5 m g /m l) S M 7 5 5 (.5 m g /m l) N = 7 mice/group for treatment, 6 mice/group for vehicle and 3 mice/group for naïve, Mean ± SEM, p<.1, ANOVA
R e la tiv e E x p re s s io n R e la tiv e E x p re s s io n R e la tiv e E x p re s s io n R e la tiv e E x p re s s io n R e la tiv e E x p re s s io n R e la tiv e E x p re s s io n SM755 inhibited Wnt signaling and attenuated fibrosis in a mouse model of Scleroderma SM755 inhibited expression of fibrotic genes and a Wnt signaling pathway gene (Axin) in bleomycin mice, compared to vehicle 1 A x in 1 T G F - 1 1 S M A 8 8 8 6 6 6 * * 1 P A I-1 3 C T G F 3 V im e n tin 8 6 * 1 P=.56 Naive Bleomycin + Vehicle Bleomycin + SM755 (7.5 μg/cm ) 1 Mean ± SEM, n=7 mice/group for treatment, 6 mice/group for vehicle, and 3 mice/group for normal, *p<.5, p<.1 *
SM755 may decrease angiogenesis Representative sections stained for CD31 on day 3 CD31 - endothelial cell marker (also found in macrophages and platelets) SM755 treatment decreased CD31 staining SM755.5mg/ml Vehicle x 1x SM755.5mg/ml x 1x x 1x
Preclinical data suggest that SM755 may ameliorate fibrosis Wnt signaling is a pivotal pathway in fibrosis Inhibiting the Wnt pathway disrupts the fibrotic process SM755 was a potent inhibitor of Wnt/β-catenin activity SM755 reduced fibrosis and may reduce angiogenesis in an in vivo bleomycin model of SCL
Current status Phase 1, single blind, topical study in healthy subjects for SM755 program Primary objectives: safety and tolerability, dose ranging Secondary objective: plasma pharmacokinetics
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