Discovery of a Small Molecule Wnt Pathway Inhibitor (SM04690) as a Potential Disease Modifying Treatment for Knee Osteoarthritis
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1 Discovery of a Small Molecule Wnt Pathway Inhibitor (SM469) as a Potential Disease Modifying Treatment for Knee Osteoarthritis Vishal Deshmukh PhD, Charlene Barroga PhD, Carine Bossard PhD, Sunil KC PhD, Tim Seo MS, Melinda Pedraza BS, Maureen Ibanez MS, Kevin Chiu BS, Long Do PhD, Shawn Cho MS, Luis Dellamary BS, Josh Stewart BS, Haide Hu PhD, Betty Tam PhD, John Hood PhD, Yusuf Yazici MD
2 Pathophysiology of Osteoarthritis Mechanical forces and inflammation result in degenerative tissue remodeling in OA Induce cartilage catabolic enzymes - matrix metalloproteinases (MMPs), aggrecanases, etc. Cartilage loss and subchondral bone remodeling Healthy Osteoarthritis Bone marrow Synovial membrane Articular Cartilage Mesenchymal Stem Cells Bone Remodeling Bone Sclerosis Synovitis Inflammatory cells and cytokines Osteophyte Cartilage Loss Impacted by Wnt signaling Cartilage Degradation MMPs, ADAMTS Chondrocyte Hypertrophy Figure adapted from Bush J & Beier F. (213) Nature Med.
3 Wnt signaling is a critical pathway in OA: Cartilage catabolism OA is characterized by increased subchondral bone and reduced cartilage 1 Wnt proteins are over-expressed and more active in OA joints 2 Wnt pathway mutations (e.g. FrzB) are associated with OA 3 Mechanical stress and inflammation increase Wnt pathway activity in the joint 3,4 Increased Wnt signaling leads to cartilage catabolism 5 Proteases (MMPs, ADAMTs) are released leading to cartilage catabolism Chondrocytes Mechanical stress Normal Cartilage + Catabolic Enzymes Cytokines Wnt activity Synovium Cartilage Degradation MMP Matrix Metalloprotease ADAMT A Disintegrin and Metalloproteinase with Thrombospondin motifs 1. Krishinan et al. (26). J Clin Invest. 2. Yuada et al. (28). Lab Invest. 3.Thomas RS, et al. (211) Arthritis Res Ther. 4.Weng, L.-H. et al. (29) Osteoarthr Cartil. 5.van den Bosch et al. (215) Am J Pathol.
4 Wnt signaling is a critical pathway in OA: Cartilage regeneration + Osteoblasts + Increased Wnt pathway activation - Wnt pathway inhibition Proliferative Progenitor Cells - Chondrocytes Progenitor cells reside in the joint and can contribute to cartilage repair 1-3 In OA, elevated Wnt signaling is involved in increased bone formation by driving progenitor cells towards an osteogenic cell fate 4,5 More Wnt signaling = More bone & less cartilage Hypothesis: Modulation of the Wnt signaling pathway protects, and may regenerate, cartilage 1. Williams R, et al. (21) PLoS One. 2. Pretzel D, et al. (211) Arthritis Res Ther. 3. Candela ME, et al. (214) Matrix Biol. 4. Rudnicki JA & Brown AM. (1997) Dev Biol. 5. Corr M. (28) Nat Clin Pract Rheumatol. Figure adaptations: and Bush J & Beier F. (213) Nature Med.
5 Proposed therapy: SM469, a small molecule Wnt pathway inhibitor SM469 is a small molecule Wnt signaling pathway inhibitor in development for the treatment of OA SM469 demonstrated the following properties in pre-clinical studies: Inhibited Wnt signaling in vitro and in vivo Regenerated cartilage Decreased cartilage catabolism Decreased inflammation Demonstrated sustained local exposure and no observable systemic toxicity
6 In vitro efficacy SM469
7 Wnt signaling inhibition: SM469 was a potent inhibitor in SW48 cells and hmscs L u m in is c e n c e (x 1 7 ) SM469 inhibited TCF/LEF-reporter in SW48 cells (EC 5 =19nM). No effect on SV4- reporter SM469 inhibited Wnt pathway gene expression in human mesenchymal stem cells (hmscs) SM469 was 5-5 fold more potent than previously reported Wnt pathway inhibitors N o rm a liz e d L u c ife ra s e S ig n a l T C F /L E F S V 4 R e la tiv e E x p re s s io n DMSO SM469 (3 nm) S M (L o g c o n c [n M ]). A S C L 1 L E F 1 T C F 4 T C F 7 C -M Y C A X IN L o g C o n c. (n M ) S M F H IW R -1 C X K Y IC G - 1 ic R T 1 4 Compound EC5 (nm) SM FH-535 >1, IWR-1 >1, CX KY2111 >1 ICG icrt14 >1 n=6, Mean ± SEM, p<.5, p<.1, p<.1
8 Wnt signaling inhibition: SM469 inhibited Wnt3a- & CHIR- induced Wnt signaling R e la tiv e E x p r e s s io n R e la tiv e E x p r e s s io n R e la tiv e E x p r e s s io n WNT Pathway Genes SM469 was a potent inhibitor of Wnt pathway gene expression (Axin2, TCF7, Lef1) in hmscs stimulated with Wnt3a or GSK3β inhibitor (CHIR-9921) SM469 inhibited the expression of several Wnt pathway genes measured by RNA-seq +2-2 DMSO SM469 3nM 1nM 4 A X IN 2 5 T C F 7 8 L E F 1 R e la tiv e E x p r e s s io n R e la tiv e E x p r e s s io n R e la tiv e E x p r e s s io n Untreated Wnt3a + DMSO Wnt3a + SM469 (3nM) Wnt3a + SM469 (1nM) 1 5 A X IN 2 4 T C F 7 4 L E F Untreated CHIR + DMSO CHIR + SM469 (3nM) CHIR + SM469 (1nM) n=4, Mean ± SEM, p<.5, p<.1, p<.1 n=6 (pooled as n=3)
9 F o l d C h a n g e ( X / u n s t i m u l a t e d ) F o l d C h a n g e ( X / u n s t i m u l a t e d ) Decreased cartilage catabolism: SM469 inhibited protease production In OA, cytokines induce cartilage catabolic enzymes 5 4 M M P 1 Upregulated Wnt signaling increases protease expression SM469 demonstrated dose-dependent inhibition of protease expression C o n t r o l 1 n M 3 n M 1 n M 3 n M SM469 (conc.) 1 Cellular assay human chondrocytes: Induce proteases Treat Measure F o l d C h a n g e ( X / u n s t i m u l a t e d ) M M P 3 TNFα + Oncostatin M SM469 or Control qpcr: MMP 1, 3, & 13 2 C o n t r o l 1 n M 3 n M 1 n M 3 n M SM469 (conc.) M M P C o n t r o l 1 n M 3 n M 1 n M 3 n M SM469 (conc.) n=3, Mean ± SEM, p<.5, p<.1, p<.1 1. Enochson L, et al. (214) OA Cart.
10 C h o n d r o c y te c o lo n ie s /w e ll Regenerated cartilage: SM469 induced chondrocyte differentiation 21 day cellular assay: Aggrecan Rhodamine B Toludine Blue CD44 hmscs treated with SM469 every 7 days DMSO Cells stained for biomarkers of chondrocyte differentiation SM469 induced differentiation of hmscs into chondrocytes SM469 (3nM) Aggrecan Safranin O Rhodamine B Alcian Blue Toludine Blue TIMP1 CD44 Col IIA 6 DMSO 4 Safranin O Alcian Blue TIMP1 Col IIA 2 SM469 (3nM) S M c o n c e n tr a tio n (n M ) Scalebar= 2μm n=9, Mean ± SEM, p<.5, p<.1.
11 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 Regenerated cartilage: SM469 induced functional chondrogenesis 21 day cellular assay hmscs: Treated with SM469 every 7 days qpcr analysis showed increased chondrogenic and decreased osteogenic gene expression as compared to DMSO control SM469 treatment increased sulfated glycosaminoglycans (sgag) Demonstrated functional cartilage matrix synthesis Chondrogenic Genes sgag Osteogenic Genes 6 DMSO SM469 (3nM) DMSO SM469 (3nM) 4 2 S O X 9 A g g r e c a n C o l2 A T G F b 1 T IM P 1 T o ta l G A G ( g /m g ) DMSO SM469 (3nM) C o l1 A O s te o - c a lc in A L P L B M P 4 n=3, Mean ± SEM, p<.5, p<.1, p<.1
12 C y to k in e le v e ls (p g /m l) Anti-inflammatory properties: SM469 decreased pro-inflammatory cytokines N o rm a liz e d fo ld c h a n g e IL-1β, IL-6, IL-8 and TNF-α are associated with the pathophysiology of OA 1 Cellular assay: Synovial fibroblasts stimulated with IL-1β or LPS to induce cytokine production, then treated with SM469 Dose dependent inhibition of IL-6 and TNF-α production, as well as several proinflammatory cytokines Mechanism under investigation Synovial fibroblasts Synovial Fibroblasts stimulated with LPS T N F - 4 IL L o g C o n c. (n M ) IL-6 EC 5 = 24nM; TNF-α EC 5 = 35nM.5. IL -1 IL -2 IL -5 IL -6 IL -8 T N F IF N DMSO SM469 (3 nm) n=3, Mean ± SEM, p<.5, p<.1, p<.1 1. Glyn-Jones S, et al. Lancet. 215;386(9991)
13 In vivo studies SM469
14 S M (n M ) Pharmacokinetics and toxicology: SM469 had sustained local exposure and no systemic toxicity Rats (Sprague Dawley): Single intra-articular injection (.3ug) Compound is retained in joint above the target tissue concentration level (~3 nm) for >6 months Compound is undetectable in plasma at all time points Expected therapeutic level (~3 nm) D a y s C a rtila g e B o n e P la s m a Intra-articular (IA) injection in Rats (Sprague Dawley) and Dogs (Beagle): Single or multiple (6 or 9 once-monthly) IA injections No systemic toxicity - body weight, target or non-target organ effects, ECG and clinical pathology at doses up to 4X the expected clinical dose
15 Effects on OA in vivo : SM469 efficacy in a rat OA model Rat ACLT + pmmx model: Anterior cruciate ligament transection (ACLT) combined with partial medial meniscectomy Cartilage degeneration within 1-2 weeks Injected SM469 intra-articularly at 1wk (.1 µg,.3 μg, 1 μg) Joint histology performed 4 and 12 weeks after injection OA induction Day Day 7 Day 35 Day 9 ACLT + pmmx surgery in Rats
16 Wnt signaling in ACLT + pmmx model : SM469 inhibited Wnt signaling in cartilage SM469 (compared to vehicle): decreased endogenous Wnt signaling activators and downstream gene expression increased expression of Wnt pathway inhibitory genes inhibited β-catenin nuclear localization in articular chondrocytes VehicleSM469 In te n s ity Max Avg Week 13 Vehicle β-catenin SM469 (.3μg) β-catenin 5 4 Total cellular β-catenin Min In te n s ity V e h ic le S M (.3 g ) β-catenin / DAPI β-catenin / DAPI 3 Nuclear β-catenin 2 1 V e h ic le S M (.3 g ) n=7 rats for vehicle, N=8 rats for SM469; Mean ± SEM, p<.5, p<.1
17 R e la tiv e E x p re s s io n Protected cartilage from catabolism: SM469 decreased cartilage degrading proteases qpcr evaluation of protease enzymes in cartilage SM469 (compared to vehicle): decreased protease expression in cartilage, likely protecting cartilage from catabolism Week 5 Protease Genes M M P 1 M M P 3 M M P 1 3 A D A M T S 5 Vehicle SM469 (.3ug) n=12, Mean ± SEM, p<.5, p<.1, p<.1
18 R e la tiv e E x p re s s io n s G A G (u g /g ) Regenerated cartilage: SM469 induced chondrogenesis and cartilage matrix production qpcr evaluation of cartilage production markers in cartilage 5 weeks after ACLT+pMMx SM469 (compared to vehicle): increased expression of cartilage markers increased sulfated glycosaminoglycans (sgag) - cartilage matrix no change in Col1a (hypertrophic marker) Chondrogenic Genes Week 5 GAG 8 6 Vehicle SM469 (.3ug) n s 2 Col2a1 COMP Aggrecan Col1a V e h ic le S M (.3 u g ) n=12, Mean ± SEM, p<.5, p<.1, p<.1, ns- not significant
19 S a fr a n in O in te n s ity /a r e a Regenerated cartilage: SM469 increased cartilage density and thickness Histology samples 13 weeks after ACLT+pMMx Safranin O-stained sections from the rat knee analyzed for OA cartilage pathology Increased Safranin O staining, cartilage thickness and decreased fissures observed with a single intra-articular injection of SM469 Vehicle Treated Knee 13 weeks SM469 (.3µg) Treated Knee 13 weeks C a r tila g e th ic k n e s s ( m ) V e h ic le S M (.3 g ) 1 5 V e h ic le S M (.3 g ) n=12, Mean ± SEM, p<.1, p<.1
20 O A R S I S c o re Regenerated cartilage: SM469 improved OARSI scores and OA biomarkers C O M P (n g /m l) P IIA N P ( n g /m l) Safranin O-stained sections from the rat knee scored (blinded) using OARSI system OARSI cartilage pathology score measures cartilage matrix loss, fissures and subchondral bone remodeling, based on stage and grade of cartilage damage SM469 (compared to vehicle): Decreased OARSI score. Decreased serum COMP (catabolic marker) and increased serum PIIANP (anabolic marker). 6 OARSI Score Week 13 4 COMP 1 5 PIIANP V e h ic le S M (.1 g ) S M (.3 g ) W e e k 3 W e e k 6 W e e k 4 W e e k 6 Vehicle SM469 (.3ug) n=12, Mean ± SEM, p<.5, p<.1
21 Regenerated cartilage: SM469 improved macroscopic cartilage appearance Rat knee samples 13 weeks after ACLT+pMMx Increased cartilage and smooth articular surface in SM469 treated rats compared to vehicle Vehicle Treated Knee 13 weeks SM469 (.3µg) Treated Knee 13 weeks
22 Summary: SM469 is a promising DMOAD candidate Wnt signaling is a critical pathway in osteoarthritis In preclinical models, SM Inhibited Wnt signaling Inhibited protease production Induced chondrogenesis Inhibited inflammatory cytokine production Demonstrated sustained local availability and no systemic exposure Demonstrated no observable systemic toxicity Human clinical trials (Phase 2) are ongoing 1. Barroga C, et al. (215) Arthritis Rheum. 2. Hood JD, et al (216) Osteoarthr. Cartil 3. Hood JD, et al. (216) Ann. Rheum. Dis. 4. Deshmukh V, et al. (216) Arthritis Rheum. 5. Deshmukh V, et al. (217) Osteoarthr. Cartil
23 Thank you
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