New family of molecules with oral therapeutic potential in NAFLD/NASH, obesity, hypertension, dyslipidemia and type 2 diabetes
Opportunity Novel family of small molecules, orally applicable • Pre-clinical stage, lead molecule (SJT4A) identified • Potential application in a broad variety of metabolic disease indications: • – NAFLD (including NASH): significant reduction in collagen gene expression (fibrosis marker) and NAS score: reduced liver steatosis, ballooning, inflammation and fibrosis Type 2 Diabetes: greater potency compared to standard glucose lowering therapies – (Metformin) Obesity: > 40% excessive weight reduction in DIO mouse model – Hypertension: reduces systolic blood pressure – – Dyslipidemia and diabetes asscociated complications: Decline of insulin resistance, reduction in blood pressure, plasma cholesterol and weight control, decrease of liver lipids in hepatic steatosis Encouraging safety profile from early toxicology studies • Simple manufacturing process • “First in Class” novel dual mechanism of action (FXR agonist and 5-HTR2A antagonist) • Strong IP portfolio with long expiry dates granted in major markets • SJT is seeking a partner for the further development and commercialization of its proprietary, • novel molecules
Discovery pathway to SJT’s novel molecules NASH AMAZON RAIN FOREST IBAMA Obesity rich source of medicinal plants Hypertension Input from local tribe elders Diabetes Type 2 Dyslipidemia 100 plants selected for further analysis (1) Animal testing Testing toxicology & efficacy (1) Multiple rounds of testing on plants: • Anti-diabetic properties 34 plants selected for • Toxicology New family of molecules: anti-diabetic properties (1) Efficacy • in vivo screening (1 lead and (2) Identification of active groups 68 additional active family Testing in pairs (alkaloids, polyphenols & glycosides ) members) (3) Scaffold selection 2 plants with synergistic • Addition of radicals Identification of best molecules activity (1) • Parent b -carboline structure Isolate and analyse Design and synthesis of new active principles (2) molecules (3) Herbal Product Synthesized molecule
Company background SJT Molecular Research is a privately-funded biotech company based in Spain (Vitoria) • Focus on the discovery and early development of novel molecules for metabolic disorders • Virtual set-up with strong network of renowned public and private institutions: • Public Institutions: Private Institutions: • Federal University of Grande Dourados (Brazil) • Eurofins , Cerep, Panlabs (France, UK, USA, Taiwan) Federal University of Paraná(Brazil) Gubra (Denmark) • • • University of Alcalá (Madrid, Spain) • Cyprotex (UK, USA) • University of the Balear Islands (Spain) • Physiogenex (France) • University of Vigo (Spain) • Amylgen (France) • Gentronix (UK) Sequani (UK) • • Softmining (IT)
Intellectual property Patent claims cover: Medical use • Cosmetic, nutraceutical or functional food • Composition of matter for the molecules • additive composition Intermediates and derivatives • Pharmaceutical formulations • Granted in: National phases: USA, US9440966 (B2) China • • Europe , EP2691394 (B1) Brazil • • Japan , JP6049216 (B2) India • • Canada , 2,831,716 • • Australia, AU2012234230 (B2) Russia, RU2615136 (C2) • Israel, 228630 • South Korea , 046182713 • Mexico , MX/a/2013/011124 • Patent filings worldwide covering novel family of molecules published as WO2012130912. New International Patent Application No. PCT/EP2018/053990 of NAFLD and NASH
Novel family of molecules • Data focused on the lead molecule ( SJT4A ) 2 backup modecules based on the same structure • Intermediate and derivate compounds of the 3 molecules covered by patent applications (66 • additional molecules) O N H 2 N H N(-ethylamine)-1- N benzosubstituted-β-carboline-3- SJT4A N carboxamide H Mw = 360 O C H 3
Pharmacokinetics (PK) • Plasma concentrations high enough to provide a therapeutic effect • Extended bioavailability by bid administration* SJT4A-HCl (mice) Qdx1** Qdx1** Qdx7** Bid*x7 PK parameter IV 15 mg/kg PO 50 mg/kg PO 50 mg/kg PO 50 mg/kg AUC (h x ng/ml) 6229 3988 4836 8132 Last time point (AUC) 6 8 8 8 C 0 (ng/ml) 12015 C max (ng/ml) 1050 949 1524 MRT (h) 1.25 2.80 3.48 4.00 T 1/2 (h) 1.36 T max (h) 2.00 4.00 4.00 CL (ml/min/kg) 40.13 Vss (L/kg) 3.58 F (%) 18.87 21.81 35.32 * bid: 2 x daily // ** qd: once daily
SJT4A reduces hyperglycemia and hyperinsulinemia DIO mice model treated with SJT4A for 22 days 260 45 40 240 35 220 * Insulin (μg/mL) 30 Glucose (mg/dL) * 200 ** 25 ** 180 20 160 15 140 10 120 5 100 0 Control SJT4A Metformin Control SJT4A Metformin Data expressed as mean ± s.e.m. values from 10 animals. *P<0.05, **P<0.01. 4A (50 mg/kg), Metformin (150 mg/kg)
SJT4A decreases insulin resistance from the first week of treatment DIO mice model treated with SJT4A Control SJT4A Metformin 35 30 25 20 HOMA-IR 15 10 * 5 * ** ** 0 days 1 8 15 22 29 36 Data expressed as mean ± s.e.m. values from 10 animals. *P<0.05, **P<0.01. 4A (50 mg/kg), Metformin (150 mg/kg)
SJT4A decreases liver lipid content associated to hepatic steatosis DIO mice model treated with SJT4A for 36 days SJT4A decreases liver lipid content associated to hepatic steatosis 18 50 14 Hepatic triglycerides (μg/mg liver) 45 Hepatic cholesterol (μg/mg liver) 16 Hepatic fatty acids (nmol/mg liver) 12 40 14 ** 35 10 12 30 10 8 25 8 ** 6 20 ** 6 15 4 4 10 2 2 5 0 0 0 Control SJT4A Metformin Control SJT4A Metformin Control SJT4A Metformin Data expressed as mean ± s.e.m. values from 10 animals. **P<0.01. 4A (50 mg/kg), Metformin (150 mg/kg)
SJT4A reduces the body excess weight (>47 %) and body weight by ≈15 % DIO mice model treated with SJT4A Control SJT4A Metformin 44 42 40 Body weight (g) 38 36 *** 34 ** *** ** *** 32 30 0 5 10 15 20 25 30 35 40 days Data expressed as mean ± s.e.m. values from 10 animals. **P<0.01, ***P<0.001. 4A (50 mg/kg), Metformin (150 mg/kg)
SJT4A reduces systolic blood pressure Systolic blood pressure in SHR hypertensive rat model Control SJT4A 260 Systolic blood pressure (mm Hg) 240 220 200 *** 180 0 5 10 15 20 25 30 days Data expressed as mean ± s.e.m. values from 6 animals. ***P<0.001. 4A (15 mg/kg)
SJT4A reduces excess weight by >40 % and body weight by ≈15 % Gubra DIO-NASH mice model treated with SJT4A for 8 weeks Data expressed as mean ± s.e.m. values from 10-12 animals. **P<0.01, ***P<0.001. 4A (50 mg/kg)
SJT4A reduces liver excess weight in DIO-NASH mice (>40 %) Gubra DIO-NASH mice model treated with SJT4A for 8 weeks Data expressed as mean ± s.e.m. values from 10-12 animals. **P<0.01, ***P<0.001. 4A (50 mg/kg)
SJT4A reduces the excess of TG and TC in liver (>50 %) Gubra DIO-NASH mice model treated with SJT4A for 8 weeks Data expressed as mean ± s.e.m. values from 10-12 animals. **P<0.01, ***P<0.001. 4A (50 mg/kg)
SJT4A decreases liver toxicity (77 % ALT & 65 % AST) Gubra DIO-NASH mice model treated with SJT4A for 8 weeks Data expressed as mean ± s.e.m. values from 10-12 animals. ***P<0.001. 4A (50 mg/kg)
SJT4A significantly lowers NAFLD activity score (NAS) Gubra DIO-NASH mice model treated with SJT4A for 8 weeks Significantly lower NAFLD activity score (NAS) affects steatosis and inflammation Pre and post-study biopsy comparison LEAN-CHOW Vehicle NAS 8 7 6 Vehicle DIO-NASH Vehicle SJT4a 5 LEAN-CHOW Vehicle DIO-NASH Vehicle SJT4a Ballooning Ballooning Ballooning Steatosis Steatosis Steatosis 4 3 2 3 3 3 1 1 1 1 0 2 2 2 e t r s o P 1 1 P 1 0 0 0 0 0 0 DIO-NASH Vehicle NAS Pre Post Pre Post Pre Post Pre Pre Post Pre Post Post 8 7 6 5 Steatosis Ballooning 4 3 2 1 0 Pre Post DIO-NASH Vehicle LEAN-CHOW Vehicle SJT4a LEAN-CHOW Vehicle DIO-NASH Vehicle Fibrosis SJT4a Fibrosis Fibrosis Inflammation Inflammation SJT4a Inflammation NAS 3 3 3 3 3 3 8 7 2 2 2 2 2 6 2 5 1 1 1 1 1 1 4 3 0 0 0 0 0 0 2 1 e t s Pre Post Pre Post r e t e t e t P o s s s 0 r r r P P o P o P o P P P e t s r P o P Inflammation Fibrosis NAS
SJT4A significantly reduces inflammation Gubra DIO-NASH mice model treated with SJT4A for 8 weeks SJT4A reduces inflammation through lowers liver galectin-3 content (inflammation marker) CHOW-LEAN Vehicle DIO-NASH Vehicle SJT4a Data expressed as mean ± s.e.m. values from 10-12 animals. ***P<0.001. 4A (50 mg/kg)
SJT4A decreases fat accumulation in liver Gubra DIO-NASH mice model treated with SJT4A for 8 weeks CHOW-LEAN Vehicle DIO-NASH Vehicle SJT4a Data expressed as mean ± s.e.m. values from 10-12 animals. ***P<0.001. 4A (50 mg/kg)
SJT4A reduces total liver collagen type I (fibrosis marker) Gubra DIO-NASH mice model treated with SJT4A for 8 weeks CHOW-LEAN Vehicle DIO-NASH Vehicle SJT4a Data expressed as mean ± s.e.m. values from 10-12 animals. *P<0.05. 4A (50 mg/kg)
Recommend
More recommend
