The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance Ursula Germann 1 , Brinley Furey 2 , Jeff Roix 3 , William Markland 2 , Russell Hoover 2 , Alex Aronov 2 , Michael Hale 4 , Guanjing Chen 5 , Gabriel Martinez-Botella 6 , Rossitza Alargova 7 , Bin Fan 8 , David Sorrell 9 , Kay Meshaw 10 , Paul Shapiro 11 , Michael J. Wick 12 , Cyril Benes 13 , Mathew Garnett 14 , Gary DeCrescenzo 15 , Mark Namchuk 16 , Saurabh Saha 15 , Dean J. Welsch 15 . 1 OnKognos Scientific Consulting and Services, MA; 2 Vertex Pharmaceuticals, MA; 3 Phoremost, United Kingdom; 4 AstraZeneca, MA; 5 Novartis, MA; 6 Sage Therapeutics, MA; 7 Blend Therapeutics, MA; 8 AVEO Pharmaceuticals, MA; 9 Horizon Discovery, Plc, United Kingdom; 10 Charles River Discovery Research Services, NC; 11 University of Maryland, Baltimore, MD; 12 South Texas Accelerated Research Therapeutics, TX; 13 Massachusetts General Hospital, Harvard Medical School, MA; 14 Wellcome Trust Sanger Institute, United Kingdom; 15 BioMed Valley Discoveries, MO; 16 Alkermes, MA. Contact: Dean Welsch (dwelsch@biomed-valley.com) AA AACR ¡An CR ¡Annual ¡M ¡Mee+ ee+ng, ¡Ap ¡April ¡1 ¡18-‑2 -‑22, ¡2 ¡2015 Se Sessio ssion ¡ n ¡Title itle: ¡ : ¡Ex Explo ploi+ng ¡ i+ng ¡the the ¡ ¡MA MAPK PK ¡ ¡Path thway ¡ y ¡in ¡ in ¡Canc ancer r Session ¡ ¡Category: ¡ ¡Experime mental ¡ ¡and ¡ ¡Molecular ¡ ¡Therapeu+cs
Disclosure Information AACR Annual Meeting 2015 Dr. Dean J. Welsch I have the following financial relationship to disclose: Employee of BioMed Valley Discoveries I will not discuss off label use and/or investigational use in my presentation 2
Mechanistic Background & Therapeutic Opportunity BVD-523 dabrafenib RTKs RAS RAF MEK ERK RSK vemurafenib trametinib • MAPK pathway mutations causally drive many cancers • 3 MAPK drugs are approved but limited by intrinsic and acquired resistance • ERK inhibition has the potential to overcome or avoid resistance from upstream mutations 3
BVD-523 Executive Summary • Highly potent, selective and reversible ATP- competitive ERK1 and ERK2 inhibitor • Tumor growth regression in BRAF- and KRAS- mutant xenograft models • Single agent inhibition of a patient-derived xenograft cross-resistant to BRAFi and MEKi • Phase 1 dose escalation completed with expansion cohorts in progress 4
BVD-523 (ulixertinib): A Potent & Selective ERK Inhibitor BVD-523 Highly potent • ERK1 K i < 300 pM • ERK2 K i = 40 pM Highly selective • > 1,000-fold vs CDK1, CDK2, CDK5, CDK6, GSK3b • > 10,000-fold vs 70 other kinases 5
BVD-523 Preferential Activity in Cells with MAPK Pathway Mutations MGH/Wellcome Genomics of Drug Sensitivity in Cancer Panel 100 MAPK mutant MAPK WT MAPK mut. MAPK wt 10 Proliferation IC50 [uM] 1 0.10 0.01 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 6
BVD-523 Mechanism of Action and Enzyme Binding BVD-523 RTKs RAS RAF MEK ERK RSK Mechanism of Action Enzyme: BVD-523 Binding BVD-523 (uM) 1 5 ppERK2 RKO E R K 2 0.5 0 2 Differential 1 2 (BRAF V600E) p p E R K 2 MEK1/2 p 3 8 a Scanning D T m ( K ) Colorectal 9 p*S217/S221 Cancer Fluorimetry 6 ERK2 D ERK1/2 Cell Line 3 p*T202/Y204 p38 α 0 RSK1/2 0 . 0 1 0 . 1 1 1 0 p*T359/S363 B V D - 5 2 3 ( µ M ) 7
BVD-523 Anti-tumor Activity in Multiple In Vivo Cancer Models BVD-523 Tumor Growth Inhibition in Colo205 Xenograft A Mean Tumor Volume (mm 3 + SEM) Vehicle 50 mpk/day 100 mpk/day 150 mpk/day Days Following Tumor Cell Implantation • Single agent activity in xenografts with -‑ BRAF mutation (Colo205 CRC, A375 Mel) -‑ RAS mutation (MiaPaCa2 Panc) • At least additive with other MAPK inhibitors 8
Response Correlates with Tumor PK and Dose pERK Levels Correlate with Tumor PK - Timecourse 100 mpk, P.O. B ppERK/Total ERK (%) [BVD-523] tumor (ng/mL) Time Post Dose (hrs) pERK IHC 0 1 3 8 16 24 C 8 hr post-dose ppERK/Total ERK (%) pERK Levels Correlate with Tumor PK-Dose 0 25 50 75 100 Dose (mpk, P.O.) 9
RSK1/2 Phosphorylation as a BVD-523 Activity Clinical Biomarker BVD-523 RTKs RAS RAF MEK ERK RSK RSK1/2 is a substrate for ERK phosphorylation RKO Dabrafenib BVD523 Trametinib Vemurafenib BRAF V600E DMSO 0.5 µ M 2 µ M CRC Cells p*T359/S363 pRSK1/2 Total BVD-523 inhibits RSK1/2 phosphorylation using an ex vivo human whole blood assay 10 Human PBMC Donors Control % of RSK1/2 p*S380 10
RSK1/2 Phosphorylation as a Clinical Biomarker for BVD-523 Activity BVD-523 inhibits ERK activity following oral dosing in canine GLP tox study Dose ERK BVD-523 Conc. (mg/kg, Inhibition (uM) BID) (%) Vehicle 0 0 2 53 0.23 5 64 0.92 15 94 3.2 • Human and canine whole blood ERK activity assays established • BVD-523 demonstrated significant ERK inhibition with chronic oral dosing in canine GLP toxicity study at tolerated doses, exposures • ERK activity assay supporting clinical studies 11
BVD-523 Effective in Models of Acquired Resistance to BRAF and MEK Inhibitors BVD-523 potency retained in cells cross-resistant to BRAFi & MEKi Vemurafenib Trametinib BVD-523 MEK1 Q56P RKO parental BVD-523 sensitivity retained in A375 cells cultured to acquire resistance to BRAFi + MEKi combination Proliferation IC 50 (nM) Cell Line Dabrafenib Trametinib BVD-523 Paclitaxel Parental 2.1 0.2 129 1.9 BRAFi + MEKi- 17.9 2.7 323 4.7 Resistant Fold Increase 8.5 13.5 2.5 2.5 12
BVD-523 Effective in Xenografts Derived from a Patient Who Progressed on BRAF Inhibitor BVD-523 sensitivity in patient-derived xenograft model Baseline Post-Progression Intrinsic ¡BRAFi ¡Sensi/vity ¡ BRAFi ¡& ¡MEKi ¡Insensi/vity ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ERKi ¡Sensi/vity ¡ 1500 Vehicle Intrinsic BRAF Sensitivity Vehicle Tumor Volume (mm 3 ) Vehicle Dabrafenib 1000 Trametinib BVD-523 500 Vemurafenib Vemurafenib BVD-523 + Dabrafenib 0 0 7 14 21 Day Tumors that escape BRAFi and MEKi may remain sensitive to ERKi ¡ 13
BVD-523 IND Enabling Studies – Summary of Findings Safety Pharmacology GLP Toxicity Studies • No CV findings observed following 28 days of • No significant interaction in in vitro screens dosing with BVD-523 against 65 receptors, transporters, and ion • 28-day studies, with reversal arms, conducted at channels doses ranging from 25-100 mg/kg/day and 4-30 • Exhibited no significant genetic toxicology risks in mg/kg/day in rat and dog, respectively reverse mutation and micronucleus assays • Inhibits the hERG current (IC 50 3.4 uM) Target Tissue Toxicities • Dog Purkinje fiber assays revealed no significant effects up to 10 ug/mL • Findings are dose-dependent, and at least partially reversible Metabolism • Rat: tissue mineralization, skin lesions/rash • Dog: gastrointestinal • Recombinant human CYP1A2, CYP2C9, • All toxicities consistent with MAPK pathway CYP2C19, CYP2D6, and CYP3A4 capable of inhibitors, further demonstrating the exquisite metabolizing BVD-523 selectivity of BVD-523 • Metabolism predominantly via oxidation and de- alkylation Starting Dose Justification • Metabolic profile of BVD-523 across mouse, rat, dog, and human liver microsomes and hepatocytes very similar (monkey was unique in • Rat identified as most sensitive species its metabolic profile) • Supported first-in-human starting dose of • Rat & dog identified as appropriate species for 10 mg, BID toxicological evaluation 14
BVD-523 Clinical Development Plan – Ongoing Studies Current Status Advanced Solid Tumor Protocol (NCT01781429) Solid > Grade 2 Tumor FIH Related AE RP2D (10 mg, BID) Group 1: BRAF V600E/K mutant melanoma, inhibitor naive Group 2: BRAF non-V600E/K mutant melanoma, inhibitor naive Group 3: BRAF mutant melanoma, progressed/refractory to BRAFi &/or MEKi Group 4: NRAS mutant melanoma, inhibitor naive Accelerated Standard Group 5: MEK mutant cancers, inhibitor naive Dose Titration “3 + 3” Group 6: BRAF mutant NSCLC, inhibitor naive (1 pt per cohort) Dose Escalation Acute Myelogenous Leukemia AML/MDS or Myelodysplastic Syndromes Protocol RP2D (NCT02296242) Solid Group 1: AML/MDS w/o RAS mutation Tumor Group 2: AML/MDS w/ RAS mutation RP2D Standard X 0.5 “3 + 3” Dose Escalation 15
BVD-523 Clinical Development Plan – Potential Studies Possible Protocols • BVD-523 + BRAFi, MEKi, or BRAFi & MEKi • BVD-523 + BRAFi, MEKi, or BRAFi & MEKi after acquired resistance • BVD-523 + non-MAPK pathway targeted agents • BVD-523 + immune response modulators • BVD-523 + chemotherapeutics • BVD-523 + ??? 16
BVD-523 Executive Summary • Highly potent, selective and reversible ATP- competitive ERK1 and ERK2 inhibitor • Tumor growth regression in BRAF- and KRAS- mutant xenograft models • Single agent inhibition of a patient-derived xenograft cross-resistant to BRAFi and MEKi • Phase 1 dose escalation completed with expansion cohorts in progress 17
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