Syros Pharmaceuticals, Inc. · OTC:SYRS
Syros Pharmaceuticals — EORTC-NCI-AACR 2018
18 slides from Syros Pharmaceuticals's conference presentation, Nov 15, 2018
Slide 1: Forward-looking statements
Forward-looking statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, inc
Slide 2: SY-1365 (CDK7 inhibitor): Controlling expression of tumor-driving genes
SY-1365 (CDK7 inhibitor): Controlling expression of tumor-driving genes First-in-class selective inhibitor of CDK7 CDK7 inhibition induces apoptosis and preferentially kills cancer cells over non-cancerous cells Currently in Phase 1 clinical trial as single and combination agent in ovarian and breas
Slide 3: CDK7 has emerged as a potentially important target across solid tumors and blood cancers
CDK7 has emerged as a potentially important target across a range of solid tumors and blood cancers Cell Cycle Transcription Certain cancers hijack transcriptional machinery to drive increased expression of oncogenic transcription factors and anti-apoptotic proteins Certain cancers develop adaptatio
Slide 4: SY-1365 is a first-in-class potent and selective CDK7 inhibitor
SY-1365 is a first-in-class potent and selective CDK7 inhibitor DiscoveRx kinome scan at 1mM SY-1365 Covalent Highly potent Highly selective Only binds to 7 out of 468 kinases screened at >90% binding Does not significantly bind to CDK9 or cell cycle CDKs Preclinical models demonstrated sustained CD
Slide 5: SY-1365 has dual effect on transcription and cell cycle
SY-1365 has dual effect on transcription and cell cycle, preferentially killing cancer cells in preclinical studies Apoptosis SY-1365 has been shown to decrease expression of oncogenic transcription factors and anti-apoptotic proteins in multiple preclinical models SY-1365 is thought to interfere wi
Slide 6: Expansion cohorts in Phase 1 trial exploring SY-1365 single agent and combination
Expansion cohorts in Phase 1 trial exploring SY-1365 as single agent and in combination in multiple ovarian and breast cancer patient populations Phase 1 clinical trial design Relapsed ovarian cancer, 3+ prior lines Single agent (N=24) Relapsed ovarian cancer, 1+ prior lines (platinum sensitive) Com
Slide 7: Dose escalation portion of SY-1365 Phase 1 trial
Dose escalation portion of SY-1365 Phase 1 trial Dosing IV dosing over one hour 3 weeks every 4 weeks Trial Endpoints Primary: DLTs and safety Secondary: PK and PD Exploratory: Anti-tumor activity Data snapshot: Oct. 15, 2018 Part 1 Dose Escalation (N=32) Weekly (mg/m2) Twice Weekly (mg/m2) Single p
Slide 8: Dose escalation: patient baseline characteristics
SY-1365 dose escalation: patient baseline characteristics 9 Characteristics N(%) N=32 Median Age, years (range) 63 (25-87) Female sex, n (%) 25 (78.1) 4 Prior Lines of Therapy 28 (87.5) Median Number Prior Lines (range) 5 (1-13) Cancer Type Breast 8 (25) Ovarian 8 (25) Endometrial 5 (16) Pancreatic
Slide 9: Dose escalation: patient disposition
SY-1365 dose escalation: patient disposition 10 *Due to progression of disease Number of Patients Enrolled N (%) Duration of Treatment: Median days (range) 46.5 (2 – 147) Patients withdrawn from treatment 28 (87.5) Progressive Disease per RECIST 1.1 16 (50.0) Clinical Progression 7 (21.9) Withdrawal
Slide 10: Safety overview: dose escalation (N=32)
SY-1365 safety overview: dose escalation (N=32) 11 Predominantly low grade, reversible, and generally manageable Most frequent related AEs include headache, nausea, vomiting, and fatigue No reports of neutropenia DLTs: headache (64 mg/m2), coronary vasospasm (80 mg/m2), and fatigue (112 mg/m2) MTD n
Slide 11: Plasma pharmacokinetics
SY-1365 plasma pharmacokinetics Plasma PK exposures (Cmax, AUC) are linear from doses of 2 to 107 mg/m2 No SY-1365 accumulation with repeat dosing SY-1365 day 1 PK parameters at 80 mg/m2 Cmax: 7,498 ± 1,116 ng/mL AUC: 11,696 ± 2,848 ng/mL•h Half-life: 17.9 ± 4.2 h 12
Slide 12: PD effects evaluated by CDK7 occupancy and transcriptional assays
SY-1365 PD effects evaluated by CDK7 occupancy and transcriptional assays Sample containing bound and free CDK7 Lyse and incubate with biotinylated probe Bound CDK7 Bound CDK7 Pull-down with Streptavidin beads Use whole lysate total CDK7 free CDK7 SY-1365 treatment (nM) SY-1365-biotin probe molecule
Slide 13: SY-1365 demonstrates dose-dependent effects on CDK7 occupancy and gene transcription
SY-1365 demonstrates dose-dependent effects on CDK7 occupancy and gene transcription Relative Expression (Log2) 3h post-dose vs. pre-dose SY-1365 Dose (mg/m2) 0 -1 -2 -3 1 4 8 16 32 53 64 80 107 PBMC Gene Expression Signature PBMC CDK7 Occupancy SY-1365 binding to CDK7 over the dosing interval excee
Slide 14: Early evidence of SY-1365 clinical activity
Early evidence of SY-1365 clinical activity Clinical activity per RECIST 1.1 criteria was observed in 7 out of 19 evaluable patients Disease Control Rate (CR+PR+SD) of 37% One confirmed PR (in clear cell ovarian cancer patient) observed at 80 mg/m2 BIW 6 additional patients with stable disease, most
Slide 15: Early evidence of SY-1365 clinical activity: CT images
Early evidence of SY-1365 clinical activity CT images of 52 year old woman with relapsed ovarian cancer on SY-1365 80 mg/m2 BIW 16 Stage IV clear cell in 4th relapse ARID1A, PIK3CA, NF1 mutations Best response to prior lines of therapy: SD Confirmed PR after 2 cycles 31.8% reduction (C3D1) Remains o
Slide 16: Dose and schedule selected for ongoing expansion cohorts
Dose and schedule selected for ongoing expansion cohorts Evaluating SY-1365 as single agent and in combination in multiple ovarian and breast cancer patient populations Dose selection supported by PK/PD analyses of drug exposure and target occupancy, tolerability profile and early signs of clinical
Slide 17: Significant need for new therapies in ovarian and HR+ metastatic breast cancer
Breast Cancer : ~266,0002 Ovarian Cancer : ~59,0001 Significant need for new therapies in advanced high-grade serous ovarian and HR+ metastatic breast cancer 70% have high-grade serous ovarian cancer and most present with advanced disease at initial diagnosis Standard-of-care includes platinum-based
Slide 18: Rapidly advancing toward our vision
Rapidly advancing toward our vision 19 Progressing to pivotal development Advancing multiple programs in clinic Preparing for commercial launch Ongoing investment in discovery Fully integrated company with medicines that provide a profound benefit for patients Driving SY-1425 and SY-1365 to key mile