Tempest Therapeutics, Inc. · NASDAQ:TPST
Tempest Therapeutics — Technical Presentation (2019)
24 slides from Tempest Therapeutics's technical presentation, 2019
Slide 1: STING at a Crossroads: Untapped Potential for Innate Immunity
STING at a Crossroads: Untapped Potential for Innate Immunity Thomas W. Dubensky, PhD Tempest Therapeutics South San Francisco, CA
Slide 2: Disclosures
Disclosures • Thomas W. Dubensky, Jr. is a paid employee of Tempest Therapeutics and holds stock options in the company, and is an inventor on multiple patents and pending applications related to the STING pathway.
Slide 3: STING at a Crossroads: Overview
STING at a Crossroads: Overview • Scientific rationale for targeting STING, revisited • Clinical-staged STING agonists, status and results • Have expectations been met—is STING at a crossroads? • Other approaches and rationale for targeting STING • Concluding remarks
Slide 4: Rationale for Targeting STING
Rationale for Targeting STING Cytosolic DNA sensing pathway STING (Stimulator of Interferon Genes): • Innate immunity is activated in response to sensing nucleic acids in the cytosol • Downstream signaling is triggered through binding of cyclic dinucleotides (CDNs) • CDNs are synthesized by bacteria
Slide 5: Rationale for Targeting STING
Rationale for Targeting STING Cytosolic DNA sensing pathway Listeria (Lm) intracellular infection Induced IFN-β expression Luster, Moors and Portnoy, 1994 (unpublished); Woodward et al., Science, (2011); qRT-PCR Burdette et al., Nature, (2011); and, Sauer et al., Infection and Immunity, (2011)
Slide 6: Rationale for Targeting STING
Rationale for Targeting STING Tumor-initiated T cell priming is STING-dependent CD8α+ DC production of IFN-β in Tumor-Initiated T cell priming and tumor control is TME required for tumor inhibition STING—but not TLR-dependent Fuertes et. al., JEM (2011); Woo, Gajewski, Immunity, (2014) CD8 T cell pr
Slide 7: Rationale for Targeting STING
Rationale for Targeting STING Synthetic cyclic dinucleotides induce in situ priming and abscopal effect ADU-S100 Innate response Corrales and Hix Glickman et al, Cell Reports (2015)
Slide 8: Rationale for Targeting STING
Rationale for Targeting STING CDN induced anti-tumor efficacy is STING-dependent W ild - T y p e C 5 7 B L /6 M ic e -/- S T IN G ( G o ld e n t i c k e t ) M ic e gt HBSS 2500 wt HBSS 2500 g t A D U -S 1 0 0 w t A D U -S 1 0 0 T u m o r V o lu m e [m m ] T u m o r V o lu m e [m m ] 3 3 2000 2000 gt
Slide 9: Multiple Groups are Targeting STING
Multiple Groups are Targeting STING IT Intratumoral Systemic Pre-clinical and clinical programs Company Agent Delivery Program Stage Aduro/ Novartis ADU-S100 IT Small-molecule STING agonist Ph1/2 Merck MK-1454 IT Small-molecule STING agonist Ph1/2 Merck MK-2118 IT/ SubQ Small-molecule STING agonist
Slide 10: First Clinical Approach to Target STING: Intratumoral (IT)
First Clinical Approach to Target STING: Intratumoral (IT) Sponsor NCT# Agent Molecule Phase / Title Study of the Safety and Efficacy of MIW815 With Aduro/ NCT03172 ADUS100 CDN PDR001 to Patients With Advanced/Metastatic Solid Novartis 936 / MIW815 Tumors or Lymphomas Aduro/ Safety and Efficacy of M
Slide 11: Clinical Results of Phase 1 Dose Escalation Studies
Clinical Results of Phase 1 Dose Escalation Studies Publicly disclosed clinical results from ongoing Phase 1 studies with IT STING agonists Aduro/Novartis (ADU-S100/MIW815): NCT03172936 Combination Monotherapy Results Results (Spartalizumab qmo) 12/53 SD (23%); 4/53 PR (8%); 1/53 CR (2%); 41 pts wit
Slide 12: Clinical Results of Phase 1 Dose Escalation Studies
Clinical Results of Phase 1 Dose Escalation Studies Publicly disclosed clinical results from ongoing Phase 1 studies with IT STING agonists • Sporadic evidence of single agent activity across diverse tumor types • No consistent observation of abscopal activity as a single agent • No clear evidence o
Slide 13: Clinical Results of Phase 1 Dose Escalation Studies
Clinical Results of Phase 1 Dose Escalation Studies Publicly disclosed clinical results from ongoing Phase 1 studies with IT STING agonists • Sporadic evidence of single agent activity across diverse tumor types • No consistent observation of abscopal activity as a single agent • No clear evidence o
Slide 14: STING at a Crossroads: Interpretation of Initial Clinical Results
STING at a Crossroads: Interpretation of Initial Clinical Results Deciphering the data • Differences between clinical studies • Differences among molecules in clinical development • Is STING being activated in the right cell types in the TME to initiate immunity? • Is STING a validated target? • Is
Slide 15: Interpretation of Initial Clinical Results: Differences between studies
STING at a Crossroads: Interpretation of Initial Clinical Results Deciphering the data Differences between clinical studies: Aduro/Novartis: NCT03172936 Dosing Schedule Doses Studied Cycle 1+ 10 µg 1600 µg IT Injections Week 1 2 3 4 Schedule A X X X Schedule B X Merck: NCT03010176 Dosing Schedule
Slide 16: Interpretation of Initial Clinical Results: Differences among molecules
STING at a Crossroads: Interpretation of Initial Clinical Results Deciphering the data CDN-STING Thermal Stability (Differential Scanning Flourimetry) • Differences among molecules in clinical * Tm Shift (oC) development * cGAMP (natural ligand) * • Aduro, Merck and BMS (IFM) molecules are CDNs Spri
Slide 17: Is STING Activated in the Right Cell Types in the TME?
STING at a Crossroads: Interpretation of Initial Clinical Results Deciphering the data Goldilocks effect of CDN-induced Is STING being activated in the right cell types in CD8+ T cell priming the TME to initiate immunity? • cGAS/STING is ubiquitously expressed • STING pathway can be epigenetically s
Slide 18: Is STING a Validated Innate Immune Target?
STING at a Crossroads: Interpretation of Initial Clinical Results Deciphering the data Is STING a validated innate immune target? • Genetic validation—interferonopathies due to dysregulation of STING pathway Humans: STING-associated vasculopathy with onset in infancy (SAVI) (ligand-independent acti
Slide 19: Is Intratumoral Injection the Optimal Approach?
STING at a Crossroads: Interpretation of Initial Clinical Results Deciphering the data Is intratumoral injection the optimal approach? • Limited scope of indications: IT is a first step in clinical development • Consistency of injection • Difficult to commercialize • Unique antigenic repertoire betw
Slide 20: Systemic Targeting of STING: Next Step in Therapeutic Development?
Systemic Targeting of STING: Next Step in Therapeutic Development? • Important next step in therapeutic advancement of innate immunity • Activation of STING in TME globally leading to T cell priming in multiple TDLNs • Challenge with systemic delivery may be therapeutic index given ubiquitous expres
Slide 21: The Race is On for Systemic Delivery
The Race is On for Systemic Delivery Intratumoral Intratumoral Delivery 1st Generation Conjugated Antibodies STING Pathway Novel Formulations Small Molecule pro- Conjugating a STING agonist cGAS, TREX1, ENPP1, IFI16 Systemic Nanoparticles, lipid-based, drugs to a tumor-directed 2nd antibody etc. Gen
Slide 22: TREX-1 Inhibitor Rationale
TREX-1 Inhibitor Rationale Systemic approach for targeting STING • STING is ubiquitously expressed in immune and somatic cell populations • TREX-1 maintains homeostasis by limiting activation of cGAS-STING in normal cells • TREX-1 is induced by cytosolic DNA resulting from inflammation, DNA repair d
Slide 23: TREX-1 Inhibitor Rationale
TREX-1 Inhibitor Rationale Systemic approach for targeting STING Radiation dose level has opposite effects on TREX-1 expression and IFN-β levels High Dose RT induces Fractionated RT Trex1 expression induces IFNβ Demaria. Nature Com, (2017), TREX1 regulates RT induced tumor immunogenicity
Slide 24: Concluding Remarks
Concluding Remarks • STING is at a crossroads—early monotherapy clinical results did not reflect promise of preclinical studies • Compelling genetic evidence in humans demonstrates that STING is a central mediator of cancer and autoimmunity • Multiple players and approaches may reveal a better clini