Full Press Release Details
Conditionally Active Antibodies for
Immuno-oncology APRIL 2023 | Nasdaq: SNSE Exhibit 99.1
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development and potential therapeutic benefits of our product candidates; the expected safety profile of our product candidates; the expected timing and design of our Phase 1/2 clinical trial of SNS-101; the availability of data from our preclinical
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Engineered Selectivity to Extend the
Clinical Reach of Immuno-oncology Agents THE CHALLENGE Systemically delivered I/O drugs often fail in the clinic due to on-target/off-tumor effects (TMDD, CRS) OUR FINANCIAL POSITION Ended 2022: $107.1M* Cash runway into 2H 2025 OUR STRATEGY
Conditionally active antibodies engineered to enable druggability of promising oncology targets OUR LEAD PROGRAM SNS-101 is a clinical stage pH-sensitive antibody targeting the VISTA receptor with first patient first dose expected in mid-2023
*Consists of cash, cash equivalents and marketable securities
Innovative Pipeline of IO Drugs with
Broad Commercial Potential *Sensei has entered into a clinical supply agreement with Regeneron supporting the planned evaluation of SNS-101 in combination with Regeneron's anti-PD-1 therapy Libtayo (cemiplimab) in a Phase 1/2 clinical
trial in solid tumors. *Sensei has entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute. The goal of this collaborative effort is to further elucidate the role of VISTA in immune checkpoint
resistance and expand the potential of SNS-101 as a combination therapy beyond anti-PD-1.
The Modern-Day Challenge in
Immuno-Oncology The PD-1/PD-L1 market is big and growing fast1 PD-1/PD-L1 monotherapy does not benefit 70% of patients2 2020 2026 Survival Benefit 20-30% No Survival Benefit 70% 1. Gerber et al., Biochemical Pharmacology 2016 2. Market estimates
from PD-1 and PDL-1 Inhibitors Market Size in 2021 - MarketWatch, 360 Research
Lack of Tumor Targeting is a Major
Obstacle to CI Innovation Industry Problem Sensei's Solution Conventional antibodies target immune checkpoints that are highly expressed in normal tissues, resulting in: Dose-limiting toxicities due to on-target/off-tumor action
Pharmacological sink effect requires higher and more frequent dosing Suboptimal activity due to poor PK and dose-limiting toxicities Conditionally active antibodies are selectively targeted to the tumor microenvironment, potentially providing:
Little or no toxicity due to selective on-target/on-tumor action Lower and less frequent doses by avoiding normal tissue binding Powerful activity selectively focused on the tumor microenvironment Only one new checkpoint inhibitor has been approved
since the original CTLA-4 and PD-1/PD-L1 group Ipilimumab (anti-CTLA-4) Pembrolizumab (anti-PD-1) Relatlimab (anti-LAG-3) 2011 2014 2022
pH-sensitive Antibodies Have
Potential to Selectively Bind Their Targets in the Low-pH Tumor Microenvironment Exploits the tumor microenvironment using pH-selective properties Intended to alleviate undesirable properties: Dose-limiting toxicities due to
on-target/off-tumor binding Higher and more frequent dosing due to poor pharmacokinetics (Target-mediated Drug Disposition, or TMDD) Bolsters specific activities Goal is to unlock previously undruggable immune targets TMAb Platform Sensei's
technology identifies pH-sensitive antibodies designed to bind only at the tumor The tumor microenvironment of pH ~6 is lower than physiological pH of 7.4
Commercially Validated Precedent for
pH-sensitive Approach Soliris (Eculizumab) KD pH 7.4 (nM) 0.03 KD pH 6.0 (nM) 0.6 t (d) 3.9 Ultomiris (Ravulizumab, ALXN1210) 0.49 22 13.4 Due to its longer half-life (13.4 d vs 3.9 d), ravulizumab given every 8 weeks achieved noninferiority
compared with eculizumab given every 2 weeks for all efficacy endpoints, while maintaining a similar safety profile. 2018: FDA approves Ultomiris (ravulizumab, ALXN1210) 2020: Ultomiris sales = $1.08 billion Revulizumab utilized
histidine insertions into the CDR regions (VH_Y27H, VH_S57H) and Fc substitutions (M428L, N434S) of eculizumab Soliris (eculizumab), an anti-C5 monoclonal antibody (mAb), was considered standard of care for patients with paroxysmal nocturnal
hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, but had a short half-life as a result of extensive TMDD. Engineering eculizumab using histidine substitutions resulted in a pH-sensitive mAb with markedly improved half-life. Sheridan et
al, PLOS One, April 2018 (https://doi.org/10.1371/journal.pone.0195909) Lee et al, Blood, (doi:10.1182/blood-2018-09-876136) Sales figures:
https://media.alexion.com/news-releases/news-release-details/alexion-reports-fourth-quarter-and-full-year-2020-results Antibody Engineering of Solaris Led to pH Sensitivity and Half-Life Improvements
VISTA is a Potent T cell Checkpoint
Extensively Expressed on Myeloid Cells1 1. Lines et al. Cancer research vol. 74,7 (2014) VISTA is a B7 family member that suppresses T cell function Immunosuppressive function believed to be mediated by PSGL-1 receptor T-cell proliferation
& activation Extensive VISTA expression on off-tumor myeloid cells demands a conditionally active antibody approach VISTA has inherent pH sensitivity: its extracellular domain is uniquely rich in histidines2 2. Johnston et al., Nature
SNS-101: Selectively Targeting VISTA
with a pH-sensitive Antibody pH 6.0 pH 7.4 0.218 132 (~No binding) Additional SNS-101 features IgG1 format Active Fc Monovalent Affinity (KD) [nM] SNS-101 strongly inhibits the VISTA:PSGL-1 interaction and all other potential
binding partners at pH 6.0 in vitro IC50 = 7nm 2.59 Resolution SNS-101 heavy chain SNS-101 light chain Human VISTA (shown in green and red) Human VISTA epitope for SNS-101 Selectivity for Active VISTApH6 over VISTApH7.4 VISTA:SNS-101
co-crystal structure demonstrates epitope of SNS-101 encompasses VISTA's PSGL-1 epitope SNS-101 is a differentiated, pH-sensitive antibody SNS-101 blocks the key receptor regulating VISTA's immunosuppressive activity
No Significant Binding of SNS-101 to
Monocytes, Neutrophils, NK Cells and T-cells in Whole blood at Physiological pH T-cells NK cells FOB 1.57 FOB 2.0 FOB 1.0 FOB 8.75 FOB 12.4 FOB 1.36 Monocytes FOB 9.9 FOB 13.5 FOB 1.4 FOB 2.2 FOB 2.5 FOB 1.0 Neutrophils CYNO HUMAN FOB 7.4 FOB 8.8
FOB 1.0 Clinical mAb #1* Clinical mAb #2* SNS-101 Control FOB 2.0 FOB 2.0 FOB 0.5 Clinical mAb #1 Clinical mAb #2 SNS-101 Control FOB 1.66 FOB 1.9 FOB 0.95 FOB 9.7 FOB 10.7 FOB 1.31 *Clinical mAb #1 & #2 are pH-independent VISTA
SNS-101 Induced Substantially Lower
Cytokine Release in Whole-blood Assay at Neutral pH Compared to pH-independent VISTA Antibody IFN- IL-8 TNF- IL-6 IL-2 *** *** *** ** * ** ** ** ** ** ** ** ** ** ** Dose ranges: 1, 10, and 100 ug/ml #2
SNS-101 Has Displayed a Favorable
Single-dose PK Profile in Preclinical Studies - No Significant TMDD in Human VISTA KI Mice or Non-human Primates Pharmacokinetics of Single Dose 5 mg/kg SNS-101 in VISTA Knock-in Mice Demonstrated a long mean residence time in the blood, indicating
a lack of significant target-mediated drug disposition (TMDD) and clearance in non-malignant tissues SNS-101 displayed linear elimination kinetics unlike a pH-independent anti-VISTA mAb, which demonstrated TMDD and rapid clearance Pharmacokinetics
of Single Dose SNS-101 in Cyno monkeys Clinical mAb #1 10 mg/kg
PK Sink Continues to be an Issue
with Non-pH-Sensitive VISTA programs* SNS-101 is designed to overcome elimination kinetics and half-life related to PK sink observed in non-pH-sensitive VISTA programs Curis CI-8993 Plasma Concentration Kineta KVA12123 Cyno PK Abcine PMC-309 Serum
Conc Cyno Hummingbird HMBD-002 Preclinical PK Linear Non-linear 1. Hummingbird SITC 2022; 2. Kineta Corporate Presentation; 3. Abcine, SITC 2022; 4. Curis, SITC 2022 *Each graph differs by time course based on data presented Clinical mAb #1 10 mg/kg
SNS-101 Drove Single-agent Activity
and Deepened Anti-tumor Responses to PD-1 in Human VISTA KI Mice ** ** MC38-7r (Anti-mPD-1 insensitive MC38 clone) *** ** ** * P<0.05; ** P<0.01; *** P<0.001 MC38
SNS-101 Increased CD8 T-cells in
Combination With Anti-PD-1 in MC38 Tumors In Vivo CTRL Anti-PD-1 1mg/kg 5mg/kg Anti-PD-1/SNS-101 3mg/kg 10mg/kg 30mg/kg Frequency of Live, CD45+ Population One-way ANOVA, Tukey Post-Hoc Analysis, * p<0.05; ** p<0.01, *** p<0.001, ****
p<0.0001 with Anti-PD-1 with Anti-PD-1
Targeting VISTA and PD-1 Checkpoints
in the TME Promotes Anti-tumoral M1 Macrophage Polarization M1 macrophages are anti-tumorigenic through secretion of pro-inflammatory cytokines and chemokines, and driving of Th1 CD4+ T cell responses M2 macrophages are immunosuppressive; pro-tumor
TAMs are a subset of M2-type cells SNS-101 targets suppressive signaling in the myeloid compartment, and in combination with anti-PD-1 may help shift the balance of macrophage polarization toward an anti-tumor M1 phenotype
SNS-101 Re-sensitized Anti-PD-1
Insensitive Sarcoma Tumors in Human VISTA Knock-in Mice 5/8 CR 1/8 CR * p<0.05
SNS-101 Phase 1/2 Study
* Safety Monitoring Committee (SMC) to determine initiation of combination arm based on emerging clinical data RP2D = Recommended Phase 2 Dose MTD = Maximum Tolerated Dose Phase 1 Dose Escalation - Monotherapy: SNS-101 alone Phase 1
Dose Escalation - Combination: SNS-101 + Libtayo 0.3 mg/kg RP2D Combo Cohort 1 RP2D Mono Cohort X Combo Cohort X Phase 2 Expansion: SNS-101 +/- Libtayo Indication 1 Indication 2 Indication X Phase 1 Study Design Dose
escalation using Bayesian Optimal Interval (BOIN) design; plan to initiate combo dosing prior to monotherapy RP2D* Patient Population Study Objectives Dosing Advanced solid tumors Primary endpoint: safety, tolerability & RP2D Secondary
endpoint: PK profile, immunogenicity & anti-tumor activity SNS-101 +/- Libtayo (350 mg/kg) dosed as an IV infusion once every 3 weeks SNS-101 starting dose = 0.3 mg/kg; Dose escalation/de-escalation will proceed following the BOIN
design until the MTD/RP2D is determined Anticipated Phase 2 Expansion Design Single-arm, Simon two-stage minimax design incorporating an interim futility analysis Patient Population Study Objectives Dosing Advanced solid tumors Tumor
types to be determined based on data from Phase 1 study and emerging results from preclinical studies Primary endpoint: Anti-tumor activity Secondary endpoint: Anti-tumor activity, safety, tolerability, PK profile & immunogenicity
SNS-101 +/- Libtayo (350 mg/kg) dosed as an IV infusion once every 3 weeks Dose will be determined from the Phase 1 study
Partner / Collaborator Goal
Description Clinical Supply Agreement Supports evaluation of SNS-101 in combination with Libtayo (cemiplimab) in planned Phase 1/2 clinical trial Sensei to fund planned clinical trial Regeneron to provide Libtayo Sensei maintains global
development and commercial rights to SNS-101 Cooperative Research & Development Agreement Further elucidate role of VISTA in immune checkpoint resistance and expand potential of SNS-101 as a combination therapy beyond anti-PD-1 Sensei
collaborating with NCI Center for Immuno-Oncology Co-Directors, Jeffrey Schlom, Ph.D., and James Gulley, M.D., Ph.D. Preclinical studies will assess SNS-101 mechanism of action in combination with therapies beyond anti-PD-1 Research Collaboration
Further study the mechanism of SNS-101's anti-tumor activity Sensei collaborating with laboratory of immuno-oncology KOL, Robert Schreiber, Ph.D. Preclinical studies will include identification of SNS-101 response biomarkers Key
Partnerships Supporting SNS-101's Clinical Development Potential opportunities for combination therapy and biomarker identification
SNS-101 Is a Fully Differentiated
Anti-VISTA Antibody Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Preclinical Preclinical (IgG1) (IgG1) (IgG1) (IgG4) (IgG1) Johnston et al., Nature 2019; Kineta website; Snyder et al, AACR Annual Meeting 2016; Pierre Fabre website; Hummingbird website;
Thakkar et al, J of Immunother Cancer, 2022; PharmAbcine website
VSIG4 is an Immunosuppressive
Receptor with On-Target, Off-Tumor Challenges See references in Appendix A B Tissue macrophages (Kupffer cells) in liver Tumor-associated macrophages in tumor and stroma (inset) In the liver, VSIG-4 Is expressed on Kupffer cells1-2
Appears to drive significant target-mediated drug disposition (TMDD) and clearance In the tumor microenvironment, VSIG-4 Correlates with immunosuppressive "M2" macrophage infiltration3 Inhibits T cell activation4 Promotes tumor growth based
on data from a syngeneic Lewis lung carcinoma model in knockout mice5
Sensei Has Identified pH-sensitive
VSIG4 Antibodies pH-Sensitive VSIG4 Parental Antibodies Selected for Further Optimization Antibody Reference # Ratio of pH Selectivity (6.0 vs 7.4) Blockage of Immobilized VSIG4- T-cell Inhibition Blockage of Cellular VSIG4- T-cell Inhibition 1 1 +
+ 2 7 + + 3 1 + + 4 3 + + 5 3 +/- + 6 25 + + 7 1 + + 8 2 - + * Ratio assessed by flow cytometry on VSIG4 overexpressing cells Program milestones to date: Identified 8 parental antibodies for optimization and are currently testing progeny antibodies;