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Kyn Therapeutics Executive Summary
Clinical-stage, patient-directed immuno-oncology pipeline in difficult to treat cancers
• Programs with robust patient selection/enrichment strategies• Rapid to clinical POC opportunities
Significant milestones expected over next year• Lead program with 2 clinical POC opportunities• Two additional programs filing INDs
Building a leading translational science-driven oncology R&D company
• Experienced team with biologics/small-molecule experience• Well funded from Series A and Celgene collaboration• Expanding pipeline through internal programs and in-licensing• IPO pending positive clinical POC and favorable market conditions
Top Tier Partners
$49M Series A
Strategic collaboration on AHR and Kynase,
$80M upfront + equity
Strong Leadership Team and Advisors
Mark Manfredi, Ph.D.Chief Executive Officer
Michelle Zhang, Ph.D.VP Translational
Karen McGovern, Ph.D.VP Discovery Biology
Jim NolanVP CMC
Alfredo Castro, Ph.D.SVP Chem & Preclin.
Jeff Ecsedy, Ph.D.Chief Scientific Officer
Maude Tessier, Ph.D.VP BD
Jason Sager, M.D.Chief Medical Officer
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Doug CarlsonChief Financial Officer
Senior Management
George Prendergast, Ph.D.Advisor
Andrew Mellor, Ph.D.Advisor
Jedd Wolchok, M.D., Ph.D.Collaborator
Francisco Quintana, Ph.D.Advisor
• IDO/TDO• Lankenau Institute
• IDO/TDO• Univ. Newcastle
• AHR• Harvard Medical
School
• IO Clinical Development
• MSKCC
Pawel Kalinski, M.D., Ph.D.Advisor
• PGE2/EP4• Translational• Roswell Park
Advisors/Collaborators
Experienced Board of Directors/Investor
David Bonita, M.D.OrbiMed
Jean Francois Formela, M.D.Atlas Venture
Ian Dukes, Ph.D.OrbiMed
George Georgiou, Ph.D.UT Austin
Mark Manfredi, Ph.D.Kyn Therapeutics
• Private Equity Partner• BOD member on many
preclinical/clinical biotechs
• Partner• BOD member on
private/public biotechs
• Venture Partner• Previously at Merck,
Amgen, GSK
• Academic founder• Founder of 2 other biotechs• Protein engineer and
immunologist
• CEO of Kyn Therapeutics• Previously at Raze
Therapeutics, Takeda Oncology, Atlas Venture
Ron RenaudChairman of Board
• Banking/analyst• Former CEO Idenix• Current CEO Translate Bio
(NASDAQ: TBIO)
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Atsushi Nagahisa, Ph.D.AskAt
• Co-founder AskAt• Previously at Pfizer,
ReQualia, DNA partners
Pioneering the Next Frontier in Cancer Immunotherapy
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Our mission is bringing breakthrough therapies to patients with cancer, particularly those who do not benefit from current treatments like checkpoint inhibitors
Our Central Thesis
• Combinations with meaningful benefit, especially in resistance setting, will inherently target multiple mechanisms of immunosuppression
• Focus on modulating pathways that stimulate the innate and adaptive immune system
• Leverage years of preclinical and clinical research to explore full potential of immuno-metabolic targets
• Core interest in fundamental immuno-metabolites likely to be effective across multiple tumor types, in resistance setting, and active in combos beyond IO
Our Approach
COX2/PGE2/EP4 pathway Associated
Poor Survival in CRC and NSCLC
Development strategy to reach rapid POC in checkpoint resistance setting
ARY-007 is the right molecule
ARY-007: EP4 InhibitorRapid POC opportunity in Oncology
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EP4 is the right target
• Ongoing Ph1b/2 studies in combo with pembrolizumab in microsatellite stable (MSS) CRC and in PD-1/PDL-1 refractory NSCLCo MSS CRC inherently resistant to anti-PD-1
therapieso NSCLC study in patients who have progressed on
PD-1 or PD-L1 therapy• Retrospective patient selection biomarkers for
possible prospective Ph2 selection
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Pathway is linked to cancer initiation and progression ↑ COX-2, PGE2 and EP4 expression associated with decreased OS, therapeutic and preventive precedent
in a number of cancers, in particular in CRC and NSCLC
Sheehan KM, JAMA 282:1254-57 (1999)
Increased COX-2 expression associated with poor prognosis in CRC
35 estimates from 32 studies were used in the meta-analysis of OTC NSAIDs and colon cancerHarris RE Inflammopharmacology 2009, 17(2):55-67
Kaplan-Meier survival estimates by COX-2 epithelial staining in CRC tumors
COX-2 blockade in the chemoprevention of colon cancer
Zhou et al, PLOS One 11(3):e0151939 (2016)
Forest plot of ORR, meta-analysis of 9 randomized clinical trials
COX-2 inhibitors increased ORR in advanced NSCLC
Prognostic, Therapeutic and Preventive Relevance of PGE2 Pathway in Cancer
AAT-008 combo with anti-PD1 in CT-26
Beneficial Combination Activity with anti-PD-1 in CT-26Need for durable pathway inhibition for benefit
TreatmentPeriod
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Increased complete responses with combination
• Tumor re-inoculation challenge in CR animals demonstrated induction of memory
• Similar beneficial combination activity observed with anti-CTLA4 in 4T-1 model (data not shown)
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ARY-007 – Ongoing Phase 1b in MicroSatellite Stable (MSS) CRCPost-2nd Line Chemotherapy
Pre-dose• Blood• Urine• Tumor biopsy• Archived tumor
Steady–State (Days 5-8):• 2nd Tumor biopsy
for Cohort 1 participants
• Blood
End of Cycle 1 to End of Cycle 3:• Blood• 2nd Tumor biopsy for Cohort 2
participants
Anytime:• 3rd Tumor biopsy in
participants with PR
ARY-007 + pembrolizumabARY-007
1 week SA run-in
15 patients
10 patientsARY-007 + pembrolizumab
Cohort 1
Cohort 2
ARY-007 dosed at 300 mg BID with no dose-escalationPembrolizumab dosed at 200 mg IV Q3WClinicalTrials.gov Identifier: NCT03658772
• Tumor immune cells• Peripheral immune cells• Chemokine / cytokine
Pharmacodynamics
• Tumor immune cells• PD-L1• COX-2• EP4• Tumor mutational burden• PGEM
Patient selection (retrospective)
Robust biomarker strategy
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ARY-007 – Ongoing Phase 1b/2 in Post-PD1/PDL1 NSCLCIn Patients who Have Progressed While on PD-1
ARY-007 + pembrolizumabPost-PD1/L1
(≥ 12 weeks of prior treatment
with anti-PD1/L1, followed by
progression while being treated with
anti-PD1/L1)
Pre-dose• Blood• Urine• Archived tumor (if available)• Tumor Biopsy (10 Patients)
End of Cycle 1 to End of Cycle 3• Tumor biopsy (for the
10 participants in the biopsy subgroup)
• Blood per SoE
Anytime for participants in biopsy subgroup:• 3rd Tumor biopsy in
participants with PR
25 patients
ARY-007 dosed at 300 mg BID with no dose-escalationPembrolizumab dosed at 200 mg IV Q3WClinicalTrials.gov Identifier: NCT03696212
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Targeting Diseases with High Unmet Medical Need
82,450
14,550
CRC
MSS MSI
Estimated Market Size (new cases per year in the U.S.)
Current Treatment Paradigm
• ORR in MSS CRC is 0% (0/18), SD at week 12 is 11% (2/18) with single agent pembrolizumab
• 1st / 2nd line chemo is SOC• Checkpoint inhibitors only active in MSI-H CRC• Microsatellite instability (MSI) is a unique
molecular alteration and hyper-mutable phenotype, present in 15% of CRC
• Microsatellite stable (MSS) is 85% of CRC
• Among 121 Treatment Past resist-defined disease Progression (TPP) subjects treated with anti-PD-1 therapy, PR rate was 8.3%
• 1st line becoming chemo + pembrolizumab • Estimated ~30% 5 year survival in Pembro treated
patients - assume 70% PD1 refractory NSCLC
High market penetration and premium pricing may be achievable if ARY-007 (in combo with pembrolizumab) shows response rate ≥ 20% in MSS CRC or PD1/PDL1 refractory NSCLC
33,270
77,630
NSCLC
PD1 sensitive PD1 refractory
• ONO-4578 / BMS-986310• Oral, selective EP4
receptor antagonist
• Ongoing Ph 1/2 • Solid tumors (Japan)• Single agent and nivolumab dose
finding / safety study
• BMS licensed ONO-4578 in Dec 2017• Ph 1 study may be ongoing in Tokyo, Japan (started 2017)• BMS initiated 280 solid tumor-patient Phase 1/2 study
alone and in combination with nivolumab (started Sept 2018)
• E7046 / AN0025• Oral, selective EP4
receptor antagonist
• Completed single agent Ph I
• Combo ongoing / planned
• Adlai Nortye licensed E7046 in Jan 2018• Eisai Ph1 monotx data – POM demonstrated• Saturated PK above 500 mg• Adlai Nortye initiated solid tumor trial in Jan 2019 in
combo with pembrolizumab
• Solid tumors• Preoperative P1b
radiation/chemo combination in rectal cancer enrolling
Company ProgramStage ofDevelopment Indication Additional information
Competitive Landscape – EP4 Inhibitor Clinical Stage Programs
• ARY-007• Oral, selective EP4
receptor antagonist
• Ongoing Ph Ib/2 • Anti-PD-1 combo in MSS CRC and PD1 refractory NSCLC
• Safety, PK, efficacy and biomarker endpoints
• Ongoing clinical studies with pembrolizumab supplied by Merck
• Safely dosed in ~1000 humans in non-oncology interventional setting
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e.g. kynurenine
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KYN-175: AHR AntagonistIndustry Leading Program in IND-Enabling Studies
Combo with Chemo (Doxil)Combo with anti-PD1Achieved target profile including but not limited toSingle agent and combination efficacy with anti-
PD1 and with chemo in multiple syngeneic models
Well tolerated in DC-enabling 14-day rat toxicity study
IND filing target: Q4 2019
Biomarker Driven Clinical Development for KYN-175Enabling Patient Selection/Enrichment Strategy
IDO TDO
Selecting Tumor Indication
• AHR dependent gene signature• Kynurenine tumor IHC• RNAscope - pathway gene expression
in TME• IDO / TDO tumor expression analysis
and IHC• Nuclear AHR localization
AHR Activation
Potential PD Biomarkers
• Plasma kynurenine• Modified gene expression /
signatures of AHR inhibition• Tumor & peripheral immune
cell, chemo/cytokine phenotyping
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Kyn Proprietary AHR Activation Gene Signature
Low signature
High signature
Indication 1 Indication 2
Novel AHR Signature Expression Correlates with Survival
Low signature
High signature
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KYN-412: Human Engineered Kynurenine Degrading Enzyme Program IND-enabling stage program that Inhibits pathway in a manner IDO selective inhibition cannot
Q1W I.v. human dosing
Well tolerated in DC-enabling rat tox study Superior to epacadostat in efficacy and immune stimulation
Durable depletion of kynurenine in mouse and cyno PD studies: superior to epacadostat
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Achieved development candidate target profile including but not limited to
IDO TDO
Kynurenine
Immunosuppression
Kynase
Co-expression IDO/TDO (mRNA/Protein)
IND filing target: Q1 2020
Kyn Continued Value Creation to 2022
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Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q41H Q1 Q2 Q3 Q42H2019
Development Candidates for AHR and Kynase
2018 2020 2021 2022
Clinical trial initiation for ARY-007 MSS CRC study
Clinical trial initiation for ARY-007 NSCLC study
Celgene strategic collaborationFor AHR and Kynase
IND filing for AHR
POC clinical data for ARY-007 MSS CRC study
Pipeline expansion (in-license and/or internal)
POC clinical data for ARY-007 NSCLC study
POC clinical data for AHR
Potential IPO
ARY-007 Phase 2 randomized study initiation
ARY-007 Phase 2 randomized study data
POM data for AHR
POM data for Kynase
POC: Proof-of-Concept; POM: Proof-of-Mechanism
Completed milestones
POC clinical data for Kynase
IND filing for Kynase
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