Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — Technical Presentation (December 2022)
63 slides from Kymera Therapeutics's technical presentation, Dec 14, 2022
Slide 1: KT-474 HS and AD Clinical Data and Oncology Pipeline Update
Exhibit 99.1 KT-474 HS and AD Clinical Data and Oncology Pipeline Update C o m p a n y W e b c a s t December 14, 2022
Slide 2: Forward-looking Statements
Forward-looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA) and other federal securities laws. These statements include information about our current and future prospects and our operations and fi
Slide 3: Presentation Agenda
1. Welcome 2. Oncology Update 15’ • IRAKIMiD (KT-413) • STAT3 (KT-333) 3. IRAK4 Update 35’ • KT-474 HS and AD Patient Cohort 4. Q&A 40’ P R E S E N TAT I O N A G E N D A
Slide 4: Introduction to Kymera
Introduction to Kymera Key accomplishments to date: Kymera is a leader in Targeted Protein • Since 2016 founding, advanced 4 clinical stage programs and Degradation (TPD) developed a deep pipeline positioned to deliver ≥1 IND/year Building a fully-integrated, • Unique target selection strategy based
Slide 5: Kymera's Pipeline of Novel Protein Degraders
Kymera’s Pipeline of Novel Protein Degraders Pathway Program Indication(s) Discovery IND Enabling Phase 1 Rights* Phase 2 Next Milestones Phase 2 Start Immuno-inflammatory KT-474 IRAK4 Diseases: HS, AD, RA, others Multiple molecules staged as potential back ups if needed 2023 IL-1R/TLR IRAKIMiD Clin
Slide 6: Presentation Summary
Presentation Summary Oncology • KT-333 and KT-413 Phase 1 trials in dose escalation phase • Both molecules demonstrating PK/PD consistent with pre-clinical models • No dose-limiting toxicities observed to date • KT-253 IND cleared; Phase 1 trial expected to commence in early 2023 KT-474 • Part C coh
Slide 7: STAT3 (KT-333)
STAT3 (KT-333)
Slide 8: STAT3 Degraders In Oncology: KT-333
STAT3 Degraders In Oncology: KT-333 U.S. R.O.W. Prevalence Incidence Prevalence Incidence • High degree of validation of JAK-STAT pathway in oncology Peripheral T-cell ~13k ~6.5k ~27k ~15k lymphoma (PTCL) and immuno-oncology supported by >25k publications Cutaneous T-cell ~30k ~2.6k ~67k ~6k lymphom
Slide 9: KT-333 Highly Active on Intermittent Dosing Regimens
KT-333 Highly Active on Intermittent Dosing Regimens Complete Tumor Regressions Associated with Robust STAT3 KD for ∼48h in Preclinical Models SU-DHL-1 Preclinical PK/PD Weekly Dosing • Dose- and degradation-dependent tumor growth inhibition observed with once-weekly dosing in ALK+ • Based on precli
Slide 10: KT-333 Phase 1 Dose-Escalation and Expansion Trial
KT-333: Phase 1, Multicenter, Dose-Escalation and Expansion Trial to Evaluate KT-333 in Adult Patients with PTCL, CTCL, LGL-L, and Solid Tumors Phase 1a (n up to 40) Phase 1b (n=40) R/R Lymphoma/Leukemia or Solid Tumors Cohort 1: PTCL Regimen: mg/kg IV Infusion weekly n=20 Cohort 2: CTCL Dec. 2022:
Slide 11: Interim Safety Data Summary
Interim Safety Data Summary Dose Level 1 • 4 patients at Dose Level 1 (DL1, 0.05 mg/kg) Dose Level 3 • All 4 patients heavily pretreated (≥3 prior lines) 0.51 mg/kg • 3 solid tumor Dose leve4 cleared by SRC, open • 1 CTCL for enrollment • No DLTs, no treatment-related SAEs, no AEs leading to discont
Slide 12: Summary of PK Data From Patients Enrolled in DL1
Summary of PK Data From 4 Patients Enrolled in DL1 Week 1 DL1 → 0.05 mg/kg PK Parameter Week 1 (n = 4) C (ng/mL) 306 (30.9%) max AUC (ng.h/mL) 1550 (66.4%) Vd (L/kg) 0.278 (17.5%) CL (L/h/kg) 0.0450 (62.5%) t (h) 6.25 (78.8%) 1/2 ©2022 KYMERA THERAPEUTICS, INC. PAGE 12
Slide 13: STAT3 Degradation in Blood at Dose Level 1
STAT3 Degradation in Blood at Dose Level 1 (DL1: 0.05 mpk) Consistent with Prediction from Preclinical Modeling Clinical PD in PBMC by MS Mean Max Degradation* Subject ID Method: Targeted MS Post-doses 1&2 (Range) n = 4 subjects DL1-1 -79.8 % (-75.6 % to -84.1 %) DL1-2 -67.8 % (-73.5 % to –62.0 %) D
Slide 14: Demonstration of Initial Proof-of-Mechanism for KT-333
Demonstration of Initial Proof-of-Mechanism (POM) for KT-333 • Accrual to first dose level completed • STAT3 degradation in blood at first dose level consistent with preclinical predictions, with mean maximum degradation following first 2 doses of Cycle 1 averaging 66%, with maximum knockdown of up
Slide 15: IRAKIMiD (KT-413)
IRAKIMiD (KT-413)
Slide 16: IRAKIMiDs are Potent Degraders of IRAK4 and IMiD Substrates
IRAKIMiDs are Potent Degraders of IRAK4 and IMiD Substrates MT Targeting Redundant Pro-survival Pathways in MYD88 DLBCL Autoantigens • Single-agent therapies targeting activated NFκB TLRs B Cell IL-1R signaling in DLBCL show limited activity Receptor IFNAR1/2 • Redundant NFκB pathway activation and
Slide 17: KT-413 Highly Active on Intermittent Dosing in Preclinical Models
KT-413 Highly Active on Intermittent Dosing in Preclinical Models Complete Tumor Regressions Associated with Robust IRAK4 and Ikaros/Aiolos Degradation for ∼72h T/C% Drug (Day 33) CR PR SD PD (REG%) • Single 10 mg/kg dose showed extended tumor CC-220 9 0 0 0 7 exposure and strong degradation of both
Slide 18: KT-413 Phase 1 Dose-Escalation and Expansion Trials
KT-413: Phase 1, Multicenter, Dose-Escalation and Expansion Trials to Evaluate KT-413 in Patients with R/R DLBCL Phase 1a (n up to 40) Phase 1b (n=40) R/R B-cell NHL R/R DLBCL Regimen: mg/kg IV Infusion q 3 weeks Dec. 2022: MT Cohort 1: MYD88 Currently n=20 enrolling MTD/RP2D Expansion* WT DLX Cohor
Slide 19: Interim Safety Data Summary
Interim Safety Data Summary Dose Levels 1-2 • All patients with heavily pretreated B-cell lymphoma (up to 3 prior lines of therapy) • Follicular lymphoma, DLBCL (all wild-type MYD88) • No DLTs, no treatment-related SAEs or AEs leading to discontinuation, no neutropenia in first two dose levels ©2022
Slide 20: Plasma PK Showing Dose-Proportional Increase in Exposure
Plasma PK Showing Dose-Proportional Increase in Exposure 0.16 0.32 Cycle 1 Plasma PK mg/kg mg/kg PK (DL1) (DL2) Parameter Cycle 1 Cycle 1 C max 140 493 (ng/mL) AUC inf 1360 3490 (ng.h/mL) Vd (L/kg) 10.1 3.99 CL (L/h/kg) 0.118 0.092 t (h) 59.3 30.2 1/2 ©2022 KYMERA THERAPEUTICS, INC. PAGE 20
Slide 21: Degradation Profile of IRAK4, Ikaros and Aiolos in DL1/DL2
Degradation Profile of IRAK4, Ikaros and Aiolos in DL1/DL2 Consistent with Preclinical Models in Blood and Tumor At least 72h of Target Degradation Observed with Once Every Three-week Dosing DL2 DL1 Target Degradation in PBMC by FLOW 0.16mg/kg 0.32mg/kg Cycle 1 Cycle 2 Dose IRAK4 Cycle 1 Cycle 2 Lev
Slide 22: Demonstration of Initial POM for KT-413
Demonstration of Initial POM for KT-413 • First two dose levels completed • PK and PD profiles in DL1 and DL2 consistent with preclinical data supporting once every three-week dosing regimen • Up to 95/100% KD of Ikaros/Aiolos and 40% KD of IRAK4 in blood • Consistent degradation in blood and tumor
Slide 23: IRAK4 (KT-474)
IRAK4 (KT-474)
Slide 24: Degrading IRAK4 Superior Approach to Block IL-1R/TLR-driven Inflammation
Degrading IRAK4 Superior Approach to Block IL-1R/TLR-driven Inflammation Degrader Advantage IL-1R/TLR Pathway secreted Inhibitor IL-1a/β, IL-18, signaling TNF-α, IFN-γ, IRAK4 IL-33, IL-36 IL-1β, IL-6, Scaffolding Kinase IL-8, IL-10, Role Role IL-12, IL-17, IL-23 TLRs NFkB JNK/p38 IRF5/7 (TLR 2,4,5,7
Slide 25: IRAK4 Degradation but Not Inhibition is Required to block IL1R/TLR Pathway
IRAK4 Degradation but Not Inhibition is Required to block IL1R/TLR Pathway IRAK4 Scaffolding Function is IRAK4 Degradation, but not IRAK4 Degradation, but not Critical in Myddosome Formation Kinase Inhibition, can Block TLR- Kinase Inhibition, can block induced NF-κB Translocation IL1R+TLR activatio
Slide 26: IRAK4 Degrader Best-in-class Potential in Immune-inflammation
IRAK4 Degrader Best-in-class Potential in Immune-inflammation Potential for Broad Activity Across Th1-Th17 and Th2 Diseases 2021 Prevalence Indication 2021 Global Sales IL-1R/TLR US/EU5/JP KT-474 AD ~82.5 M $5,760 M IRAK4 HS ~785 K $1,106 M RA ~4.6 M $27,634 M SLE ~580 K $1,333 M IBD ~3.2 M $21,710
Slide 27: KT-474 Phase 1 Trial Design
KT-474 Phase 1 Trial Design Double-blind, Placebo-controlled SAD and MAD in Adult HV; Open Label Patient Cohort in HS & AD Patients Summary of Key Findings in MAD 9 SAD cohorts • IRAK4 degradation of 80-90% in PBMC using Flow Cytometry; - 8 subjects per cohort (6:2 randomization) reduction to near l
Slide 28: KT-474 Part C: Demographics/Disposition
KT-474 Part C: Demographics/Disposition
Slide 29: Patient Demographics
Patient Demographics HS (n=13) AD (n=8) Gender, n Female 10 3 Male 3 5 Median age, years (range) 40 (21-53) 31 (23-55) Race/Ethnicity White / Hispanic, Latino 7 6 White / Non-Hispanic, Latino 1 0 Black / Hispanic, Latin 0 1 Black / Non-Hispanic, Latino 5 0 Other* 0 1 *Native American or Alaskan Nati
Slide 30: Baseline Disease Characteristics
Baseline Disease Characteristics HS (n=13) AD (n=8) Disease Severity (HS-PGA) (vIGA-AD) Mild -- 1 Moderate 10 5 Severe 1 2 Very Severe 2 -- Extent of Disease Mean (min, max) Mean (min, max) AN Count 8 (5, 18) -- Fistula Count 4 (0, 15) -- Pain-NRS* 7 (3, 10) -- Pruritus-NRS* 5 (0, 10) 8 (4, 10) EASI
Slide 31: Patient Disposition
Patient Disposition HS AD Total Enrolled patients 13 8 21 Primary reason for Treatment Completion Completed 12 7 19 • 9 Moderate• 1 Mild • 1 Severe• 4 Moderate • 2 Very Severe• 2 Severe Withdrawal by patient 1* 1** 2 * Withdrew treatment after 4 doses for personal reasons ** Withdrew treatment after
Slide 32: KT-474 PK and Degradation
KT-474 PK and Degradation
Slide 33: KT-474 Plasma PK and IRAK4 Degradation in Patients Comparable to HV
KT-474 Plasma PK and IRAK4 Degradation in Patients Dosed for 28 Days is Comparable to HV PK/PD Correlation in IRAK4 Levels in PBMC in Part C KT-474 Plasma PK Plasma/Monocytes (FLOW) Patients at Day 28 (MS) 3 ng/mL threshold Mean Day 14 C max (MAD3: 100 mg QD) Mean Day 14 C trough (MAD3: 100 mg QD) 3
Slide 34: Skin PK: High Skin Concentration In Patients at Day 28
Skin PK: KT-474 Has High Skin Concentration In Patients at Day 28 Higher than MAD3 HV Day 28 Day 42 Part C: 75 mg QD (fed)* 386 (± 103) 135 (± 33.8) * n=11 for Day 28 and n=10 for Day 42 ©2022 KYMERA THERAPEUTICS, INC. PAGE 34
Slide 35: KT-474 Reduced IRAK4 in Skin Lesions of AD and HS Patients
KT-474 Reduced IRAK4 in Skin Lesions of AD and HS Patients on Day 28 to at Least Same Level as Healthy Subjects MAD Healthy AD Patients HS Patients AD Patients HS Patients Subjects (Baseline) (Baseline) (Day 28) (Day 28) (Baseline) N 46 7 11 6 9 Mean (± SE) 0.123 (± 0.01) 0.216 (± 0.06) 0.236 (± 0.0
Slide 36: KT-474 Safety
KT-474 Safety
Slide 37: Adverse Events Related to Study Drug
Adverse Events Related to Study Drug (Occurring in > 1 Patient) Adverse Event # of Severity Outcome (Preferred Term) Patients (# of Pts) (# of Pts) Mild (5) Headache 6 Recovered (6) Severe (1) Fatigue 4 Mild (4) Recovered (4) Diarrhea 2 Mild (2) Recovered (2) No SAEs, no drug-related infections, and
Slide 38: QTc Prolongation Spontaneously Resolves to Baseline by Day 8
QTc Prolongation Spontaneously Resolves to Baseline by Day 28 • ΔQTcF in Part C is in the range observed in MAD3 (100 mg QD) up to Day 14 • Declines to baseline with continued dosing and sustained plasma exposure through Day 28 • Profile is maintained through day 42 upon cessation of dosing after Da
Slide 39: KT-474 Pharmacodynamics
KT-474 Pharmacodynamics
Slide 40: Up to 98% Inhibition of Disease-Relevant Cytokines Ex Vivo
Up to 98% Inhibition of 9 Disease-Relevant Cytokines Ex Vivo in both HS and AD Patients 0 0 MAD 3 -20 -20 Healthy Subjects 100 mg QD (n = 9) -40 -40 Part C AD Patients (n=7) -60 -60 Part C HS Patients (n=9) -80 -80 LPS R848 -100 -100 IFNγ IL10 IL12 IL17 IL1b IL23 IL6 IL8 TNFα IFNγ IL10 IL12 IL17 IL1
Slide 41: In Vivo Inhibition of Plasma Cytokines and Acute Phase Reactants
In Vivo Inhibition of Disease-Relevant Plasma Cytokines and Acute Phase Reactants by KT-474 in HS/AD Patients IL-6 Mean Max* AD Mean Max* HS Analyte (n) (n) † IL-6 -56% (3) -63% (8) † CRP NA -58% (5) IL-1b -36% (7) -48% (8) † SAA -51% (4) -41% (10) *Max % reduction through Day 42 † Analysis performe
Slide 42: Disease-Relevant Genes Downregulated in Skin Lesions
Disease-Relevant Genes Downregulated in Skin Lesions in ≥ 50% of Evaluable* AD (N=7) and HS (N=10) Patients at Day 28 (RNAseq) • Substantial AD downregulation of many disease relevant genes in both HS and AD patients † • Downregulation exceeded 90% for many genes • Broad anti-inflammatory signature
Slide 43: KT-474 Part C: Clinical Endpoints
KT-474 Part C: Clinical Endpoints
Slide 44: Clinical Endpoints Included as Exploratory Endpoints
Clinical Endpoints Included as Exploratory Endpoints • Skin lesions and global assessments performed on Days 1, 14, 28, 35 and 42 • Symptom scores performed at additional time points AD • Change from baseline in Eczema Area and Severity Index (EASI) • Peak pruritus NRS • Investigator Global Assessme
Slide 45: AD Clinical Endpoints
AD Clinical Endpoints
Slide 46: EASI Score: Mean 37% and Max 76% Reduction
EASI Score: Mean 37% and Max 76% Reduction Mean EASI Score Over Time (N=7) Mean % Change in EASI Score Over Time (N=7) 0 0 25 23 -10 21 18.9 -17.9 19 -20 17 15.3 -27.6 -37.1 15 -30 13.6 12.5 13 -36.4 -40 12.2 11 9 -50 7 5 -60 0 7 14 21 28 35 42 0 7 14 21 28 35 42 Day Day ©2022 KYMERA THERAPEUTICS, I
Slide 47: Peak Pruritus NRS: Mean Reduction and Responders
Peak Pruritus NRS: Mean 52 to 63% Reduction Peak Pruritus NRS Responders: 57 to 71% Mean % Change in Peak Pruritus % of Patients with ≥4 Unit Reduction Over Time (N=7) from Baseline in Peak Pruritus (N=7) 100 0 90 -6.6 -5.8 -10 80 71 71 -20 70 57 -30 -34.6 57 60 -32.1 -35.6 -38.9 43 57 50 -40 -44.6
Slide 48: Investigator's Global Assessment (vIGA-AD)
Investigator’s Global Assessment (vIGA-AD) vIGA-AD Score Over Time (n=7) 7 1 1 1 1 6 2 5 3 4 4 4 4 3 4 2 3 1 2 2 2 1 0 Baseline Day 14 Day 28 Day 35 Day 42 Mild Moderate Severe • IGA scores remained stable or improved in all patients ©2022 KYMERA THERAPEUTICS, INC. PAGE 48 # of Patients by AD-IGA Sc
Slide 49: AD Case Study: Patient AD-3
AD Case Study: Patient AD-3 Improvement in Disease Severity from Severe to Mild • 51-year-old Hispanic/Latino male with severe AD (vIGA-AD) Day 1 - BL Day 42 and EASI score of 28.2 at baseline • Previously treated with topical betamethasone 2018-2020 Efficacy Endpoints BL Day 28 Day 35 Day 42 IGA-AD
Slide 50: KT-474 Showed Meaningful Signs of Clinical Activity in AD
KT-474 Showed Meaningful Signs of Clinical Activity in AD, Comparing Favorably to Placebo Benchmarks and SOC Summary Results • Mean EASI score reduction up to 37%, with maximum reduction of up to 76% • Mean peak pruritus NRS reduction of 52 to 63% • Peak pruritus NRS Responder rate of 57 to 71% • In
Slide 51: HS Clinical Endpoints
HS Clinical Endpoints
Slide 52: AN Count: Mean 51% and Max 100% Reduction
AN Count: Mean 46 to 51% and Max 100% Reduction AN 0/1/2 Responders: 42 to 50% Response Rate % of Patients with AN Count 0/1/2 Mean % Change in Total AN Count Over Time 80 0 70 -10 60 -19.9 50 50 -20 50 40 -31.6 -30 40 -27.4 42 42 -40.6 30 33 -40 -46.1 20 20 -50 -45.4 17 -49.6 10 -50.7 -60 0 0 7 14
Slide 53: HiSCR50 Response Rate
HiSCR50: 42 to 50% Response Rate % of Patients with HiSCR50 80 70 60 50 50 50 40 42 42 30 30 30 25 25 20 10 0 0 7 14 21 28 35 42 Day All HS (n=12) Moderate to Severe (n=10) ©2022 KYMERA THERAPEUTICS, INC. PAGE 53 % of HiSCR Responders (80% CI)
Slide 54: Pain NRS: Mean Reduction and Pain NRS30 Response Rate
Pain NRS: Mean 49 to 55% Reduction Pain NRS30: 50 to 60% Response Rate Mean % Change in Worst % of Patients with ≥30% and ≥1 Unit Reduction Pain Over Past Week in Worst Skin Pain Over the Past Week 0 100 90 -10 -14.6 80 -20 70 -17.5 70 60 60 60 -31.2 -30 60 -40 50 -43.5 58 -40 50 -36 -46 -48.8 50 50
Slide 55: Peak Pruritus NRS: Mean to 68% Reduction
Peak Pruritus NRS: Mean 62 to 68% Reduction Mean % Change in Peak Pruritus Over Past Week 0 0 -10 -17 -26.1 -24 -20 -30 -29.1 -40 -48.6 -41.7 -41.9 -53.6 -50 -61.6 -60 -67.8 -70 -62.3 -68.4 -80 -90 -100 0 7 14 21 28 35 42 Day All HS (N=12)* Moderate to Severe (N=10) *One patient is censored for Day
Slide 56: Physician's Global Assessment (HS-PGA)
Physician’s Global Assessment (HS-PGA) HS-PGA Score Over Time Moderate to HS-PGA Score Over Time (N=12*) Severe Patients (N=10) 12 10 1 1 1 1 1 2 2 2 9 1 1 10 8 1 1 1 1 1 7 4 4 8 5 6 6 4 4 5 6 6 5 9 4 9 3 4 3 4 3 4 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 0 0 Baseline Day 14 Day 28 Day 35 Day 42 Baseline D
Slide 57: HS Case Study: Patient HS-3
HS Case Study: Patient HS-3 Complete Clearing of Lesions and Symptoms in Patient with Moderate Disease at Baseline Day 1 - BL Day 42 • 45 year old Black Female with Moderate HS (HS- PGA); Baseline AN count = 7 • Prior treatments: clindamycin (topical) and doxycycline Area of swelling Resolution of B
Slide 58: HS Case Study: Patient HS-10
HS Case Study: Patient HS-10 Improvement in Disease Severity from Moderate to Mild Day 1 - BL Day 42 • 39 year old Black Female with Moderate HS (HS-PGA); Baseline AN count = 5 • Prior treatments: benzocaine ointment Multiple Ulcerated Clearing of Ulcerated Nodules Nodules Efficacy Endpoints BL Day
Slide 59: KT-474 Showed Meaningful Signs of Clinical Activity in HS
KT-474 Showed Meaningful Signs of Clinical Activity in HS, Comparing Favorably to Placebo Benchmarks and SOC Summary Results • Mean total AN count reduction of 46 to 51%, with maximum reduction up to 100% • AN count of 0/1/2 response rate of 42 to 50% • HiSCR50 response rate of 42 to 50% • HiSCR75 r
Slide 60: Conclusions / Summary
Conclusions / Summary
Slide 61: Part C Summary
Part C Summary • KT-474 administered to HS and AD patients at 75 mg QD for 28 days shown to have safety, PK and PD comparable to healthy volunteers • Modest, non-adverse QTcF prolongation observed to spontaneously resolve back to baseline during final 2 weeks of dosing in HS and AD patients • Robust
Slide 62: Meeting Summary
Meeting Summary • Kymera platform and discovery engine have been validated across several programs in patients with cancer and inflammatory diseases, with fidelity of translation of PK, PD and safety • Kymera’s unique target selection strategy, using TPD to drug undrugged targets, has been validated
Slide 63: Kymera
‘KYMERA
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