Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — EADV Symposium 2023
21 slides from Kymera Therapeutics's conference presentation, May 18, 2023
Slide 1: Safety and Efficacy of IRAK4 Degrader KT-474 (SAR444656) for HS and AD
Safety and Efficacy of IRAK4 Degrader KT-474 (SAR444656) for Hidradenitis Suppurativa and Atopic Dermatitis Jared Gollob, M.D. - Chief Medical Officer May 18, 2023
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: Degrading IRAK4: Best Approach to Block IL-1R/TLR driven Inflammation
Degrading IRAK4: Best Approach to Block IL-1R/TLR driven Inflammation IL-1R/TLR Pathway Degrader Advantage secreted Inhibitor signaling IL-1α/β, IL-18, 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, TLRs IL-23 (TLR 2,4,5,7,8,9) IL-1R JNK/p38 NFκ
Slide 4: KT-474: Potent and Specific IRAK4 Degradation with Impact on Cytokines Superior to Kinase Inhibition
KT-474: Potent and Specific IRAK4 Degradation with Impact on Cytokines Superior to Kinase Inhibition Degradation and Selectivity Superiority over SM kinase Inhibitor 10xDC90 24hr • KT-474 DC50 = 2.1 nM in LPS + IL-1β IL-6 3 human immune cells 2.5 • KT-474 was selective for IRAK4 in human immune ce
Slide 5: KT-474 Phase 1 Design
KT-474 Phase 1 Design Double-blind, Placebo-controlled SAD and MAD in HV; Open Label Patient Cohort in HS & AD Patients 7 SAD cohorts Primary • Safety & tolerability - 8 subjects per cohort (6:2 randomization) Parts A & B - 57 adult healthy subjects dosed Single dose (25-1600 mg) • Pharmacokinetic m
Slide 6: KT-474 Achieved Robust and Sustained IRAK4 Degradation with Multiple Daily Oral Doses (14 Days)
KT-474 Achieved Robust and Sustained IRAK4 Degradation with Multiple Daily Oral Doses (14 Days) Absolute IRAK4 Levels Percent IRAK4 Reduction at Steady State • Detected by mass spectrometry in circulating PBMC • Steady state IRAK4 reduction achieved between Days 7 and 14 * p-values relative to place
Slide 7: Ex Vivo Inhibition of Disease-Relevant Cytokines, Day 7-14
Ex Vivo Inhibition of 9 Disease-Relevant Cytokines, Day 7-14 Results through MAD3 Showed Dose-Dependent Effect Tracking with Extent of Monocyte IRAK4 Degradation LPS R848 Placebo (n = 9) 50 mg QD (n = 9) 100 mg QD (n = 8-9*) IFNγ IL1β IL6 IL8 IL10 IL12 IL17 IL23 TNFα IFNγ IL1β IL6 IL8 IL10 IL12 IL17
Slide 8: KT-474 Reduced IRAK4 to Near LLOQ in the Skin (MS)
KT-474 Reduced IRAK4 to Near LLOQ in the Skin (MS) IRAK4 Levels in Skin vs PBMC at Day 14 of KT-474 treatment LLOQ • Baseline IRAK4 levels in skin substantially lower compared to PBMC • Dose-dependent IRAK4 degradation in skin by mass spectrometry • Mean IRAK4 levels at 200 mg dose nearing LLOQ, wit
Slide 9: Patient Cohort: Baseline Disease Characteristics
Patient Cohort: 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
Slide 10: KT-474 Plasma PK and IRAK4 Degradation in HS and AD Patients Dosed for 28 Days
KT-474 Plasma PK and IRAK4 Degradation in HS and AD Patients Dosed for 28 Days is Comparable to HV Part C KT-474 Plasma PK PK/PD Correlation in IRAK4 Levels in PBMC in Plasma/Monocytes (FLOW) Patients at Day 28 (MS) 3 ng/mL threshold Mean Day 14 Cmax (MAD3: 100 mg QD) Mean Day 14 Ctrough (MAD3: 100
Slide 11: KT-474 Reduced IRAK4 in Skin Lesions of AD and HS Patients on Day 28
KT-474 Reduced IRAK4 in Skin Lesions of AD and HS Patients on Day 28 to at Least Same Level as Healthy Subjects Mean (±SE) IRAK4 Levels in Skin (fmol/μg protein) 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
Slide 12: In Vivo Inhibition of Disease-Relevant Plasma Cytokines and Acute Phase Reactants by KT-474
In Vivo Inhibition of Disease-Relevant Plasma Cytokines and Acute Phase Reactants by KT-474 in HS/AD Patients Mean Max* AD Mean Max* HS IL-6 Analyte (n) (n) IL-6† -56% (3) -63% (8) CRP† NA -58% (5) IL-1β -36% (7) -48% (8) SAA† -51% (4) -41% (10) *Max % reduction through Day 42 †Analysis performed on
Slide 13: Disease-Relevant Genes Downregulated in Skin Lesions in AD and HS Patients at Day 28
Disease-Relevant Genes Downregulated in Skin Lesions in ≥ 50% of Evaluable* AD (N=7) and HS (N=10) Patients at Day 28 (RNAseq) • Substantial downregulation of many AD disease relevant genes in both HS and AD patients † • Downregulation exceeded 90% for many genes • Broad anti-inflammatory signature
Slide 14: AD: Significant Reduction in EASI Score and Pruritus
AD: Significant Reduction in EASI Score and Pruritus Patients with ≥4 Unit Mean % Change in EASI Mean % Change of Worst Reduction from Baseline Score Over Time (N=7) Pruritus Over Time (N=7) in Worst Pruritus (N=7) 0 0 10 100 0 90 % of Pruritis Responders (80% CI) -10 Mean % Change (+/-S.E. of Mean)
Slide 15: 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) and EASI score of 28.2 at baseline Day 1 - BL Day 42 • Previously treated with topical betamethasone 2018-2020 Efficacy Endpoints BL Day 28 Day 35 Day 42 IGA-AD
Slide 16: HS: Significant Reduction in AN Count Leading to HiSCR Responses
HS: Significant Reduction in AN Count Leading to HiSCR Responses Mean % Change in Total AN % of Patients HiSCR50 Responders Counts Over time with AN Count 0/1/2 0 80 80 % of Patients with AN 0/1/2 (80% CI) 70 70 Mean % Change (+/- S.E. of mean) % of HiSCR Responders (80% CI) -10 60 60 -19.9 -20 50 5
Slide 17: HS: Significant Reduction in Pain/Pruritus
HS: Significant Reduction in Pain/Pruritus % of Patients with ≥30% and ≥1 Mean % Change in Average Mean % Change in Worst Unit Reduction in Worst Pain Pain Over Past Week Pruritus Over Past Week Over the Past Week 0 100 0 90 -10 -10 Mean % Change (+/- S.E. of Mean) Mean % Change (+/- S.E. of Mean) -
Slide 18: 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 Nodules Clearing of Ulcerated Nodules Efficacy Endpoints BL Day
Slide 19: Adverse Events Related to Study Drug (Occurring in > 1 Patient)
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, a
Slide 20: Summary
Summary • Single and multiple doses of KT-474 were well-tolerated in healthy volunteers and resulted in strong degradation of IRAK4 in blood and skin associated with inhibition of ex vivo whole blood cytokine induction • KT-474 administered to HS and AD patients at 75 mg QD for 28 days shown to have
Slide 21: Acknowledgements Thank You!
Acknowledgements Kymera Investigators Ashwin Gollerkeri Rahul Karnik Lindsay Ackerman - Medical Dermatology Specialists Jennifer Culbertson Veronica Campbell Gerard Acloque - Encore Medical Research Jeffrey Davis Xiaozhang Zheng Sandro Bacchelli - Encore Medical Research Aimee Mishkin Bradley Enerso