Slide 1: KT-413, a Novel IRAKIMiD Degrader of IRAK4 and IMiD Substrates
KT-413, a Novel IRAKIMiD Degrader of IRAK4 and IMiD Substrates, has a Differentiated MOA that Leads to Single-agent and Combination Regressions in MYD88MT Lymphoma Models Michele Mayo, Rahul Karnik, Christine Klaus, Atanu Paul, Kirti Sharma, Alice McDonald, Duncan Walker, Matthew Weiss Poster # LB11
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: Financial Disclosures
Financial Disclosures Michele Mayo, Rahul Karnik, Christine Klaus, Atanu Paul, Kirti Sharma, Alice McDonald, Duncan Walker, Matthew Weiss Kymera Therapeutics Employment and Equity Ownership ©2021 KYMERA THERAPEUTICS, INC. PAGE 3
Slide 4: Targeting Redundant Pro-survival Pathways in MYD88MT DLBCL
IRAKIMiD KT-413 is a Potent Degrader of IRAK4 and IMiD Substrates Targeting Redundant Pro-survival Pathways in MYD88MT DLBCL Autoantigens TLRs IL-1R B Cell Receptor IFNAR1/2 • Single-agent therapies that target activated NFκB signaling in DLBCL show limited activity in preclinical or clinical settin
Slide 5: KT-413 is a Potent Degrader with Activity in MYD88MT Cell Lines
KT-413 is a Potent Degrader of IRAK4 and IMiD Substrates with Activity in MYD88MT Cell lines • KT-413 selectively degrades both IRAK4 and IMiD • KT-413 is more active in MYD88MT DLBCL cells substrates than the clinically active IMiD, CC-220, and an IRAK4-selective degrader, KTX-545, both in • KT-413
Slide 6: IMiDs or IRAK4-Selective Degrader Alone Cannot Fully Target Both Pathways
IMiDs or IRAK4-Selective Degrader Alone Cannot Fully Target Both NFκB and IFN Pathways KTX-545 CC-220 KT-413 DMSO KTX-545, an IRAK4-selective degrader, selectively targets MYD88-NFκB signaling • Partially downregulates IKK signaling 50 – IRAK4 • Redundant pathway signaling maintains NFκB 70 – Aiolos
Slide 7: IMiDs or IRAK4-Selective Degrader Alone Cannot Fully Target Both Pathways
IMiDs or IRAK4-Selective Degrader Alone Cannot Fully Target Both NFκB and IFN Pathways KTX-545 CC-220 KT-413 DMSO CC-220 selectively targets Type 1 IFN signaling 50 – IRAK4 • Partially downregulates NFκB signaling 70 – Aiolos MYD88 MYD88 • Activates Type 1 IFN signaling IRAK4 IRAK4 • Drives Type1-IF
Slide 8: KT-413 Drives Apoptosis by Targeting Both NFκB and IFN Signaling
KT-413 Drives Apoptosis by Effectively Targeting Both NFκB and IFN Signaling KTX-545 CC-220 KT-413 DMSO IRAKIMiD KT-413 degrades both IRAK4 and IMiD substrates 50 – IRAK4 • Strongly downregulates NFκB signaling 70 – • Overcomes redundant pathway activation MYD88 MYD88 Aiolos • Greater activation of
Slide 9: KT-413 Preferentially Modulates Cell Cycle and Apoptosis Pathways
KT-413 Preferentially Modulates Cell Cycle and Apoptosis Pathways Compared to IMiDs or IRAK4-Selective Degradation • Transcriptomics analysis in OCI-Ly10 after 48h shows preferential downregulation of NFκB and upregulation of IFN signaling leading to downregulated of cell cycle pathways and apoptosi
Slide 10: KT-413 is Highly Active on Intermittent Dosing Regimens
KT-413 is Highly Active on Intermittent Dosing Regimens • In the OCI-Ly10 MYD88MT xenograft model, intermittent dosing of KT-413 induced strong antitumor activity, including complete or partial regressions • Superior activity compared to the clinically active IRAK4-inhibitor CA-4948 or the IMiD CC-2
Slide 11: KT-413 Shows Regressions in MYD88MT PDX Models
KT-413 Shows Regressions in MYD88MT Patient-Derived Xenograft (PDX) Models KT-413 PDX Ly14019CD79mut/MYD88L265Pmut Model MYD88 CD79B TNFAIP3 Other (%TGI) LY14019 L265P MT MT 100 LY2264 L265P MT IRF4 100 LY2298 L265P MT BCL2/BCL6 90 LY12699 L265P MT 87 LY2345 WT MT 70 LY2301 WT 30 LY0257 L265P BCL2/B
Slide 12: KT-413 Additive Antitumor Activity with Ibrutinib in OCI-Ly10 Xenografts
KT-413 Has Additive Antitumor Activity in Combination with Ibrutinib in MYD88MT OCI-Ly10 Xenografts 2400 2200 Vehicle Ibrutinib, 12.5 mg/kg, PO, QD x 21 2000 KT-413, 3 mg/kg, IV, D1,2,15,16 Tumor Volume (mm3) 1800 Ibrutinib + KT-413 1600 • KT-413 administered on 1400 intermittent schedules demonstra
Slide 13: KT-413 Supra-Additive Antitumor Activity with Venetoclax
KT-413 Has Supra-Additive Antitumor Activity in Combination with Venetoclax in MYD88MT OCI-Ly10 Xenografts 2400 PO Vehicle, PO, QD x 21 2200 Venetoclax, 50 mg/kg, PO, QD x 21 2000 KT-413, 3 mg/kg, IV, D1,2,15,16 Tumor Volume (mm3) Venetoclax + KT-413 1800 1600 • KT-413 administered on intermittent s
Slide 14: KT-413 Supra-Additive Antitumor Activity with Rituxan
KT-413 Has Supra-Additive Antitumor Activity in Combination with Rituxan in MYD88MT OCI-Ly10 Xenografts • KT-413 administered on intermittent schedules • KT-413 + Rituxan showed strong tumor demonstrated deep and durable regressions in regressions in tumors that relapsed following combination with R
Slide 15: Conclusions
Conclusions • KT-413 is a potent, selective degrader of both IRAK4 and IMiD substrates in DLBCL cells KT-413 leads to greater cell kill in MYD88MT cell lines compared to IMiDs or IRAK4 degraders or inhibitors • KT-413 inhibits both MYD88-dependent NFκB signaling and upregulates Type1 IFN pathways, c