ALBERT

Description: Introduction: Rearrangements of the MLL (mixed lineage leukemia) gene on chromosome 11q23 are present in 5-10% of either acute myeloid (AML) or acute lymphoblastic leukemia (ALL), and are associated with a poor prognosis. Fusion proteins involving the MLL histone methyltransferase (HMT) result in recruitment of another HMT, DOT1L, to a multi-protein complex leading to aberrant methylation of Histone H3 lysine 79 (H3K79) at MLL target genes and enhanced expression of leukemogenic genes such as HOXA9 and MEIS1. EPZ-5676 is a small molecule inhibitor of DOT1L with sub-nanomolar affinity and 〉37,000 fold selectivity against additional HMTs. EPZ-5676 treatment of cultured cells reduced histone H3K79 methylation, decreased MLL target gene expression and resulted in selective killing of MLL-rearranged (MLL-r) leukemia cells by inducing apoptosis and differentiation. EPZ-5676 administration led to tumor regression in an MLL-r leukemia xenograft model. We report preliminary results of an ongoing Phase 1 trial of EPZ-5676 in patients with advanced hematologic malignancies, including acute leukemia with MLL-r. Methods: This is a 2-part phase 1 open label dose escalation study investigating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-leukemic activity of EPZ-5676 in adult patients (pts) with relapsed/refractory leukemia (CT.gov: NCT01684150). In the dose-escalation phase, patients with AML, ALL, acute mixed lineage leukemia, myelodysplastic syndrome, myeloproliferative neoplasia (MPN) or chronic myeloid leukemia were eligible. Eligibility in the expansion phase of the study was restricted to pts with MLL-r or partial tandem duplication of MLL (MLL-PTD). EPZ-5676 was administered via continuous intravenous infusion (CIV) for 21 days of a 28 day cycle in the dose escalation phase and CIV for all 28 days of a 28 day cycle in the expansion phase, until disease progression or unacceptable toxicity. Results: Between October 2012 and July 2014, 37 pts have enrolled; 36 are evaluable for safety (received at least 1 dose of EPZ-5676) and 28 pts (19 MLL-r, 4 MLL-PTD) are evaluable for anti-leukemia activity (completed at least one post baseline marrow evaluation). The median age at time of enrollment was 53 years (range: 20 to 81 years); the median number of prior systemic therapies was 2 (range: 1 to 6) and 14 pts had a prior allogeneic stem cell transplant. Of the treated pts, disease characteristics were: 31 pts with AML (21 MLL-r, 5 MLL-PTD), 4 pts with ALL (3 MLL-r) and 1 pt with MPN (MLL-r). Table 1: Number of evaluable pts per cohort Dose (mg/m2/day) 12 24 36 54 80 90 21 day CIV 1 5 4 6 3 - 28 day CIV - - - - - 17 The median time on study was 29 days (range: 5-196 days). Adverse events (AEs) reported in 〉15% of pts were: anemia, fever/neutropenia, thrombocytopenia, constipation, diarrhea, nausea, chills, fatigue, mucosal inflammation, peripheral edema, hypomagnesemia, dyspnea and sepsis; of which leukocytosis, nausea and hypomagnesemia were assessed by the investigator as drug related. Grade I PR interval prolongation, without associated QTc changes, was observed in 2 pts. There were no deaths attributed to study drug treatment, and there were 2 pts with treatment discontinuation for potentially drug-related AEs. Dose proportional PK was observed with rapid attainment of steady-state plasma concentrations on Day 1 of treatment. Preliminary PD data demonstrated inhibition of H3K79 methylation from baseline in marrow (median: 52%, range 0-81%) and peripheral blood mononuclear cells (median: 43%, range 25-67%) at doses above 36 mg/m2/day. PD effects were observed by day 8. The 21 day CIV pts recovered H3K79 methylation towards baseline by day 28, and the 28 day CIV pts maintained methyl-mark inhibition throughout cycle 1. To date, best responses for pts with MLL-r are morphologic CR (1 pt.), cytogenetic CR (1 pt), and resolution of leukemia cutis (2 pts). In addition, a treatment-related increase in neutrophils (PMN) and/or monocytes was observed in 6 pts with a median day of onset of 15 days (range 8-28 days). The identification of the MLL-r by split signal FISH in mature PMN suggests a differentiation effect on the leukemic clone. Conclusions: EPZ-5676 is well tolerated and exhibits anti-leukemic activity in MLL-rearranged acute leukemia. These data provide rationale for continued clinical investigation of potential utility of EPZ-5676 in patients with rearrangements of the MLL gene. Disclosures Stein: Janssen Pharmaceuticals: Consultancy. Garcia-Manero:Epizyme, Inc: Research Funding. Rizzieri:Novartis, Inc: Consultancy, Speakers Bureau; Ariad, Inc: Speakers Bureau. Savona:Karyopharm: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Altman:Astellas: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Membership on an entity's Board of Directors or advisory committees. Armstrong:Epizyme, Inc: Consultancy. Pollock:Epizyme: Employment, Equity Ownership. Waters:Epizyme, Inc: Employment, Equity Ownership. Legler:Epizyme, Inc: Employment. Thomson:Epizyme, Inc: Employment. Daigle:Epizyme, Inc: Employment, Equity Ownership. McDonald:Epizyme, Inc: Employment. Campbell:Epizyme, Inc: Employment, Equity Ownership. Olhava:Epizyme, Inc: Employment. Hedrick:Epizyme, Inc: Employment; Pharmacyclics, Inc: Equity Ownership. Copeland:New Enterprise Associates: Ad hoc consultant, Ad hoc consultant Other; Mersana: Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Employment, Equity Ownership.

Description: Iron and copper are essential for all organisms, assuming critical roles as cofactors in many enzymes. In eukaryotes, the transmembrane transport of these elements is a highly regulated process facilitated by the single electron reduction of each metal. Previously, we identified a mammalian ferrireductase, Steap3, critical for erythroid iron homeostasis. Now, through homology, expression, and functional studies, we characterize all 4 members of this protein family and demonstrate that 3 of them, Steap2, Steap3, and Steap4, are not only ferrireductases but also cupric reductases that stimulate cellular uptake of both iron and copper in vitro. Finally, the pattern of tissue expression and subcellular localization of these proteins suggest they are physiologically relevant cupric reductases and ferrireductases in vivo.

Description: Introduction: The histone methyl transferase EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and responsible for methylation of lysine 27 of histone H3 (H3K27), a modification of DNA associated with repressed transcription when trimethylated (H3K27me3). Aberrant EZH2 activity has been implicated as an oncogenic driver in non-Hodgkin's lymphoma (NHL). Here we report the phase 1 first-in-human experience to date with tazemetostat in patients (pts) with NHL. Methods: Tazemetostat was administered orally twice daily (BID) to subjects in five dose cohorts (100 mg [n=6], 200 mg [n= 3], 400 mg [n=3], 800 mg [n=14], 1600 mg [n=12], and one food effect cohort (400 mg [n=7]). Tumor response assessments were performed every 8 weeks. Archival tumor tissue from NHL pts was analysed for EZH2 hot spot mutations Y646X, A682G and A692V (by either amplicon-based next generation sequencing [NGS] or cobas ® EZH2 Mutation Test [in development]), and for additional somatic mutations by NGS focusing on a panel of 39 genes commonly mutated in NHL. In addition, cell-of-origin in Diffuse Large B-cell Lymphoma (DLBCL) patients was determined by immunohistochemistry on archival tumor tissue using the Hans algorithm (Blood, 2004). Results: As of 9-July 2015, 45 pts were enrolled to this trial (CT.gov: NCT01897571). To date 19 NHL pts: 13 DLBCL, 5 follicular lymphoma (FL) and 1 marginal zone lymphoma (MZL) were enrolled. Results to date on the 26 solid tumor pts have been reported separately (ECC, 2015). Adverse events (AE) occurring in 〉10% of the 45 pts regardless of attribution were: asthenia, anorexia, constipation, nausea, dysgeusia, vomiting and muscle spasms with 5 grade 3 or greater related AE's: thrombocytopenia, neutropenia, hypertension, anorexia and transaminase elevation. The median age of the NHL patients enrolled was 62 yrs (range 23-82) and 74% of pts were male. Of the fifteen evaluable NHL pts, objective responses were seen in: 5/9 DLBCL, 3/5 FL and 1/1 MZL. The majority of objective responses occurred at the Recommended Phase 2 Dose of 800 mg BID. EZH2 status in patient tumors was determined for 14/19 NHL patients (n=3 data pending, n=2 tissue unavailable) with 13/14 found to be wild-type (WT) and one patient, who experienced an ongoing PR at week 16, expressing an Y646H mutation. Updated data including duration of response will be presented. In addition, 10/13 patients had evidence of somatic mutations in 〉1 non-EZH2 genes among the 39 genes tested (allelic frequency 〉10% with coverage 〉1000X) known to be commonly mutated in NHL, e.g. MYD88 & CARD11, or involved in epigenetic signalling, e.g. EP300 & CREBBP. Table.Relapsed or refractory NHLTotal(n=19)Evaluable(n=15)Best Response CR+PRaBest Response SDaDLBCLGCB4220Non-GCB6520undetermined3210FL5531MZL1110aper IWG (Cheson, 2007), complete response (CR), partial response (PR), stable disease (SD) Conclusions: Tazemetostat demonstrates a safety profile favorable for chronic dosing and objective responses in pts with either EZH2 WT or mutant B-cell lymphoma, including both GCB and non-GCB sub-types of DLBCL. EZH2 pathway genes and genes commonly somatically mutated in lymphoma are under investigation to elucidate the mechanisms and biomarkers of clinical response to tazemetostat. Based upon the observed safety and efficacy profile of tazemetostat, a phase 2 trial in relapsed or refractory DLBCL and FL pts, stratified by cell-of-origin and EZH2 mutation status, is enrolling. Disclosures Ribrag: Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thomson:Epizyme, Inc: Employment. Keilhack:Epizyme: Employment, Equity Ownership. Blakemore:Epizyme: Employment. Reyderman:Eisai: Employment. Kumar:Eisai: Employment. Fine:Epizyme: Employment. McDonald:Epizyme: Employment. Ho:Epizyme, Inc: Employment.

Description: An important goal of cancer therapy is to improve patient outcomes by driving to deep and durable tumor responses. The activity of single-agent targeted therapies, such as BTK inhibitors or IMiDs alone, has been modest in relapsed and refractory DLBCL, necessitating the use of combination therapy. Targeted protein degraders are heterobifunctional small molecules that co-opt the endogenous ubiquitin-proteasome system to drive the selective degradation of target proteins. Degraders of IRAK4, a key component of the myddosome complex, show potent and selective IRAK4 degradation and preferential activity in MYD88-mutant (MYD88MT) DLBCL models. Notably, the activity of IRAK4 degradation is superior to IRAK4 kinase inhibition, supporting the essential scaffolding role of IRAK4 in myddosome signaling. We have previously described IRAKIMiDs, novel IRAK4 degraders that utilize an IMiD as a pharmacologically active cereblon binder. These degraders simultaneously degrade both IRAK4 and IMiD substrates and show synergistic antitumor activity over either IRAK4 degraders or IMiDs alone, enabling a therapeutically relevant biological combination within a single small molecule. Here we describe KTX-120, a novel IRAKIMiD development candidate. KTX-120 is an equipotent degrader of both IRAK4 and the IMiD substrates Ikaros and Aiolos in lymphoma model systems with low single-digit nM DC50 for degradation of all substrates. The cell activity of KTX-120 has shown a high dependence on MYD88MT status: across a panel of MYD88MT cell lines, KTX-120 showed consistent and potent cell activity, with IC50 ranging from 7-29nM, whereas in MYD88WT lines, cell activity was poor ranging from 1800-3400nM. In the OCI-Ly10 ABC DLBCL cell line that harbors a MYD88L265P mutation, the cell activity of KTX-120 was associated with degradation of both IRAK4 and Ikaros, supporting the combined IRAK4 and IMiD targeting of this molecule as contributing to cell activity. Notably, the onset of cell death in OCI-Ly10 cells with KTX-120 treatment was rapid, with cells becoming committed to cell death within 72h of exposure, suggesting that continuous exposure to KTX-120 may not be necessary for antitumor activity. We explored the pharmacological activity of KTX-120 in several in vivo model systems. KTX-120 is orally bioavailable and shows dose-proportional exposure in several species. A single oral dose of KTX-120 (10 mg/Kg or 30 mg/Kg) showed significant degradation of both IRAK4 and Ikaros in a dose and time-dependent manner, with degradation of both substrates being sustained for 〉96h, further supporting the potential for intermittent dosing. To assess this, we have explored the antitumor efficacy of KTX-120 in intermittent dosing schedules. KTX-120 was well tolerated and showed potent antitumor activity in several CDX models of MYD88MT DLBCL, including OCI-Ly10, TMD8 and SUDHL2, achieving regressions in all models in as little as once every 2 weeks. As an example, in OCI-Ly10, a 30mpk dose Q2W drove 〉80% degradation of both IRAK4 and Ikaros and showed regressions (including CR) by D28. Similar activity and tolerability were seen with both PO and IV dosing at doses that achieve active exposure, enabling the potential for both oral and parenteral dosing. We have further explored the activity of KTX-120 in a collection of DLBCL patient derived xenograft models. KTX-120 shows robust activity (〉85% TGI) in 4/5 models of MYD88MT DLBCL and shows no or modest activity in 2/2 models of MYD88WT DLBCL, supporting the preferential activity of this mechanism in patient samples harboring MYD88 activating mutations. Importantly, activity was observed in models with a variety of co-mutations that activate the NFkB pathway, including alterations in, CD79B and TNFAIP3, suggesting that KTX-120 has the potential for activity in MYD88MT lymphoma regardless of other mutations. Collectively, these data support the combined IRAK4 degradation and IMiD activity of KTX-120 has the potential to achieve robust and durable regressions in MYD88MT lymphomas with the increased convenience of an intermittently administered single agent and decreased potential for drug combination challenges. Disclosures Walker: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chen:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhaduri:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rusin:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Weiss:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Description: STAT3 (signal transducers and activators of transcription 3) is a transcription factor and a member of the STAT protein family that is activated through a variety of different cytokine and growth factor receptors via JAKs, as well as through oncogenic fusion proteins and gain-of-function (GoF) mutations in STAT3 itself. STAT3 hyperactivation and GoF mutations are found in numerous cancers, including clinically aggressive hematologic malignancies with high unmet medical need, such as peripheral T cell lymphomas (PTCLs) (Andersson et al., 2020). We have previously shown that a potent and selective STAT3 heterobifunctional degrader, KTX-201, strongly represses cell growth in models of STAT3-dependent heme malignancies (Csibi et al., 2019). Herein, we report on the cellular mechanisms underlying the anti-tumor effect of STAT3 degradation in PTCL and provide a model for the relationship between pharmacokinetics/ pharmacodynamics (PK/PD) and activity of KTX-201 in vivo. The relationship between STAT3 degradation by KTX-201, anti-tumor mechanism of action and in vivo activity were investigated in anaplastic large T cell lymphoma (ALCL) models, a subset of PTCLs. In vitro, a decrease of STAT3 by 90% for 48hr was required for ALCL cells to commit to death. To identify anti-tumor mechanism(s) of KTX-201 at the systems level, we performed a time-resolved analysis of the proteomic changes of SU-DHL-1 cells undergoing growth inhibition mediated by KTX-201 at GI95. We measured the abundance of 10,000 proteins and confirmed selective degradation of STAT3 by KTX-201 after 8h of treatment. Significant changes in several marker proteins known to be involved in STAT3-mediated proximal signaling in ALCL including SOCS3, Myc and Granzyme B were observed after 16h. Functional annotation analysis of proteins identified pathways that were significantly enriched in at least one time point. Using unsupervised hierarchical clustering of annotations, we found that proteins that increased in abundance over 48h of exposure to KTX-201 were associated with markers of apoptosis and those that decreased in abundance by 24h and 48h were associated with cytokine signaling and cell cycle, respectively. Based on these data, this study identifies inhibition of cytokine signaling, G1 cell cycle arrest and induction of apoptosis as key anti-tumor mechanisms associated with KTX-201 consistent with observed cell phenotypes. STAT3 degradation in tumor was characterized in mice bearing SU-DHL-1 tumors following single dose IV administration. The STAT3 PD response in tumor was correlated with exposures in tumor. At the dose of 25 mg/kg weekly where complete tumor regression was achieved, KTX-201 achieves 〉90% STAT3 degradation at 24h post dosing in SUDHL1 xenografts. STAT3 degradation was maintained at 90% at 4 days post dosing. The results from the PK/PD study suggests that STAT3 degradation in tumor of 〉90% is necessary for anti-tumor efficacy in vivo of KTX-201, but only for a limited duration, such as 4 days out of a weekly dosing cycle. Collectively, our data demonstrate that significant STAT3 degradation for a limited time during dosing interval with KTX-201 in ALCL promotes early changes in key signaling nodes involved with proliferation and cytokine stimulation, followed by profound changes in apoptotic proteins. By integrating mechanistic biology with a deep understanding of PK/PD and efficacy, this study provides a foundation for the clinical development of STAT3 degraders using intermittent dosing regimen for treatment of PTCL and other STAT3-dependent heme malignancies. Disclosures Rong: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Csibi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Yang:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rusin:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yuan:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chutake:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhu:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ji:Kymera Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Liu:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Li:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Walker:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Desavi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Description: Introduction: MYD88 mutations are found in 25% of DLBCL and are associated with an inferior survival. MYD88 is an adapter molecule, forming the core of the Myddosome complex. MYD88 mutations constitutively activate pathways such as NFқB, leading to lymphomagenesis. Essential to the Myddosome-dependent signaling pathway is the recruitment of IRAK4 which complexes with MYD88 to activate downstream effects. Targeting IRAK4 is therefore a rational therapeutic approach in MYD88-mutant lymphomas. First-in-class IRAKIMiDs, novel heterobifunctional degraders that target IRAK4 as well as the IMiD substrates Ikaros and Aiolos to enable the inhibition of both the NFkB and IRF4 pathways activated by MYD88 mutations, demonstrate potent efficacy in MYD88-mutant lymphomas (KTX-475, KTX-582, Walker D et al. AACR 2020). Herein, we compare the activity of IRAKIMiDs to IRAK4 kinase inhibitors and IMiDs alone in MYD88-mutant DLBCL, and evaluate rational combinations of IRAKIMiDs and other active agents in DLBCL for synergy. Methods: MYD88-mutant (n=4) and wild type (n=4) DLBCL cell lines were exposed to a panel of single agents (KTX-475, KTX-582, BAY1830839, CA-4948, CC-220, lenalidomide, pomalidomide, ibrutinib, umbralisib, venetoclax) in order to establish the drug concentration:cytotoxicity effect relationship. Cell viability was assessed using Celltiter-Glo assay at 24-hour intervals. IC50 values were computed. MYD88-mutant DLBCL cells were co-exposed to combinations of KTX-475 with venetoclax, ibrutinib, or umbralisib at concentrations representing their respective IC10-40 in order to determine synergy using the excess over bliss (EOB) method. Venetoclax, ibrutinib, and umbralisib were selected for combinational studies in order to target adverse pathways known to be associated in DLBCL biology. To confirm IRAK4 degradation, western blot and flow cytometry was performed. Apoptosis was evaluated with flow cytometry. Pre-treatment RNA-seq libraries were developed for the purpose of identifying GSEA and mutational analysis to predict response to IRAKIMiDs. Results: Exposure to IRAKIMiDs led to potent activity in MYD88-mutated DLBCL with IC50s in the low nanomolar range. IRAK4 degradation occured in a dose- and time-dependent manner and was observed as early as four hours after exposure. IRAKIMiDs induced superior cytotoxicity compared to two IRAK4 kinase inhibitors, including CA-4948 (Curis), which is currently under clinical investigation for relapsed/refractory NHL, as determined by lower IC50s in all cell lines. IRAKIMiD IC50s were also lower compared to pomalidomide, lenalidomide, and CC-220. KTX-475 was selected for synergy assessments based on IC50 values. Synergy was observed after exposure to KTX-475 in conjunction with venetoclax, ibrutinib, or umbralisib as determined by EOB 〉0 in the MYD88-mutant OCI-LY10 model, with maximum values peaking at 72-96 hours. After dual drug exposure, IRAK4 degradation was validated by flow cytometry demonstrating that the addition of venetoclax, ibrutinib or umbralisib to KTX-475 did not impair IRAK4 degradation capabilities. RNA-seq interpretation is currently underway. Conclusions: Collectively, our results demonstrate that dual-function degraders targeting both IRAK4 and the IMiD substrates Ikaros and Aiolos can serve as a potential therapeutic option for poor prognosis MYD88-mutant DLBCL. Our data thus far demonstrate improved efficacy of IRAKIMiDs compared to IRAK4 kinase inhibitors or IMiDs alone in vitro, as well as synergy with other active agents in combination regimens. A promising lead IRAKIMiD candidate has been identified, with initiation of a first-in-human clinical trial in B-cell lymphomas planned for 2021. Disclosures Lue: Daiichi Sankyo: Honoraria; AstraZeneca: Speakers Bureau; Astex Pharmaceuticals: Honoraria; Kymera Therapeutics: Honoraria, Research Funding; Kura Oncology: Honoraria. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kanik:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Walker:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. O'Connor:Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Servier: Consultancy; Mundipharma: Other: Consulting; Astex Pharmaceuticals: Honoraria, Research Funding; Merck: Research Funding; Nomocan: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.