Employees Of AbbVie Research Articles

MDS-090: Semi-Mechanistic Model to Aid Clinical Understanding of Myelodysplastic Syndromes

Context: Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenia, hypercellular bone marrow, and dysplastic hematopoietic progenitors. Death is commonly caused by the effects of cytopenia, leading to infections or bleeding [1]. Finding efficacious treatment regimens in MDS remains a challenge as it involves understanding of both disease induced and treatment related cytopenias. Objective: The objective was to develop a semi-mechanistic model of disease progression in MDS based on clinical data, involving relevant hematopoietic cells that can describe the effect of drug intervention with venetoclax azacitidine combination therapy. The model was subsequently used to simulate different treatment regimens (with respect to dose, dosing duration in a cycle, and number of cycles) and compare the outcomes. Study Design and Data: Data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax (400 mg or 800 mg for 28 days or 100 mg to 400 mg for 14 days in each 28-day cycle) with azacitidine (75 mg/m2 on days 1-7 of each cycle) in treatment-naive patients with higher-risk MDS were used for the analysis. The data contained venetoclax concentrations, neutrophil, red blood cell, and platelet count in the blood and blasts in the bone marrow. Methods: An integrated semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accounted for venetoclax PK and azacitidine treatment to describe time dynamics of neutrophils, red blood cells, and platelets. The model also included crowding in the bone marrow due to excess stem cells, MDS blasts, and progenitor cells, and its effect on hematopoiesis. Results: The model described the observed clinical data well and showed predictive ability across considered cell types. Complete remission (CR) and marrow complete remission (mCR) rates were predicted close to observed rates in the study. Simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints are comparable to the expected outcomes from various dosing regimens. Conclusions: A model describing drug-disease interactions in MDS was developed that integrates multiple end points and differentiates disease driven from drug-induced cytopenia. Reference: [1] Dayyani, F, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010 May 1; 116.9:2174-2179. Disclosures: The analysis presented was funded by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. NT, JZ, RM, BE, JW, SM, and SG are employees of AbbVie and may hold stock. AHW receives honoraria from Novartis, Astellas, Pfizer, Macrogenics, Abbvie, Genentech, Servier, Celgene, Amgen, Astra Zeneca and Janssen. AHW also receives research funding from Novartis, Celgene, Abbvie, Servier, Astra Zeneca and Amgen. AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. G-GM is an investigator in AbbVie funded Clinical Trials. DM is a Genentech employee and may own stock. C.M. performed the analysis at AbbVie during an internship. C.M. also receives research funding from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grunenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and Sanofi) for the PharMetrX program

P225 Inhibition of structural joint damage with upadacitinib as monotherapy or in combination with MTX in patrients with RA: one-year outcomes from the select Phase 3 programme

Abstract Background Long-term prevention of structural joint damage is a key treatment goal in the management of RA. Upadacitinib (UPA), a JAK1-selective inhibitor, inhibited the progression of structural joint damage at 6 months as monotherapy in methotrexate (MTX)-naïve RA patients and in combination with MTX in patients with inadequate response (IR) to MTX. Objectives: To evaluate the progression of structural joint damage (radiographic) through Week 48 in patients with moderately to severely active RA treated with UPA monotherapy or in combination with MTX. Methods Radiographic progression was assessed in 2 phase 3 randomized controlled trials (RCTs). MTX-naïve patients were randomized to UPA 15 or 30mg QD or MTX monotherapy [SELECT-EARLY, N = 945], while MTX-IR patients were randomized to UPA 15mg QD or adalimumab (ADA) 40 mg eow or placebo (PBO), with continuous background MTX [SELECT-COMPARE, N = 1629]. Both RCTs specifically enrolled patients at high risk for progression of joint damage (high disease activity including elevated hsCRP, presence of baseline erosions and ACPA and/or RF positivity). The mean changes (D) from baseline (BL) in modified Total Sharp Score (mTSS), joint space narrowing (JSN), and erosion scores (ES) as well as the proportion of patients with no radiographic progression (ΔmTSS ≤0) at Weeks 24/26 and 48 were determined in both RCTs. Data were analyzed by linear extrapolation (LE) for missing data imputation and treatment switching, and as observed (AO). Results BL demographics have been reported previously. At Weeks 24/26, UPA as monotherapy and in combination with background MTX significantly inhibited radiographic progression measured by mean DmTSS and the proportion of patients with no radiographic progression vs MTX and PBO, respectively. The significant inhibition of radiographic progression with UPA was maintained through Week 48 vs MTX (LE and AO) in EARLY and vs PBO (LE) in COMPARE. Following the switch of all PBO patients to UPA in COMPARE by Week 26, no further change in mean mTSS was observed through Week 48. The inhibition of radiographic progression vs comparators was not only observed for the overall mTSS scores but also its components - the JSN and ES in both RCTs (LE and AO). Conclusion UPA both as monotherapy, and in combination with background MTX, was effective in inhibiting the progression of structural joint damage through Week 48 in MTX-naïve, and MTX-IR patients, respectively. Disclosures C. Peterfy: Consultancies; AbbVie, Acerta, Amgen, AstraZeneca, Bristol-Myers Squibb, Centrexion, Daiichi Sankyu, Five Prime Therapeutics, Genentech, Hoffmann-La Roche, Janssen, Lilly USA, MedImmune, Merck, Novartis, Plexxikon, Pfizer, Sanofi, Salix-Santarus, Samsung. M.C. Genovese: Consultancies; Consultant for and has received grants from AbbVie Inc, Lilly, Pfizer, Galapagos, and Gilead. I. Song: Corporate appointments; Employee of AbbVie. A. Friedman: Corporate appointments; Employee of AbbVie. S. Hall: Consultancies; Received research grants and consultancy fees from AbbVie Inc, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis. E. Mysler: Grants/research support; Received research grants and speaker’s bureau fees from Bristol-Myers Squibb, Roche, Eli Lilly, AbbVie, Novartis, Janssen, and Pfizer. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Samsung, Pfizer, UCB, Mundipharma, Hospira, and Eli Lilly. X. Baraliakos: Grants/research support; AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer Inc, Roche and UCB. J. Enejosa: Corporate appointments; Employee of AbbVie. T. Shaw: Corporate appointments; Employee of AbbVie. Y. Li: Corporate appointments; Employee of AbbVie. S. Chen: Corporate appointments; Employee of AbbVie. V. Strand: Consultancies; Consultant for AbbVie, Amgen, AstraZeneca, BMS, Celltrion, Celgene, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sanofi, and UCB.

P209 Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the select Phase 3 clinical programme

Abstract Background Upadacitinib (UPA), a JAK1-selective inhibitor, significantly improved clinical signs and symptoms of rheumatoid arthritis (RA) in patients naïve to methotrexate (MTX) and with an inadequate response to conventional synthetic DMARDs (csDMARD-IR) or biologic DMARDs (bDMARD-IR). The objective was to assess the safety of UPA as monotherapy (mono) and as combination therapy with background csDMARDs in patients with moderately to severely active RA from the safety database of the Phase 3 clinical programme. Methods Treatment-emergent adverse events (TEAEs) from 5 pivotal, randomised, double-blind, controlled Phase 3 trials of UPA 15 mg or 30 mg QD in RA patients were analysed using integrated short-term (ST), individual studies with long-term (LT) active comparator and integrated LT (all Phase 3 exposure; E/100PY) analyses sets. Results Across the Phase 3 trials, 3834 patients received ∼1 dose of UPA 15 mg (n = 2630) or 30 mg QD (n = 1204) »4020.1 PY of UPA exposure with no option to switch doses. The ST frequencies of overall SAEs and AEs leading to discontinuation were low, but higher on both UPA doses vs PBO. LT event rates were similar on UPA 15 mg vs ADA and slightly higher on UPA vs MTX mono. Deaths occurred in all treatment groups. Serious infection (SIEs) frequencies were higher on both UPA doses vs PBO. SIE rates on both UPA doses were higher vs MTX, but similar on UPA 15 mg vs ADA. Herpes zoster (HZ) frequencies and rates were higher on both UPA doses vs PBO, and vs MTX, ADA, respectively. The rates of SIE and HZ were higher on UPA 30 vs 15 mg. Adjudicated MACE were reported in all treatment groups including PBO. LT MACE rates were similar on UPA 15 mg and ADA and on UPA 15 mg and MTX mono, but higher on UPA 30 mg mono (low number of events, 2-4 per set). Adjudicated VTEs occurred at comparable frequencies on UPA vs PBO and at comparable rates on UPA vs active comparators. Malignancy (excluding non-melanoma skin cancer [NMSC]) rates were similar on UPA vs MTX, UPA 15 mg vs ADA, and 15 vs 30 mg. The NMSC rates on UPA 15 mg and ADA were similar; the rate on 30 mg was higher than 15 mg, but both UPA NMSC rates were in the range reported for RA patients treated with DMARDS. The standardised incidence ratio (95% CI) for malignancy (15 mg: 0.98 [0.61, 1.49], 30 mg: 1.49 [0.85, 2.42]) was not elevated vs the general population. Conclusion Treatment with UPA increased the risk of SIE and HZ, but not those of VTE, MACE, and malignancy vs comparators. These data support that UPA has an acceptable safety profile in the treatment of moderately to severely active RA. Disclosures S.B. Cohen: Grants/research support; Received grants and personal fees from Amgen, Abbvie, Boehringer Ingelheim, Pfizer and Sandoz. R. van Vollenhoven: Consultancies; AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, and UCB. Grants/research support; Received grants from AbbVie, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline (GSK), Lilly, Pfizer, and UCB. K. Winthrop: Consultancies; Received consulting fees and research grants from UCB Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, AbbVie, and Roche. C. Zerbini: Consultancies; Merck, Pfizer, Sanofi-Aventis and Pfizer. Grants/research support; Received research grants from Amgen, GSK, Lilly, Merck, Novartis, Pfizer, Sanofi-Aventis, Servier and Roche. Y. Tanaka: Honoraria; Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi-kasei. Grants/research support; Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, Taisho-Toyama. L. Bessette: Grants/research support; Speaking fees, consulting fees, and research grants from Amgen, BMS, Janssen, Roche, UCB Pharma, AbbVie Inc, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, and Novartis. Y. Zhang: Corporate appointments; Employee of AbbVie. N. Khan: Corporate appointments; Employee of AbbVie. B. Hendrickson: Corporate appointments; Employee of AbbVie. J.V. Enejosa: Corporate appointments; Employee of AbbVie. G. Burmester: Honoraria; Received speaking or consulting fees from AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma.

P200 Characterisation of remission in patients with rheumatoid arthritis treated with upadacitinib or comparators

Abstract Background Across all phase 3 studies, treatment with upadacitinib (UPA), a JAK1-selective inhibitor, was associated with significantly higher remission (REM) rates, compared to placebo (PBO) or active comparators, in RA patients who were methotrexate (MTX)-naive, had inadequate response to conventional synthetic (csDMARD-IR) or had inadequate response or intolerance to biologic DMARDs (bDMARD-IR). Methods REM definitions are based on composite scores of various individual assessments of disease activity. To determine the response to UPA on REM and component assessments, we assessed the proportions of patients achieving REM using multiple REM definitions, and the improvement in their respective individual components, compared to PBO or active comparators, in 3 different RA patient populations spanning a range of RA patient populations. Methods: Three phase 3 studies included patients who were MTX naïve (SELECT EARLY, n = 945), MTX-IR (SELECT COMPARE, n = 1629) and bDMARD-IR (SELECT BEYOND, n = 498). The proportion of patients achieving REM at Week 12 by 4 definitions (DAS28-CRP<2.6; CDAI <2.8; SDAI <3.3 and Boolean, defined as < 1 for TJC, SJC, patient’s global assessment of disease activity [PtGA], and CRP <1 mg/L) were determined. For each definition of REM, the mean change in each of the respective component scores was also assessed. Binary endpoints are based on Non-responder imputation (NRI), and continuous endpoints on mixed-effect model repeat measurement (MMRM). Comparisons were made between UPA-treated groups vs respective control arms (MTX, adalimumab [ADA] or PBO). Results Patient demographics and disease characteristics have been previously reported. 1-3 At 12 weeks, in EARLY and COMPARE, a significantly greater proportion of patients receiving UPA 15 mg or 30 mg QD achieved REM by all 4 definitions vs MTX, PBO or ADA (Table). In BEYOND, (a refractory population many of whom had inadequate response to multiple bDMARDs), a significantly greater proportion of patients receiving UPA 30mg achieved all REM definitions vs PBO within the first 12 weeks, with significantly greater proportions on UPA 15mg achieving DAS28-CRP<2.6 and Boolean REM. Rates of REM in BEYOND further increased through Wk 24 for both dose groups. Compared to respective control groups, patients receiving UPA 15 or 30 mg QD had significantly greater improvements in each REM disease component (except for PhGA vs ADA in COMPARE). Significantly more patients receiving UPA also achieved the required cutoffs on the individual components of Boolean REM compared to respective controls. Conclusion Significantly greater proportions of patients receiving UPA 15 or 30mg achieved REM by multiple definitions at 12 weeks compared to PBO, MTX or ADA. All disease activity components of each REM definition were significantly improved in patients receiving UPA compared to MTX or PBO, and all Boolean components were significantly improved in patients receiving UPA 15mg compared to ADA. Disclosures S. Hall: Grants/research support; AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, Novartis. T. Takeuchi: Honoraria; Mitsubishi-Tanabe Pharma Corp, Janssen Pharma KK, Chugai Pharma, Astellas Pharma Inc., AbbVie GK, Eisai Co., Ltd, BMS, Daiichi Sankyo Company Ltd, Eli Lilly Japan KK, Pfizer Japan Inc. Grants/research support; Pfizer Japan Inc., Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corp, Nippon Kayaku Co., Ltd, Taisho Toyama Pharma, Takeda Pharma, AYUMI Pharma, Takahashi Industrial. G. Thomson: Consultancies; Amgen. Grants/research support; AbbVie. P. Emery: Grants/research support; Research grants and consulting fees from Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Samsung, Sandoz and Lilly. B. Combe: Grants/research support; Consultancy fees from Abbvie, BMS, Jansen, Lilly, MSD, Pfizer, Roche Chugai, UCB. A. Everding: None. K. Pavelka: Honoraria; Honoraria for lectures and consultations from companies: Pfizer, MSD, BMS, UCB, Amgen, Egis, Roche, AbbVie. Y. Song: Corporate appointments; Employee of AbbVie. T. Shaw: Corporate appointments; Employee of AbbVie. A. Friedman: Corporate appointments; Employee of AbbVie. I. Song: Corporate appointments; Employee of AbbVie. E. Mysler: Grants/research support; Research grants and consulting fees from AbbVie, Lilly, Pfizer, Roche, BMS, Sandoz.

P224 A matching-adjusted indirect comparison (MAIC) of upadacitinib versus tofacitinib in csDMARD-IR patients with moderate to severe RA

Abstract Background Upadacitinib (UPA), a JAK1 selective inhibitor, is being investigated as monotherapy and combination therapy with DMARDs for the treatment of moderate-to-severe RA. To date, no head-to-head trials have compared the effectiveness of UPA with tofacitinib (TOFA). Objectives: To compare the efficacy of UPA 15 mg monotherapy and combination therapy with TOFA 5 mg combination therapy using MAICs. Methods Two MAICs were conducted. MAIC is an indirect comparison technique that utilises individual patient data (IPD) for one treatment and aggregate data for the other treatment to provide comparative evidence after balancing differences in patient characteristics. The first MAIC used IPD from the SELECT-MONOTHERAPY trial of UPA monotherapy vs. methotrexate (MTX) and published data from the Oral Standard trial of TOFA+MTX vs. MTX. The second used IPD from the SELECT-COMPARE trial of UPA+MTX vs. adalimumab (ADA)+MTX and published data from the ORAL Strategy trial of TOFA+MTX vs. ADA+MTX. UPA monotherapy was not compared to TOFA monotherapy based on feasibility analysis and trial selection criteria. Patients in the UPA trials were re-weighted based on age, gender, race, swollen joint count 66/28, tender joint count 68/28, C-reactive protein (CRP), and patient’s global assessment, to match the baseline characteristics in each comparator trial. After matching, ACR20/50/70 and clinical remission (SDAI(CRP)≤3.3, CDAI≤2.8, DAS28-ESR/CRP<2.6) were compared for UPA monotherapy vs. TOFA +MTX relative to MTX at month 3 and UPA+MTX vs. TOFA+MTX relative to ADA+MTX at month 3 and 6 using a Wald test. Results After matching, baseline characteristics were balanced across the trial populations. At month 3, UPA monotherapy patients experienced significantly greater improvement in ACR70 compared to TOFA+MTX with a mean difference in difference (DD) of 9.9% (p < 0.05) while UPA+MTX was associated with a higher ACR50 compared to TOFA+MTX with a DD of 12.9% (p < 0.05). At month 6, UPA+MTX patients experienced significantly larger improvement in SDAI/CDAI/DAS28-ESR clinical remission compared to TOFA+MTX with DDs of 9.1% (p < 0.05), 7.5% (p < 0.05), and 11.3% (p < 0.01), respectively. Conclusion The results from MAICs indicate that treatment with UPA 15 mg when used as monotherapy or in combination with MTX appears to produce improved outcomes at 3/6 months as compared to TOFA 5 mg +MTX (mono: ACR70 and combination: ACR50, SDAI, CDAI and DAS28-ESR remission). Disclosures C. Edwards: Consultancies; Honoraria and research support from Abbvie, BMS, Biogen, Celgene, Fresenius, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB. R. Sawant: Corporate appointments; Employee and Stockholder of Abbvie. E.X. Du: Consultancies; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study. J. Cammarota: Consultancies; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study. P. Tang: Consultancies; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study. V. Garg: Corporate appointments; Employee and Stockholder of Abbvie. A. Friedman: Corporate appointments; Employee and Stockholder of Abbvie. K. Betts: Corporate appointments; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study.

Characterization of MC903 induced Atopic Dermatitis‐like skin inflammation in mice

Atopic Dermatitis (AD) is a chronic inflammatory skin disease that affects both adults and children worldwide. Symptoms of AD, such as recurrent dry, scaly lesions and intensive pruritus, can become an enormous burden to patients and their caregivers. Animal models are needed to better understand the pathophysiology of AD and for evaluating novel therapeutics. Topically applying MC903 (calcipotriol) on mouse skin has been reported to capture key features associated with AD. In the current study, we conducted a comprehensive characterization of MC903 induced ear skin inflammation in the mouse. An 11 day time course revealed skin thickening starting as early as day 4 and significantly progressing up to day 10. This chronicity was mirrored by increased transepidermal water loss in the ear skin. Histologically, hypervascularization, spongiosis, strong immune cell infiltration and epidermal hyperplasia were observed. The animals also manifested pruritic behaviors. The skin expression of Type 2 and other inflammatory cytokines such as IL‐4, IL‐5, IL‐31, TSLP (peak day 4), IL‐1β, IFNγ, TNFα were typically elevated by day 7 and further increased to day 10. Most of these endpoints were attenuated by administration of a selective JAK1 inhibitor (ABT‐317) or a steroid (Dexamethasone). The observations further the understanding of the utility of MC903 as a preclinical model for AD.Support or Funding Information Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Beyond Binding Kinetics: Stoichiometry via SPR can identify novel binding modes, assess ligand quality and inform functional design in biopharmaceutical discovery.

Biological therapeutics have seen a dramatic increase in molecular complexity and biological mechanisms. Antibody drug conjugates (ADCs) and multi‐specific formats are filling therapeutic pipelines and fundamentally changing traditional platform approaches to biologics discovery. These new entities pose unique challenges for characterization; as with traditional mAbs they are generally triaged through the discovery process by a series of functional assays including ELISA, FACS and binding kinetics however, we have implemented an additional and often underutilized SPR measure to characterize the function and quality of these entities: binding stoichiometry. Here we will discuss the special requirements for quality stoichiometry measures and show how stoichiometry can be used to 1) identify novel binding modes for a mAb that may have implications to ADC function, 2) identify signs of molecular instability, 3) aid in engineering functional biotherapeutic molecules and 4) assess simultaneous binding of analytes in multi‐specific formats. These examples will show an important measure that can be used to identify liabilities and to demonstrate function of biotherapeutic candidates.Support or Funding InformationAll authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Safety and Efficacy of Upadacitinib in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: Results From a Pivotal Phase 3, Randomised, Double-Blind, Placebo-Controlled Study (AD Up)

Safety and Efficacy of Upadacitinib in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: Results From a Pivotal Phase 3, Randomised, Double-Blind, Placebo-Controlled Study (AD Up)

Abstract NT-113: SC-003, AN ANTIBODY-DRUG CONJUGATE TARGETING DIPEPTIDASE 3, EXHIBITS POTENT ANTI-TUMOR ACTIVITY IN PATIENT-DERIVED XENOGRAFT MODELS OF HIGH GRADE SEROUS OVARIAN CANCER

Abstract Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Ovarian cancer describes a group of malignancies that remain a serious threat to women's health and claim more than 14,000 deaths in the US each year. Among these, high-grade serous ovarian cancers (HGSC) represent the most common and aggressive form, and tumor recurrence is near-universal following initial response to carboplatin and paclitaxel. While multiple treatment options are available for platinum-sensitive recurrent HGSC, such as continued use of carboplatin/paclitaxel with or without bevacizumab, as well as several FDA-approved PARP inhibitors, there are few effective treatment options for platinum-resistant HGSC. Its inherent heterogeneity, characterized by genomic instability and numerous DNA copy number aberrations, poses challenges to the discovery of novel therapeutic targets. Patient-derived xenograft (PDX) models are an important platform for target identification and efficacy testing of therapeutic agents, as they sustain the intratumoral heterogeneity observed in advanced human tumors more faithfully than established cell lines. The isolation of distinct tumor cell populations by flow cytometry and subsequent testing of their tumorigenic potential can identify tumor-initiating cells (TICs), which have the potential to propagate the tumor over multiple generations in immune-deficient NOD/SCID mice. Thorough characterization of these TIC populations by transcriptome profiling and flow cytometry has identified TIC-enriched cell surface proteins that are targetable by antibody drug conjugates (ADCs), including EFNA4 in mixed Müllerian and ovarian cancers and PTK7 in triple-negative breast and ovarian cancers. ADCs consist of a monoclonal antibody directed against a cell surface epitope linked to a cytotoxic agent, such as auristatin, maytansinoid, or pyrrolobenzodiazepine (PBD). Here, we describe the generation and characterization of a PDX bank for ovarian cancers that led to the identification of dipeptidase 3 (DPEP3) as a TIC-associated target in HGSC. We show that DPEP3 is enriched in the TIC fraction of platinum-sensitive and platinum-resistant HGSC PDX models, where it localizes to the plasma membrane and is detected by flow cytometry and immunohistochemistry (IHC). In contrast, DPEP3 expression is low or absent in most normal adult tissues, thus providing a therapeutic window for an antibody-based therapeutic agent. In order to target DPEP3-expressing ovarian cancer cells, we developed SC-003, an ADC consisting of a humanized monoclonal antibody linked to a PBD dimer via a cleavable linker. We show that SC-003 specifically binds to DPEP3-expressing cells and, upon internalization, elicits cytotoxicity via release of its PBD warhead following lysosomal degradation of the antibody component. A single dose of SC-003 induced tumor regression in DPEP3-positive HGSC PDX models, including platinum-resistant PDX models. Mechanistically, we show that the anti-tumor effect of SC-003 is mediated by a significant reduction in TIC frequency. Moreover, combination with an anti-PD1 antibody potentiated SC-003 efficacy in a syngeneic mouse model engineered to overexpress human DPEP3. In summary, these findings support the clinical development of SC-003 as a novel therapeutic agent for HGSC. Citation Format: Wolf R. Wiedemeyer, Sheila Bheddah, Christine Saechao, Dorothy French, Erik Huntzicker, Aaron Kempema, Julia Gavrilyuk, David Liu, Vikram Sisodiya, Alina He, Zhaomei Zhang, Monette A. Aujay, Kristyn Hayashi, Sandro Vivona, Xi Zhao, Kimberly Walter, Laura R. Saunders, Johannes Hampl, Shravanthi Madhavan, Marybeth Pysz, Alexander J. Bankovich, Holger Karsunky, Scott J. Dylla. SC-003, AN ANTIBODY-DRUG CONJUGATE TARGETING DIPEPTIDASE 3, EXHIBITS POTENT ANTI-TUMOR ACTIVITY IN PATIENT-DERIVED XENOGRAFT MODELS OF HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-113.

Pevonedistat, a Nedd-8 Activating Enzyme Inhibitor, Upregulates NOXA to Increase Effectiveness of Azacitidine and Venetoclax in Preclinical Models of Acute Myelogenous Leukemia

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, has yielded exceptional response rates in patients with acute myeloid leukemia (AML). VEN binds BCL-2 to directly inhibit sequestration of pro-apoptotic proteins such as the activator BIM. Free BIM can bind to BAX, enabling its oligomerization with BAK, mitochondrial outer membrane permeabilization (MOMP) and subsequent apoptosis (PMID 24074954, 9687260, 19641500, 20164920). VEN has limited efficacy in relapsed-refractory AML as a single agent, but when used in combination with DNA methyltransferase inhibitors (DNMTi; 5'azacitidine-AZA-or decitabine) or low-dose cytosine arabinoside (LDAC), 50-70% of untreated patients in recent clinical trials achieved complete remission (PMID 27520294, 30361262, 30892988). Despite this progress in AML therapy, the majority of AML patients treated with VEN ultimately relapse, and a large subset of patients never respond (PMID 30361262, 30892988). One postulated route of resistance to VEN is cellular upregulation of myeloid cell leukemia-1 protein (MCL-1), which, similarly to BCL-2, functions as an anti-apoptotic protein. VEN in combination with selective MCL-1 inhibitors has demonstrated added benefit over either agent alone in AML cells in vitro and in xenograft models but efficacy of this combination in the clinic has yet to be reported (PMID 30185627). Both MCL-1-dependent and MCL-1-independent mechanisms of VEN resistance are emerging (PMID 31048321, 30148320, 31262744) and new approaches aimed at addressing these are moving toward the clinic. Pevonedistat (PEV) was developed as a targeted inhibitor of NEDD-8 activating enzyme (NAE), which disrupts protein turnover mediated by Cullin-RING ligases (PMID 19360080) and has been shown to have activity in combination with AZA (PMID 29348128). PEV and AZA both upregulate NOXA, a BCL-2 family member that is known to suppress MCL-1 (PMID 26045051, Jin, Cojocari, Purkal et al.,unpublished data), so we postulated that PEV/AZA in combination synergizes with VEN in a triple combination with efficacy superior to VEN/AZA alone. Methods/Results: AML cell lines were treated with PEV, AZA and VEN alone, and compared with various VEN/PEV/AZA combinations revealing improved combinatorial activity with the triplet in the majority of cell lines and associated NOXA induction. Similar results were seen in primary AML patient samples ex vivo (Figure 1). These combinations were compared in vivo in an OCI-AML2 cell line xenograft model, also illustrating significantly improved response with the PEV/AZA/VEN combination (Figure 2). CRISPR/Cas 9 deletion of PMAIP1 in AML cell lines demonstrated that NOXA deletion abrogates this synergy. Discussion: Together, these results demonstrate that, in several pre-clinical models of AML, the PEV/AZA/VEN triple combination provides stronger anti-tumorigenic activity than either agent alone or the VEN/PEV and VEN/AZA combinations. Importantly, the three-drug combination may be effective in AML cells which do not respond to VEN/AZA alone. Further studies to delineate this mechanism of action, and a clinical trial (NCT03862157) testing the combination in newly diagnosed AML are underway. Figure 1 Disclosures Cojocari: AbbVie Inc: Employment, Other: DC, JP, ERB, JDL, and DCP are employees of AbbVie. JP, ERB, JDL & DCP are stockholders of AbbVie Inc. The design study conduct, and financial support for this research were provided by AbbVie. AbbVie Inc. participated in the interpretation of data, review. Purkal:AbbVie Inc: Employment, Other: DC, JP, ERB, JDL, and DCP are employees of AbbVie. JP, ERB, JDL & DCP are stockholders of AbbVie Inc. The design study conduct, and financial support for this research were provided by AbbVie. AbbVie Inc. participated in the interpretation of data, review. Leverson:AbbVie Inc: Employment, Other: Stock or options. Boghaert:AbbVie Inc: Employment, Other: DC, JP, ERB, JDL, and DCP are employees of AbbVie. JP, ERB, JDL & DCP are stockholders of AbbVie Inc. The design study conduct, and financial support for this research were provided by AbbVie. AbbVie Inc. participated in the interpretation of data, review. Phillips:AbbVie Inc: Employment, Other: DC, JP, ERB, JDL, and DCP are employees of AbbVie. JP, ERB, JDL & DCP are stockholders of AbbVie Inc. The design study conduct, and financial support for this research were provided by AbbVie. AbbVie Inc. participated in the interpretation of data, review. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees.

A 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids.

A 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids.

1288P - Safety and efficacy of anti-PD-1 inhibitor ABBV-181 in lung and head and neck carcinoma

BackgroundABBV-181 is a humanized anti-PD1 monoclonal antibody; dose finding and early safety, PK and pharmacodynamic data have been reported (ESMO18). This report summarizes data from the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts in the Ph1 FIH study (NCT03000257). MethodsPatients (pts) with previously treated, advanced HNSCC and NSCLC received ABBV-181 IV, 250mg Q2W or 500mg Q4W to progression. Response was assessed by RECIST v1.1 and iRECIST. ResultsAs of April 2019, 81 pts were dosed.Table1288PTablen (%)HNSCC n=41NSCLC n=40Median days on treatment, range72, 1–40771, 1–421Dose: 250mg/500mg31/1019/21AE any grade40 (98)40 (100)Grade (G) ≥3 AE23 (56)27 (67)ABBV-181 related G≥3 AE4 (10)3 (7)Immune-mediated AE15 (37)15 (37)AE resulting in discontinuation of ABBV-181 Malignant neoplasm progresion General physical health Confusion Pneumonitisa Acute kidney injurya Hypothyroidisma Immune-mediated hepatitisa Disturbance in attention Dysponea Intracranial hemorrhage Neoplasm progression Acute respiratory distress syndrome Upper respiratory tract infection5 (12) 2 (5) 1 (2) 0 0 0 1 (2) 0 0 0 0 1 (2) 1 (2) 09 (22) 3 (7) 0 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 0 0 1(2)G 5 AEsb Malignant neoplasm progression Acute respiratory distress syndrome Dyspnea Neoplasm progression Upper respiratory tract infection General physical condition abnormal7 (17) 4 (10) 1 (2) 0 1 (2) 0 1 (2)7 (18) 6(15) 0 1 (2) 0 1 (2) 0aABBV-181 related.bnone considered related to ABBV-181. Most frequent G≥1 AE (n): anemia (20), asthenia (20) and fatigue (16). ABBV-181PK is approximately dose proportional, with comparable dose-normalized exposures at both doses; trough levels resulted in sustained PD-1 saturation on circulating CD4 T cells. Transient decreases in circulating T cells and increased Ki67+ CD8 T cells and serum CXCL9/CXCL10 were observed at both doses. In pts with ≥ 1 post baseline assessment, responses by investigator: 7/40 HNSCC pts (7 partial response, 6 by RECISTv.1.1, 1 by iRECIST), 6/36 NSCLC (5 PR, 1 complete response, all by RECIST v.1.1). 3 HNSCC and 2 NSCLC responders had PD-L1+ tumors. ConclusionsSafety, PK and PD data support dosing ABBV-181 at 250mg Q2W or 500mg Q4W with expected biological and pharmacodynamic activity for an anti-PD-1 agent. Efficacy data demonstrate clinical activity per RECISTv.1.1 and iRECIST supporting continued development of ABBV-181. Clinical trial identificationNCT03000257. Editorial acknowledgementFatemeh Atashi (AbbVie employee). Legal entity responsible for the studyAbbVie Inc. FundingAbbVie Inc. DisclosureA. Italiano: Advisory / Consultancy: Roche, Daiichi Sankyo, ImmuneDesign, Epizyme, Bayer, Lilly; Honoraria (self): Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche; Research grant / Funding (self): Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck Serono. P. Cassier: Honoraria (self): Novartis, Roche/Genentech, Blueprint Medicines, Amgen; Research grant / Funding (institution): Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, Merck, Sharp and Dohme. C. Lin: Advisory / Consultancy: Novartis, Boehringer Ingelheim, Blueprint Medicines; Travel / Accommodation / Expenses: Lilly, Daiichi Sankyo, BeiGene, Novartis; Honoraria (self): Novartis, Roche, Daiichi Sankyo. K. Peltola: Advisory / Consultancy: Orion Pharma, BMS, MSD, Pfizer, Ipsen and Roche; Shareholder / Stockholder / Stock options: Faron Pharmaceuticals; Speaker Bureau / Expert testimony: BMS, Pfizer, MSD; Speaker Bureau / Expert testimony: Ipsen; Travel / Accommodation / Expenses: Roche and BMS. A. Gazzah: Travel / Accommodation / Expenses: Boehringer, Novartis, Pfizer, Roche. E. Calvo: Advisory / Consultancy: Novartis, Nanobiotix, Janssen-Cilag, PsiOxus, Seattle Genetics, EUSA Pharma, AbbVie, Celgene, AstraZeneca, Guidepoint Global, Roche/Genentech, GLG, Pfizer, Servier, Amcure; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): AstraZeneca, BeiGene, Novartis, START, Oncoart Associated, ; Leadership role: President and Founder of Foundation Intheos. D. Tosi: Advisory / Consultancy: Biomarin ; Research grant / Funding (self): Novartis, Astellas, Janssen; Travel / Accommodation / Expenses: Janssen, Pfizer, and Astellas Pharma, Nutricia and Amicus. B. Gao: Advisory / Consultancy: MSD. L. warburton: Travel / Accommodation / Expenses: MSD, Merck. M. Tanner: Advisory / Consultancy: Roche, Novartis and Pfizer; Speaker Bureau / Expert testimony: Roche, Novartis, Pfizer and Amgen. S. Englert: Full / Part-time employment: AbbVie Inc.; Shareholder / Stockholder / Stock options: AbbVie Inc. S. Lambert: Full / Part-time employment: AbbVie Inc.; Shareholder / Stockholder / Stock options: AbbVie Inc. A. Parikh: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. D. Afar: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. G. Vosganian: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. V. Moreno: Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Regeneron/Sanofi; Research grant / Funding (self): Medscape/Bayer. All other authors have declared no conflicts of interest.

Health Care Utilization and Costs Associated with Endometriosis Among Women with Medicaid Insurance.

Endometriosis is a painful chronic inflammatory disease caused by endometrial tissue implanting and growing outside the uterus, resulting in pelvic pain symptoms and subfertility. Treatment imposes a substantial economic burden on the patient and health care system. To evaluate direct health care utilization and costs among women newly diagnosed with endometriosis compared with age-matched controls in a U.S. Medicaid population. This retrospective cohort study used deidentified health care claims from the 2007-2015 MarketScan Multi-State Medicaid Database. Women (aged 18-49 years) newly diagnosed with endometriosis (ICD-9-CM 617.xx) during January 2008 through September 2014 were identified (date of first diagnosis = index date). Age-matched women without endometriosis (controls) were selected from the database and assigned index dates matching the distribution for endometriosis patients. Direct health care resource utilization (HCRU) and costs (medical and pharmacy) over the 12-month post-index period (2015 U.S. dollars) were computed by service category (hospitalization, emergency room visits, outpatient services, and prescriptions) and compared between study cohorts using the chi-square test for proportions and t-test for continuous variables. The final sample included 15,615 endometriosis patients and 86,829 matched controls. HCRU during the 12-month post-index follow-up period was significantly higher for endometriosis cases compared with controls in all measured categories. Hospital admissions occurred among 33.1% of cases and 7.2% of controls, and 65.8% of endometriosis patients were admitted for endometriosis-related surgery. Emergency room visits occurred in 71.5% of cases, and 42.2% of controls. Mean (SD) office visits were 10.4 (8.5) for endometriosis patients and 5.1 (6.9) for controls. Endometriosis patients had significantly more prescription claims than controls, 45.9 (42.0) versus 25.1 (39.1). Mean total direct health care costs were $13,670 ($29,843) for cases versus $5,779 ($23,614) for controls. All differences between cases and controls were significant at P < 0.001. Health care costs and resource utilization in all measured categories were higher among endometriosis cases than controls. The economic burden of endometriosis among patients with Medicaid insurance is substantial, underscoring the unmet medical need for earlier diagnosis and cost-effective treatments. This study was funded by AbbVie and conducted by Truven Health Analytics, an IBM Company. AbbVie participated in developing the study design, data analysis and interpretation, manuscript writing and revisions, and approval for publication. Soliman and Vora are employees of AbbVie and may own AbbVie stock/stock options. Surrey has served in a consulting role on research to AbbVie and is on the speaker bureau for Ferring Laboratories. Bonafede and Nelson are employees of Truven Health Analytics, an IBM Company, which received compensation from AbbVie for the overall conduct of the study and preparation of the manuscript. Agarwal has served in a consulting role on research to AbbVie. Preliminary results of this study were previously presented in a podium session at the 2017 American Society for Reproductive Medicine Scientific Congress and Expo; October 28-November 1, 2017; San Antonio, TX.

5-Azacytidine Induces NOXA and PUMA Expression to Prime AML Cells for Venetoclax-Mediated Apoptosis

Acute myeloid leukemia (AML) is a clonal hematologic malignancy characterized by genomic heterogeneity and epigenetic changes, including aberrant DNA hypermethylation. Phase-Ib clinical data in relapsed/refractory AML patients indicate that combining venetoclax with the hypomethylating agents (HMAs) 5-azacitidine (5-Aza) or decitabine results in an overall response (OR) of 62% (DiNardo et al. 2018) compared to the historical OR of 28-29% with HMAs treatment alone (Kantarjian et al. 2013; Dombret et al. 2015). Subsequently, a randomized phase-III clinical trial was initiated to evaluate venetoclax activity in combination with 5-Aza in treatment-naïve AML patients ineligible for standard induction therapy (M15-656, NCT02993523). However, the underlying mechanism for the combinational activity observed between venetoclax and 5-Aza is unknown.In this study, we demonstrate that both chronic low-dose 5-Aza treatment, which induced global DNA demethylation, and acute treatment (24 hours, non-epigenetic effects) can drive combinational activity with venetoclax in AML through distinct mechanisms. Chronic culture with a low-dose 5-Aza for one week sensitized AML cell lines to venetoclax in vitro. In contrast, acute treatment with 5-Aza, activated the integrated stress response (ISR) pathway to induce expression of the BH3-only proteins NOXA (PMAIP1) and PUMA (BBC3) in human AML cell lines, independent of DNA methylation. This resulted in an increase in the amount of NOXA and/or PUMA in complex with anti-apoptotic proteins like BCL-2, BCL-XL and MCL-1, thereby “priming” AML cells for induction of apoptosis by venetoclax treatment. Priming for apoptosis resulted in significant synergistic cell death in a panel of AML cell lines treated with venetoclax and 5-Aza in vitro. In this panel of cell lines, the level of the PMAIP1, BBC3, and DDIT3 gene induction correlated with the synergy observed between venetoclax and 5-Aza. Importantly, subsequent PMAIP1 deletion significantly impacted the kinetics and depth of apoptosis induced by 5-Aza or venetoclax alone or in combination. In accordance with the in vitro combinational activity, the venetoclax/5-Aza combination provided added benefit over either agent alone in two xenograft models of AML. Together, these data provide a rationale for an ongoing randomized phase-III clinical trial evaluating venetoclax activity in combination with 5-Aza (M15-656, NCT02993523).Disclosures:DC, SJ, JP, RP, NT, YX, EB, JL, and DP are employees of AbbVie. LS is a former employee of AbbVie and was employed during the duration of this study. The design, study conduct, and financial support for this research were provided by AbbVie and Genentech. AbbVie participated in the interpretation of data, review, and approval of the publication. DisclosuresCojocari:AbbVie Inc: Employment. Jin:AbbVie Inc: Employment, Equity Ownership. Purkal:AbbVie Inc: Employment, Equity Ownership. Popovic:AbbVie Inc: Employment, Equity Ownership. Talaty:AbbVie Inc: Employment, Equity Ownership. Xiao:AbbVie Inc: Employment, Equity Ownership. Solomon:AbbVie Inc: Equity Ownership. Boghaert:AbbVie Inc: Employment, Equity Ownership. Leverson:AbbVie Inc: Employment, Equity Ownership, Patents & Royalties. Phillips:AbbVie Inc: Employment, Equity Ownership, Patents & Royalties.

The BCL-2-Selective Inhibitor Venetoclax Spares Activated T-Cells during Anti-Tumor Immunity

Introduction and objectives:During an adaptive immune response antigen-specific T cells rapidly proliferate and differentiate into cytotoxic T lymphocytes. Most of these cells undergo apoptosis but some develop into high-affinity memory CD8+ T cells. The BCL-2 family of proteins regulates apoptosis and has a critical role in development and maintenance of the immune system. Venetoclax (Venclexta™, ABT-199) is a selective BCL-2 inhibitor that increases tumor cell apoptosis, and is approved by the FDA for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Given the critical role of BCL-2 in the regulation of the immune system, we hypothesized that venetoclax may affect the anti-tumor activity of immune checkpoint inhibitors.Results:To interrogate the effects of venetoclax on T cells we initially performed a series of in vitro studies using human lymphocytes treated with clinically relevant doses of the drug. As previously reported (Khaw et al., Leukemia; 28(6):1207-1215, 2014), human peripheral blood mononuclear cells (PBMCs) treated with venetoclax exhibited a dose-dependent decrease in the number of B-cells and T-cells (CD4+ and CD8+ T-cells). Upon further characterization of the surviving T cells, we found that while the proportion of naïve T-cells decreased with increasing venetoclax concentrations, the proportion of memory T-cells increased, specifically CD8+ and CD4+ T effector memory cells (Figure 1).We next examined the effects of venetoclax on T-cell function in vitro in response to immune stimulation with or without immune checkpoint blockade. To address this we performed a mixed lymphocyte reaction (MLR) assay, in which primary monocyte-derived dendritic cells from one donor were cultured with CD4+ T-cells from another donor. In the MLR reaction we observed that venetoclax reduced CD4+ T-cell viability in a dose-dependent manner, but it did not limit T-cell proliferation of surviving cells. Venetoclax did not affect IFNγ secretion within these surviving cells and, more importantly, did not reduce the effects of the checkpoint inhibitor nivolumab (Figure 2).To test the effects of venetoclax on antigen-specific T cells, we performed a cytomegalovirus (CMV) recall assay where PBMCs from CMV-positive human subjects were incubated with CMV antigen and the activity of T cells was measured by IFNg secretion. Although venetoclax treatment reduced the total number of cells, IFNg production from antigen-specific CMV+ T cells remained comparable to DMSO control and combining venetoclax with nivolumab did not affect the anti-PD-1 response (Figure 3).Finally, to investigate the effects of venetoclax in combination with anti-PD-1 therapy in vivo we used the murine syngeneic tumor model MC38. Venetoclax did not impair the efficacy of anti-PD-1, and in some studies increased efficacy relative to either anti-PD-1 or venetoclax monotherapy alone. To determine whether the efficacy of the venetoclax-anti-PD-1 combination is immune-mediated, we transplanted immunodeficient mice with MC38 cells and repeated the same treatment regimens. The lack of efficacy in any of the treatment arms indicates that the contribution of venetoclax to efficacy in this solid tumor model is immune-mediated (Figure 4).Conclusions:These data suggest that venetoclax treatment results in loss of naïve but not memory T cells. Venetoclax did not affect the viability, the induction or frequency of memory T cells. In human in vitro experiments and in an in vivo syngeneic tumor model venetoclax did not antagonize the therapeutic effect of anti-PD-1. Contrary to our initial hypothesis, we find that modulation of the immune system by venetoclax may support its potential use for immune-based cancer therapy, as memory T-cells can rapidly acquire effector and cytotoxic function to eliminate cancer cells. Taken together, we provide evidence that venetoclax in combination with immune checkpoint inhibitors should be further explored as a therapy for cancer patients.All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie and Genentech participated in the interpretation of data, review, and approval of the publication. [Display omitted] DisclosuresMathew:AbbVie Inc.: Employment. Haribhai:AbbVie Inc.: Employment. Kohlhapp:AbbVie Inc.: Employment. Duggan:AbbVie Inc.: Employment. Ellis:AbbVie Inc.: Employment. Riehm:AbbVie Inc.: Employment. Robinson:AbbVie Inc.: Employment. Shi:AbbVie Inc.: Employment. Bhathena:AbbVie Inc.: Employment. Leverson:AbbVie Inc: Employment, Equity Ownership, Patents & Royalties. Pappano:AbbVie Inc.: Employment. Donawho:AbbVie Inc.: Employment. Uziel:AbbVie Inc.: Employment.

Abstract DDT01-05: ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor

Abstract The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. The BDII bromdomains are highly conserved across BET family members (&amp;gt;70% identity), suggesting that the generation of compounds that are selective for the four BDII bromodomains relative to the four BDI bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) helped to guide the identification of structural analogs of ABBV-075 demonstrating greater than 300X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration ultimately resulted in the discovery of BDII-selective compounds with improved oral bioavailability and the identification of the clinical asset ABBV-744. In striking contrast to the broad range of cell growth inhibition effected by pan BET inhibitor ABBV-075, the anti-proliferative activity for BDII-selective ABBV-744 was largely but not exclusively restricted to AML and androgen receptor (AR) positive prostate cancer cell line models, including models of Enzalutamide resistance. In vivo, doses of ABBV-744 at fractions of its MTD induced tumor growth inhibition in AML and prostate cancer xenograft models that were comparable to those observed with ABBV-075 when dosed at its MTD. Together, these in vitro and in vivo results provide proof of concept that highly selective BDII BET family bromodomain inhibitors may have improved tolerability relative to pan-BET inhibitors while maintaining tumor growth inhibition in AML and AR positive prostate cancer. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Warren Kati. ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT01-05.

Abstract 800: ABBV-744, a first-in-class and highly selective inhibitor of the second bromodomain of BET family proteins, displays robust activities in preclinical models of acute myelogenous leukemia

Abstract Many small-molecule inhibitors that target both bromodomains of the BET family proteins (pan BET inhibitors) are undergoing studies in clinical trials. Emerging data are beginning to suggest that clinical responses to these pan BET inhibitors in subsets of hematologic malignancies may be modest and short lived, perhaps due, at least in part, to tolerability issues that limit dosing levels. We hypothesized that selective inhibition of four of the eight bromodomains in BET family proteins might retain the anticancer activities in certain tumor subsets while alleviating some of the tolerability liabilities of pan BET inhibitors, thus possibly providing better therapeutic benefits. ABBV-744 is a highly selective inhibitor for the second bromodomain (BDII) of the four BET family proteins, exhibiting greater than 300-fold more potent binding affinity to the BDII bromodomain of BRD4 relative to the first bromodomain (BDI) of BRD4. In contrast to the broad antiproliferative activities observed with pan BET inhibitors, ABBV-744 only displayed significant antiproliferative activities in a limited number of cancer cell lines, including AML and androgen receptor (AR)-positive prostate cancer. Studies in AML xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Taken together, these results suggest that ABBV-744 could be a promising second-generation BET inhibitor for AML therapy. Affiliation: Oncology Discovery, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Xiaoyu Lin, Xiaoli Huang, Richard Bellin, Emily Faivre, Paul Hessler, Lloyd Lam, Mai Ha Bui, Denise Wilcox, Tamar Uziel, Debra C. Ferguson, Terrance J. Magoc, Daniel H. Albert, Keith F. McDaniel, Warren Kati, Yu Shen. ABBV-744, a first-in-class and highly selective inhibitor of the second bromodomain of BET family proteins, displays robust activities in preclinical models of acute myelogenous leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 800.

Abstract 931: Discovery of ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor

Abstract The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. Both BDI and BDII are highly conserved across BET family members (&amp;gt; 70% identity), suggesting that the generation of compounds that are selective for the BDI bromodomains or the BDII bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) led to the identification of structural analogs of ABBV-075 demonstrating greater than 100X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration led to compounds with improved BDII-selectivity and oral bioavailability and the identification of the clinical asset ABBV-744. Disclosures: All authors are employees or former employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: George S. Sheppard, Le Wang, Steven D. Fidanze, Lisa A. Hasvold, Dachun Liu, John K. Pratt, Chang H. Park, Mai-Ha Bui, Emily J. Faivre, Xiaoli Huang, Xiaoyu Lin, Denise M. Wilcox, Yu Shen, Daniel H. Albert, Terrance J. Magoc, Ganesh Rajaraman, Warren M. Kati, Keith F. McDaniel. Discovery of ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 931.

Abstract B26: Development of a proximity ligation assay for the detection of PARP-1 trapped to chromatin

Abstract Background: PARP inhibitors (PARPi) have been under clinical investigation as anti-cancer therapies both as monotherapy and in combination. The two basic mechanisms underlying PARP inhibitor activity are catalytic inhibition and PARP-1 trapping. PARPi trap PARP-1 onto base excision repair intermediates, contributing to potentiation of DNA damage by alkylating agents. The role of PARP-1 trapping with regard to efficacy and tolerability in the clinic is still under investigation. All PARPis are capable of PARP-1 trapping; however, different clinical-stage PARPi trap with dramatically different efficiencies. High efficiency trapping agents trap at doses similar to those required for catalytic inhibition while low efficiency trapping agents trap only at doses much higher than those required for inhibition. Being able to image trapped PARP-1 complexes in the cellular context would be beneficial for identifying other proteins associated with these complexes and may have clinical application in the detection of trapped PARP in tumor biopsies. To date, detection of PARP-1 complexes has been limited to low through-put, techniques that disrupt cellular architecture and lack the sensitivity to detect PARP-1 trapping in the absence of supraphysiologic doses of alkylating agents. More sensitive methods for quantifying trapped PARP1 complexes with spatial resolution are needed to enable further understanding of PARP-1 trapping in cancer and normal cells. The objective of this study was to develop an assay capable of identifying cellular PARP-1 trapped to chromatin with enhanced sensitivity and higher assay throughput. Methods: Duolink is a 96-well plate adaptable system that uses a proprietary antibody/oligonucleotide conjugate that, when localized within 40 angstroms, will anneal, amplify and hybridize to generate a quantitative proximity ligation assay (PLA) signal. To develop a Duolink trapping assay, antibodies to PARP-1, histone H2A.X and phosphorylated (Ser139) H2A.X were identified and optimized for labeling concentrations, endogenous target protein recognition and suitability for high content imaging. Duolink PLA was performed per the manufacturer's protocol. Automated image acquisition by Cell Insight and data analysis were performed using Cellomics View Software. PARP1 trapping was also evaluated by cellular fractionation and Western blot. Results: Binding to chromatin places PARP-1 in close proximity to histone H2A.X, presumably within the distance required for successful Duolink oligonucleotide annealing and amplification reactions. Co-treating cells with alkylating agents and PARPi induces a significant increase in phosphorylation of H2A.X (Ser139) as well as trapped PARP1 complexes. Comparative analysis of Western blot and PLA signals in HeyA8 cells treated with different PARPi/alkylating agent combinations revealed positive rank-order correlation in trapping activity. Resolution of in vitro single agent PARP-1 trapping by Western blot has been elusive but PLA detection of single agent PARP1 trapping was observed. Conclusion: The PLA trapping assay provides an improved methodology for evaluation of endogenous PARP-1 complexes bound to chromatin and may have utility for clinical tissue specimens where detection of PARP-1 trapping may lead to insights regarding efficacy and tolerability of PARP inhibitors. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Todd Hopkins, Barrett Ainsworth, Vivek Abraham, David Maag, Eric Johnson, Julie Wilsbacher. Development of a proximity ligation assay for the detection of PARP-1 trapped to chromatin [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B26.

Computational Prediction of Off‐Target Pharmacology for Discontinued Drugs

Most small molecule drugs interact with unintended, often unknown targets that lead to a wide range of undesirable adverse effects in both pre‐clinical and clinical development and that result in safety‐related attrition. Undesired off‐target interactions are generally weak and quite often not detected using current drug discovery assays. Thus, improvement in the early identification of off‐target interactions is critical to reduce the drug attrition rates related to toxicities. In order to better identify potential off‐target interactions that could be linked to predictable safety issues, we have evaluated and designed a novel computational process to predict safety‐relevant low and high‐affinity interactions that are currently not covered in experimental polypharmacology screens. The result of these analyses termed Off Target Safety Assessment (OTSA) assesses more than 1500 mechanisms of action (target + actions). This approach exploits a highly curated training set of about 10 million compounds, with known in‐vitro activities, derived from patents, journals and internally installed external databases. To evaluate the tool, we used a panel of computational tools to predict both primary and secondary pharmacology for 1279 discontinued drug molecules. A total of 33,513 possible interactions were predicted for these drugs, of which 19,513 interactions (i.e. 15 interactions/compound) were associated with known safety warnings/issues at various levels. The top common safety associated off‐targets for these discontinued drugs are i) Adenosine receptor's ii) Opioid receptor's iii) PPAR's iv) PDE's v) Adrenoceptor's and vi) Potassium channel's. The computational OTSA's most often identified the right pharmacological targets, but also predicted a significant number of off‐targets that may be relevant to the observed in‐vivo effects.All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.