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The polarographic characteristics of several gibberellins have been determined and a method for determining gibberellic acid in the presence of gibberellenic acid proposed. Gibberellic acid was found to possess a characteristic prewave in addition to a larger proton reduction wave shown by all gibberellins. This prewave may be measured with an accuracy to ± 2 per cent within definite concentration limits. Average recoveries of gibberellic acid from a typical formulation measured by the method was 97 per cent. The main reduction wave was shown to be that of carboxyl proton but the prewave reduction mechanism is not yet clear.

As part of continuing study of alkaloid-bearing members of the family Apocynaceae , we have undertaken a detailed phytochemical investigation of the pantropical plant Vinca rosea Linn. (1). Twelve crystalline compounds have been obtained and characterized. Details of the procedure leading to the preparation of pure substances are described. Two of these alkaloids, leurosine and vincaleukoblastine, possess activity against P-1534 leukemia in mice.

Clinical usage of erythromycin 1 and propionyl erythromycin ester 2 has confirmed the low toxicity in experimental animals as reported from these laboratories. Propionyl erythromycin ester lauryl sulfate 3 (PELS) has been found to have very low water solubility and is easily usable in pleasantly flavored suspensions. Chronic toxicity studies in rats and dogs have demonstrated the absence of visceral or hematopoietic damage following large doses for over three months. Oral administration of PELS produced higher serum concentrations in rats than propionyl erythromycin. Both antibiotics are mainly absorbed from the intestine of rats and excreted in very small quantities in the bile. High concentrations of erythromycin activity were found in the lung, spleen, liver, kidney, and heart after oral administration. The results of absorption studies using S 35 labeled PELS will be discussed.

Pharmacological comparison of 1-phenyl-1,2,4-triazole (1-P) and 4-phenyl-1,2,4-triazole (4-P) revealed that these two-position isomers produce qualitatively opposite effects. In studies performed on intact unanesthetized mice and rats, 1-P caused depression and impairment of motor function, whereas 4-P caused excitation and clonic convulsions. Further experiments on anesthetized and spinal cats and on isolated tissue preparations suggested that both agents act at brain-stem level, and that neither triazole produces any direct peripheral autonomic effect. Investigation of interaction between isomers indicated that either compound was capable of antagonizing the action of the other.

Immediate type allergy deals with antibodies that are relatively self-contained molecules and which are frequently found in the blood serum. These antibodies account for the classical reactions of agglutination, complement fixation and so forth. Further, several investigators have shown that an appropriately timed course of whole body irradiation or of one of several cancer chemotherapeutic drugs may sometimes be arranged so as to inhibit antibody formation to first exposure to antigen (1, 2). For instance, a rabbit given high doses of 6-mercaptopurine and then injected with bovine serum albumin (BSA) fails to make anti-BSA antibody, whereas BSA injected control rabbits produce anti-BSA antibody of high titer (3).

The alkyl sulfate salts of various erythromycin 1 esters were prepared by esterification of erythromycin followed by a double decomposition salt formation. These compounds, and in particular propionyl erythromycin lauryl sulfate, are virtually tasteless and are unaffected by mixing with gastric acid. These properties render them very useful in the preparation of flavored suspensions.

Cycloserine may be determined in certain dosage forms by dilution in hydrochloric acid and measurement of the absorbance at 219 millimicrons. Combinations of cycloserine with isoniazid may be determined from a single dilution from absorbances at 219 and 272 millimicrons, respectively. In this and in other dosage forms, Values approaching the theoretical were obtained. The method requires no special apparatus and very little time. It shows good correlation with the microbiological method and is capable of following degradation in experimental preparations. The accuracy of the method is within ±2 per cent; its precision within ±1 per cent.

The presently used U. S. P. XV method for ethanol is compared with the gas chromatography method. Advantages and disadvantages of both methods are discussed. Typical results obtained by both procedures when applied to tinctures, fluidextracts, elixirs, and other products are compared. The results obtained from three gas chromatographs each having a different type thermal conductivity detector are presented. Three types of sample injectors are compared and five different stationary phases are examined.

A common disadvantage of methods for determining basic epoxides or epoxides in the presence of a base is the necessity for determining a blank correction. A fast, direct method based on reaction with a standard solution of sodium thiosulfate is presented. The excess sodium thiosulfate is titrated with standard iodine solution. No blank correction is necessary. The stoichiometry of the reaction, the effect of temperature on the rate of reaction, precision, and other factors are described.

The Lilly Research Award Program (LRAP) provides academic researchers worldwide with a gate to partner with Lilly internal scientists who are working on basic and applied research to collaboratively advance novel impactful projects. The pre-competitive nature of these projects is the most relevant feature as it permits the shared publication of the research outcomes immediately. In this article, this highly successful initiative is reviewed in the context of general academia-industry collaborations and the lessons learned from different shared projects, in the area of innovative continuous flow chemistry, will be discussed.

Background/Aims The preferential Janus kinase-1 inhibitor filgotinib (FIL) is approved to treat RA in Europe. We assessed FIL efficacy/safety in patients (pts) with inadequate response (IR) to biologic DMARDs (bDMARDs) in a long-term extension trial (LTE; NCT03025308) enrolled from a Phase 3 parent study (PS; NCT02873936). Methods bDMARD-IR pts received FIL 200mg (FIL200), 100mg (FIL100), or placebo (PBO) and stable conventional synthetic (cs)DMARDs up to 24 weeks (W). At W14 of the PS, pts with IR to FIL or PBO ( Results The PS included 147, 153, and 148 pts on FIL200, FIL100, and PBO. Of the FIL200 pts who entered LTE, 80/121 continued study drug at June 1, 2020, as did 76/110 FIL100 pts. Pts still on LTE FIL from PBO were 35/47 FIL200 and 32/46 FIL100 pts; from SOC: 13/23 FIL200 and 13/22 FIL100 pts. LTE baseline (BL) characteristics were similar in FIL200 and FIL100 pts (mean RA duration: 13.2 and 12.8 years, DAS28[CRP]: 3.5 and 3.7). During LTE, PS FIL ACR20/50/70 response rates decreased modestly by W48. Among PS PBO pts, response rates were lower at LTE BL but reached similar levels as PS FIL pts by W48; rates increased up to W48 in SOC/FIL pts (either dose) but not to levels of other groups. Percentages of pts attaining DAS28(CRP) ≤3.2, DAS28(CRP) Conclusion Efficacy was mostly maintained in PS FIL pts up to W48. Response among PS PBO and SOC pts increased from BL to W48, but response in PS SOC pts continued to be lower than in other groups; these pts may represent a refractory population. FIL safety was largely consistent between PS and LTE. Disclosure M. Buch: Honoraria; reports research support, consulting, speaker or personal fees from AbbVie; Eli Lilly and Co.; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sanofi; and UCB. Grants/research support; received funding (paid to her host institution) for research from Gilead Gilead Sciences, Inc. T. Takeuchi: Consultancies; serving as a consultant for Astellas, Chugai, and Eli Lilly Japan. Member of speakers’ bureau; Speaker’s bureau AbbVie, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe, Novartis, Pfizer Japan, Sanofi, and Dainippon Sumitomo. Grants/research support; reports receiving grant/research support from AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan. V. Rajendran: Shareholder/stock ownership; employee of and shareholder in Galapagos NV. J. Gottenberg: Consultancies; serving as a consultant for Bristol-Myers Squibb, Sanofi Genzyme, and UCB. Member of speakers’ bureau; serving on a speaker’s bureau for Gilead Sciences, Inc., Galapagos, AbbVie, Eli Lilly and Co., Roche, Sanofi Genzyme, and UCB. Grants/research support; reports receiving grant/research support from Bristol-Myers Squibb and Pfizer. A. Pechonkina: Other; employee of Gilead Sciences, Inc. and may own stock in Gilead Sciences, Inc. Y. Tan: Other; employee of Gilead Sciences, Inc. and may own stock in Gilead Sciences, Inc. Q. Gong: Other; employee of Gilead Sciences, Inc. and may own stock in Gilead Sciences, Inc. K. Van Beneden: Other; employee of and shareholder in Galapagos NV. R. Caporali: Honoraria; reports receiving speaker’s fees and consultation grants from AbbVie, BMS, Celltrion, Fresenius-Kabi, Gilead-Galapagos, Lilly, MSD, Pfizer, Roche, Samsung-Bioepis, Sanofi and UCB.

BackgroundThe preferential Janus kinase-1 inhibitor FIL significantly improved signs and symptoms of RA in Phase 2 and 3 trials.1–5 FIL is approved for treatment of moderate to severe active RA in Europe and Japan. Integrated safety analysis of FIL with patient data through 2019 was presented at the 2020 ACR virtual meeting.6ObjectivesTo report updated, as-treated data from the FIL integrated safety analysis with increased study drug exposure.MethodsData were integrated from 2 Phase 2 (NCT01668641, NCT01894516), 3 Phase 3 (NCT02889796, NCT02873936, NCT02886728), and 2 long-term extension (LTE) (NCT02065700, NCT03025308) trials. Phase 2 and 3 LTE data were through Nov 2020 and Jan 2021, respectively. The as-treated analysis set included all available data for pts receiving ≥1 dose FIL 200 (FIL200) or 100 mg (FIL100), including those rerandomized to FIL for LTE. Exposure-adjusted incidence rates (EAIR)/100 patient-y exposure (PYE) of treatment-emergent adverse events (TEAEs; onset after first dose and no later than 30 days after last dose or new drug first dose date −1 day) and TEAEs of special interest (AESIs) are presented.Results3691 pts received FIL200 or FIL100 for 8085.1 PYE (median 2.2, maximum 6.8 y). In the as-treated set, 61% of FIL200 and 45% of FIL100 pts received FIL for ≥2 y, 19% and 5% for ≥3 y, and 11% and 0.5% for ≥4.5 y, respectively. EAIR for TEAEs was higher with FIL100 than FIL200; EAIRs for deaths were 0.5 and 0.3 for FIL200 and FIL100 (Figure 1). Incidences of infections and serious infections were numerically greater for FIL100 vs FIL200, while EAIRs for other AESIs were comparable between doses (Table 1). EAIRs for AESIs tended to decrease since the previous update, except for venous thromboembolism (total FIL 0.1 to 0.2) and malignancies excluding NMSC (total FIL 0.5 to 0.6).Table 1.TEAEs of special interest, as-treated setTEAE, n (%) and EAIR per 100 PYE (95% CI)FIL 200 mgn=2267PYE=5302.5FIL 100 mgn=1647PYE=2782.6Total FILN=3691PYE=8085.1Infectious AEs1206 (53.2)747 (45.4)1927 (52.2)EAIR21.1 (19.7, 22.5)30.2 (26.8, 34.0)21.0 (19.9, 22.3)Serious infectious AEs80 (3.5)57 (3.5)137 (3.7)EAIR1.5 (1.1, 1.9)2.7 (1.9, 3.9)1.6 (1.3, 2.0)Opportunistic infections5 (0.2)4 (0.2)9 (0.2)EAIR0.1 (0, 0.2)*0.1 (0.1, 0.4)*0.1 (0.1, 0.2)*Active tuberculosis03 (0.2)3 (EAIR00.1 (0, 0.3)*0 (0, 0.1)*Herpes zoster84 (3.7)30 (1.8)114 (3.1)EAIR1.6 (1.2, 2.0)1.1 (0.8, 1.5)*1.4 (1.1, 1.7)Major adverse cardiovascular eventsa19 (0.8)14 (0.9)33 (0.9)EAIR0.3 (0.2, 0.5)0.5 (0.3, 0.8)*0.4 (0.2, 0.6)Venous thromboembolismb11 (0.5)4 (0.2)15 (0.4)EAIR0.2 (0.1, 0.4)*0.1 (0.1, 0.4)*0.2 (0.1, 0.3)*Atrial systemic thrombotic eventsa1 (1 (2 (EAIR0 (0, 0.1)0 (0, 0.3)0 (0, 0.1)Malignancy excluding NMSC32 (1.4)17 (1.0)49 (1.3)EAIR0.6 (0.4, 0.9)0.6 (0.4, 1.0)*0.6 (0.4, 0.8)NMSC15 (0.7)5 (0.3)20 (0.5)EAIR0.3 (0.2, 0.5)*0.2 (0.1, 0.4)*0.2 (0.2, 0.4)*Gastrointestinal perforations3 (0.1)1 (4 (0.1)EAIR0.1 (0, 0.2)*0 (0, 0.3)*0 (0, 0.1)**Except when any study had 0 event within the treatment, the Poisson model was not adjusted by study. PYE was defined as (last dose date − first dose date + 1)/365.25.aPositively adjudicated.bAdjudicated as deep vein thrombosis or pulmonary embolism.NMSC, nonmelanoma skin cancerConclusionWith 1 additional year of exposure since the 2020 report, FIL continues to be well tolerated with no new safety concerns emerging. EAIRs of TEAEs, including deaths, and AESIs remained stable or decreased since the 2020 report, except for slight increases in rates of NMSC and malignancies excluding NMSC. In the context of demonstrated efficacy, both FIL doses had an acceptable risk/benefit profile.References[1]Westhovens R et al. Ann Rheum Dis 2017;76:998–1008.[2]Kavanaugh A et al. Ann Rheum Dis 2017;76:1009–19.[3]Combe B et al. Ann Rheum Dis 2021;80:848–58.[4]Genovese MC et al. JAMA 2019;322:315–25.[5]Westhovens R et al. Ann Rheum Dis 2021;80:727–38.[6]Winthrop K et al. Arthritis Rheumatol 2020;72(suppl 10); abstract 0229.AcknowledgementsFunding for DARWIN 1 and 2 was provided by Galapagos NV, and funding for DARWIN 3, FINCH 1, 2, 3, and 4 was provided by Gilead Sciences, Inc., Foster City, CA. Funding for this analysis was provided by Gilead Sciences, Inc. The sponsors participated in the planning, execution, and interpretation of the research. Medical writing support was provided by Gregory Bezkorovainy, MA, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA.Disclosure of InterestsKevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, Roche, Regeneron, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, and Pfizer, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol Myers Squibb, Eisai, Chugai, AbbVie, Astellas, Pfizer, Sanofi, Asahi-Kasei, GSK, Mitsubishi-Tanabe, Gilead Sciences, Inc., and Janssen, Consultant of: AbbVie, Ayumi, Daiichi-Sankyo, Eli Lilly, GSK, Taisho, and Sanofi, Grant/research support from: AbbVie, Asahi-Kasei, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, and Takeda, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Mitsubishi-Tanabe, Novartis, Pfizer Japan, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly Japan, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan, Alan Kivitz Shareholder of: Amgen, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, and Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead Sciences, Inc., Janssen, Novartis, Pfizer, Regeneron, Sanofi, and SUN Pharma Advanced Research, Mark C. Genovese Shareholder of: Gilead Sciences, Inc., Consultant of: AbbVie, Amgen, Beigene, Eli Lilly and Co., Genentech, Inc., Gilead Sciences, Inc., Sanofi Genzyme, RPharm, and SetPoint, Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Kun Chen Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos BV, Employee of: Galapagos BV, Sander Strengholt Shareholder of: Galapagos BV, Employee of: Galapagos BV, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer, Consultant of: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer, Jacques-Eric Gottenberg Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos BV, Gilead Sciences, Inc., Roche, Sanofi Genzyme, and UCB, Consultant of: Bristol Myers Squibb, Sanofi Genzyme, and UCB, Grant/research support from: Bristol Myers Squibb and Pfizer

BackgroundOverweight and obesity are associated with greater incidence and progression of the structural defects of knee osteoarthritis, but it is unknown if weight loss is of benefit.ObjectivesTo describe the association between change in body mass index (BMI) and the incidence and progression of structural defects in knee osteoarthritis.MethodsScores from radiographic analyses of knees at baseline and at 4 to 5 years’ follow up were obtained from three independent data sets (the OAI and MOST data sets from the United States from America, and the CHECK data set from the Netherlands). The exposure of interest was change in BMI from baseline to 4 to 5 years’ follow up. To investigate the incidence of structural defects of knee osteoarthritis, we selected a total of 9732 knees (from 5802 participants) that had a Kellgren-Lawrence (KL) grade of knee osteoarthritis at baseline of ‘none’ (0) or ‘doubtful’ (1) (the ‘incidence cohort’), and determined the odds of having a KL grade at follow-up of ‘minimal’ (2), ‘moderate’ (3), or ‘severe’ (4). To investigate progression, we selected a total of 6084 knees (from 3996 participants) that had a KL grade at baseline of ‘minimal’ (2), ‘moderate’ (3), or ‘severe’ (4) (the ‘progression cohort’), and determined the odds of increasing by 1 or more KL grades by follow up. The degradation of three individual structural features of knee osteoarthritis (i.e., joint space narrowing, osteophytes on the femoral surface, and osteophytes on the tibial surface), on both the medial and lateral sides of the knee, were also investigated in both the incidence and progression cohorts. Here, degradation was defined as an increase by 1 or more Osteoarthritis Research Society International (OARSI) grades.ResultsChange in BMI was positively associated with both the incidence and progression of knee osteoarthritis, as defined by KL grade. Specifically, for each one-unit change in BMI, the adjusted odds ratio for incidence was 1.05 (95% confidence interval [CI] 1.02 to 1.09), and for progression, the same adjusted odds ratio and 95% CI was also observed. Change in BMI was also positively associated with degradation (i.e., narrowing) of joint space on the medial but not the lateral side of the knee, with an adjusted odds ratio of 1.08 (95% CI 1.04 to 1.12) in the ‘incidence cohort’ and 1.08 (95% CI 1.03 to 1.12) in the ‘progression cohort’. Degradation of the tibial and femoral surfaces (i.e., osteophytes) was also seen on the medial but not the lateral side of the knee, but only in one of the two cohorts investigated (the ‘incidence cohort’), with an adjusted odds ratio of 1.07 (95% CI 1.03 to 1.12) for osteophytes on the femoral surface, and 1.05 (95% CI 1.01 to 1.09) for osteophytes on the tibial surface.ConclusionEach one-unit reduction in BMI is associated with a 5 to 8% decrease in the odds of the incidence and progression of the structural defects of knee osteoarthritis, with lower odds of structural degradation specific to the medial – not lateral – side of the knee.AcknowledgementsWe acknowledge the provision of datasets and/or research tools from three studies: the Osteoarthritis Initiative (OAI) Study; the Multicenter Osteoarthritis Study (MOST); and the Cohort Hip and Cohort Knee (CHECK) Study.OAI is a collaborative informatics system created by the National Institute of Mental Health and the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) to provide a worldwide resource to quicken the pace of biomarker identification, scientific investigation and OA drug development. The OAI data repository is housed within the National Institute of Mental Health (NIMH) Data Archive (NDA).For the MOST data set, we wish to acknowledge the contributions of the study participants, investigators and research staff involved. MOST is comprised of four (4) cooperative grants: U01 AG18820 David T. Felson (Boston University); U01 AG18832 James Torner (University of Iowa); U01 AG18947 Cora E. Lewis (University of Alabama at Birmingham); U01 AG19069 Michael C. Nevitt (University of California, San Francisco), funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by MOST investigators. This manuscript was prepared using MOST data and does not claim, infer, or imply endorsement by MOST, by the MOST investigators and their respective institutions or by the University of California of the Data Recipients’ use of the Data, of the entity or personnel conducting the research, or of any results of the research.The CHECK study is funded by the Dutch Arthritis Foundation. Involved are: Erasmus Medical Center Rotterdam; Kennemer Gasthuis Haarlem; Leiden University Medical Center; Maastricht University Medical Center; Martini Hospital Groningen /Allied Health Care Center for Rheumatology and Rehabilitation Groningen; Medical Spectrum Twente Enschede /Ziekenhuisgroep Twente Almelo; Reade Center for Rehabilitation and Rheumatology; St.Maartens-kliniek Nijmegen; University Medical Center Utrecht and Wilhelmina Hospital Assen.Disclosure of InterestsZubeyir Salis: None declared, Helen Keen: None declared, Blanca Gallego: None declared, Tuan van Nguyen: None declared, Amanda Sainsbury Speakers bureau: ZS and AS own 50% each of the shares in Zuman International, which receives royalties for books AS has written and payments for presentations, and provides paid training for higher degree students. AS additionally reports receiving presentation fees and travel reimbursements from Eli Lilly and Co, the Pharmacy Guild of Australia, Novo Nordisk, the Dietitians Association of Australia, Shoalhaven Family Medical Centres, the Pharmaceutical Society of Australia, and Metagenics, and serving on the Nestlé Health Science Optifast VLCD advisory board from 2016 to 2018., Consultant of: ZS and AS own 50% each of the shares in Zuman International, which receives royalties for books AS has written and payments for presentations, and provides paid training for higher degree students. AS additionally reports receiving presentation fees and travel reimbursements from Eli Lilly and Co, the Pharmacy Guild of Australia, Novo Nordisk, the Dietitians Association of Australia, Shoalhaven Family Medical Centres, the Pharmaceutical Society of Australia, and Metagenics, and serving on the Nestlé Health Science Optifast VLCD advisory board from 2016 to 2018.

Background Filgotinib (FIL) is an oral, selective janus kinase 1 inhibitor under development for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. Safety and efficacy of FIL was investigated in the FINCH clinical program, which includes three Phase 3, summarized, summarized studies in patients with moderate to severely active RA. FINCH1: patients with inadequate response to MTX (NCT02889796); FINCH2: patients receiving conventional disease-modifying antirheumatic drugs (csDMARDs) with inadequate response to biological DMARDs (NCT02873936); FINCH3: MTX-naïve patients initiating MTX ± FIL, or receiving FIL monotherapy (NCT02886728). We present pooled safety data up to 24 weeks (W24). Methods The FINCH studies enrolled patients with RA (2010 ACR/EULAR criteria), ≥6 swollen joints and ≥6 tender joints at screening and Day 1. Safety analyses included patients receiving ≥1 dose of study drug. Patients in FINCH 1 and 2 who did not experience at least a 20% improvement in both swollen joint count and tender joint count by W14 discontinued study drug and switched to standard of care. W24 safety data from all studies were aggregated and ummarized. Key safety endpoints were treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of interest, deaths and treatment-emergent laboratory abnormalities. Results 3,452 patients were evaluated; 2,088 received FIL. At W24, the frequency of TEAEs and TEAEs of interest were similar for those who received FIL and those in the control groups (Table 1). Most TEAEs were infections. Laboratory abnormality rates were similar between FIL and control groups, and were mild to moderate (grades 1 and 2). Overall, the frequency of major adverse cardiac events, herpes zoster virus, deep vein thrombosis and pulmonary embolism was low, and similar across groups. Conclusion Pooled data from this large database highlights the favourable safety and tolerability profile of FIL in patients with RA both as monotherapy and in combination with MTX/csDMARD. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. K. Winthrop: Grants/research support; Received grants for clinical research from Bristol-Myers Squibb Company and Insmed Incorporated. Other; Received support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly & Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi, and UCB. M.C. Genovese: Other; Gilead Sciences Inc., Galapagos NV, AbbVie Inc. Eli Lilly and Company, Pfizer. B.G. Combe: Honoraria; Honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. Y. Tanaka: Honoraria; Received from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly and Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Received grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, and Ono. A. Kivitiz: Consultancies; Consultant for AbbVie, Celgene, Horizon, Janssen, Merck, Novartis, Pfizer, UCB, Genzyme,Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim and Flexion. Shareholder/stock ownership; Shareholder of Novartis. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Gilead Sciences, Inc. Shareholder/stock ownership; Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. E. Keystone: Consultancies; AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer, PuraPharm, Sandoz,, Sanofi-Aventis, Sanofi- Genzyme Samsung Bioepsis, and UCB. Other; AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer, PuraPharm, Sandoz,, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. R. Westhovens: Corporate appointments; An investigator and advisor for Celltrion and Galapagos/Gilead. W. Rigby: Consultancies; Consultancy for Gilead. G.R. Burmester: Consultancies; Consultancy from AbbVie, Gilead, Eli Lilly, and Pfizer. Honoraria; Honoraria from AbbVie, Gilead, Eli Lilly, and Pfizer.

Background Filgotinib (FIL) is an oral, potent, selective Janus kinase 1 inhibitor that has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objective of this study was to evaluate efficacy and safety of FIL treatment in patients with RA who have had an inadequate response to methotrexate (MTX). Methods This Phase 3, double-blind, active- and placebo (PBO)-controlled study randomised patients with active RA (3:3:2:3) to FIL 200mg, FIL 100mg, adalimumab [ADA] 40mg every 2 weeks, or PBO daily for up to 52 weeks; results through week 24 are presented. Patients also received background MTX. Primary efficacy endpoint was proportion of patients achieving ACR20 at week 12; additional clinical assessments included ACR50 and ACR70 and DAS28-CRP score ≤3.2 and 50% of ADA response) was performed for DAS28-CRP ≤3.2 and Results Of 1,759 patients randomised, 1,755 received study drug: 475 FIL 200mg; 480 FIL 100mg; 325 ADA; and 475 PBO, of which 89.5%, 90.4%, 88.9%, and 81.3%, respectively, completed 24 weeks of study drug. 81.8% were female, mean (standard deviation [SD]) duration of RA was 7.8 (7.6) years, and mean (SD) DAS28-CRP was 5.7 (0.9). At week 12, significantly more patients in the FIL 200mg and 100mg arms achieved an ACR20 improvement vs PBO (Table 1). More patients receiving FIL achieved ACR50 and ACR70 improvements, DAS28-CRP scores ≤3.2 and Conclusion FIL 200mg and 100mg led to significant improvement in signs and symptoms of RA, prevented radiographic progression, improved physical function compared to PBO, and was well-tolerated. Efficacy of FIL 200mg was non-inferior to ADA based on DAS28-CRP ≤3.2. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. B.G. Combe: Honoraria; Received honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. A.J. Kivitiz: Consultancies; Consultant to AbbVie, Celgene, Horizon, Jansses, Merck, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim, Flexion and Novartis. Shareholder/stock ownership; Shareholder of Novartis. Y. Tanaka: Honoraria; Honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly ans Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, Ono, Astellas, Eli Lilly, Pfizer, Abbvi and YL. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc.. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB.. S. Bae: None. E.C. Keystone: Consultancies; Consultant for AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer,, PuraPharm, Sandoz, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. P. Nash: Consultancies; Consultant for AbbVie, BMS, Jansses, Pfizer, Roche, Lilly, Sanofi, MSD, Novartis, Celgene and Gilead.

Background:EULAR and ACR guidelines recommend a treat-to-target approach for rheumatoid arthritis (RA). For patients failing their first conventional synthetic disease-modifying antirheumatic drug (csDMARD), EULAR recommends switching to or adding another DMARD. Understanding treatment patterns, durability, and healthcare costs associated with treatments initiated after first csDMARD can help optimize treatment for these patients.Objectives:To describe real-world healthcare costs among patients with RA who failed their first csDMARD.Methods:The study included adults with ≥2 RA claims ≥30 days apart in a large US health claims database, who started a csDMARD regimen as the first DMARD then switched to or added another DMARD (index date [ID], 1/1/2012–3/31/2017). All patients had continuous enrollment 1-year before and ≥1 year after ID. Treatment duration was defined as number of days from initial treatment fill until loss of treatment persistence. Unadjusted mean total annualized per-patient-per-year (PPPY) healthcare costs while on treatment were compared via analysis of variance. A generalized linear model with gamma distribution and log link was used to compare total costs adjusted for pre-index costs, patient characteristics, and type of initiated treatment.Results:The study involved 7,816 patients (median age of 54 yrs, 74% female). Mean (standard deviation) duration of index therapy was 14.0 (12.6) months for patients overall (9.2 [10.1] for monotherapy vs 16.9 [13.1] for combination therapy,P< .0001).Prior to switching, the unadjusted mean PPPY healthcare costs totaled $12,923: $13,923 for monotherapy vs $12,317 (P= .0009) for combination therapy. Once switched, patients accrued unadjusted mean PPPY on-treatment healthcare costs of $30,742: $28,757 on monotherapy vs $31,943 (P= .0003) on combination therapy. Figure 1 details pre- and post-ID unadjusted costs by index therapy.Patients on non-TNFi bDMARD monotherapy had higher adjusted total healthcare cost (cost ratio [CR] = 1.58,P= .0052) than the total cost on JAKi monotherapy, whereas csDMARD monotherapy (CR = 0.28,P< .0001) and csDMARD + csDMARD(s) (CR = 0.26,P< .0001) had lower total cost than the cost on JAKi monotherapy. Other factors impacting costs included baseline Charlson Comorbidity Index (CCI) = 2 or ≥3 vs CCI = 1 (CR = 1.14 and 1.25, respectively; bothP< .0001), baseline total (medical + pharmacy) healthcare costs (CR = 1.24,P< .0001), and baseline opioid use (CR = 1.11,P< .0001, Figure 2).Conclusion:Real-world data demonstrate short durability of available treatments initiated after first csDMARD. Among the initiated treatments, lowest total healthcare costs were associated with csDMARD, followed by JAKi, then TNFi, and finally non-TNFi bDMARD.Disclosure of Interests:Robin K Dore Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Jenya Antonova Employee of: Gilead Sciences. Inc., Lawrence Chang Consultant of: Gilead Sciences, Inc., Magdaliz Gorritz Consultant of: Gilead Sciences, Inc., Xin Wang Consultant of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:EULAR and ACR guidelines recommend a variety of treatment options for rheumatoid arthritis (RA) patients who failed a first conventional synthetic disease-modifying antirheumatic drug (csDMARD). The recent launches of Janus kinase inhibitors (JAKi) have stimulated interest in comorbidities such as malignancy, venous thromboembolism (VTE: deep vein thrombosis [DVT] or pulmonary embolism [PE]), anemia, and infections in patients with RA. Understanding the epidemiology of these conditions can help optimize treatment decisions within the treat-to-target approach following the first csDMARD.Objectives:Estimate the real-world prevalence, incidence, and costs of these comorbidities among patients switching from a first csDMARD to another DMARD.Methods:From a large US health claims database, the study selected adults with RA (≥2 RA claims ≥30 days apart) who started a csDMARD regimen as first DMARD, then switched (index date [ID], 1/1/2012–3/31/2017) to another DMARD regimen (monotherapy or combination with csDMARD). All patients had continuous enrollment 1 year before and ≥1 year after the ID. The study estimated baseline prevalence (%) and on-treatment incidence (per 100 patient-years [P100PY]) of malignancy, VTE, anemia, and infections (any, serious, opportunistic, and herpes zoster). Generalized linear models with gamma distribution and log link function estimated the impact of baseline characteristics on mean annualized healthcare costs per-patient-per-year (PPPY) associated with incident conditions. The recycled prediction method calculated adjusted total costs differences of these conditions.Results:Among study patients (N = 7,816, median age 54 yrs, 74% female), the 38% on monotherapy index treatments had mean (standard deviation) treatment duration 9.2 (10.1) mo and the 52% on combination therapies had treatment duration 16.9 (13.0) mo.Baseline prevalence was 1.5% for VTE, 1.3% for malignancy, 15.6% for anemia, and 71.0% for infection (Figure 1). During next treatment, the incidence rates (P100PY) were: 0.7 for VTE, 2.1 for malignancy, 7.8 for anemia and 79.4 for infection (Figure 1).Modeling showed that total healthcare cost more than doubled for RA patients with vs without incident occurrence of malignancy (2.9), followed by PE (2.7) and DVT (2.1) (P< .0001) (Figure 2). Total PPPY adjusted healthcare costs were higher in patients with vs without incident conditions: DVT $60,430 vs $28,927, PE $77,942 vs $29,000, malignancy $81,779 vs $28,565, anemia $50,097 vs $26,959, and infection $32,431 vs $22,774, including serious infections $52,935 vs $26,723, opportunistic infections $39,239 vs $28,947, and herpes zoster $30,638 vs $29,515.Conclusion:In the real world, RA patients were affected by VTE, malignancy, anemia and infections prior to switching from first csDMARD to the next treatment. While on the next treatment, patients developed new cases of these comorbidities, most of which were associated with increased adjusted total healthcare costs. Clinicians should account for the burden of these comorbidities in selecting treatments for RA patients who failed their first csDMARD.Disclosure of Interests:Robin K Dore Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Jenya Antonova Employee of: Gilead Sciences. Inc., Lawrence Chang Consultant of: Gilead Sciences, Inc., Huan Huang Consultant of: Gilead Sciences, Inc., Hyunchung Kim Consultant of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Altres ajuts: VR has served on the speakers for Eli Lilly, Rubio, and Shire in the last 5 years. She has received travel awards from Eli Lilly and Co. and Shire for participating in psychiatric meetings. The ADHD Program has received unrestricted educational and research support from Eli Lilly and Co., Janssen-Cilag, Shire, Rovi, Psious, and Laboratorios Rubió in the past 2 years. MC received travel awards for taking part in psychiatric meetings from Shire. CF received travel awards for taking part in psychiatric meetings from Shire and Lundbeck. GEM received travel awards for taking part in psychiatric meetings from Shire. EJSS-B received speaker fees, consultancy, research funding, and conference support from Shire Pharma. Consultancy from Neurotech Solutions, Copenhagen University and Berhanderling, Skolerne & KU Leuven. Book royalties from OUP and Jessica Kingsley. Financial support-Arhus University and Ghent University for visiting Professorship. Editor-in-Chief JCPP-supported by a buy-out of time to University of Southampton and personal Honorarium. King's College London received payments for work conducted by PA: consultancy for Shire, Eli Lilly, Novartis, and Lundbeck; educational and/or research awards from Shire, Eli Lilly, Novartis, Vifor Pharma, GW Pharma, and QbTech; speaker at events sponsored by Shire, Eli Lilly, Janssen-Cilag, and Novartis. JKB has been in the past 3 years a consultant to/member of advisory board of and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. In the past year, SVF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, Enzymotec, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults.com. JK has given talks at educational events sponsored by Medice; all funds are received by King's College London and used for studies of ADHD. HL has served as a speaker for Evolan Pharma and Shire and has received research grants from Shire; all outside the submitted work. K-PL served as a speaker for Eli Lilly and received research support from Medice, and travel support from Shire, all outside the submitted work. LAR reported receiving honoraria, serving on the speakers' bureau/advisory board, and/or acting as a consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years; receiving authorship royalties from Oxford Press and ArtMed; and receiving travel awards from Shire for his participation in the 2015 WFADHD meetings and from Novartis to take part of the 2016 AACAP meeting. The ADHD and juvenile bipolar disorder outpatient programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Janssen-Cilag, Novartis, and Shire. MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. BF has received educational speaking fees from Medice and Shire. JAR-Q was on the speakers' bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. The other authors have nothing to disclose. All members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. Authors of the ADHD Working group of the PGC that participated in this study: Catharina A. Hartman, Ziarih Hawi, Jennifer Crosbie, Sandra Loo, Josephine Elia, Russell Schachar, Christie Burton, Ted Reichborn-Kjennerud, Aribert Rothenberger, Søren Dalsgaard, Irwin Waldman, Mark Bellgrove, Hakon Hakonarson, Johannes Hebebrand, Anke Hinney, and Robert Oades have nothing to disclose. Joseph Biederman 2019-2020: he received research support from Genentech, Headspace Inc., Lundbeck AS, Neurocentria Inc, Pfizer Pharmaceuticals, Roche TCRC Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., and Tris. He was a consultant for Akili, Avekshan, Jazz Pharma, and Shire/Takeda. Through MGH CTNI, he participated in a scientific advisory board for Supernus. Dr Biederman's program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Tobias Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. James McGough is an expert testimony for Eli Lilly; DSMB for Sunovion. Benjamin Neale is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. Ole Andreas Andreassen received speaker's honorarium from Lundbeck, and is a consultant for HealthLytix. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 602805 (Aggressotype) as well as from the European Union H2020 Programme (H2020/2014-2020). The work was also supported by the ECNP Network "ADHD across the Lifespan" (https://www.ecnp.eu/research-innovation/ECNP-networks/List-ECNP-Networks/ADHD.aspx). Over the course of this investigation, PR is a recipient of a pre-doctoral fellowship from the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain. The iPSYCH project is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724) and the universities, and university hospitals of Aarhus and Copenhagen. ADB and NRM's work is also supported by the EU's Horizon 2020 programme. Data handling and analysis was supported by NIMH (1U01MH109514-01 to Michael O'Donovan and ADB). CSM is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain. K-PL and his team are supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/A5, no. 44541416), ERA-Net NEURON/RESPOND, no. 01EW1602B, ERA-Net NEURON/DECODE, no. 01EW1902, and 5-100 Russian Academic Excellence Project. JH thanks Stiftelsen K.G. Jebsen, University of Bergen, the Western Norwegian Health Authorities (Helse Vest). HL thanks the Swedish research council. BC received financial support from the Spanish "Ministerio de Economía y Competitividad" and AGAUR. MSA is a recipient of a contract from the Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain. MR is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain. The research leading to these results has received funding from the Instituto de Salud Carlos III , and cofinanced by the European Regional Development Fund (ERDF), from the Pla estratègic de recerca i innovació en salut (PERIS); Generalitat de Catalunya, from "la Marató de TV3" (092330/31) and from the Agència de Gestió d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya. ES's work is supported by a personal Hypatia grant from the Radboud University Medical Center. MH received a Veni grant from of the Netherlands Organization for Scientific Research (NWO, grant number 91619115). The NeuroIMAGE study was supported by NIH Grant R01MH62873 (to SVF), NWO Large Investment Grant 1750102007010 (to JKB), ZonMW grant 60-60600-97-193, NWO grants 056-13-015 and 433-09-242, and matching grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and Vrije Universiteit Amsterdam. Organization for Scientific Research (NWO; grant 016-130-669). BF and MK's work is supported by the Dutch National Science Agenda (NWA) for the NeurolabNL project (grant 400-17-602). This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. BF received additional funding from a personal Vici grant of the Dutch. Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Background:Symptomatic osteoarthritis (OA) leads to functional limitations and loss of independence. OA management focuses on pain relief and preserving physical function using non-pharmacologic and pharmacologic therapy. Additionally, patients commonly manage OA pain by avoiding activities that exacerbate their pain. Informal care, i.e. assistance from an unpaid caregiver, plays a major role in the total care provided to patients with chronic diseases like OA.Objectives:To evaluate how OA pain severity affects physical functioning and the subsequent need for assistance with mobility and daily activities in 5 EU countries: France, Germany, Italy, Spain and UK.Methods:Data were drawn from the Adelphi OA Disease Specific Programme (2017-18), a point-in-time study of physicians and their OA patients. Patients rated their average pain intensity over the last week on a 0-10 scale (0 = no pain; 10 = worst possible pain) and were then categorised into mild (0-3), moderate (4-6) and severe (7-10) pain groups. Patients also provided an assessment of their physical function (0-10 WOMAC scale where higher scores indicated greater functional impairment), impact on mobility, whether caregiver assistance was required, daily activities requiring caregiver assistance and home modifications made due to their OA. Physicians also rated patients’ functioning on a 0 to 10 scale (0 = fully functional; 10 = completely impaired). Comparisons among pain severity groups were made using chi-squared tests and analysis of variance.Results:The analysis included 1750 OA patients: 24% mild pain (n=413); 47% moderate pain (n=822); 29% severe pain (n=515). The patients were predominantly women (58%) and had a mean (SD) age of 65.6 (11.5).Increased pain severity was associated with greater functional impairment scores as reported by patients (WOMAC scores: mild pain=2.1; moderate pain=4.1; severe pain=5.9) and physician-rated functional impairment (mild pain=3.5; moderate pain=4.3; severe pain=5.6). Mobility was impacted for 78% of patients with severe pain (vs. 41% mild; 63% moderate) and the need for a walking aid such as a walking stick or walking frame increased with worsening severity; wheelchair assistance was needed for 7% of severe patients (compared with The need for assistance from a caregiver to help with daily activities was associated with an increase in patients’ pain (9% mild; 20% moderate; 42% severe [pConclusion:In this study of European patients, increased pain severity was associated with greater functional impairment and impact on mobility as expected; however, this study highlights the substantial need for assistance with daily activities as well as modifications to the home. The unseen costs to the patient with moderate to severe OA pain are significant.Disclosure of Interests:Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Lucy Abraham Shareholder of: Pfizer, Employee of: Pfizer, Peita Graham-Clarke Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Beck Shareholder of: Pfizer, Employee of: Pfizer, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Niall Hatchell: None declared, Emily Clayton: None declared, James Jackson: None declared

Background:Joint pain is the most prevalent symptom for sufferers of osteoarthritis (OA). Pharmacological management of OA is restricted by limited efficacy and considerable toxicity, with growing fears about opioid use.Objectives:To understand the current real-world prescribed drug treatment paradigm related to OA disease severity for patients in 5 EU countries; France, Germany, Italy, Spain and the UK.Methods:Data were drawn from the Adelphi OA Disease Specific Programme (2017-18), a point-in-time study of physicians and their patients. Physicians classified their patients as currently having mild, moderate or severe disease severity, and provided details on currently prescribed OA therapy and physician satisfaction with therapy, rated from very satisfied to very dissatisfied. Patients were excluded from these analyses if they suffered from back and neck OA only, and shoulder OA that had not been diagnosed by X-ray. Comparisons among disease severity groups were made using analysis of variance and chi-squared tests.Results:The study included 489 physicians (primary care physicians, rheumatologists, orthopaedists) reporting on 3596 of their OA patients: 24% mild (n=874), 53% moderate (n=1904), and 23% severe (n=818). Overall, 73% patients were prescribed at least one drug for their OA (65% of mild; 76% of moderate; 77% of severe patients [Table 1.Prescribed treatment by physician-reported OA severityMild(n=874)Moderate(n=1904)Severe(n=818)Current class of medication prescribed for OA, n (%)Paracetamol186 (21.3)663 (34.8)313 (38.3)NSAIDs267 (30.5)605 (31.8)237 (29.0)Any opioid93 (10.6)501 (26.3)386 (47.2)Weak opioid82 (9.4)407 (21.4)255 (31.2)Strong opioid11 (1.3)99 (5.2)146 (17.8)Opioid + analgesic (combined)6 (0.7)15 (0.8)7 (0.9)Corticosteroid31 (3.5)150 (7.9)92 (11.2)Glycosaminoglycan50 (5.7)149 (7.8)62 (7.6)Viscosupplement12 (1.4)93 (4.9)42 (5.1)Number of currently prescribed drug classes, mean (SD)0.9 (0.8)1.4 (1.1)1.6 (1.2)Conclusion:Physicians reported decreasing satisfaction with treatment for their OA patients as disease severity increased, despite increasing use of opioids and numbers of classes of prescribed drugs.Disclosure of Interests:Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Lucy Abraham Shareholder of: Pfizer, Employee of: Pfizer, Peita Graham-Clarke Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Beck Shareholder of: Pfizer, Employee of: Pfizer, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Niall Hatchell: None declared, Emily Clayton: None declared, James Jackson: None declared

Background:Osteoarthritis (OA) is a chronic joint disease associated with pain and impaired activity. With increasing obesity trends and an ageing population, the prevalence of OA is expected to rise in the future. This represents an increasing societal problem which will lead to an increased burden on healthcare services.Objectives:To understand the pattern of healthcare resource utilisation (HCRU) across France, Germany, Italy, Spain and the UK, as OA disease severity increases.Methods:Data were drawn from the Adelphi OA Disease Specific Programme (2017-18), a point-in-time study of physicians and their OA patients. OA disease severity was reported by physicians, who categorised patients’ OA severity as mild, moderate or severe. Patients were excluded from the analyses if they suffered from back and neck OA only, and shoulder OA that had not been diagnosed by X-ray. Physicians provided information, on a patient record form, about OA-related visits to healthcare professionals (HCPs), tests/scans conducted, emergency room (ER) visits and surgeries. Statistical comparisons among disease severity groups were made by analysis of variance and chi-squared tests.Results:The study included 489 physicians (primary care physicians, rheumatologists, orthopaedists) reporting on 3596 of their patients with OA: 24% mild (n=874), 53% moderate (n=1904) and 23% severe (n=818). Over the last 12 months, the mean number of consultations with HCPs increased with disease severity (3.7 mild, 4.2 moderate and 5.7 severe [Table 1.Physician-reported healthcare burden by OA disease severityMild(n=874)Moderate(n=1904)Severe(n=818)Number of patient visits to ER in the last 12 months, mean (SD)0.1 (0.4)0.1 (0.6)0.5 (1.0)Patients with ≥1 emergency visit in the last 12 months, n (%)13 (1.5)43 (2.3)79 (9.7)Patients with ≥1 hospitalisation in the last 12 months, n (%)11 (0.1)9 (0.5)26 (3.2)Number of patient outpatient hospital visits in the last 12 months, mean (SD)0.5 (1.4)0.6 (1.1)1.2 (1.4)Conclusion:This real-world data demonstrated an increase in visits to HCPs, monitoring tests and scans, hospitalisations, ER visits and surgery as OA disease severity worsened.Disclosure of Interests:Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Lucy Abraham Shareholder of: Pfizer, Employee of: Pfizer, Peita Graham-Clarke Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Beck Shareholder of: Pfizer, Employee of: Pfizer, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Niall Hatchell: None declared, Emily Clayton: None declared, James Jackson: None declared

Background:EULAR and ACR guidelines recommend a treat-to-target approach for patients with RA including regular assessments of disease activity. Glucocorticoids are commonly used to control inflammation associated with uncontrolled disease. However, patients using glucocorticoids may develop short- and long-term side effects.Objectives:To examine the real-world use of glucocorticoids among patients with RA who are disease-modifying antirheumatic drug (DMARD)-naïve or failing their first conventional synthetic DMARD (csDMARD) or biologic DMARD (bDMARD).Methods:From a large US health claims database, this study included adults with ≥2 RA claims ≥30 days apart who started (index date [ID], 1/1/2012–3/31/2017) a first DMARD (DMARD-naïve) or patients who newly initiated a csDMARD and then switched to or added another DMARD (csDMARD switchers), and patients who initiated a first bDMARD and then switched to another bDMARD or Janus kinase inhibitor (JAKi; bDMARD switchers). All patients had continuous enrollment 1-year before and ≥1 year after ID and were evaluated for pre- and post-ID use of glucocorticoids (oral or injectable), prednisone equivalent dose (PED), and duration of exposure ≥30 days.Results:The study included 28,201 patients in the DMARD-naïve cohort, 7,816 csDMARD switchers, and 4,656 bDMARD switchers (median age 54 years for all, 73%–78% female).Among DMARD-naïve patients, 66.5% used glucocorticoids during the pre-ID period (Figure 1) and 61.2% had >7.5 mg/day PED, 21.2% had >30 mg/day PED, and 21.2% had ≥30 days of exposure to glucocorticoids (Figure 2). Post-ID, 69.4% of patients used glucocorticoids, while 54.7% had >7.5 mg/day PED, 13.5% had >30 mg/day PED, and 44.9% had ≥30 days of exposure to glucocorticoids.Among csDMARD switchers, 84.5% of patients used glucocorticoids during the pre-ID period (Figure 1), and 73.4% had >7.5 mg/day PED, 16.0% had >30 mg/day PED, and 56.4% had ≥30 days of exposure to glucocorticoids (Figure 2). During the post-ID treatment, 74.1% of patients used glucocorticoids, 56.2% had >7.5 mg/day PED, 14.4% had >30 mg/day PED, and 45.8% had ≥30 days of exposure to glucocorticoids.Among bDMARD switchers, 85.1% of patients used glucocorticoids in the pre-ID period (Figure 1), and 70.2% had >7.5 mg/day PED, 17.4% had >30 mg/day PED, and 55.2% had ≥30 days of exposure to glucocorticoids (Figure 2). During post-ID treatment, 75.4% of patients used glucocorticoids and 59.7% of patients had >7.5 mg/day PED, 16.7% had >30 mg/day PED, and 45.6% had ≥30 days of exposure to glucocorticoids.Conclusion:Real world glucocorticoid use was high in all categories of DMARD-treated RA patients, at baseline and during their next treatment, suggesting ongoing medical needs. Glucocorticoid doses exceeded 7.5 mg/day for most patients. In addition, many patients had ≥30 days exposure to glucocorticoids, posing an additional safety risk.Disclosure of Interests:Robin K Dore Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Jenya Antonova Employee of: Gilead Sciences. Inc., Magdaliz Gorritz Consultant of: Gilead Sciences, Inc., Lawrence Chang Consultant of: Gilead Sciences, Inc., Handing Xie Consultant of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background Psoriatic Arthritis (PsA) and Psoriasis (PsO), have a significant impact on health-related quality of life and work productivity loss. In patients with both PsA and PsO, the full extent of the physical and emotional burden due to either joint related or skin related symptoms is not well understood from the perspective of the patient. Objectives To evaluate the patients’ perspective on the overall burden of skin and joint related symptoms of PsA in a cross-sectional online survey. Methods A 20 min web based survey was developed based on analysis of 1-on-1 interviews with 30 PsA patients from the US, France and Germany. The final survey contained validated instruments including the PSA Quality of Life (PSAQoL) and Work Productivity and Activity Impairment (WPAI) questionnaires as well as custom questions designed to capture emotional burden of PsA and its impact on daily activities/situations. Additional data collected included demographics, severity of PsO by patient-reported body surface area involvement (BSA), severity of PsA by RAPID3, impact of PsO and PsA by a Patient Global Assessment scale with focus on skin or joint symptoms. In total, 439 psoriatic arthritis (PsA) patients from the US (68%), Germany (20%) and France (12%) were recruited to complete the survey. Results Among all participants, 30% had mild and 70% had mod-severe PsA based on RAPID-3 cutoffs, while 51% had mild and 48% had mod-severe PsO based on BSA cutoffs. According to multiple regression analyses, severity of joint symptoms and skin symptoms were signifcantly associated with lower PsAQoL (p Conclusions In this survey of patients with PsA, we evaluated the patient‘s perspective on the burden of both skin-related and joint-related symptoms with the PsAQoL and WPAI as well as with a set of novel questions. Both skin and joint symptoms have a broad and meaningful impact on patient QoL, work productivity and patients reported a range of emotions as well as a variety of impacts on their daily activities with respect to skin and joint symptoms. This data highlights that there is a unique impact of PsA for each patient. Disclosure of Interest J. Merola Grant/research support from: Amgen; Biogen Idec, Boehringer Ingelheim, Pfizer, Consultant for: Abbvie, Amgen, Biogen Idec, Celgene, Eli Lilly and Company, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Mallingkrodt, Merck, Momenta, Novartis, Pfizer, Samumed, Sanofi, Science37, and UCB, D. Shrom Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, J. Eaton Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, C. Dworkin: None declared, C. Kresbach: None declared, B. Shah-Manek: None declared, J. Birt Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co

Background Patients often describe pain as the most important symptom of RA. Despite advances in RA therapy to improve disease control, some patients continue to have significant pain1,2. The relative impact of pain on RA patients’ evaluations of overall health and RA-specific global assessments is unknown. Objectives Determine the relative role of pain in RA patients’ health assessments. Methods Data derived from the Forward (The National Databank for Rheumatic Diseases) longitudinal cohort, collected January-May 2017. Respondents (n=5471) have rheumatologist-confirmed RA. Two health assessments were examined:1 overall satisfaction with health (SAT) measured by the item: “How satisfied are you with your health now?” with responses of very unsatisfied to very satisfied; and2 patient global assessments of RA impact (GBL) measured using a numeric rating scale (NRS): “Considering all the ways that your RA affects you, rate how you are doing on a scale of 0–10, where 0=very well and 10=very poor.” For regression analyses, SAT was dichotomized as “very satisfied” or “somewhat satisfied” vs. other responses. Current pain severity was rated on an NRS from 0 (no pain) to 10 (extreme pain). Spearman correlations examined the association of pain with SAT and GBL. Initial multiple regression analyses (table 1, Model 1) examined the following as predictors of SAT and GBL: age, sex, education, disease duration, obesity (BMI ≥30), conventional and biologic DMARD use, Rheumatic Disease Comorbidity Index3 (RDCI), self-report of depression, fatigue, and functional limitations (Health Assessment Questionnaire [HAQ] score). Follow-up models (Model 2) added pain to determine its relative independent role in health assessments. Results The sample was 84% female, mean age 65 years, mean RA duration 22 years. 53% were satisfied with their health, and mean GBL was 3.6±2.5. Mean pain severity rating was 3.8±2.8. Correlations of pain with SAT and GBL were 0.58 and 0.71, respectively (each p Regression models included age, sex*, education, disease duration, obesity, medications, RDCI, depression, fatigue*, and HAQ*. Variables noted with asterisk were also statistically significant (p Conclusions Pain plays a critical role in RA patients’ assessments of general and RA-specific health. Analyses suggest that pain may be more important to RA global assessments than to overall health satisfaction, though the clinical relevance of this difference is not known. RA global assessments are included in some indices of disease activity. Future research should focus on distinguishing between non-inflammatory and inflammatory causes, which may lead to more accurate assessment of RA disease activity. References [1] Lee YC, et al. Arthritis Res Ther2011;13:R83. [2] Altawil R, et al. Arthritis Care Res2016;68:1061. [3] England BR. Arthritis Care Res2015;6:865. Disclosure of Interest P. Katz Grant/research support from: Eli Lilly and Co, Y. Lee Grant/research support from: Eli Lilly and Co, A. Quebe Employee of: Eli Lilly and Co, L. Sun Employee of: Eli Lilly and Co, H. Patel Employee of: Eli Lilly and Co, C. Gaich Employee of: Eli Lilly and Co, N. Boytsov Employee of: Eli Lilly and Co, K. Michaud Grant/research support from: Eli Lilly and Co

Background JIA is the most common chronic inflammatory rheumatic disease of childhood. TNF inhibitors are used for long-term control of pJIA disease. Objectives To evaluate the 7 year (y) safety of Adalimumab treatment with or without methotrexate (ADA±MTX) when used in current clinical practice for treatment of patients (pts) with active pJIA. Methods This is a 7 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with pJIA with up to10 y safety follow-up. Included pts were treated with ADA±MTX or MTX alone as comparison arm according to routine clinical care in PRINTO/PRCSG centres in EU, USA and Australia. MedDRA observational adverse events (AEs) were recorded from 1st day in the registry through last contact, irrespective of duration of registry treatment. Results In January 2014, enrollment was complete. As of June 1, 2016 cut-off date, 838 pts (301- MTX arm and 537 - ADA±MTX arm) were treated in the registry. There were 39 pts who rolled over from MTX to ADA±MTX arm. At registry entry mean pJIA disease duration was 1.3 y and 3.7 y and mean AJC71 was 5.8 and 5.2 for MTX and ADA±MTX arms, respectively. CHAQ disability index was 0.6 for both arms. Mean duration of study drug exposure in registry was 2.0 y (range: 0.0 – 7.1) and 2.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Mean duration of observation in registry was 3.9 y (range: 0.0 – 7.2) and 3.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Overall, 213 pts (70.8%) in MTX and 225 pts (41.9%) in ADA±MTX arms discontinued registry drug through 7 y. Main reasons (not exclusively) for registry drug discontinuation for MTX arm: pts required additional therapy (32.6%), other (13.3%), lack of efficacy (11.6%), AEs (9.3%), or pts achieved JIA remission (8.6%); for ADA±MTX arm: lack of efficacy (17.9%), other (7.3%), lost to follow-up (5.6%), AEs (5.4%), or pts achieved JIA remission (5.0%). Frequencies and rates of treatment-emergent AEs (from 1st dose date of registry drug in registry up to last dose + 70 days in registry, excluding AEs occurring during treatment interruption) were similar to those reported for observational AEs (from 1st day in registry up to last contact irrespective of drug treatment duration) (Table). Rate of serious infections was similar between MTX and ADA±MTX arms. One pt (0.2%) reported an event of opportunistic infection (fungal oesophagitis) in ADA±MTX arm. No reports of deaths, malignancies, active tuberculosis, oral candidiasis, demyelination, or congestive heart failure. Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. The retention rate for registry drug was higher in ADA±MTX arm compared to MTX arm. Acknowledgements AbbVie sponsored the study & contributed with PRINTO & PRCSG to analysis, review, approval of the abstract. X. Leahy & A. Deshmukh (AbbVie) contributed to research. Medical writing: G. Patki (AbbVie). Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Takeda, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, K. Nanda Consultant for: Medac Pharma, Inc., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, C. Rabinovich Grant/research support from: UCB Pharma, Janssen, D. Kingsbury: None declared, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, and Sanofi, K. Minden Grant/research support from: Pfizer, AbbVie and Roche/Chugai, Consultant for: Pfizer, Roche, and Pharma-Allergan, Speakers bureau: Pfizer, Roche, and Pharma-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, Novartis, and Roche, Speakers bureau: AbbVie, Novartis, Sobi, Pfizer, and Roche, R. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune, D. Lovell Consultant for: AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech, Amgen and Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Background: Tirzepatide (LY3298176) was approved by U.S. Food and Drug Administration (FDA) on May 13th, 2022. The drug was developed by Eli Lilly and Co. and marketed under the trade name of ‘Mounjaro’, a first-in-class ‘Twincretin’, which is a dual activator of GIP and GLP-1 receptors, resulting in improved blood sugar control in type 2 diabetics The review covered the comprehensive insight on the drug discovery journey of tirzepatide. Methods: Using the keywords "Tirzepatide", "Twincretin", "Type 2 Diabetes", "GLP-1", and "GIP," data were gathered from Medline, PubMed, Google Scholar, and Science Direct. Results: The review covers comprehensive insight into the drug discovery journey of tirzepatide. The drug-target structural specialty has been discussed to establish the dual inhibition mechanism of action of tirzepatide. The results of in vitro studies, preclinical and clinical trial data, pharmacokinetic profile, dosing regimen, side effects, and toxicities of tirzepatide are reviewed to account for the potency, efficacy, and safety of the newly approved drug. The drug molecule may attain a privileged status in the anti-diabetic market as the clinical data showed that it effectively reduces HbA1c level in monotherapy as well as in add-on therapy, compared to placebo, semaglutide, insulin degludec, and insulin glargine, and found effective in type 2 diabetes associated conditions like atherogenic dyslipidemia and non-alcoholic steatohepatitis. Conclusion: Tirzepatide is a clinically efficient drug, exhibiting a good safety profile as evident from the existing clinical data, and could be a new alternative to the currently available antidiabetics for the treatment of T2D.

Background JIA is the most common chronic inflammatory rheumatic diseases of childhood. Due to their long-term safety and efficacy, biologic disease modifying antirheumatic drugs (DMARD) are commonly necessary for control of pJIA patients (pts). Objectives To evaluate 6-year (y) safety and 2 y effectiveness profile of Adalimumab with or without methotrexate (ADA±MTX) when used in current clinical practice for the treatment of moderately to severely active pJIA. Methods This is a 6 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA with up to10 y safety follow-up. Included pts are treated with either ADA±MTX or MTX alone as part of their routine clinical care enrolled in the US, EU, and Australia. MedDRA observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of the duration of registry treatment. Effectiveness was assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. Results As of January 2014, enrollment was complete. As of June 1, 2015 cut-off date, 846 pts (543 in ADA±MTX and 303 in MTX groups) were treated in the registry. There were 39 pts who rolled over from the MTX to the ADA±MTX arm. At registry entry mean pJIA disease duration was 1.4 y and 3.7 y for MTX and ADA±MTX arms, respectively. At baseline (BL), mean AJC71 was 5.8 and 5.3 for MTX and ADA±MTX arms, respectively, and Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) was 0.6 for both arms. At data cutoff, the mean duration of study exposure was 1.81 y and 2.15 y for MTX and ADA±MTX arms, respectively. Overall, 206 pts (68%) in the MTX and 216 pts (39.8%) in the ADA±MTX arms discontinued registry drug through 6 y. The main reasons for registry drug discontinuation for the MTX arm: pts required additional therapy (32.3%), other (11.9%), lack of efficacy (10.9%), AEs (8.3%), or pts achieved JIA remission (7.6%), and for ADA±MTX arm: lack of efficacy (16%), lost to follow-up (7.2%), other (5.9%), and AEs (5.3%). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs (Table). There were no reports of deaths, malignancies, opportunistic infections, active TB, oral candidiasis, or CHF. Mean JADAS27 (CRP) improved from 12.2 at BL to 9.7, 5.2, 4.4, 3.5, 2.2 at months 1, 6, and 12, 18, 24 for pts in the MTX and from 11.8 at BL to 7.0, 4.-2, 4.2, 3.6, 3.9 in the ADA±MTX arms, respectively (observed data). Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. Discontinuations from the registry drug were relatively high through 6 y, but greater in the MTX only arm. Acknowledgement AbbVie sponsored the study & contributed with PRINTO & PRCSG to the analysis, review, and approval of the abstract. Xiaolei Leahy & Ashish Deshmukh of AbbVie contributed to the research. Medical writing support was provided by Gaurav Patki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfgroupaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Phgroupaceuticals., Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, D. J. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, and Genentech, Speakers bureau: Wyeth Pharmaceuticals, and served on data and safety monitoring boards for Amgen and Forest Research, C. Wallace Grant/research support from: Pfizer and Amgen, Consultant for: Amgen and Novartis., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., and AbbVie, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie., P. Quartier Grant/research support from: AbbVie, Novartis, Consultant for: AbbVie, Novartis, K. Minden Grant/research support from: Pfizer and Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac and Pharma-Allergan., E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche, Speakers bureau: AbbVie, Novartis, Pfizer, and Roche, R. M. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Heinrich Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, H. Kupper Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, J. Kalabic Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune., H. I. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals.

Background Ph3 studies demonstrated clinical efficacy of 2 different once-daily (QD) doses of baricitinib (bari) (2mg and 4mg) in patients (pts) with active rheumatoid arthritis (RA) and an inadequate response (IR) to conventional synthetic DMARDs1 or biologic DMARDs2. In general, larger, more rapid and more consistent treatment effects were observed for the 4mg dose across measures. Objectives To investigate the effects of bari dose step-down in patients who had achieved sustained low disease activity (LDA) or remission with bari 4mg QD. Methods Pts who completed a bari Ph3 Study (RA-BEGIN, RA-BEAM, RA-BUILD, or RA-BEACON) could enter a long-term extension study, RA-BEYOND. In RA-BEYOND, pts who had received bari 4mg for at least 15 months and who had achieved sustained LDA or remission (defined by CDAI score at 2 consecutive visits at least 3 months apart) were re-randomized in a double blind manner to continue receiving bari 4mg or to step down to a 2mg QD dose. Disease activity was assessed at a 12 week (wk) landmark following re-randomization. Results Among pts who achieved satisfactory and sustained disease control with bari 4mg QD, randomized, double blind dose reduction to 2mg QD was associated with modest, statistically significant increases in disease activity across measures at a subsequent 12 wk landmark assessment (Table). However, a large majority of pts (in both the continued 4mg and reduced to 2mg groups) retained the state of LDA or remission that led to their re-randomization. Conclusions Consistent with completed studies, these data indicate that 4mg QD was the most efficacious dose of bari for pts with RA in clinical studies. Most pts who had achieved sustained disease control with bari 4mg sustained LDA or remission 12 wks after randomized, blinded dose taper to 2mg QD. References Dougados M et al.Ann Rheum Dis 2015;74(S2):79; Genovese M et al.Ann Rheum Dis 2015;74(S2):75–76. Disclosure of Interest T. Takeuchi Grant/research support from: Eli Lilly & Co., Astellas, Bristol-Myers K.K., Chugai, Ltd, Daiichi Sankyo, Eisai, AYUMI Pharmaceutical Corporation, Takeda, Teijin Pharma, AbbVie GK, Asahikasei Pharma, Taisho Toyama Pharmaceutical Co., Consultant for: Eli Lilly & Co., Astra Zeneca K.K., Novartis, Mitsubishi Tanabe, Asahi Kasei Medical, AbbVie GK, Daiichi Sankyo, Bristol-Myers K.K., Nipponkayaku, Janssen, Merck Serono, Takeda, Astellas, Speakers bureau: AbbVie GK, Bristol-Myers K.K., Chugai, Eisai, Janssen, Mitsubishi Tanabe, Pfizer, Takeda, Astellas, Daiichi Sankyo, Celtrion, Nipponkayaku, M. Genovese Grant/research support from: AbbVie, Astellas, Eli Lilly & Co., Galapagos, Pfizer, Vertex, Consultant for: AbbVie, Astellas, Crescendo Bioscience, Eli Lilly &Co., Galapagos, Pfizer, L. Xie Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co., M. Issa Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., A. L. Pinto Correia Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., T. Rooney Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., K. Emoto Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., J. Smolen Grant/research support from: AbbVie, Janssen, Eli Lilly & Co., MSD, Pfizer, Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Eli Lilly & Co., Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB

This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20).Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C(max)), time to C(max) (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G).For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced t(max) by 51% (P = 0.0006) and 58% (P = 0.0002), increased C(max) by 90% (P = 0.0003) and 142% (P0.0001), increased early exposure (AUC(0-2h)) by 85% (P0.0001) and 211% (P0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P0.0001) and 48% (P0.0001). Similarly, rHuPH20 reduced tGIR(max) by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated.Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.

Background Baricitinib (bari), an oral Janus Kinase (JAK)1/JAK2 inhibitor, is being investigated to treat inflammatory diseases, including rheumatoid arthritis (RA). Baricitinib is primarily cleared renally (75% of the dose is excreted in urine). In vitro studies showed that bari is a substrate for CYP3A4 and the renal transporters, P-glycoprotein (Pgp) and organic anion transporter 3 (OAT3). In vitro studies also showed that bari did not inhibit or induce a panel of CYPs, but did inhibit OAT1, OAT3, organic cation transporter 1 (OCT1), and OCT2. Nevertheless, the potential for clinically meaningful drug-drug interactions (DDIs) is predicted to be low, as the unbound Cmax/IC50 ratios were all Objectives Confirm lack of clinically relevant DDIs in clinical pharmacology (CP) studies. Methods Seven CP studies in healthy subjects (HS) and 1 CP study in patients with RA were conducted. Studies in HS examined the potential for bari to be a CYP3A, CYP2C19, or CYP2C9 substrate, a Pgp or OAT3 substrate, a Pgp inhibitor, or a CYP3A inducer or inhibitor. Methotrexate (MTX), a substrate of several transporters and a commonly used medication for RA, was studied in combination with bari in patients with RA. Each study was powered to evaluate statistically significant differences in exposure. Results In HS, co-administration of the CYP3A inhibitor (ketoconazole) or the CYP2C19/CYP2C9/CYP3A inhibitor (fluconazole) with bari had no significant effects on the pharmacokinetics (PK; AUC and Cmax) of bari. Rifampicin, a potent CYP3A inducer, decreased bari AUC by 34% without affecting Cmax. The Pgp inhibitor, ciclosporin, increased bari AUC by 29% and tmax, by 1 hour without affecting Cmax. Probenecid, a potent OAT3 inhibitor, had no effect on bari Cmax, but decreased renal clearance by 69% and increased AUC by 2-fold. When tested as a possible Pgp inhibitor or as a possible CYP3A inducer, bari had no effect on the PK of digoxin or the components of Microgynon® (Bayer, United Kingdom), respectively. When tested as a possible CYP3A inhibitor, bari decreased the exposure of simvastatin (AUC: -15%; Cmax: -29%) and its active metabolite (AUC: -16%; Cmax: -12%), consistent with a modest decrease in absorption, without CYP3A interaction. The combination of MTX and bari in patients with RA had no significant effect on the PK of bari or MTX. Baricitinib was well tolerated in all CP DDI studies. Conclusions Potential interactions between bari and various drug transporter and CYP substrates, inhibitors, and inducers were evaluated. In most studies, including those evaluating CYP effects, no clinically significant interactions were seen. Probenecid, a strong inhibitor of the transporter OAT3, reduced bari clearance. The current data indicate a low risk of clinically significant DDIs between bari and other drugs that may be concomitantly administered to patients with RA. Disclosure of Interest C. Payne Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co., X. Zhang Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co., N. Shahri Employee of: inVentiv Health Clinical, W. Williams Shareholder of: Incyte Corp., Employee of: Incyte Corp., E. Cannady Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co.

Background Juvenile idiopathic arthritis (JIA) is one of the most common childhood rheumatic diseases. Adalimumab (ADA) is approved for moderate to severe polyarticular JIA (pJIA) in patients (pts) ≥4 yrs in Australia and Japan and for pts ≥2 yrs in the US and EU. Objectives To evaluate long-term safety and effectiveness of ADA in pts with moderately to severely active pJIA who are prescribed and treated with ADA in routine clinical practice. Methods This is an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA who are treated with either ADA ± methotrexate (MTX) or MTX alone as part of their routine clinical care. 800 pts (500 ADA/300 MTX) were to be enrolled in the US, EU, and Australia. The follow-up observational period is 10 yrs from enrollment into one of the treatment arms. Observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of registry treatment duration. Clinical outcomes were assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. 5 yr interim data are presented. Results As of January 2014, enrollment is complete. 842 pts (540 ADA/302 MTX) were treated as of the March 28, 2014 cutoff. Mean pJIA disease duration at enrollment was 1.3 and 3.7 yrs and mean duration of study exposure was 643 and 653 days for MTX and ADA arms, respectively. Baseline mean AJC73 was 5.8 and 5.4 for MTX and ADA, respectively, and CHAQ-DI was 0.6 for both groups. Overall, 153 pts (50.7%) in the MTX arm and 132 pts (24.4%) in the ADA arm discontinued registry drug. Of those, 22 (7.3%) and 23 (4.3%) in the MTX and ADA arm, respectively, discontinued due to an AE, and 39 of the 153 pts in the MTX arm discontinued as they switched to the ADA arm. The observational AEs are summarized (Table). No deaths, malignancies, or opportunistic infections were reported. In the ADA arm, there were 13 (2.4%) pts with serious infectious AEs (abdominal abscess, acute tonsillitis, appendicitis, cellulitis, gastroenteritis, mononucleosis, viral meningitis, pneumonia, pyelonephritis, scarlet fever, subcutaneous abscess, tonsillitis, urinary tract infection, and varicella). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs. Mean JADAS27 improved from 12.1 at baseline to 9.4, 6.1, 5.1, 4.4 at months 1, 3, 6, and 12 for pts in the MTX arm and from 12.1 at baseline to 7.4, 5.5, 4.4, 4.5 in the ADA arm, respectively (observed data). Conclusions Overall, ADA is well-tolerated in these pts with active pJIA. No new safety signals were observed, and based on this interim analysis, the known safety profile of ADA remains unchanged. Acknowledgements AbbVie sponsored the study (NCT00783510), contributed with PRINTO and PRCSG to the design, and participated in data collection, analysis, and interpretation, and in the writing, review, and approval of the abstract. Medical writing support was provided by Jessica L. Suboticki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals. NR has served on speaker9s bureau for Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, C. Wallace Grant/research support from: Pfizer, Amgen, Consultant for: Amgen, Novartis, M. Toth: None declared, I. Foeldvari Consultant for: AbbVie, Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech, Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., AbbVie, P. Vavrincova: None declared, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum; Participates on a data management committee of a phase 3 trial by Sanofi, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, Speakers bureau: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche and speaker9s fees from AbbVie, Novartis, Pfizer, Roche, R.-M. Kuester Grant/research support from: AbbVie, Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac GmbH, UCB Biosciences, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, MedImmune, D. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech; served on data and safety monitoring boards for Amgen, Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.

Aim: Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. Methods: Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75. Results: Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR was 0.866 (95% CI 0.717, 1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p 5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO. Conclusions: No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation. Disclosure: J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to "Instituto do Cancer do Estado de Sao Paulo" ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.

BackgroundThe preferential Janus kinase-1 inhibitor FIL is approved for treatment of moderate to severe active RA in Europe and Japan.ObjectivesEfficacy and safety of FIL were assessed in patients (pts) with IR to bDMARDs in a LTE trial (NCT03025308) enrolled from a Phase 3 PS (NCT02873936).1MethodsbDMARD-IR pts received FIL 200 mg (FIL200), FIL 100 mg (FIL100), or placebo (PBO), all with stable conventional synthetic (cs)DMARDs up to 24 weeks (W). At W14 of the PS, pts with IR to FIL or PBO (ResultsThe PS included 147, 153, and 148 pts on FIL200, FIL100, and PBO. Pts continuing on LTE FIL200 and FIL100 at data cutoff: 80/121 (66%) and 76/110 (69%) from PS FIL200 and FIL100; 35/47 (75%) and 32/46 (70%) from PS PBO, and 13/23 (57%) and 13/22 (59%) from PS SOC. LTE baseline (BL) characteristics were similar in FIL200 and FIL100 pts. During LTE, PS FIL ACR20/50/70 response rates decreased modestly by W48 (Figure 1). Among PS PBO pts, response rates were lower at LTE BL, reaching similar levels to PS FIL pts by W48; rates increased to W48 in PS SOC pts on either FIL dose but not to levels of other groups. Percentages of pts attaining DAS28(CRP) ≤3.2, DAS28(CRP) Table 1.EAIRs of TEAEs in LTE, as of June 1, 2020EAIR (95% CI)FIL200+csD → FIL200+csD n=121PYE 228.4PBO+csD → FIL200+csD n=47PYE 98.1SOC+csD → FIL200+csD n=23PYE 42.1FIL100+csD → FIL100+csD n=110PYE 223.3PBO+csD → FIL100+csD n=46PYE 91.1SOC+csD → FIL100+csD n=22PYE 38.2TEAE46.9 (38.8, 56.6)38.7 (28.2, 53.2)52.2 (34.4, 79.3)40.3 (32.8, 49.5)40.6 (29.4, 56.1)49.8 (31.8, 78.0)TEAE Grade ≥310.5 (7.0, 15.7)10.2 (5.5, 18.9)19.0 (9.5, 38.0)10.3 (6.8, 15.5)13.2 (7.5, 23.2)18.3 (8.7, 38.5)TE serious AE12.3 (8.5, 17.8)12.2 (6.9, 21.5)21.4 (11.1, 41.1)8.1 (5.1, 12.8)13.2 (7.5, 23.2)21.0 (10.5, 41.9)Death1.3 (0.4, 4.1)1.0 (0, 5.7)0 (0, 8.8)0.4 (0.1, 3.2)0 (0, 4.0)0 (0, 9.7)TE infections34.2 (27.4, 42.6)22.4 (14.8, 34.1)35.6 (21.5, 59.1)22.4 (17.0, 29.5)26.3 (17.7, 39.3)39.3 (23.7, 65.2)TE serious infections3.5 (1.8, 7.0)2.0 (0.5, 8.2)7.1 (2.3, 22.1)0.9 (0.2, 3.6)2.2 (0.5, 8.8)7.9 (2.5, 24.4)Opportunistic infections0 (0, 1.6)0 (0, 3.8)0 (0, 8.8)0 (0, 1.7)0 (0, 4.0)0 (0, 9.7)TE herpes zoster2.2 (0.7, 5.1)1.0 (0.1, 7.2)0 (0, 8.8)0 (0, 1.7)2.2 (0.5, 8.8)2.6 (0.1, 14.6)TE MACE (adjudicated)1.3 (0.4, 4.1)1.0 (0.1, 7.2)0 (0, 8.8)0.9 (0.2, 3.6)1.1 (0.2, 7.8)0 (0, 9.7)TE DVT/PE (adjudicated)0.9 (0.2, 3.5)0 (0, 3.8)2.4 (0.1, 13.2)0.4 (0.1, 3.2)0 (0, 4.0)0 (0, 9.7)Malignancies (excluding NMSC)1.3 (0.4, 4.1)3.1 (1.0, 9.5)4.7 (0.6, 17.2)1.8 (0.7, 4.8)3.3 (1.1, 10.2)0 (0, 9.7)NMSC0 (0, 1.6)0 (0, 3.8)4.7 (0.6, 17.2)0 (0, 1.7)0 (0, 4.0)0 (0, 9.7)DVT, deep vein thrombosis; MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; PE, pulmonary embolism; TE, treatment-emergentConclusionEfficacy was mostly maintained in PS FIL pts up to W48. Response among PS PBO and SOC pts increased from BL to W48, but response in PS SOC pts continued to be lower than in other groups; these pts may represent a refractory population. FIL safety was largely consistent between PS and LTE.References[1]Genovese MC et al. JAMA 2019;322:315–25.AcknowledgementsThis study was funded by Gilead Sciences, Inc., Foster City, CA. Medical writing support was provided by Claudine Bitel, PhD, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA.Disclosure of InterestsMaya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Galapagos, Gilead, and Pfizer, Grant/research support from: Gilead and Pfizer, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe, Novartis, Pfizer Japan, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly Japan, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan, Vijay Rajendran Shareholder of: Galapagos, Employee of: Galapagos, Jacques-Eric Gottenberg Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., Roche, Sanofi Genzyme, and UCB, Consultant of: Bristol Myers Squibb, Sanofi Genzyme, and UCB, Grant/research support from: Bristol Myers Squibb and Pfizer, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Katrien Van Beneden Shareholder of: Galapagos, Employee of: Galapagos, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, Fresenius-Kabi, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB

Background MF, PV, and ET are neoplasms characterized by activation of JAK2 signaling, and the majority of cases are associated with the gain of function JAK2 V617F mutation. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. LY2784544 is a selective inhibitor of JAK2 which demonstrates dose dependent selectivity for JAK2 V617F/STAT5 signaling. LY2784544 entered clinical testing in a Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). We have previously reported early interim analysis from this study and provide here an update following completion of study enrollment. Methods The study’s primary objectives were to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives included determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria (2006), European Leukemia Net response criteria for PV and ET (EULN 2009), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). Study design included a standard 3+3 dose-escalation to define the maximum tolerated dose (MTD) and was amended to allow cohort expansions at multiple doses demonstrating potential clinical merit. Results Patients Prior to closing to enrollment, 47 patients were consented; 9 did not meet eligibility screening. The 38 treated patients included 31 MF (22 pMF, 6 post-PV MF and 3 post-ET MF), 6 PVs, and 1 ET patient(s), and 86% had received prior systemic therapy for their MPN. Dosing and tolerability of LY2784544: Systemic exposures were approximately dose proportional across the tested range from 30 to 300 mg. Daily doses of 200 mg or greater were associated with CTCAE Grade 3 increases in serum creatinine. In general, increases in serum creatinine occurred within the first 2 weeks of either starting treatment or after an increase in study drug dose. With the available data, the elevations in serum creatinine appear to be fully reversible after dose reduction or drug holiday in the majority of patients. The maximum tolerated daily dose of LY2784544 when given on a continuous daily basis was determined to be 120 mg per day. Serious AEs, across all grades and doses, included increased creatinine/acute renal insufficiency (4 grade 3, 5 grade 2, 1 grade 1), hyperuricemia (2 grade 4, 1 grade 1), hyperkalemia (1 grade 1), and anemia (1 grade 3). This study allowed intrapatient dose escalation, and 34 patients received 120 mg during their study participation. There were 4 patients dosed at 120 mg with SAEs but all were unrelated to study drug treatment (anemia, influenza, enterococcal bacteremia, hematuria and pneumonia). At 120 mg, the most frequently reported drug-related AEs across all grades were diarrhea (44%), nausea (29%), increased creatinine (21%), and anemia, vomiting, fatigue (9% each). Of these related AEs at 120 mg, there was 1 Grade 3 anemia, 3 Grade 3 increased creatinine, and 2 Grade 3 fatigue. There were no Grade 4 AEs. Efficacy Among a cohort of 10 MF patients who only received 120 mg, 3 achieved a clinical improvement. Analyzing across dose levels, a palpable spleen length reduction of ≥50% was seen in 15 of 27 evaluable patients (56%) at any time. The median duration of these responses was 18.3 weeks (range from 0.7 to 148.1 weeks). At 12 weeks, 56% of patients (15/27) reported a ≥50% improvement in Total Symptom Score on the MPN-SAF. Of the 6 PV patients, 3 achieved a clinicohematologic PR. Findings from a central pathology review of serial bone marrow samples will be presented at the meeting. Conclusions A recommended phase II dose for daily dosing of LY2784544 was identified as 120 mg. This dose has been well tolerated and associated with clinical improvements, supporting ongoing Phase II testing of LY2784544 in MPNs. Disclosures: Verstovsek: Eli Lilly and Co: Research Funding. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding. Salama:Eli Lilly and Co: Research Funding. Giles:Eli Lilly and Co: Employment. Pitou:Eli Lilly and Co: Employment. Hayden Zimmermann:Eli Lilly and Co: Employment. Price:Eli Lilly and Co: Employment. Walgreen:Eli Lilly and Co: Employment. Prchal:Eli Lilly and Co: Research Funding.

Background Limited information is available on the effects of etanercept (ETN) on the juvenile idiopathic arthritis (JIA) subtypes, extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA). Objectives To assess the efficacy and safety of ETN in paediatric subjects with eoJIA, ERA, and PsA. Methods CLIPPER is an ongoing, Phase 3b, open-label, multi-centre study; the primary analyses (12-week data) are reported here. Subjects with eoJIA (2–17 y old), ERA (12–17 y old), or PsA (12–17 y old) received ETN 0.8 mg/kg once weekly (max. dose 50 mg). Endpoints included the percentage of subjects achieving American College of Rheumatology (ACR) Paediatric 30 (primary endpoint) and 50/70/90/100 criteria at Week 12. Logistic regression analysis was used to compare the ACR Paediatric 30 data with historical placebo data from a meta-analysis of JIA studies [1] and a juvenile-onset spondyloarthropathy study [2]. Results 127 subjects (mean age 11.7 y) received ≥1 dose of ETN; 5 (3.9%) subjects discontinued the study. Concomitant disease-modifying anti-rheumatic drugs, corticosteroids, and non-steroidal anti-inflammatory drugs were received by 109 (85.8%), 16 (12.6%), and 74 (58.3%) subjects, respectively. ACR Paediatric 30/50/70/90/100 response rates (Tables 1 and 2) were similar across all JIA subtypes. Odds ratios for ACR Paediatric 30 showed a significant advantage of ETN over the historical placebo data. Treatment-emergent adverse events (TEAEs), treatment-emergent infections, serious TEAEs, and malignancies were reported in 45 (35.4%), 58 (45.7%), 4 (3.1%), and 0 (0.0%) subjects, respectively. Serious TEAEs were 1 (0.8%) case each of abdominal pain, bronchopneumonia, gastroenteritis, and pyelocystitis. One (0.8%) subject reported an opportunistic infection of herpes zoster. No clinically meaningful differences in safety were observed across the JIA subtypes. Conclusions Etanercept treatment for 12 weeks was effective in treating subjects with the JIA subtypes, eoJIA, ERA, or PsA, with no unexpected safety findings. References Ruperto N, et al. Arthritis Rheum 2003;48(Suppl 9):S90. Burgos-Vargas R, et al. Ann Rheum Dis 2008;67(Suppl 2):69. Disclosure of Interest G. Horneff Grant/Research support from: Abbott, Pfizer Inc., Wyeth., N. Ruperto Grant/Research support from: Abbott, AstraZeneca, Bristol-Myers Squibb, Centocor Research and Development, Eli Lilly and Co., “Francesco Angelini” s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer Inc., Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Wyeth, Xoma, Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Novartis, Roche, R. Burgos-Vargas Grant/Research support from: Abbott, Consultant for: Abbott, Bristol-Myers Squibb, Janssen, Pfizer Inc., Roche, Speakers Bureau: Abbott, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc., Roche, V. Panaviene: None Declared, D. Alvarez Employee of: Pfizer Inc., C. Zang Employee of: Pfizer Inc., J. Wajdula Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Woodworth Employee of: Pfizer Inc., B. Vlahos Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., A. Martini Grant/Research support from: Abbott, AstraZeneca, Bristol-Myers Squibb, Centocor Research and Development, Eli Lilly and Co., “Francesco Angelini” s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer Inc., Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Wyeth, Xoma, Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Novartis, Roche

Disclosure K. Mansouri: K. Mansouri is an employees of Eli Lilly and Co. L. Cirri: L. Cirri is an employees of Eli Lilly and Co. P. Shi: P. Shi is an employees of Eli Lilly and Co. O. Hamid: O. Hamid is an mployees of Eli Lilly and Co. All other authors have declared no conflicts of interest. AIs are used as first-line treatment for postmenopausal women with hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI resistance in several studies. We examined whether Enza, a serine/threonine kinase inhibitor that targets PKC, could improve the effect of Ful in pts who progressed following first-line AI treatment for MBC. Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle thereafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg twice daily (BID). Primary endpoint was the clinical benefit rate (CBR). Secondary endpoints were response rate (RR), duration of CB, progression-free survival (PFS) and safety. A total of 156 pts was randomly assigned to therapy; 152 received at least 1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were balanced across arms. There was no statistically significant difference in CBR between pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and 46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO (17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in the BID arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]). 8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related respiratory failure (both in the Enza BID arm). Ful + Enza [QD + BID] N = 94 Ful + PBO N = 58 P-value vs PBO CBR Number of responders, n (%), (95% CI) 41 (43.6) (33.4, 54.2) 24 (44.8) (31.7, 58.5) 0.62 RR, % (95% CI) 5.3 (1.7, 12.0) 5.2 (1.1, 14.4) 0.64 PFS, months (95% CI) 5.2 (3.5, 7.4) 5.5 (3.8, 7.4) 0.59 Median duration of CB, months 9.6 9.7 0.86 CBR = complete response + partial response + stable disease Addition of Enza to Ful does not improve disease outcome in pts with locally advanced or MBC after progression on AI.

MUSTAFA, OZGUROGLU/0000-0002-8417-8628 WOS:000468121800002 PubMed ID: 30735435 Background: Treatment options for patients with advanced esophageal or esophagogastric junction (EGJ) cancer are limited. Current guidelines for first-line treatment of advanced esophageal or EGJ cancer recommend chemotherapy containing a platinum and a fluoropyrimidine agent. Pembrolizumab demonstrated antitumor activity in previously treated patients with advanced esophageal cancer and in patients with gastroesophageal junction cancer. Aim: To describe the design and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-590 study, which will be conducted to investigate pembrolizumab in combination with chemotherapy as first-line treatment in patients with advanced esophageal or EGJ cancer. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA.K Kato has received research funding from Merck Sharp & Dohme Corp., Merck Serono, ONO Pharmaceutical Co. Ltd and Shionogi, Inc.MA Shah has received research funding from Boston Biomedical, Inc., F Hoffmann-La Roche AG and Merck Sharp & Dohme Corp. P Enzinger has acted as an advisor for Astellas Pharma, Inc., BeiGene Co, Celgene Corp., Eli Lilly and Co., Five Prime Therapeutics, Inc. and Merck Sharp & Dohme Corp.J Bennouna has received honoraria from and acted as an advisor for AstraZeneca Plc, Boehringer-Ingelheim GmbH, F Hoffmann-La Roche AG, Merck Sharp & Dohme Corp. and Shire Plc.A Adenis has received honoraria from Bayer AG, Bristol-Myers Squibb and Sanofi SA; acted as an advisor for Bayer AG, Bristol-Myers Squibb and Servier Laboratories; received research funding from Bayer AG, Bristol-Myers Squibb, Merck Sharp & Dohme Corp., Pfizer, Inc. and Sanofi SA; and received travel, accommodation or expenses from Bayer AG, Bristol-Myers Squibb and Merck Sharp & Dohme Corp.JM Sun has acted as an advisor for Boehringer-Ingelheim GmbH and received research funding from AstraZeneca Plc.BC Cho has received honoraria and acted as an advisor for AstraZeneca Plc, Boehringer-Ingelheim GmbH, Bristol-Myers Squibb, F Hoffmann-La Roche AG, Merck Sharp & Dohme Corp., Novartis International AG and Yuhan Co. Ltd; served on speaker bureaus for AstraZeneca Plc, Bristol-Myers Squibb, Merck Sharp & Dohme Corp. and Novartis International AG; and received research funding from AstraZeneca Plc, Bayer AG, Novartis International AG and Yuhan Co. Ltd. M Ozguroglu has received honoraria from Janssen Pharmaceutica NV and acted as an advisor for Astellas Pharma, Inc. and Janssen Pharmaceutica NV.T Kojima has received honoraria from Oncolys Biopharma, Inc. and has intellectual property interests in Amgen, Inc., Astellas Pharma, Inc., Merck Sharp & Dohme Corp., Oncolys Biopharma, Inc., ONO Pharmaceutical Co. Ltd and Shionogi, Inc.Y Zhu, LA McLean and S Shah are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. LA McLean and S Shah own stock in the company.T Doi has acted as an advisor for Amgen Inc., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Kyowa Hakko Kirin Co. Ltd, Eli Lilly Japan KK, Merck Sharp & Dohme Corp. and Novartis International AG; and received research funding from Astellas Pharma, Inc., Bayer AG, Boehringer Ingelheim GmbH, Celgene Corp., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Janssen Pharmaceutica NV, Kyowa Hakko Kirin Co. Ltd, Eli Lilly Japan KK, Merck Serono, Merck Sharp & Dohme Corp., Novartis International AG, Pfizer, Inc., Sumitomo Corp., Taiho Pharmaceutical Co. Ltd and Takeda Pharmaceutical Co. Ltd.C Hierro has received research funding from Bayer and lecture fees and travel grants from Lilly, Ignyta and Roche.L Shen and V Kostorov report no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

A. Nasir, R.D. Van Horn, B. Domazet, X.S. Ye, K.M. Credille, A. Kyshtoobayeva, J.T. Brandt, E.H. Westin, A.E. McGlothlin, T.R. Holzer. Eli Lilly and Co., Diagnostic and Experimental Medicine, Indianapolis IN, USA; Eli Lilly and Co., Lilly Research Labs, Indianapolis IN, USA; Clarient, Immunopathology, Aliso Viejo CA, USA; Eli Lilly and Co., Oncology Business Unit, Indianapolis IN, USA; Eli Lilly and Co., Statistics, Indianapolis IN, USA

A. Nasir, R.D. Van Horn, B. Domazet, X.S. Ye, K.M. Credille, A. Kyshtoobayeva, J.T. Brandt, E.H. Westin, A.E. McGlothlin, T.R. Holzer. Eli Lilly and Co., Diagnostic and Experimental Medicine, Indianapolis IN, USA; Eli Lilly and Co., Lilly Research Labs, Indianapolis IN, USA; Clarient, Immunopathology, Aliso Viejo CA, USA; Eli Lilly and Co., Oncology Business Unit, Indianapolis IN, USA; Eli Lilly and Co., Statistics, Indianapolis IN, USA

7195 Background: The improved efficacy of pemetrexed (ALIMTA, Eli Lilly and Co) in combination with cisplatin versus cisplatin alone, in a phase 3 trial of patients with MPM, has led to a demand for patient access to pemetrexed prior to regulatory approval. An Eli Lilly and Co EAP was opened to allow access to all eligible patients with malignant mesothelioma. This non-randomized study was designed to gather additional efficacy and safety data on pemetrexed alone and in combination with cisplatin. The experience of those previously treated patients with MPM is reported here. Methods: Previously treated patients with malignant mesothelioma were enrolled in this study. Treatment consisted of pemetrexed 500mg/m2 alone or in combination with cisplatin 75mg/m2. Treatment was administered once every 21 days for a maximum of 6 cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilence database. R...

[Image: see text] We present Admiral (Automated Docking and Molecular dynamics InfoRmatics and AnaLysis), a platform which automates the process of running molecular docking and molecular dynamics on compound designs for medicinal chemistry project teams. In addition to running the simulations, Admiral analyzes the simulation and automatically generates a PowerPoint slide, with the goal of having all the information required to decide whether to synthesize the compound in one place. This information includes results and analyses from the MD simulation, predicted ADME and physical-chemical properties, information on similar compounds in the SAR, and an animated GIF of the simulation. This report is then emailed to the compound designer, generally within the same day. Within Eli Lilly and Co., we have developed and deployed Admiral on an internal discovery project where it has been heavily used by the project team. Several additional discovery projects have adopted the platfom in recent months.