1730. Outcomes of Patients With Detectable Cytomegalovirus (CMV) DNA at Randomization in the Double-blind, Placebo-Controlled Phase 3 Trial of Letermovir (LET) Prophylaxis for CMV-Seropositive Allogeneic Hematopoietic-Cell Transplantation (HCT) Recipients

Abstract Background LET prophylaxis through HCT Week 14 was highly effective in preventing clinically significant CMV infection (CS-CMVi), had a good safety profile, and was associated with lower all-cause mortality by HCT Week 24 compared with placebo (PBO). Patients with detectable CMV DNA at randomization were excluded from the trial’s efficacy analyses (NCT02137772). Here we report the outcomes of these patients. Methods We compared patients randomized 2:1 and treated with LET or PBO who had detectable CMV DNA at randomization (n = 70) to those with undetectable CMV DNA (n = 495; primary efficacy population, PEP). CS-CMVi was defined as CMV viremia requiring antiviral preemptive therapy (PET) or CMV disease; patients with missing data were imputed as events. PET was prescribed blinded to study drug. We analyzed CS-CMVi incidence, CMV viral load (VL) kinetics, and mortality using post study vital status. Detectable, nonquantifiable CMV VL (<151 c/mL) was imputed as 150 c/mL. Results Of 70 patients with detectable CMV DNA at randomization (48 LET, 22 PBO), CMV VL was 150 c/mL in 63 patients (range, 150–716). All patients had undetectable CMV VL ≤5 days before randomization. Baseline characteristics were similar to the PEP, except for more patients with myeloablative conditioning (62.9% vs. 48.3%) and longer median days post-HCT to start of study drug (15 days vs. 8 days). Median study drug exposure was 70 days (range, 1–113) in LET group and 14 days (range, 7–99) in PBO group. By HCT Week 14, CS-CMVi occurred in 15 (31.3%) LET-treated patients and 17 (77.3%) PBO patients; CS-CMVi with imputed events were 22 (45.8%) in LET group and 20 (90.9%) in PBO group (difference –44.8%; 95% CI, –64.7% to –24.8%; P < 0.0001). Median CMV VL at time of PET was 413 c/mL (range, 150–31,847) and was similar between groups. Eight patients had quantifiable CMV VL (range, 171–1,728 c/mL) 1 week after starting study drug: 6 did not receive PET (5 LET [10.4%], 1 PBO [4.5%]). CMV VL was undetectable subsequently; other 2 withdrew from study. One (2.1%) LET-treated patient developed breakthrough CMV viremia with a UL56 C325W mutation. HCT Week 48 all-cause mortality was 26.5% in LET and 40.9% in PBO (figure). Conclusion LET prevented CS-CMVi compared with PBO among patients with detectable CMV DNA at randomization. Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium. Astellas: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Fate Therapeutics: Consultant, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee. LFB: Consultant, Consulting fee. Roche Molecular Diagnostics: Consultant, Consulting fee. Shire: Consultant and Investigator, Consulting fee and Research support. Cidara: Investigator, Research support. Ansun: Investigator, Research support. Gilead: Investigator, Research support. WHISCON: Investigator, Research support. P. Ljungman, Merck: Investigator, Research support. AiCuris: Consultant, Consulting fee. Astellas: Investigator, Research support. Oxford Immunotec: Consultant and Investigator, Consulting fee and Research support. R. F. Chemaly, Merck: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Astellas: Consultant, Consulting fee. Novartis: Investigator, Research support. Oxford Immunotec: Consultant, Consulting fee. H. Wan, Merck: Employee and Shareholder, Salary. V. L. Teal, Merck: Employee and Shareholder, Salary. J. Butterton, Merck: Employee and Shareholder, Salary. W. W. Yeh, Merck: Employee and Shareholder, Salary. R. Y. Leavitt, Merck: Employee and Shareholder, Salary. C. Badshah, Merck: Employee and Shareholder, Salary.

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Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.970.970 ◽

2013 ◽

Vol 122 (21) ◽

pp. 970-970 ◽

Cited By ~ 4

Author(s):

Jonathan W. Stocker ◽

Debra Mandarino ◽

Ziad Kawar ◽

Richard Alvarez ◽

David Falconer ◽

...

Keyword(s):

Single Dose ◽

Sickle Cell ◽

Multiple Dose ◽

Study Drug ◽

Cell Disease ◽

Employment Equity ◽

Double Blind ◽

Equity Ownership ◽

Clinically Significant ◽

Dose Dependent

Abstract SelG1 is a humanized anti-P-selectin monoclonal antibody being developed as a treatment for sickle cell disease (SCD). Extensive data have been published that suggest a pivotal role for P-selectin in the pathophysiology of SCD. Much of this work has been conducted in mice engineered to express human β hemoglobin S (sickle cell hemoglobin). These mice have a remarkably similar disease pathology to that observed in human SCD including vasoocclusion. Using these mice, investigators have demonstrated P-selectin interactions between the endothelium and sickled red blood cells, leukocytes and platelets. Additional studies have demonstrated direct P-selectin mediated binding of leukocytes with platelets. All of these cell-cell interactions have been implicated in SCD vasoocclusion. Further, blockade or genetic absence of P-selectin decreases or eliminates these cell-cell interactions and vasoocclusion. A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SelG1. This was a single-center, double-blind, placebo-controlled, first-in-human, ascending single dose and multiple dose study of intravenous (IV)-administered SelG1 in healthy adult male and female subjects. There were 5 dosing cohorts in the study (A through E): Ascending single dose cohorts: Cohort A:0.2 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort B:0.5 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort C:1.0 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort D:5.0 mg/kg IV dose of SelG1 (n=6) or placebo (n=2). Multi-dose cohort: Cohort E:two 8.0 mg/kg IV doses of SelG1 (n=5) or placebo (n=2); the doses were given 2 weeks apart. In Cohorts A through D, SelG1 was slowly eliminated (mean t1/2 = 75.6 to 500 hours). Mean t1/2 values increased in a dose dependent manner. The exposure to SelG1 (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than proportional manner over the dose range. In Cohort E, SelG1 was slowly eliminated (mean t1/2 = 363 hours for the second infusion). The mean Cmax and AUC0-336values were 1.6- and 1.7-fold higher, respectively, after the second infusion relative to the first infusion. The PD data demonstrate that P-selectin function was completely blocked for a minimum of 28 days in Cohort D and at least 56 days in Cohort E. Twenty-six of the 27 subjects who received study drug completed the study, with 1 placebo subject in Cohort D withdrawing himself from the study due to the required travel commitment. There were no deaths, serious adverse events, or severe AEs reported in any subject. There were no increases in the number or severity of AEs with increasing dosages or with multi-dose administration. The percentage of subjects experiencing an AE was similar between the SelG1-treated subjects and the placebo-treated subjects; in Cohorts A-D, 66.7% of SelG1-treated subjects and 60.0% of placebo subjects reported at least 1 AE, while in Cohort E, 60.0% of SelG1-treated subjects and 50.0% of placebo-treated subjects reported at least 1 AE. Only 1 AE occurred in more than 1 subject; vessel puncture site hematoma occurred in 1 subject of Cohort A, 1 subject of Cohort C, and 2 subjects of Cohort E. All other AEs occurred in only 1 subject and were mild to moderate in severity. No AEs in any subject were deemed “related” to study drug. No clinically significant findings were noted from vital sign measurements, physical examinations, or 12-lead ECGs for this study. No biochemistry, hematology, or other laboratory data were reported as clinically significant or were reported as AEs; there were no trends that indicated increases or decreases in mean or median values over time, and there were no dose-dependent increases or decreases in mean or median values. There were no demonstrable changes in coagulation parameters or increased bleeding tendencies. No specific antibody response to SelG1 occurred in any of the subjects. In summary, the administration of SelG1 was well tolerated in this group of healthy male and female subjects. A Phase II clinical study to evaluate the clinical efficacy of SelG1 in SCD patients is currently underway. Disclosures: Stocker: Selexys Pharmaceuticals: Employment, Equity Ownership. Mandarino:Selexys Pharmaceuticals: CRO Other. Kawar:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Alvarez:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Falconer:Selexys Pharmaceuticals: Employment, Equity Ownership. Rollins:Selexys Pharmaceuticals: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Rother:Selexys Pharmaceuticals: Employment, Equity Ownership.

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P173 Efficacy and safety of upadacitinib versus placebo and adalimumab in patients with active PsA and inadequate response to non-biologic DMARDs (SELECT-PSA-1): a double-blind, randomised controlled phase III trial

Rheumatology ◽

10.1093/rheumatology/keab247.168 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Iain McInnes ◽

Jaclyn Anderson ◽

Marina Magrey ◽

Joseph F Merola ◽

Yi Liu ◽

...

Keyword(s):

Study Drug ◽

Control Measures ◽

Phase Iii ◽

Musculoskeletal Symptoms ◽

Stock Ownership ◽

Inadequate Response ◽

Efficacy And Safety ◽

Research Support ◽

Double Blind ◽

Secondary Endpoints

Abstract Background/Aims Upadacitinib (UPA) is a JAK inhibitor under evaluation for PsA treatment. We aimed to assess efficacy and safety of UPA vs placebo (PBO) and adalimumab (ADA) in patients with prior inadequate response (IR) or intolerance to ≥ 1 non-biologic DMARD. This research was previously presented at EULAR; published in Annals of Rheumatic Diseases. Methods Patients with active PsA (≥3 swollen, ≥3 tender joints), active/historical psoriasis, ≤2 non-bDMARDs were randomized 1:1:1:1 to once-daily UPA 15mg (UPA15), UPA 30mg (UPA30), ADA 40mg every other week, or PBO. Primary endpoint: proportion of patients achieving ACR20 for UPA vs PBO at Wk12. Secondary endpoints: change in HAQ-DI, FACIT-F, SF-36-PCS (Wk12), sIGA of Psoriasis 0/1, PASI75, change in Self-Assessment of Psoriasis Symptoms (Wk16), change in modified Sharp/van der Heijde Score (mTSS), proportion patients achieving MDA, resolution of enthesitis (LEI=0) and dactylitis (LDI=0) (Wk24), non-inferiority and superiority vs ADA for ACR20, superiority for HAQ-DI, patient assessment of pain NRS (Wk12). Additional secondary endpoints: ACR50/70 at Wk12 and ACR20 at Wk2. Treatment-emergent adverse events (TEAEs) through Wk24 reported for patients receiving ≥1 dose of study drug. Results 1,705 patients were randomised; 1,704 received study drug (mean age 50.8 yrs, mean duration of PsA diagnosis 6.1 yrs). 82% on ≥ 1 concomitant non-bDMARD. At Wk12, ACR20 rates were 70.6% with UPA15 and 78.5% with UPA30 vs 36.2% with PBO (p < 0.001 for UPA15/30 vs PBO) and 65.0% with ADA (non-inferiority, p < 0.001 for UPA15/30 vs ADA; superiority, p < 0.001 for UPA30 vs ADA). More patients achieved ACR50/70 with UPA15/30 vs PBO and UPA30 vs ADA. Improvements were observed with UPA15/30 vs PBO for all secondary endpoints and for UPA 15/30 vs ADA for HAQ-DI and UPA30 vs ADA for improvement in pain. At Wk24, change in mTSS was 0.25 for PBO, -0.04 for UPA15, 0.03 for UPA30, and 0.01 for ADA (p < 0.001 for UPA15/30 vs PBO). Rates of TEAEs and serious AEs, including serious infections, were similar in PBO, UPA15, and ADA arms and higher with UPA30. Herpes zoster rates were similar for PBO and UPA15/30. No MACE was reported with UPA. One malignancy occurred in both the PBO and UPA15 arms; 3 malignancies were reported in both UPA30 and ADA arms. VTE were reported in 1 PBO patient, 1 UPA30 patient and 2 ADA patients. One death occurred in the PBO arm. Conclusion In this non-bDMARD-IR PsA population UPA15/30 demonstrated improvement in musculoskeletal symptoms, psoriasis, physical function, pain, fatigue and inhibited radiographic progression; improvements observed by Wk2. At Wk12, UPA15/30 were non-inferior to ADA for ACR20, with superiority demonstrated for UPA30. Greater percentages of UPA vs PBO patients achieved stringent disease control measures (MDA, ACR50/70, sIGA 0/1). No new safety signals were identified compared to the safety profile observed in RA. Disclosure I. McInnes: Other; I.McI has received research grants and honoraria from Abbvie, BMS, Celgene, Novartis Lilly, Janssen, Pfizer, UCB. J. Anderson: Shareholder/stock ownership; J.A. may be a stock/ shareholder of AbbVie Inc. M. Magrey: Consultancies; M.M. has received consulting fees from Novartis, Eli Lilly, Pfizer, and Janssen. Grants/research support; M.M. has received grants/ research support from Amgen, AbbVie, and UCB Pharma. J.F. Merola: Consultancies; J.F.M. is a consultant for Merck, Abbvie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and Leo Pharma. Y. Liu: None. M. Kishimoto: Consultancies; M.K. has received consulting fees from AbbVie, Eli Lilly, Celgene, Pfizer, Gilead, Janssen, and UCB Pharma. Honoraria; M.K. has received honoraria/ speakers fees from AbbVie, Eisai, Celgene, Pfizer, Novartis, Eli Lilly, Tanabe-Mitsubishi, Ayumi, Janssen, Astellas, and UCB Pharma. S. Jeka: None. C. Pacheco-Tena: None. X. Wang: Shareholder/stock ownership; X.W. may be a shareholder of AbbVie Inc. L. Chen: Shareholder/stock ownership; L.C. may be a stock/shareholder of AbbVie Inc. P. Zueger: Shareholder/stock ownership; P.Z. may be a stock/shareholder of AbbVie Inc. A. Pangan: Shareholder/stock ownership; A.P. may be a stock/shareholder of AbbVie Inc. F. Behrens: Honoraria; F.B. has received honoraria and speakers fees from Pfizer, AbbVie, Sanofi, Lilly, Novartis, UCB, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai. Grants/research support; F.B. has received grants/ research support from Pfizer, Janssen, Chugai, Celgene and Roche.

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SAT0151 EFFICACY AND SAFETY OF UPADACITINIB VERSUS ABATACEPT IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (SELECT-CHOICE): A DOUBLE-BLIND, RANDOMIZED CONTROLLED PHASE 3 TRIAL

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2059 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1015-1016

Author(s):

A. Rubbert-Roth ◽

J. Enejosa ◽

A. Pangan ◽

R. Xavier ◽

B. Haraoui ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Study Drug ◽

Signs And Symptoms ◽

Drug Discontinuation ◽

Inadequate Response ◽

Research Support ◽

Phase 3 ◽

Double Blind ◽

Biologic Dmards

Background:Upadacitinib (UPA) is an oral, reversible, selective JAK 1 inhibitor approved for the treatment of moderate to severe rheumatoid arthritis (RA). The efficacy/safety of UPA has been demonstrated in phase 3 studies, including superiority to adalimumab in patients (pts) with prior inadequate response (IR) to methotrexate.1-4Objectives:To assess the efficacy/safety of UPA vs abatacept (ABA) in pts with prior IR or intolerance to biologic DMARDs (bDMARDs).Methods:Pts were randomized to once daily UPA 15 mg or intravenous ABA (at Day 1, Weeks [Wks] 2, 4, 8, 12, 16 and 20 [< 60 kg: 500 mg; 60-100 kg: 750 mg; >100 kg: 1,000 mg]), with all pts continuing background stable csDMARDs. The study was double-blind for 24 wks. Starting at Wk 12, pts who did not achieve ≥20% improvement from baseline (BL) in both tender and swollen joint counts at two consecutive visits, had background medication(s) adjusted or initiated. The primary endpoint was change from BL in DAS28(CRP) at Wk 12 (non-inferiority). The non-inferiority of UPA vs ABA was tested using the 95% CI of treatment difference against a non-inferiority margin of 0.6. The two key secondary endpoints at Wk 12 were change from BL in DAS28(CRP) and the proportion of pts achieving clinical remission (CR) based on DAS28(CRP), defined as DAS28(CRP) <2.6. Both endpoints were to demonstrate the superiority of UPA vs. ABA. Treatment-emergent adverse events (TEAEs) are reported up to Wk 24 for all pts who received at least one dose of study drug.Results:Of 612 pts treated; 67% of pts had received 1 prior bDMARD, 22% received 2 prior bDMARDs, and 10% received ≥ 3 prior bDMARDs. 549 (90%) completed 24 wks of treatment. Common reasons for study drug discontinuation were AEs (UPA, 3.6%; ABA, 2.6%) and withdrawal of consent (UPA, 1.7%; ABA, 2.6%).Non-inferiority and superiority were met for UPA vs ABA at Wk 12 for change from BL in DAS28(CRP) (-2.52 vs -2.00; -0.52 [-0.69, -0.35]; p <0.001 for UPA vs ABA). UPA also demonstrated superiority to ABA in achieving DAS28(CRP) <2.6 (30.0% vs 13.3%; p <0.001 for UPA vs ABA; Figure 1). Improvements in disease activity and remission rates were maintained through Wk 24. The proportions of pts achieving low disease activity (defined as DAS28(CRP) ≤3.2), ACR20, ACR50, and ACR70 responses were greater with UPA compared with ABA at Wk 12 (nominal p <0.05). More stringent outcome measures – CR, ACR50, and ACR70 responses - remained higher with UPA than ABA through Wk 24 (nominal p <0.05). Incidence of serious TEAEs, AEs leading to discontinuation, hepatic disorders, and CPK elevations were numerically higher with UPA versus ABA (Figure 2). Eight cases of herpes zoster were reported (4 in each treatment arm). No malignancies were reported. One case of adjudicated MACE, two adjudicated cases of VTE (1 pt with DVT and 1 pt with PE; both pts had at least one risk factor for VTE), and one treatment-emergent death were reported with UPA.Conclusion:In RA pts with a prior IR or intolerance to bDMARDs, UPA demonstrated superior improvement in signs and symptoms vs ABA based on change in DAS28(CRP) and in achieving CR at Wk 12. The safety profile of UPA was consistent with the phase 3 RA studies with no new risks identified.References:[1]Burmester GR, et al. Lancet. 2018;391(10139):2503-12[2]Fleischmann R, et al. Arthritis Rheumatol. 2019;71(11):1788-800[3]Genovese MC, et al. Lancet. 2018;391(10139):2513-24[4]Smolen JS, et al. Lancet. 2019;393(10188):2303-11Disclosure of Interests:Andrea Rubbert-Roth Consultant of: Abbvie, BMS, Chugai, Pfizer, Roche, Janssen, Lilly, Sanofi, Amgen, Novartis, Jeffrey Enejosa Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Aileen Pangan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ricardo Xavier Consultant of: AbbVie, Pfizer, Novartis, Janssen, Eli Lilly, Roche, Boulos Haraoui Grant/research support from: Abbvie, Amgen, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, BMS, Janssen, Pfizer, Roche, and UCB, Consultant of: Abbvie, Amgen, Lilly, Pfizer, Sandoz, UCB, Consultant of: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Janssen, Merck, Pfizer, Roche, and UCB, Speakers bureau: Pfizer, Speakers bureau: Amgen, BMS, Janssen, Pfizer, and UCB, Maureen Rischmueller Consultant of: Abbvie, Bristol-Meyer-Squibb, Celgene, Glaxo Smith Kline, Hospira, Janssen Cilag, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Nasser Khan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ying Zhang Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Naomi Martin Shareholder of: AbbVie Inc., Employee of: AbbVie 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

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194. Combinatorial Polyfunctionality Analysis of Antigen-specific T-cell Subsets (COMPASS) as a Predictor for Clinically Significant CMV Infection in the Letermovir Era

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.504 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S225-S226

Author(s):

Danniel Zamora ◽

Elizabeth Duke ◽

Hu Xie ◽

Bradley Edmison ◽

Brenda Akoto ◽

...

Keyword(s):

T Cell ◽

Panel Member ◽

T Cell Responses ◽

Preemptive Therapy ◽

Cmv Infection ◽

Research Support ◽

Review Panel ◽

Cell Responses ◽

Cytokine Responses ◽

Clinically Significant

Abstract Background Increased CMV reactivation is observed following discontinuation of letermovir prophylaxis after hematopoietic cellular transplantation (HCT) and decreased CMV-specific polyfunctional T-cell immunity has been proposed as a possible mechanism (BBMT 2020;26:S68). COMPASS is a novel analytical tool that integrates polyfunctional T-cell cytokine responses into a single score value (Nat Biotechnol 2015;33:610). We employed COMPASS for the first time in the HCT setting to determine if CMV-specific immunodeficiency is associated with late CMV events in a prospective cohort of allogeneic HCT recipients receiving either letermovir or preemptive therapy. Methods Peripheral blood mononuclear cells were collected 3 months post-HCT and assessed with a 13-color intracellular cytokine staining (ICS) assay that includes 5 functional markers. Intermediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) were used to stimulate polyfunctional T-cell responses that were defined using COMPASS generated polyfunctionality scores (PFS). CMV DNAemia was monitored by weekly plasma PCR and patients who reactivated were treated with preemptive therapy per institutional standards. Cumulative incidence of clinically significant CMV infection (cs-CMV; ≥500 IU/mL or CMV disease) by day 270 was assessed. Univariable and multivariable Cox regression were used to estimate the association of polyfunctional T-cell responses (upper quartile versus lower 3 quartiles) with cs-CMV infection by day 270 post-HCT. Results 56 letermovir recipients and 93 preemptive controls were evaluated. Time to first clinically significant CMV (cs-CMV) infection after HCT and among day 100 survivors in both groups is shown in Figure 1. COMPASS PFS at 3 months were significantly lower in letermovir recipients (Figure 2). After adjusting for CMV infection before day 100, CD4 and CD8 PFS to IE-1 and pp65 below the upper quartile were associated with higher risk of late cs-CMV infection, with IE-1 CD8 PFS reaching statistical significance (Figure 3). Conclusion Our findings demonstrate that COMPASS is a valuable tool to evaluate multiple, T-cell cytokine responses to CMV in HCT recipients. COMPASS appears to be useful to identify patients at risk for late cs-CMV infection. Disclosures Elizabeth Duke, MD, Merck (Grant/Research Support) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support)

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Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2018016493 ◽

2018 ◽

Vol 2 (16) ◽

pp. 2159-2175 ◽

Cited By ~ 37

Author(s):

Kaiwen Chen ◽

Matthew P. Cheng ◽

Sarah P. Hammond ◽

Hermann Einsele ◽

Francisco M. Marty

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Preemptive Therapy ◽

Antiviral Prophylaxis ◽

Cmv Infection ◽

Allogeneic Hct ◽

All Cause Mortality ◽

Cmv Disease

Abstract Patients treated with allogeneic hematopoietic cell transplantation (HCT) are at risk of cytomegalovirus (CMV) reactivation and disease, which results in increased morbidity and mortality. Although universal antiviral prophylaxis against CMV improves outcomes in solid organ transplant recipients, data have been conflicting regarding such prophylaxis in patients undergoing allogeneic HCT. We conducted a systematic review of randomized trials of prophylactic antivirals against CMV after allogeneic HCT to summarize the evolution of the field over the last 35 years and evaluate the prophylactic potential of antiviral agents against CMV after allogeneic HCT. Electronic databases were queried from database inception through 31 December 2017. For included studies, incidence of CMV infection and all-cause mortality were collected as primary outcomes; CMV disease incidence, use of preemptive therapy, and drug toxicities were collected as secondary outcomes. Nineteen clinical trials conducted between 1981 and 2017 involving a total of 4173 patients were included for review. Prophylactic strategies included use of acyclovir, valacyclovir, ganciclovir, maribavir, brincidofovir, and letermovir compared with placebo or a comparator antiviral. Fourteen trials that compared antiviral prophylaxis with placebo demonstrated overall effectiveness in reducing incidence of CMV infection (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.42-0.58), CMV disease (OR, 0.56; 95% CI, 0.40-0.80), and use of preemptive therapy (OR, 0.51; 95% CI, 0.42-0.62; 6 trials); however, none demonstrated reduction in all-cause mortality (OR, 0.96; 95% CI, 0.78-1.18) except the phase 3 trial of letermovir (week-24 OR, 0.59; 95% CI, 0.38-0.98). Additional research is warranted to determine patient groups most likely to benefit from antiviral prophylaxis and its optimal deployment after allogeneic HCT.

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1742. Kinetics of CMV Viremia with Letermovir Prophylaxis in the First 100 Days post Hematopoietic Cell Transplantation (HCT): A Single-center Experience

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1605 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S638-S638

Author(s):

Phaedon D Zavras ◽

Anat Stern ◽

Yiqi Su ◽

Jiaqi Fang ◽

Sergio Giralt ◽

...

Keyword(s):

Retrospective Cohort ◽

Hematopoietic Cell Transplantation ◽

Preemptive Therapy ◽

Single Center ◽

Cmv Infection ◽

Single Center Experience ◽

Clinically Significant ◽

Kinetics Of ◽

Cmv Reactivation ◽

Historical Controls

Abstract Background Letermovir (LTV) is approved for the prevention of CMV infection in CMV seropositive (R+) HCT recipients. Low rates of CMV breakthrough viremia have been reported with LTV prophylaxis. We studied the kinetics of CMV reactivation up to day (D) +100 in patients (patients) receiving LTV prophylaxis and compared them to historical controls not receiving LTV. Methods Retrospective cohort study of CMV R+ recipients of peripheral blood or marrow allografts at MSKCC during 2017–2018. Routine LTV prophylaxis was implemented in MSKCC in December 2017. Patients were categorized based on LTV prophylaxis to LTV group (LTV prophylaxis) and no LTV group [managed with preemptive therapy (PET)]. Routine CMV monitoring was performed weekly by a qPCR assay in plasma from D +14 through D +100. CMV viremia was defined as any detectable CMV viral load (VL). Clinically significant CMV viremia (csCMV) was defined as any CMV VL treated preemptively. CMV end-organ disease (EOD) was assessed by standard criteria. LTV resistance was tested at Viracor-Eurofins Laboratories after May 2018. Results Of 193 R+ HCT, 98 (50.8%) were in the LTV and 95 (49.2%) in the no LTV group. CMV viremia occurred in 43 (43.9%) patients in LTV and 63 (66.3%) in no LTV (Figure 1). CMV viremia occurred earlier in LTV compared with no LTV (median, 19 vs. 26 days post HCT, respectively, P = 0.009). The duration of CMV viremia was shorter in LTV compared with no LTV (median 16 days vs. 35 days, respectively; P < 0.0001). The peak CMV VL was lower in LTV compared with no LTV (median, 137 IU/mL vs. 578 IU/mL, respectively); P < 0.0001. Rates of csCMV viremia were significantly lower in LTV compared with no LTV (5.1% vs. 54%, respectively); P < 0.0001 (Figure 2). LTV group received a total of 134 PET-days and no LTV group received 2,160 PET-days by D +100. No patient in LTV developed CMV EOD, while two patients in no LTV developed CMV duodenitis. LTV resistance was documented in 2 patients (2% of the LTV group). Overall survival by D +100 was similar between LTV and no LTV groups. Conclusion Implementation of LTV prophylaxis significantly reduced rates of csCMV infection and resulted in 93.8% reduction in total PET days. Among patients with csCMV viremia, LTV group had a shorter duration of viremia and lower peak CMV VL compared with no LTV. Disclosures All authors: No reported disclosures.

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167. A Phase 1b, Randomized, Double-blind, Placebo-controlled, Multiple-ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S in Patients with staphylococcus Aureus Bacteremia Receiving Standard-of-care Antibiotics

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.477 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S213-S213

Author(s):

Jeremy Lim ◽

Nicholas Lewin-Koh ◽

Tom Chu ◽

Sharon M Rymut ◽

Aklile Berhanu ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Healthy Volunteers ◽

Study Drug ◽

Standard Of Care ◽

Research Support ◽

Double Blind ◽

Double Blind Placebo ◽

Staphylococcus Aureus Bacteremia ◽

Phase 1B ◽

Research Grant

Abstract Background New treatment approaches for complicated Staphylococcus aureus bacteremia (SAB) are needed. DSTA4637S is a THIOMABTM antibody-antibiotic conjugate consisting of an engineered human IgG1 monoclonal antibody that binds to wall teichoic acid at the surface of S. aureus, a protease-cleavable linker, and a novel rifamycin class antibiotic, dmDNA31. This Phase 1b study assessed the safety, tolerability, and pharmacokinetics of DSTA4637S in patients with complicated SAB. Methods Multicenter, double-blind, placebo controlled, multiple-ascending dose clinical trial. Patients 18–79 years old with complicated SAB requiring at least 4 weeks of IV anti-staphylococcal standard-of-care (SOC) antibiotics were randomized to receive 4–6 doses of 15, 45, and 100 mg/kg IV DSTA4637S or placebo (6 active:2 placebo) every 7 days in combination with SOC antibiotics. Patients needed ≥ 1 blood culture positive for S. aureus collected within 120 hours prior to randomization. Patients were followed for 120 days after the end of treatment. Results Twenty-five patients with complicated SAB (bone & joint, n=14; endocarditis, n=5; other endovascular, n=5; pneumonia, n=1) were randomized and received 1–6 doses of study drug (19 active:6 placebo). Nine patients (36%) had MRSA. Ten patients completed ≥4 doses of DSTA4637S. The most common treatment-related adverse events were infusion-related reactions (IRRs) (5/19), and abnormal serum color (5/19)/skin discoloration (3/19 (due to dmDNA31). IRRs were not dose-dependent and were reversible with supportive care. Ten of 19 patients (40%) discontinued study drug (9 DSTA4637S,1 placebo); 4/19 (21%) due to IRR. DSTA4637S recipients showed no dose-related changes in laboratory values or vital signs vs. placebo. Observed exposures (Cmax and AUC) were lower in patients immediately after dosing compared to a prior study in healthy volunteers; minimal accumulation occurred. No obvious trends in exploratory bacterial and inflammatory biomarkers were observed between treatment groups. Conclusion DSTA4637S in patients with complicated SAB demonstrated increased IRRs and decreased exposure compared to healthy volunteers, highlighting the importance of Phase I studies of novel treatments in infected SAB patients and not simply healthy controls. Disclosures Jeremy Lim, PharmD, Roche (Employee, Shareholder) Nicholas Lewin-Koh, PhD, Genentech (Employee) Tom Chu, MD, PhD, Genentech (Employee) Sharon M. Rymut, PhD, Genentech (Employee, Shareholder) Aklile Berhanu, PhD, Genentech, Inc. (Employee, Equity interest (Stock/Stock Options)) Montserrat Carrasco-Triguero, PhD, Genentech (Employee) Carrie C. Rosenberger, PhD, Genentech (Employee, Shareholder) Wouter L. Hazenbos, PhD, Genentech (Employee) Loren G. Miller, MD, MPH, genentech (Grant/Research Support) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) Jose M Miro, MD PhD, GENENTECH (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member) Jessica A. Couch, PhD, Genentech (Employee, Shareholder) Melicent C. Peck, MD, PhD, Genentech (Employee)

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A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus (CMV) in CMV-seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation

Clinical Infectious Diseases ◽

10.1093/cid/ciz490 ◽

2019 ◽

Vol 70 (8) ◽

pp. 1525-1533 ◽

Cited By ~ 23

Author(s):

Per Ljungman ◽

Michael Schmitt ◽

Francisco M Marty ◽

Johan Maertens ◽

Roy F Chemaly ◽

...

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Phase 3 ◽

Kaplan Meier ◽

Hazard Ratios ◽

All Cause Mortality ◽

Clinically Significant ◽

Status Data

Abstract Background In a phase 3 trial, letermovir reduced clinically significant cytomegalovirus infections (CS-CMVi) and all-cause mortality at week 24 versus placebo in CMV-seropositive allogeneic hematopoietic cell transplantation (HCT) recipients. This post hoc analysis of phase 3 data further investigated the effects of letermovir on all-cause mortality. Methods Kaplan-Meier survival curves were generated by treatment group for all-cause mortality. Observations were censored at trial discontinuation for reasons other than death or at trial completion. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox modeling, adjusting for risk factors associated with mortality. Results Of 495 patients with no detectable CMV DNA at randomization, 437 had vital-status data available through week 48 post-HCT at trial completion (101 deaths, 20.4%). Following letermovir prophylaxis, the HR for all-cause mortality was 0.58 (95% CI, 0.35–0.98; P = .04) at week 24 and 0.74 (95% CI, 0.49–1.11; P = .14) at week 48 post-HCT versus placebo. Incidence of all-cause mortality through week 48 post-HCT in the letermovir group was similar in patients with or without CS-CMVi (15.8 vs 19.4%; P = .71). However, in the placebo group, all-cause mortality at week 48 post-HCT was higher in patients with versus those without CS-CMVi (31.0% vs 18.2%; P = .02). The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21–1.00; P = .05) at week 48 for letermovir versus placebo. Conclusions Letermovir may reduce mortality by preventing or delaying CS-CMVi in HCT recipients. Clinical Trials Registration clinicaltrials.gov, NCT02137772.

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LB0001 EFFICACY AND SAFETY OF UPADACITINIB VERSUS PLACEBO AND ADALIMUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND INADEQUATE RESPONSE TO NON-BIOLOGIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (SELECT-PsA-1): A DOUBLE-BLIND, RANDOMIZED CONTROLLED PHASE 3 TRIAL

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6727 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 16.2-17

Author(s):

I. Mcinnes ◽

J. Anderson ◽

M. Magrey ◽

J. F. Merola ◽

Y. Liu ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Study Drug ◽

Musculoskeletal Symptoms ◽

Inadequate Response ◽

Efficacy And Safety ◽

Research Support ◽

Self Assessment ◽

Double Blind ◽

Biologic Dmard ◽

Secondary Endpoints

Background:Upadacitinib (UPA) is an oral, reversible, JAK inhibitor approved for treatment of rheumatoid arthritis (RA) and currently under evaluation for treatment of psoriatic arthritis (PsA).Objectives:To assess the efficacy and safety of UPA vs placebo (PBO) and adalimumab (ADA) in patients (pts) with PsA and prior IR or intolerance to ≥1 non-biologic DMARD (non-bDMARD).Methods:Pts with active PsA (≥3 swollen and ≥3 tender joints), active or historical psoriasis, and on ≤2 non-bDMARDs were randomized 1:1:1:1 to once daily UPA 15 mg (UPA15), UPA 30 mg (UPA30), ADA 40 mg every other week, or PBO. The primary endpoint was the proportion of pts achieving ACR20 for UPA vs PBO at Wk 12. Multiplicity controlled secondary endpoints for each dose of UPA vs PBO included change in HAQ-DI, FACIT-F, and SF-36 PCS (Wk 12); static Investigator Global Assessment of Psoriasis of 0 or 1, PASI75, and change in Self-Assessment of Psoriasis Symptoms (Wk 16); change in modified Sharp/van der Heijde Score (mTSS), proportion of pts achieving MDA, and resolution of enthesitis (LEI=0) and dactylitis (LDI=0) (Wk 24). For each dose of UPA, the multiplicity-controlled analysis also included non-inferiority and superiority vs ADA for ACR20 and superiority for HAQ-DI and pt’s assessment of pain NRS (Wk 12). ACR50/70 at Wk 12 and ACR20 at Wk 2 were additional secondary endpoints. Treatment-emergent adverse events (TEAEs) through 24 wks are reported for pts who received ≥1 dose of study drug.Results:1705 pts were randomized; 1704 received study drug (53.2% female, mean age 50.8 yrs, mean duration of PsA diagnosis 6.1 yrs). 82% were on ≥1 concomitant non-bDMARD, of whom 84% received MTX +/- another non-bDMARD.At Wk 12, ACR20 rates were 70.6% with UPA15 and 78.5% with UPA30 vs 36.2% with PBO (p < .001 for UPA15/30 vs PBO) and 65.0% with ADA (non-inferiority, p < .001 for UPA15/30 vs ADA; superiority, p < .001 for UPA30 vs ADA). A greater proportion of pts achieved ACR50/70 with UPA15/30 vs PBO and UPA30 vs ADA. Improvements were observed with UPA15/30 vs PBO for all multiplicity controlled secondary endpoints and for UPA 15/30 vs ADA for HAQ-DI and UPA 30 vs ADA for improvement in pain (Figure 1A-1B). At Wk 24, change in mTSS was 0.25 for PBO, -0.04 for UPA15, 0.03 for UPA30, and 0.01 for ADA (p < 0.001 for UPA15/30 vs PBO). The rates of TEAEs and serious AEs, including serious infections, were similar in the PBO, UPA15, and ADA arms and higher with UPA30 (Figure 2). The rate of herpes zoster was similar for PBO and UPA15/30. No MACE was reported with UPA. One malignancy occurred in each of the PBO and UPA15 arms, and 3 malignancies were reported in each of the UPA30 and ADA arms. VTE were reported in 1 pt on PBO, 1 pt on UPA30, and 2 pts on ADA. One death occurred in the PBO arm.Conclusion:In this non-bDMARD-IR PsA population, treatment with UPA15/30 demonstrated improvement in musculoskeletal symptoms, psoriasis, physical function, pain, and fatigue and inhibited radiographic progression; improvements were observed by Wk 2. At Wk 12, UPA15/30 were non-inferior to ADA for ACR20, with superiority demonstrated for UPA30. Greater percentages of UPA vs PBO pts achieved stringent measures of disease control (MDA, ACR50/70, sIGA 0/1). No new safety signals were identified compared with the safety profile observed in RA.Disclosure of Interests:Iain McInnes: None declared, Jaclyn Anderson Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Marina Magrey Grant/research support from: Amgen, AbbVie, and UCB Pharma, Consultant of: Novartis, Eli Lilly, Pfizer, and Janssen, Joseph F. Merola Consultant of: Merck, Abbvie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and Leo Pharma, Yi Liu: None declared, Mitsumasa Kishimoto Consultant of: bbVie, Eli Lilly, Celgene, Pfizer, Gilead, Janssen, and UCB Pharma, Speakers bureau: AbbVie, Eisai, Celgene, Pfizer, Novartis, Eli Lilly, Tanabe-Mitsubishi, Ayumi, Janssen, Astellas, and UCB Pharma, Sławomir Jeka Speakers bureau: AbbVie, Pfizer, Roche, Novartis, MSD, Sandoz, Eli Lilly, Egis, UCB, Celgene, Cesar Francisco Pacheco Tena: None declared, xin wang Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Liang Chen Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Patrick Zueger Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Aileen Pangan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, UCB, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai

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The Efficacy and Safety of Fentiazac and Diclofenac Sodium in Peri-Arthritis of the Shoulder: A Multi-Centre, Double-Blind Comparison

Journal of International Medical Research ◽

10.1177/030006058701500601 ◽

1987 ◽

Vol 15 (6) ◽

pp. 327-334 ◽

Cited By ~ 9

Author(s):

N. Thumb ◽

G. Kolarz ◽

O. Scherak ◽

F. Mayrhofer

Keyword(s):

Rating Scales ◽

Rating Scale ◽

External Rotation ◽

Treated Patient ◽

Diclofenac Sodium ◽

Pain Severity ◽

Efficacy And Safety ◽

Double Blind ◽

Clinically Significant ◽

Blind Comparison

In a double-blind parallel group comparison of efficacy and safety, 19 patients with peri-arthritis of the shoulder received 200 mg fentiazac twice daily and 19 received 50 mg diclofenac sodium twice daily, with both drugs given orally for 3 weeks. In both groups, observers' verbal rating scales of pain severity at rest and on movement showed decreases that were significant by week 1. Both groups also had significant improvement in abduction, external rotation, retroversion and anteversion. At week 1, the patients reported improvement, on a verbal rating scale, of global effectiveness, but there were no subsequent changes. There were no statistically significant differences between the treatments in any of these variables. Five (26%) fentiazac-treated patients and four (21%) diclofenac sodium-treated patients reported adverse effects, mostly gastro-intestinal. One case of rash in each group and one case of pruritus in a diclofenac sodium-treated patient were severe enough for the patients to be withdrawn from therapy. There were no clinically significant changes in laboratory values. It was concluded that fentiazac (400 mg/day) and diclofenac sodium (100 mg/day) were equally effective within 1 week in decreasing pain severity and improving shoulder mobility.

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