Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia: A Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).

Cost-effectiveness of tildrakizumab for the treatment of moderate-to-severe psoriasis in the United States.

OBJECTIVE: To evaluate the relative cost-effectiveness of tildrakizumab and other biologic and targeted systemic treatments compared with a mix of topical therapies, phototherapies, and other conventional systemic therapies as first-line treatment for moderate-to-severe plaque psoriasis from a United States payer's perspective. METHODS: A Markov model consisting of health states based on Psoriasis Area Severity Index (PASI) response rate categories and death was developed. The probabilities of achieving PASI responses were derived from a network meta-analysis based on published efficacy data. Health care costs and effectiveness measured in quality-adjusted life-years (QALYs) were estimated. Incremental costs per QALY gained of each biologic/targeted first-line treatment versus a mix of conventional treatments were compared to provide relative cost-effectiveness among biologic and targeted first-line treatments. RESULTS: Over 10 years, the incremental cost per QALY gained compared with a mix of topical therapies, phototherapies, and other oral systemic therapies was lowest for brodalumab, infliximab, apremilast, and tildrakizumab, followed by secukinumab, ixekizumab, guselkumab, adalimumab, ustekinumab, and etanercept. The position of tildrakizumab relative to the other treatments remained the same across multiple scenarios. CONCLUSIONS: Tildrakizumab is among the most cost-effective first-line therapies for moderate-to-severe plaque psoriasis and is more cost-effective than secukinumab, ixekizumab, guselkumab, adalimumab, ustekinumab, and etanercept.

Efficacy of Antistaphylococcal Lysin LSVT-1701 in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus.

We utilized the rabbit model of aortic valve infective endocarditis to examine the combined efficacy of the lysin LSVT-1701 plus daptomycin. The combination of LSVT-1701 plus daptomycin was highly effective at reducing methicillin-resistant Staphylococcus aureus (MRSA) counts in target tissue. When given for four daily doses, both lysin dose regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as an adjunctive therapy for the treatment of invasive MRSA infections.

Comparative cost-effectiveness of tildrakizumab and other commonly used treatments for moderate-to-severe psoriasis.

OBJECTIVES: To compare the cost-effectiveness of tildrakizumab with other commonly used biologics and apremilast as the first-line treatment for moderate-to-severe plaque psoriasis from a US health plan's perspective. METHODS: A 10-year cost-effectiveness model was developed to compare the incremental cost per extra month with a Psoriasis Area and Severity Index (PASI) 75 response. Patients were assumed to receive one of the treatments evaluated as their first-line treatment at the outset of the analysis. Nonresponders (PASI <75) discontinued their current treatment; 25% went on to receive a mix of topical therapies, phototherapies, and other systemic therapies, while 75% received a second-line therapy before receiving a mix of topical therapies, phototherapies, and other systemic therapies. Direct medical costs were calculated based on drug acquisition, administration, and monitoring costs. RESULTS: The incremental cost per extra month a patient had a PASI 75 response was lowest for brodalumab ($3,685), infliximab ($4,102), apremilast ($4,770), and tildrakizumab ($5,150), followed by risankizumab ($5,319), secukinumab ($5,675), guselkumab ($5,784), ixekizumab ($5,900), adalimumab ($5,943), ustekinumab ($6,131), etanercept ($6,618), and certolizumab pegol ($13,476). CONCLUSION: Tildrakizumab was among the most cost-effective first-line treatments for moderate-to-severe psoriasis and was more cost-effective than risankizumab, secukinumab, guselkumab, ixekizumab, adalimumab, ustekinumab, etanercept, and certolizumab pegol.

The Budget Impact of Introducing Tildrakizumab to a United States Health Plan for Managing Moderate-to-Severe Plaque Psoriasis.

OBJECTIVE: The aim of this study was to evaluate the budget impact of introducing tildrakizumab for moderate-to-severe plaque psoriasis from a US health plan perspective. METHODS: A budget impact model estimated costs before and after the adoption of tildrakizumab to a hypothetical US health plan with 1 million covered lives over 5 years. Additionally, the model included adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab, ustekinumab, and apremilast; biosimilars were not included. Model input data were obtained from the published literature, clinical trials, and prescription data. Market uptake for tildrakizumab was assumed as 1% annually over 5 years. Patients initiating or switching treatments required induction dosing; all others treated required maintenance dosing. The model compared the total annual costs for tildrakizumab versus treatment without tildrakizumab to calculate budget impact in 2018 US dollars. Scenarios exploring alternative assumptions for adverse events and market uptake rates were assessed, and a one-way sensitivity analysis was conducted. RESULTS: Within a health plan of 1 million members with an estimated 1048 patients receiving biologics or apremilast for psoriasis, the total annual health plan cost after introducing tildrakizumab decreased by $5585, $137,025, $205,538, $274,051, and $342,563 in years 1-5, respectively, resulting in a cumulative reduction of $964,763 over 5 years. The impact on total cost was largely due to drug acquisition costs. The incremental per member per month (PMPM) cost reductions were negligible in year 1, $0.01 in year 2, $0.02 in years 3-4, and $0.03 in year 5. Scenario and sensitivity analyses confirmed the model robustness. CONCLUSIONS: The introduction of tildrakizumab with a 1% annual uptake over 5 years has the potential to reduce the cost of treating patients with moderate-to-severe plaque psoriasis for a US health plan.

Sustained and continuously improved efficacy of tildrakizumab in patients with moderate-to-severe plaque psoriasis.

Background: Tildrakizumab is a high-affinity, humanized, IgG1 κ, anti-interleukin-23 monoclonal antibody approved for moderate-to-severe plaque psoriasis.Objectives: This analysis examined whether tildrakizumab's week-28 efficacy can be sustained or improved to week 52.Methods: Psoriasis patients on the same-dose tildrakizumab (100 or 200 mg) in the first 52 weeks achieving week-28 PASI ≥50 were pooled from two phase-3 randomized controlled trials, and grouped into four mutually exclusive week-28 PASI response groups. Patients' week-52 PASI responses were compared to their week-28 PASI responses.Results: Of 352 patients receiving 100-mg tildrakizumab, 10.5%, 25.3%, 38.4%, and 25.9% achieved PASI 50-74, 75-89, 90-99, and 100 at week 28, respectively. Among patients achieving PASI ≥90, ≥75, or ≥50 at week 28, 89.4%, 91.1%, or 97.4% maintained their week-28 PASI responses at week 52, respectively. Among patients achieving PASI 50-74, 75-89, or 90-99 at week 28, 64.8%, 33.7%, or 25.2% improved their week-28 PASI responses at week 52, respectively.Limitations: This post hoc analysis may be less robust than an a priori analysis.Conclusions: Most tildrakizumab-treated patients with week-28 PASI ≥75 maintained their week-28 PASI improvement at week 52. More than half of week-28 partial responders (PASI 50-74) improved their PASI responses to PASI ≥75 at week 52. Clinicaltrials.gov identifiers: NCT01722331, NCT01729754.

Pharmacokinetics of recombinant human antithrombin in delivery and surgery patients with hereditary antithrombin deficiency.

Population pharmacokinetic (PK) analyses were conducted to refine dosing recommendations for recombinant human anti-thrombin therapy in surgery and delivery patients with hereditary antithrombin deficiency (HD). Single-dose PK data from patients with HD and nonlinear mixed-effects modeling were used to devise a dosing regimen to target antithrombin (AT) activity levels between 80% and 120% of normal. External validation with data from a phase 3 trial confirmed the correctness of a covariate-free model for surgery patients, but dosing adjustment was necessary for delivery patients. After different covariates were tested, the model was updated to incorporate the influential covariate, delivery. Simulations were used to develop a therapeutic drug-monitoring scenario that results in steady state AT activity levels within the target range as quickly as practically feasible. Data from a second clinical trial provided additional external validation and confirmed the accuracy of the dosing model for both groups of patients.

Exploring the role of antithrombin replacement for the treatment of preeclampsia: a prospective randomized evaluation of the safety and efficacy of recombinant antithrombin in very preterm preeclampsia (PRESERVE-1).

PROBLEM: Antithrombin (AT) replacement has been described in patients with hereditary AT deficiency undergoing delivery; however, the kinetics of AT replacement in preeclampsia is not adequately understood. Therefore, the Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia (PRESERVE-1) study has been proposed. METHODS: Sixty women aged≥18 years at 24 0/7-28 0/7 weeks' gestation and with hypertension and proteinuria will be enrolled and randomly assigned to receive recombinant human AT or placebo until fetal and/or maternal indications cause cessation of expectant management or until 34 0/7 weeks' gestation. The primary endpoint is the increase in gestational age from randomization to delivery. Safety assessments and laboratory assays will also be performed. RESULTS: PRESERVE-1 study enrollment will begin during the second half of 2013. CONCLUSION: The PRESERVE-1 study will provide further insight into the pharmacokinetic activity and safety of AT therapy in preeclampsia.

Analgesic effectiveness of celecoxib and diclofenac in patients with osteoarthritis of the hip requiring joint replacement surgery: a 12-week, multicenter, randomized, double-blind, parallel-group, double-dummy, noninferiority study.

BACKGROUND: The hip is the second most common large joint that is affected by osteoarthritis (OA), with prevalence ranging from 3% to 11% in patients aged > or = 35 years. OA is often associated with significant pain, disability, and impaired quality of life. Treatment should be tailored according to the level of pain, disability, and handicap. Pharmacologic treatment options for hip OA include acetaminophen (recommended by the European League Against Rheumatism as a first-line treatment), NSAIDs such as diclofenac, and cyclooxygenase-2-selective NSAIDs such as celecoxib. OBJECTIVE: The purpose of this study was to determine whether celecoxib 200 mg QD is noninferior to diclofenac 50 mg TID in the treatment of OA of the hip. METHODS: This was a 12-week, randomized, double-blind, parallel-group, double-dummy, noninferiority study conducted at 40 centers in the United Kingdom. Patients with OA flare at baseline (determined by visual analog scale [VAS] measurement of > or = 40 to < 90 mm and patient's and physician's global assessments of arthritis ratings of "poor" or "very poor") and awaiting joint replacement surgery were randomized to receive celecoxib QD or diclofenac TID. Patients were excluded if surgery was anticipated within 8 weeks. The United Kingdom National Health Service initiatives on waiting-list times caused a reduction in the number of potential patients available for participation. Therefore, the study protocol was amended such that change from baseline to week 6 (as opposed to week 12) in the patient's assessment of arthritis pain on walking, measured by VAS (0-100 mm), was the primary outcome. Primary analysis was carried out on the evaluable population (subjects with baseline and week 6 arthritis pain on walking VAS scores and no major protocol deviations). Celecoxib was declared noninferior to diclofenac if the upper limit of the 2-sided 95% CI of the treatment difference (celecoxib vs diclofenac) in the mean change from baseline in VAS did not exceed 10 mm. Tolerability was assessed by the documentation of observed and volunteered adverse events (AEs), physical examination findings, sitting blood pressure, and pulse at screening and at the end of the study (week 12 or early withdrawal). RESULTS: A total of 249 patients aged > or = 45 years were randomized to treatment. There were 126 patients in the celecoxib group and 123 patients in the diclofenac group. One patient in the celecoxib group did not receive any treatment and was excluded from analysis. Additionally, 54 patients in the celecoxib group and 45 patients in the diclofenac group discontinued treatment due to AEs and/or lack of treatment effectiveness. Therefore, 71 patients in the celecoxib group and 78 patients in the diclofenac group completed the study. No significant differences in demographic characteristics were observed between treatment groups. The mean (SD) age was 64.0 (9.0) years, 53.9% (76/141) of the patients were men and 46.1% (65/141) were women, and 99.3% (140/141) were white. At weeks 6 and 12, the patient's assessment of arthritis pain on walking (VAS) improved in both groups (-20.0 [23.6] mm in the celecoxib group and -35 [27.0] mm in the diclofenac group [mean treatment difference, 14.4 mm; 95% CI, 6.1 to 22.7]). However, treatment differences in change from baseline favored diclofenac at week 6 (14.4 mm; 95% CI, 6.1 to 22.7) and week 12 (12.2 mm; 95% CI, 2.2 to 22.1). A post hoc analysis, performed after unblinding due to an imbalance in the numbers of patients previously receiving NSAIDs, found a greater treatment difference at week 6 between celecoxib and diclofenac in arthritis pain, favoring diclofenac, in previous nonusers of NSAIDs (n = 49, 18.6 mm; 95% CI, 4.5 to 32.8) compared with previous NSAID users (n = 92, 9.5 mm; 95% CI, -0.4 to 19.3). Celecoxib and diclofenac were generally well tolerated. A similar proportion of patients in both treatment groups experienced AEs (all causality): 67/125 of celecoxib-treated patients (53.6%) compared with 66/123 of diclofenac-treated patients (53.7%). CONCLUSION: This study did not demonstrate noninferiority of celecoxib 200 mg QD to diclofenac 50 mg TID in treating arthritis pain in patients with OA of the hip requiring joint replacement.