Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies.

OBJECTIVES: The phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases. METHODS: MANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for 'reversibility'. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints. RESULTS: Across both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ-1.7% (95% CI -9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events. CONCLUSIONS: Results suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract.

BACKGROUND: Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). METHODS: Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. RESULTS: From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. CONCLUSIONS: Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.

A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients.

BACKGROUND: Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections. METHODS: Patients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/µL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28. RESULTS: From 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, -0.33 log10 copies/mL; 95% confidence interval [CI] -.64 to -.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22-1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo. CONCLUSIONS: Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia. CLINICAL TRIALS REGISTRATION: NCT02254408; EUDRA-CT#2014-002474-36.

Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus.

This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported. Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but they had similar clinical outcomes. Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with genotypic resistance development had decreased virologic responses compared to those without genotypic resistance but had comparable clinical outcomes.

Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus.

Background: Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection. Methods: Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen-free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received. Results: Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen-free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]). Conclusions: Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen-free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.

The association between platelet transfusion and idiopathic pneumonia syndrome is unaffected by platelet product type.

BACKGROUND: Methods used to produce platelet (PLT) components, pooling of PLT-rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). STUDY DESIGN AND METHODS: We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. RESULTS: Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP-PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p = 0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p = 0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p = 0.97; 7-day HR 0.98, 95% CI 0.78-1.12, p = 0.47). CONCLUSION: The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS.

Development and validation of a prehospital prediction model for acute traumatic coagulopathy.

BACKGROUND: Acute traumatic coagulopathy (ATC) is a syndrome of early, endogenous clotting dysfunction that afflicts up to 30% of severely injured patients, signaling an increased likelihood of all-cause and hemorrhage-associated mortality. To aid identification of patients within the likely therapeutic window for ATC and facilitate study of its mechanisms and targeted treatment, we developed and validated a prehospital ATC prediction model. METHODS: Construction of a parsimonious multivariable logistic regression model predicting ATC - defined as an admission international normalized ratio >1.5 - employed data from 1963 severely injured patients admitted to an Oregon trauma system hospital between 2008 and 2012 who received prehospital care but did not have isolated head injury. The prediction model was validated using data from 285 severely injured patients admitted to a level 1 trauma center in Seattle, WA, USA between 2009 and 2013. RESULTS: The final Prediction of Acute Coagulopathy of Trauma (PACT) score incorporated age, injury mechanism, prehospital shock index and Glasgow Coma Score values, and prehospital cardiopulmonary resuscitation and endotracheal intubation. In the validation cohort, the PACT score demonstrated better discrimination (area under the receiver operating characteristic curve 0.80 vs. 0.70, p = 0.032) and likely improved calibration compared to a previously published prehospital ATC prediction score. Designating PACT scores ≥196 as positive resulted in sensitivity and specificity for ATC of 73% and 74%, respectively. CONCLUSIONS: Our prediction model uses routinely available and objective prehospital data to identify patients at increased risk of ATC. The PACT score could facilitate subject selection for studies of targeted treatment of ATC.

An International Normalized Ratio-Based Definition of Acute Traumatic Coagulopathy Is Associated With Mortality, Venous Thromboembolism, and Multiple Organ Failure After Injury.

OBJECTIVES: Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy's relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio-based definitions for acute traumatic coagulopathy. DESIGN: Multicenter prospective observational study. SETTING: Nine level I trauma centers in the United States. PATIENTS: A total of 1,031 blunt trauma patients with hemorrhagic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p < 0.001), hemorrhagic shock-associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p < 0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes. CONCLUSIONS: Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold.

The association between red blood cell and platelet transfusion and subsequently developing idiopathic pneumonia syndrome after hematopoietic stem cell transplantation.

BACKGROUND: Blood transfusions are common during hematopoietic stem cell transplantation (HSCT) and may contribute to lung injury. STUDY DESIGN AND METHODS: This study examined the associations between red blood cell (RBC) and platelet (PLT) transfusions and idiopathic pneumonia syndrome (IPS) among 914 individuals who underwent myeloablative allogeneic HSCT between 1997 and 2001. Patients received allogeneic blood transfusions at their physicians' discretion. RBCs, PLTs, and a composite of "other" transfusions were quantified as the sum of units received each 7-day period from 6 days before transplant until IPS onset, death, or Posttransplant Day 120. RBC and PLT transfusions were modeled as separate time-varying exposures in proportional hazards models adjusted for IPS risk factors (age, baseline disease, irradiation dose) and other transfusions. Timing of PLT transfusion relative to myeloid engraftment and PLT ABO blood group (match vs. mismatch) were included as potential interaction terms. RESULTS: Patients received a median of 9 PLT and 10 RBC units. There were 77 IPS cases (8.4%). Each additional PLT unit transfused in the prior week was associated with 16% higher IPS risk (hazard ratio, 1.16; 95% confidence interval, 1.09-1.23; p < 0.001). Recent RBC and PLT transfusions were each significantly associated with greater risk of IPS when examined without the other; only PLT transfusions retained significance when both exposures were included in the model. The PLT association was not modified by engraftment or ABO mismatch. CONCLUSION: PLT transfusions are associated with greater risk of IPS after myeloablative HSCT. RBCs may also contribute; however, these findings need confirmation.

Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment.

Firsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7-fold, and 30-fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment.

Derivation and validation of a noninvasive prediction tool to identify pulmonary hypertension in patients with IPF: Evolution of the model FORD.

BACKGROUND: The administration of inhaled prostanoids to patients with pulmonary hypertension (PH) related to idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases improves functional outcomes. Selection of patients with IPF at risk for concomitant PH to undergo right heart catheterization (RHC) remains challenging. We sought to develop a clinical prediction tool based on common noninvasive parameters to identify PH in patients with IPF. METHODS: A prediction model based on noninvasive parameters was derived from patients enrolled in the ARTEMIS-IPF randomized, placebo-controlled clinical trial. Predictor variables were tested for association with the presence of PH diagnosed based on RHC. The derived multivariable logistic regression model and associated point-score index were then externally validated in a real-world cohort of patients with IPF. RESULTS: Of the 481 patients included in the ARTEMIS-IPF study, 9.8% (N = 47) were diagnosed with PH related to IPF. Four variables were associated with PH and were included in the final model: forced vital capacity/diffusing capacity for carbon monoxide ratio (F), oxygen saturation nadir during 6-minute walk test (6MWT) (O), race (R), and distance ambulated during 6MWT (D). A model containing continuous predictors (FORD calculator) and a simple point-score system (FORD index) performed similarly well in the derivation cohort (area under the curve [AUC]: 0.75 and 0.75, respectively) and validation cohort (AUC: 0.69 and 0.69, respectively). CONCLUSIONS: The FORD models are simple, validated tools incorporating noninvasive parameters that can be applied to identify patients at risk of PH related to IPF who may benefit from invasive testing.

ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis.

BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.

Filgotinib in Active Noninfectious Uveitis: The HUMBOLDT Randomized Clinical Trial.

Importance: Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. Objective: To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. Design, Setting, and Participants: The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Interventions: Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. Main Outcomes and Measures: The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Results: Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Conclusions and Relevance: Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. Trial Registration: ClinicalTrials.gov Identifier: NCT03207815.

Cilofexor in Patients With Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: An Open-Label Phase 1B Study.

INTRODUCTION: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. METHODS: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. DISCUSSION: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

Anemia in critical illness: insights into etiology, consequences, and management.

Anemia is common in the intensive care unit, and may be associated with adverse consequences. However, current options for correcting anemia are not without problems and presently lack convincing efficacy for improving survival in critically ill patients. In this article we review normal red blood cell physiology; etiologies of anemia in the intensive care unit; its association with adverse outcomes; and the risks, benefits, and efficacy of various management strategies, including blood transfusion, erythropoietin, blood substitutes, iron therapy, and minimization of diagnostic phlebotomy.

Pharmacokinetics, pharmacodynamics, safety and tolerability of cilofexor, a novel nonsteroidal Farnesoid X receptor agonist, in healthy volunteers.

Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n = 15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least one dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose-proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor area under the plasma concentration versus time curve (AUC) by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses >30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in phase II studies in patients with NASH and PSC.

Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.

Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.

BACKGROUND AND OBJECTIVE: Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator. METHODS: In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters. RESULTS: In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone. CONCLUSION: Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.

Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Firsocostat, a liver-targeted acetyl-coenzyme A carboxylase inhibitor, and cilofexor, a nonsteroidal farnesoid X receptor agonist, are being developed in combination for treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated firsocostat and cilofexor pharmacokinetics and tolerability in participants with severe renal impairment (SRI) and healthy matched controls (HMCs). Ten participants with SRI (estimated glomerular filtration rate by Modification of Diet in Renal Disease <30 mL/min/1.73 m2 ), and 10 HMCs received single oral doses of firsocostat (20 mg) on day 1 and cilofexor (100 mg) on day 7 in a fasted state. Plasma concentrations of firsocostat (and nonactive metabolite GS-834773) and cilofexor (and nonactive metabolites GS-716070 and GS-1056756) were collected over 96 hours and quantified; plasma exposures (area under the concentration-time curve [AUC] and peak concentration [Cmax ]) and plasma protein binding were characterized. Firsocostat AUC was ≈40% higher in SRI versus HMC, while Cmax was 8% lower. Observed exposures of the firsocostat metabolite were ≈4.6-fold higher in SRI participants versus HMC. Exposures (AUC and Cmax ) of cilofexor and metabolites and percentages of protein binding of all analytes were similar between SRI and HMC groups. Treatment-emergent adverse events were generally mild and not considered related to study drug. A <50% increase in firsocostat exposure was observed among SRI participants but was deemed not clinically relevant. There was no apparent effect of SRI on cilofexor exposure. Based on this trial, firsocostat and cilofexor dosing are not expected to require modification in patients who are renally impaired.