Phase 1 drug-drug interaction study to assess the effect of CYP3A4 inhibition and pan-CYP induction on the pharmacokinetics and safety of fosmanogepix in healthy participants.

Immunocompromised patients are susceptible to fungal infections, and drug-drug interactions with antifungals may occur due to concomitant medications. Fosmanogepix [FMGX; active moiety manogepix (MGX)] targets glycosylphosphatidylinositol-anchored mannoprotein synthesis and maturation, essential for fungal virulence. This phase 1, fixed-sequence study in healthy participants evaluated the effect of strong CYP3A4 inhibitor itraconazole [Cohort 1 (n = 18); FMGX 500 mg intravenous (IV) twice a day (BID )+ itraconazole 200 mg oral once a day (QD)] and pan-CYP inducer rifampin [Cohort 2 (n = 18); FMGX 1,000 mg IV BID + rifampin 600 mg oral QD] on the pharmacokinetics of FMGX and MGX. In cohort 1, geometric mean (GM) MGX Cmax, AUC0-t, and AUCinf were almost similar with and without itraconazole administration. In Cohort 2, GM MGX Cmax was slightly lower and AUC0-t and AUCinf were significantly lower after rifampin administration, with the least squares GM ratio associated 90% confidence intervals (CIs) below 80 - 125% (no effect window). No deaths, serious adverse events (SAEs), or FMGX-related withdrawals were reported. In both cohorts, a total of 188 AEs (n = 30; 186 mild; two moderate) were reported. In all, 37 of 188 AEs (n = 12) were considered FMGX related (most frequent: headache, nausea, and hot flush). Administration of FMGX alone and with itraconazole or rifampin was safe and well tolerated. A strong CYP3A4 inhibitor had no effect on FMGX or MGX exposure. A strong pan-CYP inducer had no effect on FMGX exposure but demonstrated ~45% decrease in MGX exposure. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04166669 and with EudraCT as number 2019-003586-17.

A phase 1 open label study to assess the human mass balance and metabolite profile of 14C-fosmanogepix, a novel Gwt-1 inhibitor in healthy male participants.

Fosmanogepix [FMGX; active form manogepix (MGX)], a novel antifungal, is currently being studied for the treatment of invasive fungal diseases caused by Candida spp., Aspergillus spp., and other rare molds. This Phase 1, single-dose study used 14C-radiolabeled FMGX to determine the disposition and metabolism of FMGX. Ten healthy male participants were enrolled equally into: oral cohort {FMGX 500 mg oral + 3.1 megabecquerel [MBq, 84.0 microcurie (µCi)] 14C} and intravenous (IV) cohort [FMGX 600 mg IV + 3.4 MBq (93.0 µCi) 14C]. At the end of the sampling period (456 h post-dose), 90.2% of radioactivity administered was recovered (46.4% from urine; 43.8% from feces) in oral cohort (82.3% within 240 h), and 82.4% was recovered (42.5% from urine; 39.9% from feces) in IV cohort (76.2% within 264 h), indicating that FMGX elimination occurs via renal and hepatic routes. Radioactivity transformation pathways (oral and IV) indicated multiple major routes of metabolism of FMGX, mainly via MGX, and included oxidation, oxidative deamination, and conjugation. All except one key human plasma metabolite was observed in toxicity species, but its proportion (<10%) in the human area under the curve plasma samples was not of toxicological concern. No deaths, serious, or severe adverse events (AE) were reported, and there were no AE-related withdrawals. The results of this study indicated extensive metabolism of FMGX, with similar key human plasma metabolites observed in the animal studies. The elimination of FMGX was equally through renal and hepatic routes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04804059.

Pharmacokinetics, safety, and tolerability of fosmanogepix IV to oral switch and multiple IV doses in healthy participants.

Fosmanogepix [FMGX, APX001; active form: manogepix (MGX), APX001A] is a first-in-class, intravenous (IV)/oral antifungal currently being evaluated for invasive fungal disease treatment. Data from two phase 1, placebo-controlled studies [IV-oral switch (study 1) and multiple IV doses (study 2)] evaluating FMGX tolerability, and pharmacokinetics (PK) are presented. Healthy adults (study 1: 18-65 years; study 2: 18-55 years) were eligible (randomized 3:1 to FMGX: placebo). Eleven participants completed study 1. In study 2, 51 participants (48 planned + 3 replacement) were enrolled in six cohorts (8 participants each; 34 completed the study). In study 1, overall MGX systemic exposures were comparable from day 1 to day 42 of dosing; steady-state plasma concentrations were achieved in ≤24 h following two IV loading doses (1,000 mg) and exposures maintained after switching [IV (600 mg) to daily oral doses (800 mg)]. FMGX was safe and well-tolerated. In study 2, FMGX IV doses (loading doses twice daily/maintenance doses once daily; 3-h infusion) of 1,500/900 mg (cohort A), 900/900 mg (cohort B), and 1,000/900 mg (cohort C: with ondansetron) were not well-tolerated; most participants reported nausea and infrequent vomiting. FMGX IV doses of 1,000/750 mg (cohort D), 1,000/850 mg (cohort E), and 1,000/900 mg (cohort F: ondansetron prn) were relatively better tolerated. Steady-state systemic exposures were achieved between days 2 and 4. All cohorts had similar geometric mean (GM) concentrations during maintenance dosing and similar GM PK parameters. Dosing regimen evaluated in study 1 was safe, well-tolerated, and may be used for future clinical evaluations.

Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers.

Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (Cmax) (SAD: 0.16 to 12.0 µg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 µg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 µg · h/mL). With single and repeat p.o., dose-proportional increases in Cmax (SAD: 1.30 to 6.41 µg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 µg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 µg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens.

Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris: Results from a Phase 2 Trial.

Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. In vitro susceptibility of Candida isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent in vitro activity against all C. auris isolates (MIC range: 0.008 to 0.015 µg/mL [CLSI]; 0.004-0.03 µg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.

Phase 1b safety and pharmacokinetics of intravenous and oral fosmanogepix in patients with acute myeloid leukaemia and neutropenia.

OBJECTIVES: Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/µL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix. METHODS: Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data. RESULTS: Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers. CONCLUSIONS: Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.

Efficacy and safety of ceftazidime/avibactam in patients with infections caused by ß-lactamase-producing Gram-negative pathogens: a pooled analysis from the Phase 3 clinical trial programme.

OBJECTIVES: This post hoc pooled analysis evaluated clinical and microbiological outcomes and safety in patients with infections caused by ß-lactamase-producing Gram-negative pathogens across five Phase 3, randomized, controlled, multicentre trials of ceftazidime/avibactam in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis and nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP). METHODS: In each trial, RECLAIM/RECLAIM 3 (cIAI), REPRISE (cIAI/cUTI), RECAPTURE (cUTI) and REPROVE (NP, including VAP) patients were randomized 1:1 to IV ceftazidime/avibactam (plus metronidazole for patients with cIAI) or comparators (carbapenems in >97% patients) for 5-21 days. Clinical and microbiological responses at the test-of-cure visit were assessed for patients with ESBLs, and/or plasmidic and/or overexpression of chromosomal AmpC, and/or serine carbapenemases without MBLs identified in baseline Gram-negative isolates by phenotypic screening and molecular characterization in the pooled microbiological modified ITT (mMITT) population. RESULTS: In total, 813 patients (ceftazidime/avibactam, n = 389; comparator, n = 424) had ≥1 ß-lactamase-producing baseline pathogen identified, amongst whom 792 patients (ceftazidime/avibactam, n = 379; comparator, n = 413) had no MBLs. The most frequent ß-lactamase-producing pathogens across treatment groups were Escherichia coli (n = 381), Klebsiella pneumoniae (n = 261) and Pseudomonas aeruginosa (n = 53). Clinical cure rates in the pooled non-MBL ß-lactamase-producing mMITT population were 88.1% (334/379) for ceftazidime/avibactam and 88.1% (364/413) for comparators; favourable microbiological response rates were 76.5% (290/379) and 68.8% (284/413), respectively. The safety profile of ceftazidime/avibactam was consistent with previous observations. CONCLUSIONS: This analysis provides supportive evidence of the efficacy and safety of ceftazidime/avibactam in patients with infections caused by ESBLs, AmpC and serine carbapenemase-producing Gram-negative pathogens. TRIAL REGISTRATION: NCT01499290; NCT01726023; NCT01644643; NCT01595438/NCT01599806; NCT01808092.

Clinical safety and efficacy of novel antifungal, fosmanogepix, for the treatment of candidaemia: results from a Phase 2 trial.

BACKGROUND: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration. METHODS: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (<96 h of treatment start) composed the modified intent-to-treat (mITT) population. Primary efficacy endpoint was treatment success at the end of study treatment (EOST) as determined by the Data Review Committee. Success was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at the EOST. RESULTS: Treatment success was 80% (16/20, mITT; EOST) and Day 30 survival was 85% (17/20; 3 deaths unrelated to fosmanogepix). Ten of 21 (48%) were switched to oral fosmanogepix. Fosmanogepix was well tolerated with no treatment-related serious adverse events/discontinuations. Fosmanogepix had potent in vitro activity against baseline isolates of Candida spp. (MICrange: CLSI, 0.002-0.03 mg/L). CONCLUSIONS: Results from this single-arm Phase 2 trial suggest that fosmanogepix may be a safe, well-tolerated, and efficacious treatment for non-neutropenic patients with candidaemia, including those with renal impairment.

In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial.

Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 µg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 µg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 µg/ml and 64 µg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.).

Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam.

An extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (PK) modeling and Monte Carlo simulations using clinical PK data supported modified ceftazidime-avibactam dosage adjustments for patients with moderate or severe renal impairment (comprising a 50% increase in total daily dose compared with the original dosage adjustments) to reduce the risk of subtherapeutic drug exposures in the event of rapidly improving renal function. The modified dosage adjustments were included in the ceftazidime-avibactam labeling information at the time of initial approval and were subsequently evaluated in the final phase 3 trial (in patients with HAP, including VAP), providing supportive data for the approved U.S. and European ceftazidime-avibactam dosage regimens across renal function categories. This review describes the analyses supporting the ceftazidime-avibactam dosage adjustments for renal impairment and discusses the wider implications and benefits of using modeling and simulation to support dosage regimen optimization based on emerging clinical evidence.

Evaluation of anidulafungin in the treatment of intra-abdominal candidiasis: a pooled analysis of patient-level data from 5 prospective studies.

The incidence of nosocomial invasive fungal infections involving Candida spp. has increased markedly in recent years in patients undergoing abdominal surgery. This post hoc analysis aimed to determine the efficacy and safety of anidulafungin treatment in patients with intra-abdominal candidiasis (IAC) from five prospective studies (one comparative and four open-label) of adult surgical patients with microbiologically confirmed Candida intra-abdominal infection. Patients received an intravenous (IV) loading dose of anidulafungin 200 mg, followed by a daily 100-mg maintenance dose. Per study protocols, some patients could be switched to an oral azole after ≥ 5 or ≥ 10 days of IV treatment. Antifungal treatment was maintained for ≥ 14 days after the last positive Candida culture and resolution of symptoms. The global response rate (GRR) at the end of IV treatment (EOIVT) was the primary endpoint. GRR at the end of therapy (EOT), all-cause mortality at days 14 and 28, and safety was also evaluated. Seventy-nine patients had IAC from peritoneal fluid or hepatobiliary tract. C. albicans (72.2%) and C. glabrata (32.9%) were the most common pathogens. Overall GRR was 73.4% and 67.1% at EOIVT and EOT, respectively. All-cause mortality was 17.7% at day 14 and 24.1% at day 28 in the modified intent-to-treat population. Anidulafungin was well tolerated in this population, with most adverse events mild or moderate in severity. In these patients with IAC, anidulafungin showed a GRR at EOIVT similar to the anidulafungin registrational trial, and the results of our analysis confirmed the known safety profile of anidulafungin. ClinicalTrials.gov registration number NCT00496197, registered July 3, 2007, https://clinicaltrials.gov/ct2/show/study/NCT00496197 ; ClinicalTrials.gov registration number NCT00548262, registered October 19, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00548262 ; ClinicalTrials.gov registration number NCT00537329, registered September 25, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00537329 ; ClinicalTrials.gov registration number NCT00689338, registered May 29, 2008, https://clinicaltrials.gov/ct2/show/study/NCT00689338 ; ClinicalTrials.gov registration number NCT00805740, registered November 26, 2008, https://clinicaltrials.gov/ct2/show/NCT00805740.

Retrospective cohort study comparing the risk of severe hepatotoxicity in hospitalized patients treated with echinocandins for invasive candidiasis in the presence of confounding by indication.

BACKGROUND: To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults. METHODS: This retrospective cohort study combined data from two large US- based hospital electronic medical record databases. Severe hepatotoxicity was a Grade ≥ 3 liver function test (LFT) post-echinocandin initiation. Adjusted incidence rate ratios (IRRs) were estimated for anidulafungin versus caspofungin and micafungin, overall and in patients with normal baseline LFT (Grade 0). RESULTS: Treatments included anidulafungin (n = 1700), caspofungin (n = 4431), or micafungin (n = 6547). The proportions with LFT Grade ≥ 3 pre-echinocandin initiation were: anidulafungin 40.4% versus caspofungin 25.9% (p <  0.001) and micafungin 25.6% (p <  0.001). Rates of severe underlying diseases or comorbidities were: critical care admissions: 75.3% versus 52.6 and 48.6%; and organ failures: 69.4% versus 46.7 and 51.5%. Adjusted IRRs of severe hepatotoxicity for anidulafungin versus caspofungin and micafungin were 1.43 (p = 0.002) and 1.19 (p = 0.183) overall, and 0.88 (P = 0.773) and 0.97 (P = 0.945) for normal baseline LFT, respectively. CONCLUSIONS: Accounting for confounders, severe hepatotoxicity risk was not significantly different across echinocandins in this real-world head-to-head study. Anidulafungin was used more frequently in patients with more comorbidities. Those with normal baseline LFT (least susceptible to confounding by indication), showed no elevated hepatotoxicity risk for anidulafungin.

Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.

BACKGROUND: New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. METHODS: In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591. FINDINGS: Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. INTERPRETATION: In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. FUNDING: Pfizer Inc.

HIV economic burden of illness in the Veterans Health Administration population.

The objective was to assess the human immunodeficiency virus (HIV) economic burden of illness in the Veterans Health Administration (VHA) population. Adults (aged 18-64 years) with a HIV diagnosis (International Classification of Diseases 9th Revision, Clinical Modification [ICD-9-CM] code 042.x, V08) from 1 June 2007 to 31 May 2012 were selected from VHA Medical SAS(®) data-sets. Continuous VHA insurance coverage 12-month pre- and postindex date, with no antiretroviral therapy (ART) prescriptions within 180 days pre-index date, was required for treatment-naive (TN) HIV-infected patients. One baseline CD4 count or HIV viral load measured within three months after HIV diagnosis or one ART anchor drug claim postindex date was required for group comparison. All-cause health-care costs and utilizations were evaluated and stratified by CD4 cell count, viral load, nonnucleoside reverse transcriptase inhibitor (NNRTI) anchor drugs (efavirenz/non-efavirenz), and ART (NNRTI/PI/INSTI/CCR-5 Antagonist-based) regimen cohorts. The overall economic burden was compared between HIV-infected vs. non-HIV-infected patients. CD4 count, viral load, and treatment patterns and the associated costs were compared among TN patients. A 1:1 propensity score matching (PSM) was used to adjust for baseline differences. A total of 25,648 HIV-infected patients were identified (mean age 51; 96.4% male; 49.7% non-Hispanic black) of which 11,371 were TN. HIV-infected patients incurred higher PSM-adjusted total costs than non-HIV-infected patients ($25,232 vs. $10,206, p < 0.0001). Total costs for TN with CD4 cell counts ≤50 cells/mm(3) were higher than all other CD4 cell strata (p < 0.001). Total costs for TN with viral loads >100,000 copies/mL were higher than all other viral load categories (p < 0.001). Efavirenz-treated patients incurred higher ART-related ($8663 vs. $2846, p = 0.0266), but lower non-ART-related ($2339 vs. $6628, p = 0.0042) pharmacy costs than non-efavirenz patients. NNRTI-based cohort incurred lower total costs than protease inhibitor-based ($32,829 vs. $39,073, p = 0.0005) but no significant differences compared to integrase strand transfer inhibitor cohorts. This study offers new health-care costs and resource utilization estimates associated with the burden of HIV in the VHA population.

Efficacy and safety of lersivirine versus etravirine for the treatment of HIV-1 infection in patients with prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance: a randomized phase 2B trial.

OBJECTIVE: To assess the efficacy and safety of lersivirine versus etravirine in patients with HIV-1 and prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance. METHODS: In this 96-week, phase 2b study, 97 patients were randomized and treated with lersivirine 750 mg qd (n = 31), lersivirine 1,000 mg qd (n = 32), and etravirine 200 mg bid (n = 34), plus one optimized nucleoside reverse transcriptase inhibitor and darunavir/ritonavir 600/100 mg bid. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/mL at week 24. RESULTS: At week 24, HIV-1 RNA <50 copies/mL was achieved by fewer patients receiving lersivirine 750 mg (48.4%) and 1,000 mg (43.8%) qd compared with etravirine 200 mg qd (67.7%) (intention to treat [ITT], missing/switch/discontinuation equals failure [MSDF]). At week 48, HIV-1 RNA <50 copies/mL and <400 copies/mL were also achieved by fewer patients receiving lersivirine 750 mg (41.9% and 41.9%, respectively) and 1,000 mg (31.3% and 34.4%, respectively) qd compared with etravirine 200 mg bid (61.8% and 70.6%, respectively) (ITT, MSDF). Least squares means (SE) change from baseline in log transformed HIV-1 RNA at week 48 was -1.42 (0.27) and -0.95 (0.28) copies/mL for lersivirine 750 mg and 1,000 mg qd, respectively, versus -2.02 (0.26) copies/mL for etravirine 200 mg bid (ITT). Lersivirine and etravirine were generally safe and well-tolerated. CONCLUSIONS: Lersivirine 750 mg and 1,000 mg qd was associated with lower rates of viral suppression at week 24 and week 48 versus etravirine in patients with prior NNRTI use and evidence of NNRTI resistance. No new safety signals were detected.

Review of the impact of NNRTI-based HIV treatment regimens on patient-reported disease burden.

While the burden of HIV disease is well documented, the value of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy regimens in reducing patient burden is not well understood. The purpose of this study was to examine patient-reported health among those receiving NNRTI-based regimens to understand their incremental value in reducing the burden of HIV. We conducted a structured literature review using PubMed to identify NNRTI trials utilizing validated patient-reported outcome (PRO) instruments during 2005-2011. The search strategy included a PubMed search to identify relevant studies based on disease, instrument, PRO, and NNRTI medication terms; and a manual search of bibliographies of identified papers. Data abstracted from each study included study type, treatment regimen(s), and PRO results. Of 11 trials identified, 8 (73%) reported significance of changes in a PRO over time and 10 (91%) reported significance of PRO changes between groups. Several domains were assessed, with significant findings (between or within groups) observed in: physical health/well-being (n = 5), emotional status/well-being (n = 2), symptoms (n = 2), anxiety (n = 2), gastrointestinal upset (n = 2), psychological health (n = 1), functional and global well-being (n = 1), fatigue/energy (n = 1), depression (n = 1), change in body appearance (n = 1), pain (n = 1), headache (n = 1), bad dreams/nightmares (n = 1), problems having sex (n = 1), and general health perception (n = 1). In conclusion, NNRTIs have been observed most frequently to improve patient-reported physical health and well-being. Treatments are needed that can also reduce patient burden in areas of emotional well-being, cognitive functioning, and overall symptom profile.

Ceftazidime-Avibactam in the Treatment of Patients with Bacteremia or Nosocomial Pneumonia: A Systematic Review and Meta-analysis.

INTRODUCTION: Ceftazidime-avibactam (CAZ-AVI) is a combination of the third-generation cephalosporin ceftazidime and the novel, non-ß-lactam ß-lactamase inhibitor avibactam that is approved for the treatment of pediatric (≥ 3 months) and adult patients with complicated infections including hospital-acquired and ventilator-associated pneumonia (HAP/VAP), and bacteremia. This systematic literature review and meta-analysis (PROSPERO registration: CRD42022362856) aimed to provide a quantitative and qualitative synthesis to evaluate the effectiveness of CAZ-AVI in treating adult patients with bacteremia or nosocomial pneumonia caused by carbapenem-resistant Enterobacterales (non metallo-ß-lactamase-producing strains) and multi-drug resistant (MDR) Pseudomonas aeruginosa infections. METHODS: The databases included in the search, until November 7, 2022, were Embase and PubMed. A total of 24 studies (retrospective: 22, prospective: 2) with separate outcomes for patients with bacteremia or pneumonia were included. RESULTS: The outcomes assessed were all-cause mortality, clinical cure, and microbiological cure. Qualitative (24 studies) and quantitative (8/24 studies) syntheses were performed. The quality of the studies was assessed using the MINORS checklist and the overall risk of bias was moderate to high. CONCLUSIONS: In studies included in the meta-analysis, lower all-cause mortality for patients with bacteremia (OR = 0.30, 95% CI 0.19-0.46) and improved rates of clinical cure for patients with bacteremia (OR = 4.90, 95% CI 2.60-9.23) and nosocomial pneumonia (OR = 3.20, 95% CI 1.55-6.60) was observed in the CAZ-AVI group compared with the comparator group. Data provided here may be considered while using CAZ-AVI for the treatment of patients with difficult-to-treat infections. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022362856.

Responsiveness of the MOS-HIV and EQ-5D in HIV-infected adults receiving antiretroviral therapies.

BACKGROUND: Selection of an appropriate patient-reported outcome (PRO) instrument for a clinical trial requires knowledge of the instrument's responsiveness to detecting treatment effects. The purpose of this study was to examine the responsiveness of two health-related quality of life (HRQL) instruments used in clinical trials involving HIV-infected adults: the HIV-targeted Medical Outcomes Study HIV Health Survey (MOS-HIV), and a generic measure, the EuroQol-5D (EQ-5D). METHODS: A systematic review identified clinical trials using the MOS-HIV or EQ-5D to assess outcomes for HIV-infected adults. Data abstracted from each study included study type, treatment regimen(s), PRO results, and effect size (either reported or calculated). Effect size was calculated as the difference between baseline and follow-up mean scores divided by the baseline standard deviation. Magnitude was categorized as small (d=0.20), medium (d=0.50), and large (d=0.80). RESULTS: Between 2005 and 2010, the MOS-HIV was administered in 12 trials. Significant differences were observed between groups and over time in physical health summary (PHS) and mental health summary (MHS) scores (P<0.05) in subjects switching therapy after experiencing Grade-2 adverse events. Effect sizes were medium (0.55 and 0.49 for PHS and MHS, respectively) among treatment-naïve adults beginning therapy (two studies), but negligible among treatment-experienced adults (0.04 and 0.13 for PHS and MHS, respectively; three studies). The EQ-5D was used in five trials between 2001 and 2010. It was responsive to occurrences of adverse events and opportunistic infections, with small-to-medium effect sizes (range 0.30-0.50) in each of its five dimensions. CONCLUSIONS: A systematic review of PRO study results showed both the MOS-HIV and EQ-5D were responsive to changes between groups and/or over time in treatment-naïve HIV-infected patients. These instruments may be used either individually or together in clinical trials to measure changes in HRQL.

Patient reported outcome instruments used in clinical trials of HIV-infected adults on NNRTI-based therapy: a 10-year review.

BACKGROUND: Patient-reported outcomes (PROs) may provide valuable information to clinicians and patients when choosing initial antiretroviral therapy. OBJECTIVE: To identify and classify PRO instruments used to measure treatment effects in clinical trials evaluating NNRTIs. METHODS: We conducted a structured literature review using PubMed to identify NNRTI trials published from March 2003 to February 2013. Studies identified--based on disease, instrument, PRO, and NNRTI medication terms were reviewed--to identify PRO instruments. Domains measured within each instrument were recorded to understand key areas of interest in NNRTIs. RESULTS: Of 189 articles reviewed, 27 validated instruments were administered in 26 unique trials, with a mean of 1.9 instruments (median: 1; range: 1-7) per trial. The Medical Outcomes Study HIV Health Survey (MOS-HIV) was the most commonly used instrument (n = 8 trials). Seventeen trials (65%) included at least one multidimensional health-related quality of life (HRQL) instrument (HIV-targeted, n = 11; general, n = 8). Other validated instruments measured sleep (n = 5), depression (n = 5), anxiety (n = 4), psychiatric symptoms (n = 2), beliefs about HIV medications (n = 2), HIV symptoms (n = 1), and stress (n = 1). CONCLUSIONS: Although review of recent NNRTI trials suggests a lack of consensus on the optimal PRO instruments, a typical battery is comprised of a multidimensional HRQL measure coupled with one or more symptom measures. Further work is needed to clarify advantages and disadvantages of using specific PRO instruments to measure relevant constructs and to identify the most useful batteries of instruments for NNRTI trials.

No effect of a single supratherapeutic dose of lersivirine, a next-generation nonnucleoside reverse transcriptase inhibitor, on corrected QT interval in healthy subjects.

The objective of this study was to investigate the effect of a supratherapeutic dose of lersivirine (LRV) on corrected QT (QTc) interval using Fridericia's equation (QTcF) in healthy subjects. In this randomized, single-dose, placebo- and active-controlled 3-way crossover study, healthy adult males (n = 48) were randomized to receive LRV (2,400 mg), moxifloxacin (400 mg), or placebo for each treatment period. Triplicate 12-lead electrocardiogram measurements were performed, PK samples were collected, and vital signs were measured. Adverse event monitoring and safety laboratory testing were performed. All subjects were white (mean age, 39 years; body mass index [BMI], 25.6 kg/m(2)) and completed the study. Following LRV administration, the upper bound of the 90% confidence interval (CI) for time-matched adjusted mean differences to placebo QTcF at each time point postdose was below the regulatory threshold of 10 ms, satisfying the criteria for a negative thorough QT/QTc study. The highest upper bound of QTcF 90% CI occurred at 6 h for LRV (3.32 ms; 90% CI, 1.47 to 5.17 ms). The study was deemed adequately sensitive as the lower bound of the 90% CI for the adjusted mean QTcF differences between moxifloxacin and placebo at the moxifloxacin historical T(max) of 3 h was >5 ms (15.29 ms; 90% CI, 13.44 to 17.14 ms). There was no statistically significant relationship between LRV exposure and placebo-adjusted change from baseline QTcF or clinically significant changes in QRS complex, pulse rate (PR) interval, heart rate, or blood pressure. LRV (2,400 mg) did not prolong the QTcF interval, and no clinically relevant electrocardiogram or vital sign changes were observed in healthy subjects.