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The title compound, (E)-5-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)benzo[d]oxazol-2(3H)-one, was synthesized by the acid- and base-catalyzed aldol condensation of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde and 3,4,5-trimethoxyacetophenone. The structure of the target compound was confirmed using [sup.1]H NMR, [sup.13]C NMR, HRMS, and elemental analysis.

Quabodepistat (formerly OPC-167832) showed potent activity in preclinical studies and in the first stage of an early bactericidal activity study in adults with smear-positive, drug-susceptible pulmonary tuberculosis. Stage 2 of this study was designed to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both versus rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy for 14 days. Stage 2 of this open-label, active-controlled, randomised, parallel-group study was conducted at two research sites in South Africa in adults (aged 18–64 years) with drug-susceptible pulmonary tuberculosis. Eligible participants had a BMI of 16–32 kg/m2 and the ability to produce an adequate volume of sputum (≥10 mL overnight) and were excluded if they had drug-resistant tuberculosis or previous treatment for Mycobacterium tuberculosis within the past 3 years. Participants were centrally randomly assigned via interactive web response technology system, with no stratification, into four treatment groups in a ratio of 14:14:14:4 (quabodepistat 30 mg plus delamanid 300 mg, quabodepistat 30 mg plus bedaquiline 400 mg, or quabodepistat 30 mg plus delamanid 300 mg plus bedaquiline 400 mg orally once daily for 14 days, or rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy [control] according to local standard of care for 20 days). The primary outcomes were safety and tolerability during and after 14 days of treatment in all participants who received any study medication and pharmacokinetics at day 1 and day 14 in participants in the quabodepistat groups with adequate data for deriving pharmacokinetics parameters. The main secondary outcome was bactericidal activity from baseline to day 14 in all eligible participants who were quantitatively culture-positive at baseline. The study was not powered for formal statistical hypothesis testing; therefore, data were summarised by treatment group with descriptive statistics. This study is registered with ClinicalTrials.gov (NCT03678688) and is closed to new participants. 98 participants were screened for entry into stage 2 of the trial between Feb 1, 2021, and Jan 27, 2022, of whom 46 were randomly assigned (14 to each quabodepistat group, 4 to the control group) and 44 received at least one dose of study medication (one patient excluded from the quabodepistat plus delamanid and quabodepistat plus bedaquiline groups). 32 (73%) of 44 participants had at least one treatment-emergent adverse event. Most events (30/32 [94%]) were mild or moderate; the most common treatment-emergent adverse events (≥2 participants; not related to study drugs) were headache (4/44 [9%]), dizziness (3/44 [7%]), abdominal pain (2/44 [5%]), pruritus (2/44 [5%]), and nausea (2/44 [5%]). Two serious adverse events were reported in two participants in the quabodepistat and bedaquiline cohort (anal abscess [n=1], pneumothorax [n=1]); both were deemed not related to study drug. Quabodepistat exposure was minimally affected by coadministration of delamanid or bedaquiline, with lower exposure in the quabodepistat and bedaquiline cohorts (maximum plasma concentration for quabodepistat plus delamanid 208 ng/mL [SD 61; n=11]; quabodepistat plus bedaquiline 175 ng/mL [31; n=10]; quabodepistat plus delamanid plus bedaquiline 183 ng/mL [52; n=11]). Maximum quabodepistat concentrations were achieved approximately 3 h after administration in all combinations. Mean elimination half-life was shorter in combinations with bedaquiline than without bedaquiline (12·3–14·5 h vs 15·2 h). Mean changes from baseline to day 14 of sputum log10 colony-forming units per mL were −2·73 (SD 1·51) for quabodepistat plus delamanid plus bedaquiline (n=12) and −2·71 (SD 0·92) for control (n=19); mean change was −2·17 (SD 1·83) in the quabodepistat plus delamanid cohort (n=11) and −1·97 (SD 1·29) in the quabodepistat plus bedaquiline cohort (n=11). In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted. Otsuka Pharmaceutical Development & Commercialization and the Bill & Melinda Gates Foundation.

Tedizolid phosphate is the second commercially available oxazolidinone antibiotic, although the first one in class that is dosed once daily. It is a prodrug that is rapidly converted to the active compound tedizolid. Tedizolid has activity against a wide range of gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. It is approved to treat acute bacterial skin and skin structure infections (ABSSSIs). In 2 randomized controlled phase 3 trials, 6 days of tedizolid (200 mg once daily) has been proven to be noninferior to 10 days of linezolid (600 mg twice daily). These 2 ABSSSI studies have positioned tedizolid among the growing armamentarium of newer, novel, anti-gram-positive agents. Tedizolid appears to differ from linezolid in the incidence of gastrointestinal and hematologic side effects and appears to lack drug interactions with selective serotonin reuptake inhibitors. Conditions other than ABSSSI are currently being evaluated in clinical studies.

In this report on the treatment of multidrug-resistant (MDR) tuberculosis, the authors found that delamanid, a novel anti-TB medication, led to more rapid sputum culture conversion to negative when added to a background regimen than the background regimen alone. The emergence over the past two decades of multidrug-resistant tuberculosis, or tuberculosis caused by strains of Mycobacterium tuberculosis that are resistant to isoniazid and rifampin, with or without resistance to other agents, has greatly complicated efforts to control the global tuberculosis epidemic. Approximately 440,000 cases of multidrug-resistant tuberculosis occur worldwide annually, accounting for nearly 5% of the global burden of tuberculosis. 1 Multidrug-resistant tuberculosis requires treatment with combination therapy consisting of four to six medications, including the more toxic and less potent second-line drugs, administered for up to 2 years. Cure rates are lower and mortality is higher with multidrug-resistant tuberculosis . . .

In women with HER2-positive metastatic breast cancer who had previously received HER2-targeted therapy, tucatinib, a new selective inhibitor of the HER2 tyrosine kinase, was added to trastuzumab and capecitabine and compared with trastuzumab and capecitabine plus placebo. Progression-free survival at 1 year was 33% with tucatinib and 12% with placebo.

Linezolid plays a crucial role in the first-line treatment of drug-resistant tuberculosis globally. Its prolonged use can lead to neurological and haematological toxicity, highlighting the need for safer oxazolidinones. Delpazolid, a novel oxazolidinone, might be safer. We aimed to evaluate the safety and efficacy of delpazolid and identify an optimal dose. PanACEA-DECODE-01 was a prospective, randomised, open-label, phase 2b, multicentre, dose-finding trial done in five tuberculosis trial sites in Tanzania and South Africa. Adults aged 18–65 years, who weighed 40–90 kg, and had newly diagnosed, smear positive pulmonary tuberculosis were randomly assigned (1:1:1:1:1) through centralised allocation, using a probabilistic minimisation algorithm to receive no delpazolid (D0), delpazolid 400 mg once daily (D400), delpazolid 800 mg once daily (D800), delpazolid 1200 mg once daily (D1200), or delpazolid 800 mg twice daily (D800BD), all administered orally for 16 weeks with follow-up to week 52. All participants received bedaquiline (400 mg orally once daily for the first 14 days, then 200 mg orally thrice weekly), delamanid (100 mg orally twice daily), and moxifloxacin (400 mg orally once daily). Randomisation was stratified based on bacterial load in sputum as measured by GeneXpert cycle threshold (<16 vs ≥16), site, and HIV status. The primary efficacy objective was to establish an exposure–response model with the primary endpoint, measured in the modified intention-to-treat population, of change in mycobacterial load measured by time to positivity using the liquid culture mycobacterial growth indicator tube system. A secondary outcome was the time on treatment to sustained conversion to negative sputum culture in liquid media. The primary safety outcome was the occurrence of oxazolidinone class toxicities defined as peripheral or optical neuropathy, incident leukopenia, anaemia or thrombocytopenia, or adverse events in line with tyramine pressor response, all of grade 2 or higher, possibly, probably or definitely related to delpazolid. This study was registered with ClinicalTrials.gov, NCT04550832. Between Oct 28, 2021, and Aug 31, 2022, 156 individuals were screened for eligibility, 76 of whom were enrolled and randomly assigned to D0 (n=15), D400 (n=15), D800 (n=15), D1200 (n=16), or D800BD (n=15). 60 (79%) of 76 participants were male and 16 (21%) were female. Population pharmacokinetic–pharmacodynamic modelling suggests maximal microbiological activity at a daily total exposure of delpazolid (area under the concentration curve from 0 h to 24 h [AUC0–24]) of 50 mg/L per h; close to the median exposure observed after a 1200 mg dose. This maximal effect was estimated at a 38% (95% CI 4–83; p=0·025) faster decline in bacterial load compared with no delpazolid. In the secondary time-to-event analysis, there was no significant difference in time to culture conversion between treatment arms or exposure tertile. When all delpazolid-containing groups were combined, the hazard ratio for the time to sustained culture conversion to negative, comparing all delpazolid-containing groups with the group without delpazolid was 1·53 (95% CI 0·84–2·76). Two drug-related serious adverse events (one gastritis and one anaemia) occurred in the D800BD group, with high individual AUC0–24. Apart from the anaemia and one event of brief, moderate neutropenia observed at only one visit in the D800 group not in line with the characteristics of oxazolidinone class toxicity, no oxazolidinone class toxicities occurred. The pharmacokinetic–pharmacodynamic modelling results suggest that delpazolid adds efficacy on top of bedaquiline, delamanid, and moxifloxacin; and that a dose of 1200 mg once daily would result in exposures with maximum efficacy. That dose was shown to be safe, raising hope that linezolid toxicities could be averted in long-term treatment. Delpazolid is a promising drug for future tuberculosis treatment regimens and could be widely usable if safety and efficacy are confirmed in larger trials. LigaChem Biosciences, EDCTP2 programme supported by the EU; German Ministry for Education and Research; German Center for Infection Research; Swiss State Secretariat for Education, Research and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

In PIK3CA -mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib–fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib–fulvestrant.

Nemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate. In this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic. APSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC0–t: 17,200 h∙pg/mL; 95% CI, 10,900–27,200 h∙pg/mL and 13,100; 95% CI, 8130–21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses. After single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.

Linezolid is a key component globally in first-line therapy for drug-resistant tuberculosis but has considerable toxicity. New and safer alternative oxazolidinones are needed. Sutezolid is one such promising alternative. We aimed to evaluate preliminary efficacy and safety of sutezolid and to identify an optimal dose. PanACEA-SUDOCU-01 was a prospective, open-label, randomised, phase 2b dose-finding study in four tuberculosis trial sites in Tanzania and South Africa. Adults aged 18–65 years with newly diagnosed, drug-sensitive, smear-positive tuberculosis were enrolled and randomly assigned (1:1:1:1:1) by a probabilistic minimisation algorithm using a web-based interface, stratified by site, sex, and HIV status, to receive no sutezolid (U0), sutezolid 600 mg once daily (U600), sutezolid 1200 mg once daily (U1200), sutezolid 600 mg twice daily (U600BD), or sutezolid 800 mg twice daily (U800BD), all administered orally for 12 weeks followed by standard therapy for 6 months. All participants received oral bedaquiline (400 mg once daily for 14 days followed by 200 mg thrice weekly), oral delamanid (100 mg twice daily), and oral moxifloxacin (400 mg once daily). For the primary endpoint, measured in the modified intention-to-treat population, sputum samples were taken weekly to measure the change in bacterial load measured by time to positivity using the mycobacterial growth indicator tube system. Safety was assessed through weekly electrocardiography, safety blood tests, vision testing, and physical and neurological examinations. Intensive pharmacokinetic measurements were done on day 14 to determine exposure to sutezolid, bedaquiline, delamanid, and moxifloxacin. This trial is registered with ClinicalTrials.gov (NCT03959566). Between May 20, 2021, and Feb 17, 2022, 186 individuals were screened for eligibility, 75 of whom were enrolled and randomly assigned to U0 (n=16), U600 (n=15), U1200 (n=14), U600BD (n=15), or U800BD (n=15). 56 (75%) participants were male and 19 (25%) were female. The final pharmacokinetic–pharmacodynamic model showed a benefit of sutezolid, with an increase in time to positivity slope steepness of 16·7% (95% CI 0·7–35·0) at the maximum concentration typical for the 1200 mg dose, compared with no sutezolid exposure. A maximum effect of sutezolid exposure was not observed within the investigated dose range. Six (8%) participants (one in the U600 group, two in the U600BD group, one in the U800BD group, and two retrospectively identified in the U600 group) had an increase in a QT interval using Fridericia correction greater than 60 ms from baseline. Two (3%) participants in the U600BD group had grade 4 adverse events, one each of neutropenia and hepatotoxicity, but they were not deemed associated with the use of sutezolid by the investigators. No neuropathy was reported. Sutezolid, combined with bedaquiline, delamanid, and moxifloxacin, was shown to be efficacious and added activity to the background drug combination, although we cannot make a final dose recommendation yet. This study provides valuable information for the selection of sutezolid doses for future studies, and described no oxazolidinone class toxicities at the doses used. EDCTP2 programme funded by the EU; German Ministry for Education and Research; German Center for Infection Research; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

Tedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant Staphylococcus aureus. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects. A block-randomized, double-blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events. Thirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the Tmax of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration–time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUClast value (29,441–78,062 μg · h/L) and in the Cmax value (2679–6980 μg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%–97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment. Tedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043.