GlaxoSmithKline (Spain)

Objectives LN increases the risk of end-stage kidney disease and mortality.Belimumab selectively inhibits B-lymphocyte stimulator, and has been shown to prevent organ damage progression in SLE and preserve kidney function in LN.We evaluated whether belimumab is associated with a lower risk of progression to LN among patients with SLE versus standard of care (SOC) in real-world practice.Methods A retrospective, longitudinal cohort study (GSK Study 217533) using claims linked with electronic health record data (Optum Market Clarity database).Index: date of initiation of belimumab or SOC (immunosuppressant [IS, except as LN initial therapy], intravenous glucocorticoids [GCs], or oral GC

Uncomplicated urinary tract infections (uUTIs) can cause distressing symptoms seriously impacting daily activities. Early symptom relief during treatment, though fundamental to patients, is often overlooked in clinical trials. Gepotidacin, a new antibacterial agent, was noninferior to the first-line treatment nitrofurantoin in two randomized controlled trials (EAGLE-2 [NCT04020341] and EAGLE-3 [NCT04187144]). The current analysis utilized pooled data from these two trials to evaluate symptom responses during and after treatment in participants with uUTI. Participants were aged ≥12 years with at least two uUTI symptoms, urinary nitrite and/or pyuria, and no complicating factors. Participants were randomized 1:1 to oral gepotidacin (1500 mg) or nitrofurantoin (100 mg), both taken twice daily for 5 days. At baseline (Day 1), on-therapy (OT; Day 2-4), and test-of-cure (TOC; Day 10-13) visits, urinary symptoms were assessed (0-3; none-severe) from which a total score (0-12) was derived. Overall, 3136 participants were randomized (1572 gepotidacin, 1564 nitrofurantoin). Mean (median) baseline symptom scores for gepotidacin and nitrofurantoin arms were 7.1 (7.0) and 7.2 (7.0), respectively; at OT, this decreased to 3.6 (3.0) for both arms. At the OT visit, >80% of participants had clinical improvement/resolution. Among those with baseline symptoms affecting everyday activities (moderate or severe), 53.2% (728/1369) assigned gepotidacin and 53.6% (738/1377) assigned nitrofurantoin reported at OT that symptoms no longer affected everyday activities (mild or absent); at TOC, these percentages were 93.8% (1232/1313) and 93.3% (1254/1344), respectively. Gepotidacin and nitrofurantoin provide meaningful and similar early relief from uUTI symptoms.

A bromoindazole was reported with the ability to rapidly and extensively kill Mycobacterium tuberculosis (Mtb) in vitro, but only in the presence of sublethal levels of reactive nitrogen species (RNS) (Warrier et al., ACS Infectious Diseases 1:585-560, 2015). After learning that that compound was poorly tolerated in mice, we identified a diaryl-aminoindazole with even more pronounced ability to kill Mtb in vitro in an RNS-dependent manner, along with RNS-dependent mycobactericidal activity against Mycobacterium avium and RNS-dependent mycobacteristatic activity against Mycobacterium abscessus. The compound was orally bioavailable and well tolerated in mice. However, 4- to 8-week treatment of mice with the diaryl-aminoindazole did not reduce their pulmonary burden of Mtb. Possible explanations include the low levels of compound detected in plasma at trough and the low levels of RNS detected in the lungs of these mice.

Bepirovirsen is an investigational drug; its multimodal mechanism of action (MoA) is under evaluation. Observations in treated participants show transient alanine aminotransferase (ALT) increases, alongside hepatitis B surface antigen (HBsAg) declines. We investigated bepirovirsen's MoA in relation to virological response, hepatocyte death, and ALT increases. In B-Together (NCT04676724), 108 participants on stable nucleos(t)ide analogs received bepirovirsen for 24 (Arm 1) or 12 (Arm 2) Weeks, then up to 24Weeks of pegylated interferon-α-2a. This post hoc peripheral longitudinal biomarker exploratory analysis examined serum proteomics and whole blood transcriptomics from peripheral blood mononuclear cell samples from 82 participants. Relative expressions of immune- and disease-related biomarkers were measured, and differential expression determined across arms and response subgroups. Increases from baseline in mean expression of serum proteins with immune effector and apoptotic functions (Week 3) and transcripts associated with immune cell proliferation and activation (Week 5) were observed regardless of arm or response subgroup. By Week 8, serum liver and apoptosis-specific proteins were increased; this was more pronounced in responders than non-responders, with the difference more marked in Arm 1 versus Arm 2. Increased abundance of these proteins was highly correlated with ALT levels, which were often associated with transient hepatitis B virus (HBV) DNA elevations and HBsAg decreases. These findings provide evidence that bepirovirsen may modulate the immune system to facilitate infected hepatocyte killing in chronic HBV infection in addition to its direct antiviral effects; therefore, ALT increases could reflect a therapeutic response to bepirovirsen. NCT04676724 and NCT04449029.

<bold>Background:</bold> Asthma onset age and duration impact treatment responses. In SWIFT-1/2, depemokimab, a first ultra-long-acting biologic with enhanced IL-5 affinity, high potency and extended half-life, enabling twice-yearly dosing in patients with asthma, significantly reduced exacerbations with sustained suppression of inflammation assessed by blood eosinophil count in patients with type 2 asthma. <bold>Aims:</bold> Assess depemokimab efficacy by asthma onset age and duration. <bold>Methods:</bold> Patients with asthma for ≥2 years were randomised 2:1 to receive depemokimab 100 mg subcutaneous or placebo every 26 weeks, plus standard of care, for 52 weeks. Analyses examined annualised exacerbation rate by asthma onset age (<18/≥18 years; post hoc) and duration (quartiles; <10/≥10–<18/≥18–<34/≥34 years; pre-specified). <bold>Results:</bold> Exacerbation reductions with depemokimab versus placebo were similar for patients across age of onset subgroups (<18 years: 52%; ≥18 years: 55%; Figure). Patients with duration <10 years had numerically higher exacerbation rate reduction (72%) than ≥10 years (45–52%; Figure). <bold>Conclusions:</bold> Depemokimab reduces exacerbations versus placebo in patients with type 2 asthma across asthma onset age and duration subgroups with greatest reduction for patients with duration <10 years, supporting earlier biologic initiation. <bold>Funding:</bold> GSK (206713/213744; <ext-link>NCT04719832</ext-link>/NCT04718103). <fig><object-id>erj;66/suppl_69/PA2488/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

COPD is characterised by recurrent exacerbations, which are strongly associated with increased mortality and accelerated disease progression. It has been proposed that the frequent exacerbator (FE) phenotype is biologically distinct from those of non-frequent exacerbators (NFE) and controls. However, comprehensive metabolomic profiling remains unexplored. <bold>Methods:</bold> We performed LC-MS/MS untargeted metabolomics analysis on plasma samples from 226 participants (66 ± 9 y.o, 34% ♀) from the BIOMEPOC cohort: 35 FE, 127 NFE, and 64 controls. We analysed the differences between the groups using a t-test with empirical Bayes shrinkage, adjusting for sex, age, and FEV1. Additionally, we developed AI models using Flame to assess the predictive potential of metabolomic profiles as a clinical management tool. <bold>Results:</bold> Compared to controls, 49 metabolites were significantly altered in the FE group and 14 in the NFE group (FDR adj.<0.05). 8 underrepresented metabolites (2-Deoxy-D-Glucose, urate, nicotinamide, kynurenine, 6-Methylindole and 4-Indolecarbaldehyde, testosterone sulphate, and L-carnitine) distinguished FE from NFE, suggesting disturbances in energy metabolism, antioxidant defence, immunomodulation, and hormonal function in FE. This signature achieved a >95% accuracy, identifying FE among the three groups in a 5-fold cross-validation. <bold>Conclusion:</bold> Our findings provide evidence for a specific metabolomic substrate that characterises the FE phenotype in COPD, distinct from those of NFE and healthy controls. Further mechanistic investigations and validation are required. <italic>Co-Funded: PI21/00785,BA22/00009,FI22/00003&M-AES MV23/00012 from ISCiii & EU; SEPAR 2019, SOCAP 2020 & Menarini Spain 2015</italic>

<bold>Background:</bold> Depemokimab is the first ultra-long-acting biologic with enhanced IL-5 binding affinity, high potency, and extended half-life, enabling twice-yearly dosing in patients with asthma. Previously approved biologics are recommended as add-on treatment to high-dose ICS. In SWIFT-1/2, depemokimab significantly reduced exacerbations, with sustained suppression of inflammation as assessed by blood eosinophil count in patients with type 2 asthma. <bold>Aims:</bold> Assess depemokimab efficacy in SWIFT-1/2 patients by medium- and high-dose ICS subgroup. <bold>Methods:</bold> Patients randomised 2:1 (stratified by medium-/high-dose ICS) with any ACQ-5 score were studied for 52 weeks and received depemokimab 100 mg subcutaneous or placebo at Week 0 and 26, plus standard of care. Pre-specified analyses examined exacerbation rate and change from baseline in St George’s Respiratory Questionnaire (SGRQ) score by baseline ICS dose. <bold>Results:</bold> Depemokimab reduced exacerbations vs placebo by 61% and 49% in patients on medium- and high-dose ICS, respectively (Figure). There was a greater SGRQ improvement for depemokimab vs placebo in patients on medium- vs high-dose ICS (Figure). <bold>Conclusions:</bold> Depemokimab reduces exacerbations in patients with asthma across baseline ICS dose subgroups, supporting potential initiation prior to ICS escalation. <bold>Funding:</bold> GSK (206713/213744; <ext-link>NCT04719832</ext-link>/NCT04718103). <fig><object-id>erj;66/suppl_69/PA2469/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

There is currentlya public health crisis due to the rise of multidrug-resistanttuberculosis cases, as well as the rise in the number of deaths fromtuberculosis. To achieve the United Nations Sustainable DevelopmentGoal of ending the tuberculosis epidemic by 2030, new treatments areurgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the lysyl tRNA synthetase(LysRS). In this report, the full medicinal chemistry program is reviewedfrom the original hit through to the optimized lead. The work wasguided by the first crystal structures of LysRS. The physicochemical and pharmacokinetic properties were optimizedto afford compounds suitable for evaluation in mouse efficacy modelsof tuberculosis and with the potential for clinical development.