Explore the vast range of titles available.

In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a lower rate of total worsening heart failure events and death from cardiovascular causes than placebo.

In this double-blind trial, patients with stage 1 to 4 chronic kidney disease and type 2 diabetes were randomly assigned to receive finerenone or placebo. Finerenone treatment was superior with regard to the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.

Anti-malarial artemisinin-based combination therapies (ACTs) might be losing efficacy in east Africa, with the spread of artemisinin partial resistance and reduced partner drug activity. Our trial aimed to measure the efficacies of artemether–lumefantrine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, and artesunate–pyronaridine in three sites in Uganda. This randomised, open-label, phase 4 clinical trial was carried out at three sites in the Agago, Arua, and Busia districts of Uganda. Children aged 6 months to 10 years with uncomplicated Plasmodium falciparum malaria were randomly assigned to receive either artemether–lumefantrine (20 mg artemether; 120 mg lumefantrine; twice a day for 3 days) in all sites or dihydroartemisinin–piperaquine (40 mg dihydroartemisinin and 320 mg piperaquine, once a day for 3 days) in Agago, artesunate–amodiaquine (25 mg artesunate and 67·5 mg amodiaquine for children <9 kg or 50 mg artesunate and 135 mg amodiaquine for children ≥9 kg, once a day for 3 days) in Busia; and artesunate–pyronaridine (60 mg artesunate and 180 mg pyronaridine for children >15 kg or 20 mg artesunate and 60 mg pyronaridine for children <15 kg, once a day for 3 days) in Arua, with follow-up to 42 days. Participants were not blinded to group assignments; however, investigators and those assessing outcome were masked. The primary outcome was parasitaemia, assessed by microscopy, either uncorrected or PCR-corrected to distinguish recrudescence from new infection. All participants who received the treatment per protocol and were not lost to follow-up were included in the primary outcome. All participants who were randomly allocated to treatment groups were included in the safety analyses. This study is registered with the Pan African Clinical Trials Registry, number PACTR202301796134887, and is complete. Between Nov 7, 2022, and March 24, 2023, 808 participants (437 [54%] female) were enrolled and assigned to treatment groups; 15 (2%) were lost to follow-up and 793 (98%) completed follow-up. The uncorrected adequate clinical and parasitological response for artemether–lumefantrine was 87 (51·8%; 95% CI 44·0–59·5) of 168 participants in Arua, 88 (51·8%; 44·0–59·4) of 170 and Busia, and 131 (79·4%; 72·3–85·1) of 165 in Agago. This response for artemether–lumefantrine was lower than that of the other ACTs at all sites: 97 (98·0%; 92·2–99·6) of 99 for dihydroartemisinin–piperaquine in Agago, 95 (99·0%; 93·5–99·9) of 96 for artesunate–amodiaquine in Busia, and 73 (73·7%; 63·8–81·8) of 99 for artesunate–pyronaridine in Arua. PCR-corrected 28-day efficacies were 88 (81·5%; 72·6–88·1) of 108 for artemether–lumefantrine and 95 (100%; 95·2–100·0) of 95 for artesunate–amodiaquine in Busia; 131 (97·0%; 92·1–99·0) of 135 for artemether–lumefantrine and 97 (100%; 95·3–100·0) of 97 for dihydroartemisinin–piperaquine in Agago; and 87 (82·1%; 73·2–88·6) of 106 for artemether–lumefantrine and 73 (92·4%; 83·6–96·9) of 79 for artesunate–pyronaridine in Arua. All regimens were well tolerated. The most common adverse events were upper respiratory tract infection, diarrhoea, and anaemia. None of the reported adverse events were attributed to the study drugs. There were two serious adverse events, both cases of severe malaria in Arua, one in each of the treatment groups. Parasite clearance half-lives were prolonged with parasites carrying the PfK13 Cys469Tyr (median 4·2 h; IQR 3·4–4·9) and Ala675Val (4·9 h; 3·4–5·7) mutations compared with wild-type parasites (2·8 h; 2·3–3·6; p<0·0001). Artemether–lumefantrine was associated with a higher risk of recurrent malaria than other antimalarial combinations tested, and K13 mutations were associated with delayed parasite clearance. Changes in first-line therapy for uncomplicated malaria must be considered in response to suboptimal efficacy of artemether–lumefantrine. US President's Malaria Initiative, US Agency for International Development, through the Uganda Malaria Reduction Activity and the National Institutes of Health (AI075045 and AI117001). For the Swahili translation of the abstract see Supplementary Materials section.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [ 18 F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V T ), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V T  > 0%) of ≥80%. Results Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V T at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: − 9 to 42%). The posterior probability that the true % reduction in V T  > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration clinicaltrials.gov: NCT03069989 ; date of registration: 3 March 2017.

Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25–20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025–0.167mmol/L) compared with the placebo group (−0.075mmol/L); no patients developed hyperkalemia. When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

In this double-blind trial, patients with chronic kidney disease and type 2 diabetes were randomly assigned to receive the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone or placebo. Treatment with finerenone resulted in lower risks of chronic kidney disease outcomes and cardiovascular outcomes than placebo.

A novel oral combination of the long‐acting antimalarials pyronaridine (PYR) and piperaquine (PQP) has potential for malaria chemoprevention. This single‐center randomized, double‐blind, placebo‐controlled study assessed the effects of PYR and PQP alone and when co‐administered on Fridericia‐corrected QT interval (QTcF). Between February 14, 2022, and May 31, 2022, thirty‐seven healthy black adults of African sub‐Saharan origin were enrolled and randomized to PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8) or double placebo (n = 6) administered once daily (fasted) for 3 days at doses approved for malaria treatment. Triplicate digitalized electrocardiogram (ECG) recordings and pharmacokinetic samples were taken at matched timepoints. Concentration–response analysis was performed for QTcF changes from baseline (ΔQTcF), and the impact of PYR, PQP, and PYR + PQP administration on placebo‐corrected ΔQTcF (ΔΔQTcF) was assessed. The final qualified and validated concentration–QTc model included a linear component for PYR and an Emax component for PQP. The maximum predicted effect on ΔΔQTcF on day 3 was +4.94 msec (90% CI 0.338, 9.54) with PYR + placebo, +19.2 msec (14.6, 23.8) with PQP + placebo, and + 23.1 msec (18.5, 27.6) with PYR + PQP. As expected, PQP increased ΔΔQTcF above the regulatory threshold of concern (+10 msec), whereas PYR did not. The small additional increase in ΔΔQTcF with PYR + PQP coadministration was explained mainly by an increase in PQP Cmax (1.4‐fold) versus monotherapy. In healthy adults, PYR + PQP coadministration does not appear to increase significantly the effect of PQP on ΔΔQTcF versus PQP administered alone. However, further studies are needed in malaria patients to confirm these findings in the target population. Trial Registration: ClinicalTrials.gov identifier: NCT05160363; EudraCT number: 2021‐005698‐21

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy. The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor has therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. In this first-in-human study, we investigate the safety, tolerability and pharmacokinetics (PK) of JPI-289 in healthy male volunteers. In single ascending dose (SAD) study, 35, 75, 150, 300, 600 mg JPI-289 or placebo was infused intravenously over 30 minutes to 40 subjects. In multiple ascending dose (MAD) study, 150, 300, 450 mg JPI-289 or placebo was infused over 1 hour every 12 hours to each of 24 subjects for 3.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined. In the SAD study, AUC and C tended to increase supra-proportionally especially at higher doses in SAD study. However, C showed dose-proportionality in the range of 75-600mg. JPI-289 reached a mean T within 0.50 hour after dosing and a mean elimination half-life (t ) was 2.18 to 3.21 hours. In the MAD study, observed accumulation index ranged from 1.52 to 1.76. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that the plasma JPI-289 concentration rapidly reaches steady state. % recovered of JPI-289 measured in urine was 1.59-9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Adverse events reported in the study were all mild in intensity and resolved without any sequelae. The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be useful in further clinical development of JPI-289.

New therapies to treat malaria are needed. In this report, in which the authors studied 1271 patients from Asia and Africa, pyronaridine–artesunate was found to be noninferior to mefloquine plus artesunate in the treatment of uncomplicated Plasmodium falciparum malaria. Artemisinin-based combination therapy is critical for the effective treatment and control of Plasmodium falciparum malaria. 1 – 4 However, reports from the Cambodian–Thai border indicate the emergence of artemisinin tolerance or resistance in P. falciparum . 2 – 8 Pyronaridine–artesunate is a fixed-dose, artemisinin-based combination therapy that is being developed for the treatment of uncomplicated P. falciparum and P. vivax malaria. 9 – 11 In phase 2 and 3 clinical trials, a fixed-dose, 3:1 ratio of pyronaridine to artesunate has shown high efficacy in the treatment of falciparum malaria, with cure rates on day 28 of more than 98% (corrected for reinfection with the use of . . .