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Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications. We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011. 2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (−7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus. Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications. Shionogi.

In a randomized, double-blind trial that treated household contacts of patients with influenza with a single dose of baloxavir or placebo, participants taking baloxavir had a lower risk of influenza (1.9%) than placebo controls (13.6%). Adverse events were similar in the two groups.

Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing. Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported. Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia. Bristol Myers Squibb.

Vorasidenib (VORANIGO ® ; Servier) is an orally administered, first-in-class, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes being developed for use in IDH -mutant diffuse glioma. Vorasidenib received its first approval on 6 August 2024, in the USA, for the treatment of adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery, including biopsy, sub-total resection, or gross total resection. Approval was based on results from the multinational phase III INDIGO trial, in which vorasidenib significantly improved progression-free survival and time to the next anticancer intervention relative to placebo. In the EU and other countries worldwide, regulatory review of vorasidenib in IDH -mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma.

In this randomized trial of three common treatments for childhood absence epilepsy, ethosuximide and valproic acid were more effective than lamotrigine, and adverse effects on attention were less frequent with ethosuximide than with valproic acid. These findings suggest that ethosuximide has the best efficacy and safety profile. The findings of this randomized trial of three common treatments for childhood absence epilepsy suggest that ethosuximide has the best efficacy and safety profile. Childhood absence epilepsy accounts for 10 to 17% of all cases of childhood-onset epilepsy, making it the most common form of pediatric epilepsy. 1 , 2 The syndrome is characterized by daily frequent but brief staring spells, typically beginning at 4 to 8 years of age, in an otherwise apparently healthy child. 3 The classic electroencephalogram (EEG) shows generalized spike-wave bursts (of 3 Hz) with normal background activity. 3 , 4 Often misperceived as a benign form of epilepsy, childhood absence epilepsy is associated with variable remission rates; affected children have cognitive deficits and long-term psychosocial difficulties. 5 – 7 Three medications are commonly used as initial . . .

Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

In a phase 3 trial, vorasidenib, an oral brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), resulted in improved progression-free survival (primary endpoint) and time to next intervention (key secondary endpoint) at second interim analysis, resulting in study unblinding. We report 6 months of additional double-blind data, from second interim analysis (Sept 6, 2022) to unblinding (March 7, 2023), and the effect of vorasidenib on volumetric tumour growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control. INDIGO was a randomised, double-blind, placebo-controlled, phase 3 trial done in 92 hospitals in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the UK, and the USA. Patients aged 12 years or older with residual or recurrent grade 2 IDH1/2-mutant diffuse glioma, a Karnofsky performance-status score of 80 or higher, at least one previous surgery, and no other previous anticancer treatment were eligible. Patients were randomly assigned (1:1; stratified according to locally determined chromosome 1p/19q codeletion status and baseline tumour size) to oral vorasidenib (40 mg) or placebo once a day in continuous 28-day cycles until disease progression or unacceptable toxicity. Progression-free survival per masked independent review committee was the primary endpoint, and time to next intervention was the key secondary endpoint. Prespecified secondary endpoints included tumour growth rate (6-monthly change in tumour volume) and HRQOL (Functional Assessment of Cancer Therapy–Brain [FACT-Br]). Prespecified exploratory endpoints included neurocognitive function (cognitive performance instruments) and seizure activity (self-reported). The full analysis set was used for all efficacy analyses and included all randomly assigned patients, and the safety analysis set was used for all safety analyses and included all patients who received one or more doses of vorasidenib or placebo. The trial is registered with ClinicalTrials.gov, NCT04164901. Recruitment is complete and the trial is ongoing. Between Jan 9, 2020, and Feb 22, 2022, 331 patients were enrolled and randomly assigned to vorasidenib (n=168) or placebo (n=163). 187 (56%) patients were male, 144 (44%) were female, and 257 (78%) were White. Median follow-up was 20·1 months (IQR 15·9 to 23·8). With an additional 6 months of follow-up, median progression-free survival (not reached [95% CI 22·1 to not estimated] vs 11·4 months [95% CI 11·1 to 13·9]; hazard ratio [HR] 0·35 [95% CI 0·25 to 0·49]) and time to next intervention (not estimated [not estimated to not estimated] vs 20·1 months [17·5 to 27·1]; HR 0·25 [0·16 to 0·40]) remained substantially improved with vorasidenib versus placebo. Tumour growth rate was –1·3% (95% CI –3·2 to 0·7) with vorasidenib and 14·4% (95% CI 12·0 to 16·8) with placebo (difference 15·9% [95% CI 12·6 to 19·3]). Mean FACT-Br total scores were similar between the vorasidenib and placebo groups (158·2 [SD 26·4] and 158·8 [23·3]) at baseline and remained high (154·2 [29·8] and 153·2 [29·4]) by the end of treatment. There was no difference between vorasidenib or placebo in neurocognitive functions of verbal learning, executive function, attention, working memory, and psychomotor function from baseline through to end of treatment. The vorasidenib group had lower rates of seizures than the placebo group (18·2 seizures per person-year [95% CI 8·4 to 39·5] vs 51·2 seizures per person-year [22·9 to 114·8]). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) in the vorasidenib and placebo groups, respectively, were increased alanine aminotransferase (17 [10%] and two [1%]), increased aspartate aminotransferase (eight [5%] and none), seizures (seven [4%] and five [3%]), and increased γ-glutamyltransferase (five [3%] and two [1%]). Serious TEAEs occurred in 20 (12%) patients in the vorasidenib group and ten (6%) in the placebo group; the most common were seizures. There were no treatment-related deaths. Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition. Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma. These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy. Servier.

Background Seasonal influenza virus leads to more than half a million deaths each year worldwide. Due to its capacity to evolve, it is considered the most likely pathogen to cause a future pandemic. Antiviral treatment options are currently limited, with the most widely used drugs being neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir marboxil. In adult hospitalized patients, due to the lack of placebo-controlled trials, current available evidence on antiviral treatment benefits is essentially based on observational studies. A placebo-controlled clinical trial is needed to fill this knowledge gap. Methods This is an investigator-initiated, randomized, triple-blind, placebo-controlled, superiority, multi-center trial to assess the clinical efficacy of single-dose baloxavir in decreasing time to clinical improvement in adult immunocompetent patients hospitalized with influenza. Patients ( n  = 484) with confirmed, severe infection (NEWS2 score ≥ 4) will be recruited over three influenza seasons in four large Swiss hospitals. Primary outcome: time to clinical improvement (in hours), calculated from treatment administration until NEWS2 score ≤ 2 maintained for 24 h or until hospital discharge, whichever comes first. The primary outcome is calculated in all patients independently of the duration of symptoms at treatment administration, as well as in participants treated early (<72 h) post onset of symptoms. The main secondary outcomes are the risk of serious influenza complications, length of hospitalization, and difference in viral load at D3 post-treatment administration. Discussion This trial’s results, whether positive or negative, will impact clinical guidance. If baloxavir’s clinical benefit is demonstrated, a single-dose pill would be the easiest implementable treatment option in case of large seasonal outbreaks or a new influenza pandemic. If a clear treatment benefit is not shown, antiviral treatment administration in the hospitalized patient population could be reconsidered to prevent unnecessary medication, lower the risk of resistance development linked to treatment overuse, and ultimately save unnecessary treatment-related expenses. Trial registration ClinicalTrials.gov NCT06653569. Registered on October 22, 2024, https://clinicaltrials.gov/study/NCT06653569?term=NCT06653569&rank=1 .

Background This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. Objectives Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. Patients and Methods Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D. Results The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m 2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n  = 5) or endometrial cancer (one partial response, n  = 1) and KRAS mutations. Conclusions Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.

Background Epoxyeicosatrienoates (EETs) are endogenous regulators of neuroinflammation and cerebral blood flow. Their metabolism to dihydroxyeicosatrienoates (DHETs) is catalyzed by soluble epoxide hydrolase (sEH). After subarachnoid hemorrhage (SAH), EETs’ pathway amplification may be a therapeutic target for the prevention of delayed cerebral ischemia (DCI). We conducted a double-blind, placebo-controlled, phase Ib randomized trial of GSK2256294, a pharmacologic inhibitor of sEH, to evaluate the safety profile and to assess biomarkers of neurovascular inflammation in patients with aneurysmal SAH. Methods Patients were randomly assigned to receive 10 mg of GSK2256294 or a placebo treatment once daily for 10 days, beginning within 72 hours after aneurysm rupture. The primary study end point was safety. Secondary end points included serum and cerebrospinal fluid (CSF) EETs-to-DHETs ratio, cytokine levels, and serum endothelial injury biomarkers, measured at day 7 and day 10 after SAH. Tertiary end points included neurologic status, disposition, length of stay, incidence of DCI, and mortality; these were assessed at hospital discharge and at 90 days. Results Ten patients received GSK2256294 and nine patients received a placebo. There were no adverse events related to the study drug. GSK2256294 administration resulted in a significant increase in the EET/DHET ratio at day 7 and day 10 in serum, but not in the CSF. There was a trend for decreased CSF inflammatory cytokines following GSK2256294 administration, but this did not reach statistical significance. Conclusions GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions. Clinical trial registration ClinicalTrials.gov: NCT03318783.