There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.
BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.
METHODS: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.
RESULTS: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.
CONCLUSIONS: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).
Recent studies have suggested that a relationship could exist between 25-hydroxyvitamin D [25(OH)D] deficiency and erectile dysfunction (ED). The present study evaluated the relationship between 25(OH)D levels and ED in male patients with type 2 diabetes mellitus (DM). The study included 98 patients with type 2 DM aged between 18–80 years. The International Index of Erectile Function (IIEF-5) Questionnaire was administered. The patients were divided into three groups according to IIEF-5 scoring: IIEF-5 score between 5–10, severe ED; IIEF-5 score between 11–20, moderate ED; IIEF-5 score between 21–25, no ED. Biochemical parameters, 25(OH)D and hormonal analysis tests were obtained in all patients. All parameters were compared between these three groups. Of 98 patients included in the study, 32 had severe ED, 45 had moderate ED and 21 had no ED. The mean age was 55.12 ± 9.39 years and the mean 25(OH)D level was 13.69 ± 8.15 ng/ml. When the three groups were compared, 25(OH)D levels were significantly lower in patients with the IIEF-5 score between 5–10 (p = 0.020). There was a moderate positive relationship between IIEF-5 score and 25(OH)D level (r = 0.21, p = 0.038). The patients with severe ED have considerably lower 25(OH)D levels.
Background Smoking cessation programmes delivered via mobile phone text messaging show increases in selfreported quitting in the short term. We assessed the eff ect of an automated smoking cessation programme delivered
via mobile phone text messaging on continuous abstinence, which was biochemically verifi ed at 6 months.
Methods In this single-blind, randomised trial, undertaken in the UK, smokers willing to make a quit attempt were
randomly allocated, using an independent telephone randomisation system, to a mobile phone text messaging
smoking cessation programme (txt2stop), comprising motivational messages and behavioural-change support, or to
a control group that received text messages unrelated to quitting. The system automatically generated intervention or
control group texts according to the allocation. Outcome assessors were masked to treatment allocation. The primary
outcome was self-reported continuous smoking abstinence, biochemically verifi ed at 6 months. All analyses were by
intention to treat. This study is registered, number ISRCTN 80978588.
Findings We assessed 11 914 participants for eligibility. 5800 participants were randomised, of whom 2915 smokers
were allocated to the txt2stop intervention and 2885 were allocated to the control group; eight were excluded because
they were randomised more than once. Primary outcome data were available for 5524 (95%) participants. Biochemically
verifi ed continuous abstinence at 6 months was significantly increased in the txt2stop group (10·7% txt2stop
vs 4·9% control, relative risk [RR] 2·20, 95% CI 1·80–2·68; p<0·0001). Similar results were obtained when participants
that were lost to follow-up were treated as smokers (268 [9%] of 2911 txt2stop vs 124 [4%] of 2881 control [RR 2·14,
95% CI 1·74–2·63; p<0·0001]), and when they were excluded (268 [10%] of 2735 txt2stop vs 124 [4%] of 2789 control
[2·20, 1·79–2·71; p<0·0001]). No signifi cant heterogeneity was shown in any of the prespecifi ed subgroups.
Interpretation The txt2stop smoking cessation programme signifi cantly improved smoking cessation rates at 6 months
and should be considered for inclusion in smoking cessation services.
Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease.
We randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro–B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed.
A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m2 of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was −11.0 mm Hg (95% confidence interval [CI], −13.9 to −8.1) in the chlorthalidone group and −0.5 mm Hg (95% CI, −3.5 to 2.5) in the placebo group. The between-group difference was −10.5 mm Hg (95% CI, −14.6 to −6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.
Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research)
Little is known about ECG abnormalities in patients with heart failure and normal ejection fraction (HeFNEF) and how they relate to different etiologies or outcomes.
Methods and results
We searched the literature for peer-reviewed studies describing ECG abnormalities in HeFNEF other than heart rhythm alone. Thirty five studies were identified and 32,006 participants. ECG abnormalities reported in patients with HeFNEF include atrial fibrillation (prevalence 12%-46%), long PR interval (11%-20%), left ventricular hypertrophy (LVH, 10%-30%), pathological Q waves (11%-18%), RBBB (6%-16%), LBBB (0%-8%), and long JTc (3%-4%). Atrial fibrillation is more common in patients with HeFNEF compared to those with heart failure and reduced ejection fraction (HeFREF). In contrast, long PR interval, LVH, Q waves, LBBB, and long JTc are more common in patients with HeFREF. A pooled effect estimate analysis showed that QRS duration ≥120 ms, although uncommon (13%-19%), is associated with worse outcomes in patients with HeFNEF.
There is high variability in the prevalence of ECG abnormalities in patients with HeFNEF. Atrial fibrillation is more common in patients with HeFNEF compared to those with HeFREF. QRS duration ≥120 ms is associated with worse outcomes in patients with HeFNEF. Further studies are needed to address whether ECG abnormalities correlate with different phenotypes in HeFNEF.
Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.
We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19–related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19–related medically attended visit or death from any cause by day 28.
A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.
Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952. opens in new tab; EudraCT number, 2020-003510-12. opens in new tab.)
Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results.
Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments.
Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms.
Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.
The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis ( UMIN000027887 ). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.
Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1–2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.
In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.
Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7–28·0) for the nivolumab group and 13·4 months (5·7–25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9–18·4) with nivolumab and 14·7 months (11·9–17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72–1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.
First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.
Bristol Myers Squibb in collaboration with Ono Pharmaceutical.