Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: a randomized, double-blinded, placebo-controlled phase 3 trial

Background Children with severe atopic dermatitis (AD) have limited treatment options. Objective We report efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6–11 years with severe AD inadequately controlled with topical therapies. Methods In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300mg dupilumab every 4 weeks (300mg-q4w), a weight-based regimen of dupilumab every 2 weeks (100mg-q2w, baseline weight <30kg; 200mg-q2w, ≥30kg), or placebo; with concomitant medium-potency TCS. Results Both the q4w and q2w dupilumab+TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QoL) versus placebo+TCS in all prespecified endpoints. For q4w/q2w/placebo, 32.8%/29.5%/11.4% of patients achieved Investigator’s Global Assessment scores of 0/1; 69.7%/67.2%/26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%/58.3%/12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300mg-q4w in children <30kg and 200mg-q2w in children ≥30kg. Conjunctivitis and injection-site reactions were more common with dupilumab+TCS than placebo+TCS. Limitations Short-term 16-week treatment period; severe AD only. Conclusion Dupilumab+TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QoL

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19

BACKGROUND REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. METHODS We randomly assigned, in a 1:1 ratio, participants (=12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARSCoV- 2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-CoV-2 infection (as measured by reverse-transcriptase- quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). RESULTS Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. CONCLUSIONS Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load

The causes of mutation accumulation in mitochondrial genomes

A fundamental observation across eukaryotic taxa is that mitochondrial genomes have a higher load of deleterious mutations than nuclear genomes. Identifying the evolutionary forces that drive this difference is important to understanding the rates and patterns of sequence evolution, the efficacy of natural selection, the maintenance of sex and recombination and the mechanisms underlying human ageing and many diseases. Recent studies have implicated the presumed asexuality of mitochondrial genomes as responsible for their high mutational load. We review the current body of knowledge on mitochondrial mutation accumulation and recombination, and conclude that asexuality, per se, may not be the primary determinant of the high mutation load in mitochondrial DNA (mtDNA). Very little recombination is required to counter mutation accumulation, and recent evidence suggests that mitochondrial genomes do experience occasional recombination. Instead, a high rate of accumulation of mildly deleterious mutations in mtDNA may result from the small effective population size associated with effectively haploid inheritance. This type of transmission is nearly ubiquitous among mitochondrial genomes. We also describe an experimental framework using variation in mating system between closely related species to disentangle the root causes of mutation accumulation in mitochondrial genomes

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial

Background: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. Methods: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. Findings: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8–18). An objective response per independent central review was observed in 26 (31%; 95% CI 21–42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3–4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. Interpretation: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. Funding: Regeneron Pharmaceuticals and Sanofi. © 2021 Elsevier Lt