Efficacy, Safety, and Pharmacokinetics of AZD7442 (Tixagevimab/Cilgavimab) for Prevention of Symptomatic COVID-19: 15-Month Final Analysis of the PROVENT and STORM CHASER Trials.

INTRODUCTION: The phase 3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies. METHODS: In PROVENT, participants were randomized 2:1 to receive 300 mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8 days of exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300 mg AZD7442 (n = 749) or placebo (n = 372). RESULTS: In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day 183 (95% CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day 366 (95% CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day 366 (95% CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95% CI - 25.9, 64.7; p = 0.212), 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day 366 (95% CI - 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day 366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration-time profiles over 457 days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90 days). CONCLUSION: This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article. GOV IDENTIFIERS: PROVENT (NCT04625725) and STORM CHASER (NCT04625972).

Antibodies are proteins produced by the body's immune system to specifically target foreign substances, such as viruses. AZD7442 is made up of an antibody pair (tixagevimab and cilgavimab) that specifically bind and neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). AZD7442 was designed to give several months of protection against the virus. These antibodies were tested in two clinical trials to see if they could either protect people from getting COVID-19 (PROVENT trial) or prevent people already exposed to SARS-CoV-2 from getting COVID-19 (STORM CHASER trial). In the two trials, approximately 6000 adults received AZD7442 or placebo (injections that look exactly like AZD7442 but contain no medicine). Protection against COVID-19 was monitored for up to 1 year, and safety for up to 15 months. The percentage of trial participants who reported side effects was similar in the AZD7442 and placebo groups, in both trials. The PROVENT trial showed that AZD7442 reduced the risk of getting COVID-19 up to 6 months and protected against severe COVID-19 for up to 1 year. In STORM CHASER, participants were treated after SARS-CoV-2 exposure but before a positive COVID-19 test. Some participants were already infected with SARS-CoV-2 at the start of the trial, others were not. STORM CHASER showed that AZD7442 protected people against COVID-19 for up to 6 months if they were not already infected at the start. The results of these trials provide proof of concept to support the long-term safety of AZD7442 for the prevention of COVID-19.

Assessing the impact of protonating acid combinations in e-cigarette liquids: a randomised, crossover study on nicotine pharmacokinetics.

The addition of protonating acids to e-cigarette liquid formulations (e-liquids) enhances nicotine bioavailability in e-cigarette use. However, little is known about the impact of different combinations of protonating acid on nicotine pharmacokinetics. The objectives of this study were to compare pharmacokinetics of nicotine absorption following use of a closed-system e-cigarette, containing e-liquids with two different nicotine levels and with different ratios of three common protonating acids-lactic, benzoic and levulinic. In a randomised, controlled, crossover study, nicotine pharmacokinetics and product liking were assessed for prototype e-liquids used in a Vuse e-cigarette containing either 3.5% or 5% nicotine and varying ratios of lactic, benzoic and/or levulinic acid. During an 8-day confinement period, 32 healthy adult current cigarette smokers/e-cigarette dual users used a single study e-liquid each day during 10-min fixed and ad libitum use periods after overnight nicotine abstinence. For most comparisons, Cmax and AUC0-60 following both fixed and ad libitum puffing were significantly higher for e-liquids containing 5% nicotine compared with 3.5% nicotine. However, Cmax and AUC0-60 were not statistically different for 5% nicotine e-liquids containing varying ratios of lactic, levulinic and benzoic acid when compared to an e-liquid containing lactic acid only. Mean scores for product liking were similar for all e-liquid formulations assessed, regardless of nicotine concentration, acid content, and whether the product was used in a fixed or ad libitum puffing regimen. While e-liquid nicotine concentration significantly affected users' nicotine uptake, the different combinations of benzoic, levulinic and lactic acid in the e-liquids assessed had limited impact on nicotine pharmacokinetics and product liking scores.

Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated With AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants.

BACKGROUND: We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants identified from breakthrough infections in the PROVENT preexposure prophylaxis trial. METHODS: Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles. RESULTS: At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough coronavirus disease 2019 (COVID-19) cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and nonbreakthrough cases. CONCLUSIONS: Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure. CLINICAL TRIALS REGISTRATION: NCT04625725.

Biomarkers of exposure and potential harm in exclusive users of electronic cigarettes and current, former, and never smokers.

Electronic cigarette (EC) aerosol emissions generally contain fewer and lower concentrations of harmful and potentially harmful constituents, compared with cigarette smoke. Further studies are needed to establish whether decreased emissions translate to reduced health risks for EC users. In a cross-sectional study, biomarkers of exposure (BoE) to certain tobacco smoke toxicants and biomarkers of potential harm (BoPH), associated with biological processes linked to the potential development of smoking-related diseases and oxidative stress, were assessed in solus Vuse ECs users and current, former, and never smokers. In total, 213 participants were enrolled, and smoking status was confirmed by urinary cotinine, exhaled carbon monoxide, and N-(2-cyanoethyl)valine levels (EC users and former smokers only). During confinement participants used their usual product (EC or cigarette) as normal and BoE and BoPHs were assessed via blood, 24-h urine, and physiological assessment. Significantly lower levels of all urinary BoE; MHBMA, HMPMA, 3-HPMA, NNN, 3-OH-B[a]P, S-PMA, NNAL (all p < 0.0001), and TNeq (p = 0.0074) were observed in EC users when compared with smokers. Moreover, significantly lower levels were observed in EC users for 3 of the 7 BoPH measured, carboxyhaemoglobin (p < 0.0001), soluble intercellular adhesion molecule-1 (p = 0.0028), and 11-dehydrothromboxane B2 (p = 0.0012), when compared with smokers. As compared with smokers, solus Vuse EC users have significantly lower exposure to tobacco toxicants for the BoE, and 3 BoPH measured. These results add to the weight of evidence supporting EC as part of a tobacco harm reduction strategy.

Assessment of biomarkers of exposure and potential harm, and physiological and subjective health measures in exclusive users of nicotine pouches and current, former and never smokers.

Background: Oral nicotine pouches (NPs) are smokeless, tobacco-free products that have a potential role in tobacco harm reduction strategies.Methods: In a cross-sectional study in Sweden/Denmark, several recognised biomarkers of potential harm (BoPHs) linked to smoking-related diseases/their initiating biological processes, and biomarkers of exposure (BoEs) to tobacco/tobacco smoke toxicants were compared among exclusive adult users of Velo NPs and current/former/never smokers. Over 24 h, participants used their usual product (Velo NP or cigarette) as normal, and BoEs/BoPHs were assessed via blood/24-h urine/exhaled breath/physiological assessments.Results: Among the primary endpoints, total NNAL (16.9 ± 29.47 vs 187.4 ± 228.93 pg/24 h), white blood cell count (5.59 ± 1.223 vs 6.90 ± 1.758 × 109/L), and COHb (4.36 ± 0.525 vs 8.03 ± 2.173% saturation) were significantly lower among Velo users than among smokers (91%, 19% and 46% lower, respectively, all P < 0.0001), while fractional exhaled NO, previously shown to be lower in smokers, was significantly higher (23.18 ± 17.909 vs 11.20 ± 6.980 ppb) among Velo users (107% higher, P < 0.0001). Furthermore, sICAM-1 tended to be lower (185.9 ± 42.88 vs 204.5 ± 64.85 ng/mL) among Velo users than smokers (9% lower). Several secondary endpoints, including six BoEs (3-HPMA (246.7 ± 91.07 vs 1165.7 ± 718.35 µg/24 h), 3-OH-B[a]P (82.4 ± 217.58 vs 258.3 ± 190.20 pg/24 h), HMPMA (135.1 ± 77.85 vs 368.8 ± 183.15 µg/24 h), MHBMA (0.22 ± 0.166 vs 3.39 ± 2.943 µg/24 h), S-PMA (0.10 ± 0.059 vs 3.53 ± 2.736 µg/24 h) and total NNN (7.5 ± 24.84 vs 9.7 ± 5.93 ng/24 h)), were significantly lower among Velo users (78.8%, 68.1%, 63.4%, 93.5%, 97.2% and 22.7% lower, respectively, P < 0.0001-0.0011), while total nicotine equivalents was significantly higher among Velo users (22.6 ± 12.69 vs 12.1 ± 7.92 mg/24 h, P < 0.0001), although Velo user levels are comparable to those previously reported among oral tobacco users, and Velo user and smoker mean levels were similar in Denmark.Conclusion: As compared with smokers, exclusive users of Velo NPs have significantly less exposure to tobacco toxicants and more favourable BoPHs associated with initiating biological processes of smoking-related diseases.International Standard Registered Clinical Trial number: ISRCTN16988167.

Biomarkers of Exposure and Potential Harm in Exclusive Users of Nicotine Pouches and Current, Former, and Never Smokers: Protocol for a Cross-sectional Clinical Study.

BACKGROUND: Tobacco harm reduction (THR) aims to reduce the health burden of cigarettes by encouraging smokers to switch to using alternative tobacco or nicotine products. Nicotine pouches (NPs) are smokeless, tobacco-free, oral products that may be beneficial as part of a THR strategy. OBJECTIVE: This 2-center, cross-sectional confinement study conducted in Denmark and Sweden aimed to determine whether biomarkers of exposure (BoEs) to tobacco toxicants and biomarkers of potential harm (BoPHs) in exclusive users of NPs show favorable differences compared with current smokers. METHODS: Participants were healthy NP users (target n=100) and current, former, or never smokers (target n=40 each), as confirmed by urinary cotinine and exhaled carbon monoxide concentrations. During a 24-hour confinement period, participants were asked to use their usual product (NP or cigarette) as normal, and BoEs and BoPHs were measured in blood and 24-hour urine samples, with compliance determined using anabasine, anatabine, and N-(2-cyanoethyl)valine. BoEs and BoPHs were compared between NP users and current, former, and never smokers. Urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (BoE to nicotine-derived nitrosamine ketone) and urinary 8-epi-prostaglandin F2α type III, exhaled nitric oxide, blood carboxyhemoglobin, white blood cell count, soluble intercellular adhesion molecule-1, and high-density lipoprotein cholesterol (BoPHs) were evaluated as primary outcomes. Other measures included urinary 11-dehydrothromboxane B2, forced expiratory volume, carotid intima-media thickness, self-reported quality of life, and oral health. RESULTS: The results of this study were received in mid-2022 and will be published in late 2022 to early 2023. CONCLUSIONS: The results of this study will provide information on toxicant exposure and biomarkers associated with the development of smoking-related diseases among users of NPs compared with smokers, as well as on the potential role of NPs in THR. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) ISRCTN16988167; https://www.isrctn.com/ISRCTN16988167. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39785.

A randomised study to assess the nicotine pharmacokinetics of an oral nicotine pouch and two nicotine replacement therapy products.

Nicotine replacement therapies (NRTs) are intended for short-term use to help cigarette smokers to quit. Some smokers find NRTs ineffective or seek a more satisfactory source of nicotine. Tobacco-free oral nicotine pouch (NP) products have emerged as a potential reduced risk product compared with cigarettes and other tobacco products. In a randomised crossover clinical study, thirty-four healthy adult smokers were enrolled and their nicotine Cmax and AUC0-T determined for three 4 mg nicotine products (NP, gum, lozenge) under fasting conditions. The NP, lozenge and gum mean Cmax values were 8.5, 8.3 and 4.4 ng/mL, AUC0-T values were 30.6, 31.5 and 14.3 ng*h/mL, respectively. The NP showed similar nicotine bioavailability to the lozenge (p = 0.6526 (Cmax), p = 1.0000 (AUC0-T)), and superior bioavailability to the gum (p < 0.0001 for Cmax and AUC0-T). Compared with the lozenge, the NP demonstrated greater product satisfaction with a higher number of positive responses to subjective satisfaction questions. All products were judged to be well-tolerated; the incidence of minor adverse events was lower for the NP (18.2%) than the lozenge (33.3%) or gum (18.8%). In summary, NPs may provide smokers with a more satisfying alternative nicotine source as compared to the reference NRTs.Study Registry/Registered Trial No: ISRCTN/ISRCTN65708311.

Enamel staining with e-cigarettes, tobacco heating products and modern oral nicotine products compared with cigarettes and snus: An in vitro study.

PURPOSE: To evaluate the effect of cigarette smoke, smokeless tobacco (e.g. snus), tobacco heating products (THP), electronic cigarettes (EC), and modern oral nicotine products on tooth staining. METHODS: In this in vitro study, staining was assessed for 86 days following exposure of bovine enamel samples to a scientific reference cigarette (1R6F), a THP (glo), an EC (ePen 3), a reference snus product (CRP1.1), and a modern oral product (LYFT). Red wine and coffee were used as positive controls and DMSO and complete artificial saliva as negative controls. Whether brushing could reduce staining levels was also assessed. Changes in staining levels were assessed using the Commission Internationale de L'éclairage L*a*b* method. RESULTS: Enamel staining increased with incubation time, and cigarette smoke, snus, coffee and wine induced statistically higher staining levels. THP, EC and modern oral exposure induced minimal staining levels that were also comparable to negative control samples. At day 86, ΔE mean and SD values were 28.50 ± 3.14, 19.76 ± 1.26, 17.35 ± 3.44, 16.22 ± 2.07, 18.30 ± 3.82, 4.10 ± 1.99, 11.30 ± 2.60, 49.56 ± 2.44 for cigarette, glo, EC with blended tobacco, EC with rich tobacco, reference snus product, modern oral product, coffee or wine. The control ΔE mean and SD values at day 86 were 18.68 ± 3.89 for DMSO and 2.17± 0.78 for complete artificial saliva. The ΔE values for all DMSO extracted samples and control increased from day 1 to 86, which suggests that the DMSO used to extract the samples contributes to the enamel sample staining levels. Staining levels were reduced by brushing. CLINICAL SIGNIFICANCE: Cigarette smoke, red wine, snus and coffee stained enamel. Exposure to THP, EC or modern oral product extracts for 86 days resulted in minimal enamel staining. Further studies are required to assess the long-term impact on staining and the oral cavity following consumer exclusive use of EC, THP or modern oral products.

The Evolving E-cigarette: Comparative Chemical Analyses of E-cigarette Vapor and Cigarette Smoke.

Background: E-cigarette designs, materials, and ingredients are continually evolving, with cotton wicks and diverse coil materials emerging as the popular components of atomisers. Another recent development is the use of nicotine salts in e-liquids to replicate the form of nicotine found in cigarette smoke, which may help cigarette smokers to transition to e-cigarettes. However, scientific understanding of the impact of such innovations on e-cigarette aerosol chemistry is limited. Methods: To address these knowledge gaps, we have conducted a comparative study analyzing relevant toxicant emissions from five e-cigarettes varying in wick, atomiser coil, and benzoic acid content and two tobacco cigarettes, quantifying 97 aerosol constituents and 84 smoke compounds, respectively. Our focus was the potential for benzoic acid in e-liquids and cotton wicks to form aerosol toxicants through thermal degradation reactions, and the potential for nickel-iron alloy coils to catalyze degradation of aerosol formers. In addition, we analyzed e-cigarette emissions for 19 flavor compounds, thermal decomposition products, and e-liquid contaminants that the FDA has recently proposed adding to the established list of Harmful and Potentially Harmful Constituents (HPHCs) in tobacco products. Results: Analyses for benzene and phenol showed no evidence of the thermal decomposition of benzoic acid in the e-cigarettes tested. Measurements of cotton decomposition products, such as carbonyls, hydrocarbons, aromatics, and PAHs, further indicated that cotton wicks can be used without thermal degradation in suitable e-cigarette designs. No evidence was found for enhanced thermal decomposition of propylene glycol or glycerol by the nickel-iron coil. Sixteen of the 19 FDA-proposed compounds were not detected in the e-cigarettes. Comparing toxicant emissions from e-cigarettes and tobacco cigarettes showed that levels of the nine WHO TobReg priority cigarette smoke toxicants were more than 99% lower in the aerosols from each of five e-cigarettes as compared with the commercial and reference cigarettes. Conclusions: Despite continuing evolution in design, components and ingredients, e-cigarettes continue to offer significantly lower toxicant exposure alternatives to cigarette smoking.