Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5.

BACKGROUND: Mepolizumab, an anti-interleukin-5 (IL-5) antibody, reduces disease flares in patients with hypereosinophilic syndrome (HES). Factors predicting treatment response are unknown. OBJECTIVE: To assess mepolizumab efficacy by baseline blood eosinophil count (BEC) and serum IL-5 level in patients with HES. METHODS: This post hoc analysis used data from the phase III study assessing mepolizumab in patients with HES (NCT02836496). Patients 12 years old or older, with HES for 6 or more months, 2 or more flares in the previous year, and BEC ≥1,000 cells/µL at screening were randomized (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. The proportion of patients experiencing 1 or more flares (wk 32), annualized flare rate, and proportion of patients with change from baseline in Brief Fatigue Inventory (BFI) item 3 (wk 32), were analyzed by baseline BEC (<1500/≥1500 to <2500/≥2500 cells/µL). Flare outcomes were assessed by baseline serum IL-5 (<7.81/≥7.81 pg/mL). RESULTS: Across baseline BEC subgroups, mepolizumab reduced the proportion of patients experiencing 1 or more flares by 63% to 90% and flare rate by 58% to 84% (treatment-by-eosinophil interaction P = .76 and P = .90, respectively); patients had improved BFI item 3 score with mepolizumab versus placebo (cells/µL: <1,500: 54% vs 37%; ≥1,500 to <2,500: 47% vs 31%; ≥2,500: 61% vs 0%; treatment-by-eosinophil interaction P = .42). Most patients had undetectable baseline serum IL-5 levels; among these, mepolizumab versus placebo reduced the proportion of patients with 1 or more flares (77%) and flare rate (67%). CONCLUSIONS: Mepolizumab was efficacious in the patients with HES studied, irrespective of baseline BEC. Undetectable IL-5 levels should not preclude mepolizumab treatment.

Assessment of tobacco heating product THP1.0. Part 8: Study to determine puffing topography, mouth level exposure and consumption among Japanese users.

A four-arm study was undertaken in Japan to determine the puffing topography, mouth level exposure and average daily consumption by consumers of the tobacco heating products (THPs): the non-mentholated THP1.0(T), the mentholated THP1.0(M) and a tobacco heating system (THS). The extent of lip blocking of air inlet holes while using THP1.0(T) was also assessed. Groups 1, 2, and 4 included smokers, and group 3 included regular THP users. Smokers of 7-8 mg ISO nicotine free dry particulate matter (NFDPM) non-mentholated cigarettes took on average larger mean puff volumes from THPs than from conventional cigarettes, but puff numbers and durations were similar. Mouth level exposure to NFDPM and nicotine levels were significantly lower when using THPs than conventional cigarettes. Similar trends were observed among smokers of 7-8 mg ISO NFDPM mentholated cigarettes who used mentholated cigarettes and THP1.0(M). Regular users of commercial THS had similar puffing behaviours irrespective of whether they were using THS or THP1.0(T), except for mean puff volume which was lower with THP1.0(T). No smokers blocked the air inlet holes when using THP1.0(T). The puffing topography results support the machine puffing regime used to generate toxicant emissions data and in vitro toxicology testing.

Assessment of tobacco heating product THP1.0. Part 4: Characterisation of indoor air quality and odour.

The tobacco heating product THP1.0, which heats but does not burn tobacco, was tested as part of a modified-risk tobacco product assessment framework for its impacts on indoor air quality and residual tobacco smoke odour. THP1.0 heats the tobacco to less than 240 °C ± 5 °C during puffs. An environmentally controlled room was used to simulate ventilation conditions corresponding to residential, office and hospitality environments. An analysis of known tobacco smoke constituents, included CO, CO2, NO, NO2, nicotine, glycerol, 3-ethenyl pyridine, sixteen polycyclic aromatic hydrocarbons, eight volatile organic compounds, four carbonyls, four tobacco-specific nitrosamines and total aerosol particulate matter. Significant emissions reductions in comparison to conventional cigarettes were measured for THP1.0. Levels of nicotine, acetaldehyde, formaldehyde and particulate matter emitted from THP1.0 exceeded ambient air measurements, but were more than 90% reduced relative to cigarette smoke emissions within the laboratory conditions defined Residual tobacco smoke odour was assessed by trained sensory panels after exposure of cloth, hair and skin to both mainstream and environmental emissions from the test products. Residual tobacco smoke odour was significantly lower from THP1.0 than from a conventional cigarette. These data show that using THP1.0 has the potential to result in considerably reduced environmental emissions that affect indoor air quality relative to conventional cigarettes.

Assessment of tobacco heating product THP1.0. Part 2: Product design, operation and thermophysical characterisation.

A novel tobacco heating product, THP1.0, that heats tobacco below 245 °C is described. It was designed to eliminate tobacco combustion, while heating tobacco to release nicotine, tobacco volatiles and glycerol to form its aerosol. The stewardship assessment approach behind the THP 1.0 design was based on established toxicological principles. Thermophysical studies were conducted to examine the extent of tobacco thermal conversion during operation. Thermogravimetric analysis of the tobacco material revealed the major thermal behaviour in air and nitrogen up to 900 °C. This, combined with the heating temperature profiling of the heater and tobacco rod, verified that the tobacco was not subject to combustion. The levels of tobacco combustion markers (CO, CO2, NO and NOx) in the aerosol of THP1.0 were significantly lower than the levels if there were any significant pyrolysis or combustion. Quantification of other tobacco thermal decomposition and evaporative transfer markers showed that these levels were, on average, reduced by more than 90% in THP1.0 aerosol as compared with cigarette smoke. The physical integrity of the tobacco consumable rod showed no ashing. Taken together, these data establish that the aerosol generated by THP1.0 is produced mainly by evaporation and distillation, and not by combustion or pyrolysis.