Early Use of Sarilumab in Patients Hospitalised with COVID-19 Pneumonia and Features of Systemic Inflammation.

In this phase II, open-label, randomized, controlled clinical trial of 115 patients hospitalized with COVID-19 and systemic inflammation, early use of sarilumab was associated with a low risk of acute respiratory distress syndrome requiring high-flow devices or mechanical ventilation. Objective: To investigate the efficacy and safety of early treatment with sarilumab, added to standard of care (SOC), in hospitalised adults with COVID-19. Methods: Phase II, open-label, randomized, controlled clinical trial of hospitalised patients with COVID-19 pneumonia and interleukin (IL)-6 levels ≥ 40 pg/mL and/or D-dimer > 1500 ng/mL. Participants were randomized (1:1:1) to receive SOC (control group), SOC plus a single subcutaneous dose of sarilumab 200 mg (Sarilumab-200) or SOC plus a single subcutaneous dose of sarilumab 400 mg (Sarilumab-400). The primary outcome variable was the development of acute respiratory distress syndrome (ARDS) requiring high-flow nasal oxygenation (HFNO), non-invasive mechanical ventilation (NIMV) or invasive mechanical ventilation (IMV) at day 28. Results: One-hundred and fifteen participants (control group, n = 39; Sarilumab-200, n = 37; Sarilumab-400, n = 39) were included. At randomization, 104 (90%) patients had supplemental oxygen and 103 (90%) received corticosteroids. Eleven (28%) patients in the control group, ten (27%) in Sarilumab-200 and five (13%) in Sarilumab-400 developed the primary outcome (hazard ratio [95% CI] of Sarilumab-400 vs control group: 0.41 [0.14-1.18]; p=0.09). Seven (6%) patients died: three in the control group and four in Sarilumab-200. There were no deaths in Sarilumab-400 (p = 0.079, log-rank test for comparisons with the control group). Conclusion: In patients recently hospitalised with COVID-19 pneumonia and features of systemic inflammation, early IL-6 blockade with a single dose of sarilumab 400 mg was safe and associated with a trend for better outcomes.

Comparison of the Intestinal Pharmacokinetics of Two Different Florfenicol Dosing Regimens and Its Impact on the Prevalence and Phenotypic Resistance of E. coli and Enterococcus over Time

In order to mitigate the food animal sector’s role in the growing threat of antimicrobial resistance (AMR), the World Health Organization (WHO) suggests the use of lower tier antimicrobials, such as florfenicol. Florfenicol has two dosing schemes used to treat primarily bovine respiratory disease. In this study, the objective was to characterize the plasma and gastrointestinal pharmacokinetics of each dosing regimen and assess the effect of these dosing regimens on the prevalence of resistant indicator bacteria over time. Twelve steers underwent abdominal surgery to facilitate the placement of ultrafiltration probes within the lumen of the ileum and colon, as well as placement of an interstitial probe. Following surgery, cattle were dosed with either 20 mg/kg IM every 48 h of florfenicol given twice (n = 6) or a single, subcutaneous dose (40 mg/kg, n = 6). Plasma, interstitial fluid, gastrointestinal ultrafiltrate, and feces were collected. Pharmacokinetic analysis demonstrated high penetration of florfenicol within the gastrointestinal tract for both the high and low dose group (300%, 97%, respectively). There was no significant difference noted between dosing groups in proportion or persistence of phenotypically resistant bacterial isolates; however, the percent of resistant isolates was high throughout the study period. The recommendation for the use of a lower tier antimicrobial, such as florfenicol, may allow for the persistence of co-resistance for antibiotics of high regulatory concern.

Novel Long-Acting Ropeginterferon Alfa-2b: Pharmacokinetics, Pharmacodynamics, and Safety in a Phase I Clinical Trial

AIM Ropeginterferon alfa-2b is a new site-specific conjugated 40 kDa branched polyethylene-glycol recombinant interferon (IFN). The aim of the study was to determine its safety, pharmacokinetics (PK) and pharmacodynamic (PD). METHODS Ropeginterferon alfa-2b was evaluated first in human in 48 healthy male volunteers after a single dose subcutaneous injection by either 24, 48, 90, 180, 225, 270mcg of the product or 180mcg of marketed pegylated (peg)-IFN alfa-2a. Within each dosing group, 6 subjects received ropeginterferon alfa-2b and 2 subjects received peg-IFN alfa-2a. RESULTS Dose-related increases in ropeginterferon alfa-2b PK parameters (Cmax, AUC, and AUC0-t) were observed over the dose range 24 to 270mcg. The geometric mean values for these PK parameters of ropeginterferon alfa-2b were higher than that of peg-IFN alfa-2a at the 180mcg dose level of 176%, 166%, and 182%, respectively. Mean PD parameters (Emax, Tmax, and AUC0-t) for ropeginterferon alfa-2b increased with dose for both biomarkers neopterin and 2’, 5’-OAS. Ropeginterferon alfa-2b has similar PD profiles as peg-IFN alfa-2a. The treatment related adverse events are similar between the two study drugs, but the overall incidence was numerically lower for ropeginterferon alfa-2b (83%) than peg-IFN alfa-2a (100%) at the 180mcg dose level. CONCLUSIONS Single subcutaneous dose of Ropeginterferon alfa-2b of up to 270mcg is safe and well tolerated. It displays dose related increase in PK and PD parameters, potentially less frequent injection, and better safety profiles. Ropeginterferon alfa-2b is being developed for diseases in which previous peg-IFN use has been limited by side effects.

Field safety experience with an autologous cancer vaccine in tumor-bearing cats: a retrospective study of 117 cases (2015–2020)

Objectives The aim of this study was to determine the frequency and severity of adverse events (AEs) reported from use of an adjuvanted whole-cell autologous cancer vaccine in cats with solid tumors under field conditions. Methods The case accession database at Torigen Pharmaceuticals was searched to identify client-owned cats that underwent biopsy or surgical resection of their primary tumor, had histologic confirmation of neoplasia and received at least one subcutaneous dose of an adjuvanted whole-cell autologous cancer vaccine. Records were reviewed for any reported AEs. Results In total, 117 cats met the inclusion criteria and received 422 doses of autologous cancer vaccine. Six (5.1%) cats had seven reported AEs, with the majority of these (85.7%) being characterized as grade 1 or 2 (mild) and resolving without medical intervention. Conclusions and relevance AEs were infrequent in cats treated with an adjuvanted whole-cell autologous cancer vaccine under typical field use conditions. This form of active cancer immunotherapy appears to be well tolerated by cats and may represent a treatment option for owners who are concerned about AEs associated with chemotherapy or radiotherapy. Additional studies are warranted to determine the efficacy of this form of individualized immunotherapy in cats with solid tumors.

An oral antisense oligonucleotide for PCSK9 inhibition

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.

Dasiglucagon: A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia Results of Phase 3 Randomized Double-Blind Clinical Trial

OBJECTIVE To evaluate the efficacy and safety of dasiglucagon – a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing – for treatment of severe hypoglycemia in adults with type 1 diabetes. <p>RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomized to receive a single subcutaneous dose of dasiglucagon 0.6 mg, placebo, or reconstituted glucagon 1 mg (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference.</p> <p>RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared to 40 (30, 40) minutes for placebo (<i>P</i><0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 minutes in all but one participant (99%), superior to placebo (2%; <i>P</i><0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20 and 30 minutes after dosing. The most frequent side effects were nausea and vomiting, as expected for glucagon treatment.</p> <p>CONCLUSIONS Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to that reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide a rapid and reliable treatment for severe hypoglycemia.</p>

Dasiglucagon: A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia Results of Phase 3 Randomized Double-Blind Clinical Trial

OBJECTIVE To evaluate the efficacy and safety of dasiglucagon – a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing – for treatment of severe hypoglycemia in adults with type 1 diabetes. <p>RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomized to receive a single subcutaneous dose of dasiglucagon 0.6 mg, placebo, or reconstituted glucagon 1 mg (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference.</p> <p>RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared to 40 (30, 40) minutes for placebo (<i>P</i><0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 minutes in all but one participant (99%), superior to placebo (2%; <i>P</i><0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20 and 30 minutes after dosing. The most frequent side effects were nausea and vomiting, as expected for glucagon treatment.</p> <p>CONCLUSIONS Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to that reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide a rapid and reliable treatment for severe hypoglycemia.</p>

Time-sensitive effects of Zhuang Medicated Thread Moxibustion on Estrogen Level in female perimenopausal Model Rats.

Background: To ascertain the estrogenic effect of Zhuang Medicated Thread Moxibustion (ZMTM) and explore its time-sensitive impact on estradiol in female perimenopausal rats. Methods: Female rats were randomized into four groups of 10 rats, each consisting of the control, model, ZMTM, and acupuncture groups. The perimenopausal syndrome was induced in the last three groups with a daily subcutaneous dose of 80 mg/kg of 4- vinylcyclohexene diepoxide for 15 days. Afterward, rats in the model and control groups were fed routinely, while rats in the ZMTM and acupuncture groups were treated with six ZMTM and acupuncture courses, respectively. The rats’ general condition and estradiol (E2) levels in the rats’ serum were assessed. Results: Following the six courses of treatment, the E2 level in the model group was significantly the lowest, while the regular group was the highest (P < 0.05). There was also a gradual increase in the E2 level of the ZMTM group compared to the model and acupuncture groups, such that after the 5th and 6th courses of treatment, their E2 level was significantly higher than the model and acupuncture groups (P < 0.05). The control group had a better condition than all other groups, while the ZMTM group was better than the model and acupuncture groups. Conclusion: ZMTM can improve perimenopausal induced rats’ estrogen level, and this effect becomes better with each further treatment course.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized placebo-controlled trial in 120 patients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint, NCT04331899). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively (HR 0.94; 95% CI 0.64 to 1.39). At enrollment; 41% of subjects were SARS-CoV-2 IgG seropositive; compared to placebo, lambda tended to delay shedding cessation in seronegatives (aHR 0.66, 95% CI 0.39-1.10) and to hasten shedding cessation in seropositives (aHR 1.58, 95% CI 0.88-2.86; p for interaction = 0.03). Liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.