ABSTRACT
Dexamethasone has been widely used since its initial approval by the FDA in 1958, either individually or as part of a therapeutic regimen for a variety of diseases and disorders, including lymphoma and leukemia and most recently, COVID-19 mediated disease. During a preclinical experiment with A20 B-cell lymphoma bearing mice, a suprapharmacologic dose of dexamethasone phosphate, equivalent to a Human (Equivalent) Dose of 17.5 mg/kg, was inadvertently administered. Blood samples were collected and analyzed by flow cytometry, revealing the presence of a new cell 48 hours after dosing. Subsequent experiments confirmed this finding following a single dose of AVM0703. This cell has since been identified as a bi-specific gamma-delta+ NKT cell, or AVM-NKT cell. One of the challenges of being able to deliver suprapharmacologic dexamethasone doses was the drug product itself. These limitations led to the development of a new drug product, AVM0703, which permits the safe administration of the doses necessary to mobilize these cells. AVM0703 is supplied as a sterile, single-use 50 mL, 24 mg/mL solution for infusion, without preservatives. The ability to rapidly mobilize and activate these cells following a single dose of AVM0703 in as little as 6 hours is the subject of an on-going clinical trial, in patients with lymphoid malignancies (NCT04329728), specifically no-option, R/R ALL, MCL, DLBCL, Primary Mediastinal Large B-cell, Burkitt, CLL/SLL and B-or T-ALL. The study consists of 2-parts, dose-escalation to determine the Phase 2 dose, followed by an adaptive-design, expansion cohort study in the same patient population. Concurrently, clinical data has also been obtained from Expanded Access-Single Patient INDs. Based on the murine model, a theoretically effective HED was determined to be at least 18 mg/kg. Because the maximum dose approved for generic injectable dexamethasone is 6 mg/kg, the starting dose for the clinical trial was set at 6 mg/kg. The dose escalation study design is a 3 x 3 design, originally consisting of cohorts escalating by 3 mg/kg to 21 mg/kg (6, 9, 12, 15, 18 and 21 mg/kg). Since that time and based on safety data (see below), the FDA has permitted a revision to the study, in which the 12 and 15 mg/kg cohorts are skipped. Table 1 provides the original and current study design, with the corresponding total dose for a 70 kg patient. For example, 18 mg/kg is 1.26 g for a 70 kg patient. The trial also incorporates a validated Quality of Life questionnaire and a 12-month follow-up period. In Expanded Use, Single-Patient IND setting, 4 patients received at least one AVM0703 dose: glioblastoma: one 6 mg/kg;B-cell ALL: one 18 mg/kg dose;and two prostate cancer patients: one 18 mg/kg dose and patient #2: repeat doses for the past year as depicted in Table 2. Figure 1 depicts the flow cytometry analysis 24 hours following an 18 mg/kg AVM0703 dose. From a safety perspective, there have been no reports of drug-related or treatment emergent SAE's. The murine model safety findings correlate to the human experience. Adverse events reported to date have been self-limiting and mild to moderate. Frequent AEs include slight elevations of blood pressure, glucose and BUN that resolve without treatment in < 1 week post dose. Leukocytosis and lymphocytosis were reported 24 hours post infusion from the B-cell ALL patient but resolved by 7-days without reported intervention. Because a single AVM0703 dose triggers the rapid mobilization and activation of an endogenous bi-specific gamma-delta+ NKT cell with a favorable emerging safety profile, AVM0703 shows promise as a therapeutic agent in treating this serious disease. [Formula presented] Disclosures: Rea: AVM Biotechnology, LLC: Current Employment. Deisher: AVM Biotechnology, LLC: Current Employment. Jarzyna: AVM Biotechnology, LLC: Current Employment. Zahid: AVM Biotechnology, LLC: Ended employment in the past 24 months. Suwito: AVM Biotechnology, LLC: Current Employment. Poulin: AVM Biotechnology, LLC: Current Employment.
ABSTRACT
The death rate of people is increasing globally during the current outbreak of coronavirus. To combat with COVID-19 havoc, the world has adopted lockdown policies, including Pakistan. Ironically, the invisible virus is suffocating humans at a fast rate but on the other side, there is a visible monster in the world gobbling up human health, i.e., air pollution. Therefore, the main rationale of the present research is to visualize the air quality during the ‘Lockdown’ period in Lahore, Pakistan by mapping via online tools and techniques using a geospatial system. According to the present findings, the concentrations of air pollutants, such as particulate matters (PM10 and PM2.5), nitrogen oxides as NO and NO2, and sulphur dioxide, are below the maximum permissible levels of the Punjab Environmental Quality standards (PEQs), although ozone exceeds its PEQs. So in light of the results, once this COVID-19 crisis is over, the government should speed up measures to lessen air pollution to achieve targets of sustainable development goals (SDGs). Moreover, the present results of air assessment during COVID-19 would serve as a useful reminder for the government of Punjab to cut down air emission levels after the pandemic. © 2020, Faculty of Environment and Resource Studies,Mahidol University. All rights reserved.