No Dose Adjustments for Cyp3a4 Substrates When Coadministered with Bemnifosbuvir

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug in development for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor [competitive and time-dependent inhibition (TDI)] and inducer of CYP3A4, prompting evaluation of the clinical relevance of these results in a Ph 1 drug-drug interaction (DDI) study in healthy participants using midazolam (MDZ), a sensitive CYP3A4 substrate as an index drug. Method(s): Two groups of 12 healthy participants were enrolled and received a single dose of 2mg MDZ alone on Day 1. Between Days 3 and 7 inclusive, all participants received oral BEM 550mg twice daily (BID). On day 3 and day 7, Group A received a single dose of 2mg MDZ simultaneously with BEM;Group B on these two days received 2mg MDZ 2h after BEM. Serial plasma samples were obtained and measured for MDZ and 1-OH-MDZ levels. Result(s): A single dose (simultaneous or staggered) of BEM slightly increased the plasma exposure of MDZ (14%-26%). Staggered BEM had less impact (8%-17%) on 1-OH-MDZ than simultaneous dosing (22%-31%). Inhibitory effect of BEM was more pronounced with repeat dosing, consistent with in vitro data showing TDI on CYP3A4. After repeat dosing, simultaneously administered BEM increased plasma MDZ exposure by 83%-98%, without affecting the exposure of 1-OH-MDZ. With repeat dosing, staggered BEM showed less effect on both MDZ and 1-OH-MDZ. There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): BEM is a weak inhibitor (ratio between 1.25 and 2) of CYP3A4. No dose adjustment is needed for drugs that are substrates of CYP3A4 when co-administered with BEM.

BEMNIFOSBUVIR HAS LOW POTENTIAL TO INHIBIT P-gp, BCRP, AND OATP1B1 MEDIATED TRANSPORT

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.

Stochastic ordering of systemic risk in commodity markets

The contribution of commodity risks to the systemic risk is assessed in this paper through a novel approach that relies on the stochastic property of concordance ordering of CoVaR. Considering the period that spans from 2005 to 2022 and the VIX as the proxy for the stability of the financial system, we build the stochastic ordering of systemic risk for 35 commodities belonging to four sectors: Agriculture, Energy, Industrial Metals, and Precious Metals. The estimates of the ΔCoVaR signal that contagion effects from commodity markets to the financial system have been stronger during the years 2017–2019. Backtests validate CoVaR as a more resilient risk measure than the VaR, especially during periods of market turmoils. The stochastic ordering of CoVaR shows that severe losses (downside risk) in commodity markets tend to exacerbate systemic financial distress more than gains (upside risk). Commodity risks arising from WTI and EUA are threatening triggers for systemic risk. In contrast, the financial system is less vulnerable to a broader range of scenarios arising from fluctuations in Gold prices. As top contributors to the systemic risk, among the sectors we find Energy and Precious Metals with respect to upside risk and downside risk. The Covid-19 crisis has deeply amplified the systemic influence arising from the downside risk of WTI, Gasoline, and Natural Gas UK and has confirmed the safe-haven role of Gold. © 2022 Elsevier B.V.

High lung levels of active triphosphate predicted with oral at-527 in COVID patients

Background: AT-527 is a guanosine nucleotide prodrug with potent in vitro antiviral activity against flaviviruses and coronaviruses including SARS-CoV-2 (EC90=0.5 μM), the virus responsible for COVID-19. AT-527 exhibits a unique mechanism of action predominantly targeting the NiRAN function of the SARS-CoV-2 polymerase. The clinical safety to date and in vitro potency of AT-527 prompted evaluation of this drug candidate in patients with COVID-19. The purpose of this study was to assess the safety and pharmacokinetics (PK) of AT-527 dosed 550 mg twice a day (BID) in healthy subjects and to predict human lung exposure of the active triphosphate metabolite AT-9010. Methods: Twenty healthy subjects were randomized 1:1 to receive orally AT-527 550 mg BID or matching placebo for 5 days. Safety assessments included adverse events (AEs), vital signs, electrocardiograms (ECGs) and standard safety laboratory tests. Intensive PK sampling was performed after the first and last two doses and assayed for plasma AT-511, the free base form, and metabolites including AT-273, the guanosine nucleoside metabolite, a surrogate for intracellular AT-9010. Results: AT-527 was well tolerated with no discontinuations, serious AEs, clinically significant changes in vital signs or ECGs based on still blinded safety data. AT-511 was rapidly absorbed followed by fast and extensive metabolic conversion to an L-alanyl intermediate metabolite AT-551 and ultimately intracellular AT-9010, reflected by plasma AT-273. Steady state levels were quickly achieved by the third dose of AT-527. Plasma levels of AT-273 were used to predict lung concentrations of AT-9010 using a scaling factor of 1.2X previously determined from in vivo tissue distribution of the triphosphate metabolite in cynomolgus monkeys. As early as 3 hours after the first dose and maintained from the second dose throughout 5 days of dosing, the predicted lung AT-9010 levels were consistently above the EC90 of the drug candidate in inhibiting SARS-CoV-2 replication in vitro. Conclusion: AT-527 orally administered with a regimen of 550 mg BID for 5 days was well-tolerated in healthy subjects. A favorable PK profile was demonstrated: rapid attainment of steady state with a fast build-up of trough levels of AT-273, which were reflective of efficacious active triphosphate metabolite levels in the lungs. AT-527, with a 550 mg BID dosing regimen, is currently being evaluated in Phase 2 clinical studies as an early treatment option for COVID-19.