A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness.

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.

Physical Activity in Long COVID: A Comparative Study of Exercise Rehabilitation Benefits in Patients with Long COVID, Coronary Artery Disease and Fibromyalgia.

Exercise in long COVID is poorly studied. Nevertheless, exerciserehabilitation could improve cardiorespiratory, muscular and autonomic functions. We aimed to investigate improvement in physical and autonomic performances of long COVID patients (n = 38) after a 4-week exercise rehabilitation program (3 sessions/week) compared to two control groups composed of coronary artery disease (n = 38) and fibromyalgia patients (n = 38), two populations for whom exercise benefits are well known. Efficacy of exercise training was assessed by a cardiopulmonary exercise test, a handgrip force test, and a supine heart rate variability recording at rest before and after the rehabilitation program. Cardiorespiratory and muscular parameters were enhanced after exercise rehabilitation in the three groups (p < 0.001). No significant difference was observed for the autonomic variables. Through this comparative study with control groups, we confirm and reinforce the interest of caring for long COVID patients without post-exertional symptom exacerbation by exercise rehabilitation of both strength and endurance training, by personalizing the program to the patient and symptoms.

In vivo biodistribution and pharmacokinetics of sotrovimab, a SARS-CoV-2 monoclonal antibody, in healthy cynomolgus monkeys.

PURPOSE: Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys. METHODS: 89Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values. RESULTS: SUVmean uptake in the pulmonary bronchi for 89Zr-VIR-7831 was statistically higher than for 89Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the antibodies except in the liver. While the lung:blood SUVmean uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT. CONCLUSION: The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of 89Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the 89Zr label sheds light on the sites of antibody catabolism.

Glucagon-receptor-antagonism-mediated ß-cell regeneration as an effective anti-diabetic therapy.

Type 1 diabetes mellitus (T1D) is a chronic disease with potentially severe complications, and ß-cell deficiency underlies this disease. Despite active research, no therapy to date has been able to induce ß-cell regeneration in humans. Here, we discover the ß-cell regenerative effects of glucagon receptor antibody (anti-GcgR). Treatment with anti-GcgR in mouse models of ß-cell deficiency leads to reversal of hyperglycemia, increase in plasma insulin levels, and restoration of ß-cell mass. We demonstrate that both ß-cell proliferation and α- to ß-cell transdifferentiation contribute to anti-GcgR-induced ß-cell regeneration. Interestingly, anti-GcgR-induced α-cell hyperplasia can be uncoupled from ß-cell regeneration after antibody clearance from the body. Importantly, we are able to show that anti-GcgR-induced ß-cell regeneration is also observed in non-human primates. Furthermore, anti-GcgR and anti-CD3 combination therapy reverses diabetes and increases ß-cell mass in a mouse model of autoimmune diabetes.

Effects of Cardiac Telerehabilitation During COVID-19 on Cardiorespiratory Capacities in Patients With Coronary Artery Disease.

Background: The COVID-19 pandemic led to the closure of most cardiac therapy centers. One of the solutions was to adapt the existing cardiac rehabilitation (CR) program in an institute to a remote approach offered by home-based telerehabilitation. The aim of this study was to measure the cardiorespiratory effects of telerehabilitation compared to conventional center-based CR. Methods: Patients were assigned to two 3-week CR programs: telerehabilitation and conventional center-based CR. The telerehabilitation group wore a connected watch to monitor heart rate (HR) and gave their perception of effort according to a modified Borg scale. The exercise training (four sessions/week) consisted of 1-h aerobic endurance and strength training session at the target HR zone determined by results based on cardiopulmonary exercise test (CPET) and perception of effort, respectively. The exercise protocol was the same for conventional CR participants except the duration of session that lasted 2 h instead of one. The week before and after the training program, peak oxygen uptake (VO2 peak), oxygen uptake at first ventilatory threshold (VO2 at VT1), peak workload, percent of predicted maximum HR, and the absolute differences in HR and systolic blood pressure between maximum and recovery at 1 and 3 min were measured using a CPET. A two-way ANOVA with one repeated measure and one independent factor was performed. Results: Fifty-four patients (mean age: 61.5 ± 8.6 years, 10 women) equally split in the two groups were included in this experiment. A significant increase was observed in both groups on VO2 peak (telerehabilitation: 8.1 ± 7.8% vs. conventional: 10.1 ± 9.7%, p < 0.001), VO2 at VT1 (telerehabilitation: 8.8 ± 4.4% vs. conventional: 7.3 ± 19.0%, p = 0.02) and peak workload (telerehabilitation: 16.6 ± 18.9% vs. conventional: 17.2 ± 7.0%, p < 0.001) after the 3-week telerehabilitation and conventional CR, respectively. No significant difference was noticed between both groups. Conclusion: A 3-week exercise program improved patients' cardiorespiratory fitness. Telerehabilitation was as effective and represents a safe alternative CR program during the COVID-19 period. In the future, this approach could facilitate the continuity of care for patients unable to participate in center-based CR.

Performance Determinants in Trail-Running Races of Different Distances.

PURPOSE: While the physiological determinants of road running have been widely studied, there is a lack of research in trail-running racing performance. The aim of our study was to determine the physiological predictors of trail-running performance in races of different distances in similar terrain and weather conditions. METHODS: Seventy-five trail runners participating in one of the races of the Ultra-Trail du Mont-Blanc were recruited. Previous to the race, each runner was evaluated with (1) an incremental treadmill test to determine maximal oxygen uptake, ventilatory thresholds, cost of running, and substrate utilization; (2) a power-force-velocity profile on a cycle ergometer; (3) maximal voluntary contractions of the knee extensors and plantar flexors; and (4) anthropometric characteristics. Neuromuscular fatigue was evaluated after the races. Twenty-four runners finished a SHORT (<55 km), 16 finished a MEDIUM (101 km), and 14 finished a LONG (>145 km) race. Correlations and multiple linear regressions were used to find the determinants of performance in each race distance. RESULTS: Performance in SHORT was explained by maximal oxygen uptake and lipid utilization at 10 km/h (r2 = .825, P < .001). Performance in MEDIUM was determined by maximal oxygen uptake, maximal isometric strength, and body fat percentage (r2 = .917, P < .001). A linear model could not be applied in LONG, but performance was correlated to peak velocity during the incremental test. CONCLUSIONS: Performance in trail running is mainly predicted by aerobic capacity, while lipid utilization also influences performance in races <60 km and performance in approximately 100 km is influenced by muscle strength and body composition.

Fatigue Measured in Dynamic Versus Isometric Modes After Trail Running Races of Various Distances.

PURPOSE: Fatigue has previously been investigated in trail running by comparing maximal isometric force before and after the race. Isometric contractions may not entirely reflect fatigue-induced changes, and therefore dynamic evaluation is warranted. The aim of the present study was to compare the magnitude of the decrement of maximal isometric force versus maximal power, force, and velocity after trail running races ranging from 40 to 170 km. METHODS: Nineteen trail runners completed races shorter than 60 km, and 21 runners completed races longer than 100 km. Isometric maximal voluntary contractions (IMVCs) of knee extensors and plantar flexors and maximal 7-second sprints on a cycle ergometer were performed before and after the event. RESULTS: Maximal power output (Pmax; -14% [11%], P < .001), theoretical maximum force (F0; -11% [14%], P < .001), and theoretical maximum velocity (-3% [8%], P = .037) decreased significantly after both races. All dynamic parameters but theoretical maximum velocity decreased more after races longer than 100 km than races shorter than 60 km (P < .05). Although the changes in IMVCs were significantly correlated (P < .05) with the changes in F0 and Pmax, reductions in IMVCs for knee extensors (-29% [16%], P < .001) and plantar flexors (-26% [13%], P < .001) were larger (P < .001) than the reduction in Pmax and F0. CONCLUSIONS: After a trail running race, reductions in isometric versus dynamic forces were correlated, yet they are not interchangeable because the losses in isometric force were 2 to 3 times greater than the reductions in Pmax and F0. This study also shows that the effect of race distance on fatigue measured in isometric mode is true when measured in dynamic mode.

Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection.

BACKGROUND AND OBJECTIVE: VIR-2218 is an investigational N-acetylgalactosamine-conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology. This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers. METHODS: Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50-900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods. RESULTS: In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3'VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration (tmax) of 4-7 h, and had a short median plasma half-life of 2-5 h. Plasma exposures for area under the plasma concentration-time curve up to 12 h (AUC0-12) and mean maximum concentrations (Cmax) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for Cmax. A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3'VIR-2218, with a median tmax of 6-10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3'VIR-2218 was similar to that of VIR-2218, with plasma AUC0-12 and Cmax values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3'VIR-2218 were detectable in urine through the last measured time point, with approximately 17-48% of the administered dose recovered in urine as unchanged VIR-2218 over 0-24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data). CONCLUSIONS: VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection. CLINICAL TRIAL REGISTRATION NO: NCT03672188, September 14, 2018.

Dynamic Force Production Capacities Between Coronary Artery Disease Patients vs. Healthy Participants on a Cycle Ergometer.

BACKGROUND: The force-velocity-power (FVP) profile is used to describe dynamic force production capacities, which is of great interest in training high performance athletes. However, FVP may serve a new additional tool for cardiac rehabilitation (CR) of coronary artery disease (CAD) patients. The aim of this study was to compare the FVP profile between two populations: CAD patients vs. healthy participants (HP). METHODS: Twenty-four CAD patients (55.8 ± 7.1 y) and 24 HP (52.4 ± 14.8 y) performed two sprints of 8 s on a Monark cycle ergometer with a resistance corresponding to 0.4 N/kg × body mass for men and 0.3 N/kg × body mass for women. The theoretical maximal force (F 0) and velocity (V 0), the slope of the force-velocity relationship (S fv) and the maximal mechanical power output (P max) were determined. RESULTS: The P max (CAD: 6.86 ± 2.26 W.kg-1 vs. HP: 9.78 ± 4.08 W.kg-1, p = 0.003), V 0 (CAD: 5.10 ± 0.82 m.s-1 vs. HP: 5.79 ± 0.97 m.s-1, p = 0.010), and F 0 (CAD: 1.35 ± 0.38 N.kg-1 vs. HP: 1.65 ± 0.51 N.kg-1, p = 0.039) were significantly higher in HP than in CAD. No significant difference appeared in Sfv (CAD: -0.27 ± 0.07 N.kg-1.m.s-1 vs. HS: -0.28 ± 0.07 N.kg-1.m.s-1, p = 0.541). CONCLUSION: The lower maximal power in CAD patients was related to both a lower V 0 and F 0. Physical inactivity, sedentary time and high cardiovascular disease (CVD) risk may explain this difference of force production at both high and low velocities between the two groups.