Dosing of Convalescent Plasma and Hyperimmune Anti-SARS-CoV-2 Immunoglobulins: A Phase I/II Dose-Finding Study.

BACKGROUND AND OBJECTIVE: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing anti-SARS-CoV-2 antibody titers following the administration of ConvP or hyperimmune globulins (COVIg). METHODS: Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination, received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19. RESULTS: Forty-four patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter-individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile range: 17-25 days). Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody titers for > 90% of the time. However, as a result of hybrid immunity and/or repeated vaccination, plasma donors with extremely high antibody titers are now readily available, and a > 90% target attainment should be possible. CONCLUSION: The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg. CLINICAL TRIAL REGISTRATION NUMBER: NL9379 (The Netherlands Trial Register).

The efficacy assessment of convalescent plasma therapy for COVID-19 patients: a multi-center case series.

Convalescent plasma (CP) transfusion has been indicated as a promising therapy in the treatment for other emerging viral infections. However, the quality control of CP and individual variation in patients in different studies make it rather difficult to evaluate the efficacy and risk of CP therapy for coronavirus disease 2019 (COVID-19). We aimed to explore the potential efficacy of CP therapy, and to assess the possible factors associated with its efficacy. We enrolled eight critical or severe COVID-19 patients from four centers. Each patient was transfused with 200-400 mL of CP from seven recovered donors. The primary indicators for clinical efficacy assessment were the changes of clinical symptoms, laboratory parameters, and radiological image after CP transfusion. CP donors had a wide range of antibody levels measured by serology tests which were to some degree correlated with the neutralizing antibody (NAb) level. No adverse events were observed during and after CP transfusion. Following CP transfusion, six out of eight patients showed improved oxygen support status; chest CT indicated varying degrees of absorption of pulmonary lesions in six patients within 8 days; the viral load was decreased to a negative level in five patients who had the previous viremia; other laboratory parameters also tended to improve, including increased lymphocyte counts, decreased C-reactive protein, procalcitonin, and indicators for liver function. The clinical efficacy might be associated with CP transfusion time, transfused dose, and the NAb levels of CP. This study indicated that CP might be a potential therapy for severe patients with COVID-19.

Cost-Effectiveness Analysis of Bezlotoxumab Added to Standard of Care Versus Standard of Care Alone for the Prevention of Recurrent Clostridium difficile Infection in High-Risk Patients in Spain.

INTRODUCTION: Clostridium difficile infection (CDI) is the major cause of infectious nosocomial diarrhoea and is associated with considerable morbidity, mortality and economic impact. Bezlotoxumab administered in combination with standard of care (SoC) antibiotic therapy prevents recurrent CDI. This study assessed the cost-effectiveness of bezlotoxumab added to SoC, compared to SoC alone, to prevent the recurrence of CDI in high-risk patients from the Spanish National Health System perspective. METHODS: A Markov model was used to simulate the natural history of CDI over a lifetime horizon in five populations of patients at high risk of CDI recurrence according to MODIFY trials: (1) ≥ 65 years old; (2) severe CDI; (3) immunocompromised; (4) ≥ 1 CDI episode in the previous 6 months; and (5) ≥ 65 years old and with ≥ 1 CDI episode in the previous 6 months. The incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: In all patient populations (from 1 to 5), bezlotoxumab added to SoC reduced CDI recurrence compared to SoC alone by 26.4, 19.5, 21.2, 26.6 and 39.7%, respectively. The resulting ICERs for the respective subgroups were €12,724, €17,495, €9545, €7386, and €4378. The model parameters with highest impact on the ICER were recurrence rate (first), mortality, and utility values. The probability that bezlotoxumab was cost-effective at a willingness-to-pay threshold of €21,000/QALY was 85.5%, 54.1%, 86.0%, 94.5%, 99.6%, respectively. CONCLUSION: The results suggest that bezlotoxumab added to SoC compared to SoC alone is a cost-effective treatment to prevent the recurrence of CDI in high-risk patients. The influence of changes in model parameters on DSA results was higher in patients ≥ 65 years old, with severe CDI and immunocompromised. Additionally, PSA estimated that the probability of cost-effectiveness exceeded 85% in most subgroups. FUNDING: Merck Sharp & Dohme Corp.

Preclinical toxicological assessment of a novel monoclonal antibody targeting human platelet-derived growth factor CC (PDGF-CC) in PDGF-CChum mice.

Platelet-derived growth factor CC (PDGF-CC) is important during foetal development but also in pathogenesis of neurologic diseases, cancer and fibrosis. We have previously demonstrated that blocking the PDGF-CC/PDGF receptor alpha (PDGFRα) axis resulted in reduction of stroke volume and cerebrovascular permeability after experimentally induced stroke. Recently, we could translate these findings into the clinic showing that imatinib, a small tyrosine kinase inhibitor targeting PDGF receptors, can significantly improve neurological outcome after ischemic stroke in human. Herein we report preclinical toxicological analyses of our newly generated monoclonal anti-human PDGF-CC antibody 6B3 (mAb 6B3) in PDGF-CC humanized mice. Beside histological organ assessment, we also analysed serum, urine, haematological parameters and the general health status of the treated mice. We could not find any indications that mAb 6B3 is toxic or has other significant side effects neither in short, nor in long treatment regimens. Our results indicate that mAb 6B3 can be further developed for clinical use. This opens up the possibility to assess the therapeutic potential of blocking PDGF-CC in diverse pathological conditions such as neurologic diseases, cancer and fibrosis.