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1.
Muscle Nerve ; 62(2): 254-258, 2020 08.
Article in English | MEDLINE | ID: covidwho-2209145

ABSTRACT

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic, but little is known about its potential impact on patients with myasthenia gravis (MG). METHODS: We studied the clinical course of COVID-19 in five hospitalized patients with autoimmune MG (four with acetylcholine receptor antibodies, one with muscle-specific tyrosine kinase antibodies) between April 1, 2020-April 30-2020. RESULTS: Two patients required intubation for hypoxemic respiratory failure, whereas one required significant supplemental oxygen. One patient with previously stable MG had myasthenic exacerbation. One patient treated with tocilizumab for COVID-19 was successfully extubated. Two patients were treated for MG with intravenous immunoglobulin without thromboembolic complications. DISCUSSION: Our findings suggest that the clinical course and outcomes in patients with MG and COVID-19 are highly variable. Further large studies are needed to define best practices and determinants of outcomes in this unique population.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/therapy , Hypoxia/therapy , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Myasthenia Gravis/therapy , Pneumonia, Viral/therapy , Respiratory Insufficiency/therapy , Adult , Aged, 80 and over , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Disease Progression , Female , Humans , Hypoxia/etiology , Immunosuppressive Agents/therapeutic use , Intubation, Intratracheal , Male , Middle Aged , Myasthenia Gravis/complications , Myasthenia Gravis/immunology , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/complications , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Respiration, Artificial , Respiratory Insufficiency/etiology , SARS-CoV-2
2.
Mult Scler Relat Disord ; 66: 104025, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2181739

ABSTRACT

BACKGROUND: This analysis evaluated long-term safety findings from the SAkuraSky and SAkuraStar studies with satralizumab in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: SAkuraSky (satralizumab in combination with baseline immunosuppressive therapy; IST) and SAkuraStar (satralizumab monotherapy) are international, multicenter, randomized, placebo-controlled, phase 3 studies consisting of a double-blind (DB) period followed by an open-label extension (OLE). The overall satralizumab treatment (OST) period safety population comprised patients receiving ≥1 dose of satralizumab in the DB and/or OLE periods (cut-off date: 22 February 2021). Safety was evaluated in the DB and OST periods. RESULTS: In the SAkuraSky DB period, patients received satralizumab (n = 41) or placebo (n = 42) in addition to stable baseline IST; 75 patients were included in the OST population. In the SAkuraStar DB period, 63 patients received satralizumab monotherapy and 32 received placebo; 91 patients were included in the OST population. Median treatment exposure in the OST period was 4.4 years (range 0.1-7.0) in SAkuraSky and 4.0 years (range 0.1-6.1) in SAkuraStar. Rates of adverse events (AEs per 100 patient-years) and serious AEs in the OST period were comparable with satralizumab and placebo in the DB periods of both studies. Similarly, overall rates of infections and serious infections were consistent between the OST and DB periods with satralizumab, with no increase in rates of infections or serious infections over time. In the OST periods, longer exposure to satralizumab was not associated with a higher risk of severe (grade ≥3) laboratory changes versus the DB periods. No deaths or anaphylactic reactions to treatment with satralizumab were reported during the OST periods of both studies. CONCLUSION: The safety profile of satralizumab as a monotherapy or in combination with IST was maintained in the OLE, and no new safety concerns versus the DB period were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02028884 (SAkuraSky) and NCT02073279 (SAkuraStar).


Subject(s)
Antibodies, Monoclonal, Humanized , Neuromyelitis Optica , Humans , Double-Blind Method , Neuromyelitis Optica/drug therapy , Antibodies, Monoclonal, Humanized/adverse effects
3.
Mult Scler Relat Disord ; 63: 103921, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-2181738

ABSTRACT

BACKGROUND: Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization (HRU). The infection risk and HRU costs may vary between disease-modifying therapies (DMTs); however, the individual risks and differences associated with DMTs are not well characterized. Some DMTs may increase the risk for infections in PwMS; however, previous studies have reported an intact humoral immune response in dimethyl fumarate (DMF)-treated patients. The objective was to compare infection-related HRU and healthcare costs (HCCs) between PwMS treated with DMF or ocrelizumab (OCR). METHODS: Eligible patients were identified from the Optum US claims database between April 2017 and September 2020 (DMF n = 1429; OCR n = 3170). Patients were followed from index date to first occurrence of: (1) end of study, (2) end of insurance eligibility, (3) discontinuation of index DMT, or (4) switch from index DMT to another DMT. Outcomes were annualized rate of infection encounters (defined as infection encounters [n] during follow-up window / days followed [n] × 365); annualized infection-related HCCs (defined as aggregated costs of infection encounters during follow-up window / days followed [n] × 365); location-specific infections, and overall infection-related events. Propensity score matching (PSM) 1:1 method was used; PS was calculated via logistic regression for probability of DMF treatment conditional on demographics and comorbidities. Mean differences (MD) were reported for infection encounter measures. RESULTS: After PSM, DMF and OCR cohorts (n = 1094 in each cohort) were balanced based on baseline characteristics (standardized MD of adjusted baseline characteristics <0.1). Mean (standard deviation) follow-up was 296 (244) days for DMF patients and 297 (243) for OCR patients. DMF patients experienced lower annualized rates of overall infection encounters vs OCR patients (MD -0.51 [95% confidence interval (CI): -0.92 to -0.11], p = 0.01). When stratified by type of infection encounter, DMF patients experienced significantly lower annualized rates of outpatient (MD [95% CI]: -0.44 [-0.80 to -0.08], p = 0.02) and inpatient/hospitalization infection encounters (-0.08 [-0.14 to -0.02], p<0.01) vs OCR patients. A trend towards a shorter duration of infection-related hospitalization in the DMF vs the OCR group was observed (MD [95% CI]: -2.20 [-4.73 to 0.26] days, p = 0.08). The most common infection types in both DMT groups were urinary tract infections, sepsis, and pneumonia. DMF patients experienced lower annualized infection-related HCCs (MD [95% CI]: -$3642 [-$6380 to -$904], p < 0.01) vs OCR patients, which were driven largely by infection-related hospitalization costs (-$3639 [-$6019 to -$1259], p < 0.01). CONCLUSION: DMF-treated patients PS-matched with OCR patients experienced lower annualized rates of infection encounters and lower infection-related HCCs.


Subject(s)
Dimethyl Fumarate , Multiple Sclerosis , Antibodies, Monoclonal, Humanized/adverse effects , Dimethyl Fumarate/therapeutic use , Health Care Costs , Humans , Multiple Sclerosis/chemically induced , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Retrospective Studies
4.
Clin Immunol ; 244: 109130, 2022 11.
Article in English | MEDLINE | ID: covidwho-2177621

ABSTRACT

Here, we report a case of atopic dermatitis (AD) in a patient who received biweekly doses of dupilumab, an antibody against the IL-4 receptor α chain (IL-4Rα). Single cell RNA-sequencing showed that naïve B cells expressed the highest levels of IL4R compared to other B cell subpopulations. Compared to controls, the dupilumab-treated patient exhibited diminished percentages of IL4R+IGHD+ naïve B cells and down-regulation of IL4R, FCER2 (CD23), and IGHD. Dupilumab treatment resulted in upregulation of genes associated with apoptosis and inhibition of B cell receptor signaling and down-regulation of class-switch and memory B cell development genes. The dupilumab-treated patient exhibited a rapid decline in COVID-19 anti-spike and anti-receptor binding domain antibodies between 4 and 8 and 11 months post COVID-19 vaccination. Our data suggest that intact and persistent IL-4 signaling is necessary for maintaining robust survival and development of naïve B cells, and maintaining a long term vaccine response.


Subject(s)
COVID-19 , Receptors, Interleukin-4 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , COVID-19 Vaccines , Humans , Interleukin-4 , RNA , Receptors, Antigen, B-Cell
5.
Ther Drug Monit ; 42(3): 360-368, 2020 06.
Article in English | MEDLINE | ID: covidwho-2152206

ABSTRACT

BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.


Subject(s)
Antiviral Agents/adverse effects , Coronavirus Infections/drug therapy , Drug Monitoring , Immunosuppressive Agents/adverse effects , Pneumonia, Viral/drug therapy , Transplant Recipients , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized , Antiviral Agents/therapeutic use , Betacoronavirus , COVID-19 , Drug Interactions , Glucocorticoids , Humans , Hydroxychloroquine , Immunosuppressive Agents/therapeutic use , Pandemics , Protease Inhibitors , SARS-CoV-2
7.
J Manag Care Spec Pharm ; 28(5): 555-565, 2022 May.
Article in English | MEDLINE | ID: covidwho-2145820

ABSTRACT

BACKGROUND: Most patients infected with SARS-CoV-2, resulting in COVID-19, have only mild symptoms that can be managed in an ambulatory setting. However, a significant number of patients develop a more severe form of the disease and require hospital care, with the risk of long-term sequelae or death. Casirivimab/imdevimab is a combination of 2 recombinant human monoclonal antibodies that has been shown to significantly reduce the risk of hospitalization or death in patients with mild to moderate COVID-19 in the ambulatory setting. OBJECTIVE: To establish the cost-effectiveness of casirivimab/imdevimab in ambulatory individuals with COVID-19. METHODS: A cost-effectiveness model was constructed to simulate the natural history of COVID-19 in ambulatory patients and to identify those patients for whom casirivimab/imdevimab may be a cost-effective treatment from a US payer perspective. Patients enter the model in the ambulatory health state and can receive either active treatment with casirivimab/imdevimab or usual care. Patients can either recover from the infection or be hospitalized, from where they can recover from infection or die. Following this acute phase, patients enter a Markov model to estimate lifetime quality-adjusted life years. The model uses the risk of hospitalization in both the active treatment and usual care cohorts, and age- and sex-specific risk of mortality. Other model inputs include hospitalization costs and health-related utilities in the ambulatory acute treatment phase, the hospitalized setting, and the post-acute phase. Accounting for the heterogeneity of risk by age and comorbidities, results are presented separately for various combinations of baseline age and usual care risk in a 7 × 9 matrix. Outcomes related to "long COVID" are assessed in scenario analyses. RESULTS: In the base case, at a willingness-to-pay threshold of $100,000, treatment with casirivimab/imdevimab was found to be cost-effective in most patients, including those older than 40 years of age with a baseline hospitalization risk greater than or equal to 2% and patients aged 20 years with a baseline risk of hospitalization greater than or equal to 4%, whereas for hospitalization risk greater than or equal to 10%, casirivimab/imdevimab is dominant. Casirivimab/imdevimab was not cost-effective in patients aged 20 years with a 3% or lower risk of hospitalization or in patients aged 30 years with a 2% risk. CONCLUSIONS: This economic analysis found that casirivimab/imdevimab is a cost-effective treatment for most ambulatory patients with COVID-19. DISCLOSURES: N. Jovanoski and U. Becker are employees of F Hoffman-La Roche Ltd.; A. Kuznik and M. Hussein are employees of Regeneron Pharmaceuticals Inc. and hold stock and stock options; A. Briggs has provided consultancy to F Hoffman-La Roche Ltd. and has received consultancy fees from Merck and Co., Inc., GlaxoSmithKline plc., and Novartis. This study was funded by Regeneron Pharmaceuticals, Inc.


Subject(s)
COVID-19 , Adult , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Cost-Benefit Analysis , Female , Humans , Male , SARS-CoV-2
8.
Int J Med Sci ; 19(5): 834-841, 2022.
Article in English | MEDLINE | ID: covidwho-2144950

ABSTRACT

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.


Subject(s)
COVID-19 , Pandemics , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , SARS-CoV-2 , Treatment Outcome
9.
Front Immunol ; 13: 980526, 2022.
Article in English | MEDLINE | ID: covidwho-2142008

ABSTRACT

Objective: The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood. Methods: We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls. Results: We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1). Interpretation: In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.


Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , COVID-19 Vaccines , Humans , Immunity, Cellular , Multiple Sclerosis/drug therapy , SARS-CoV-2 , Vaccination
10.
Headache ; 62(9): 1218-1221, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2136842

ABSTRACT

Erenumab is a monoclonal antibody (mAb) approved for the preventive treatment of migraine. While preclinical studies on calcitonin gene-related peptide mAbs did not identify any reproductive toxicity, pregnant and breastfeeding women were excluded from the pivotal human studies, and therefore the safety of calcitonin gene-related peptide medications in this population must be studied. So far, postmarketing data of accidental exposures have not brought to light any specific toxicities. Three women treated with erenumab in our series conceived while exposed to the drug. All had previous successful pregnancies, were on erenumab for more than 6 months, and had ≥80% reduction in headache frequency. The one who stopped erenumab only 1 month before conceiving had a spontaneous abortion during the first trimester due to a gestational trophoblastic neoplasia and has since conceived with an uneventful gestation. The other two women stopped treatment during the first trimester, and both pregnancies went to term with no complications. All babies have shown normal development. No plausible explanation relates the mechanism of action of erenumab and the serious complication that occurred in one patient. Continuous follow-up and reporting of all exposures are encouraged to gather safety data on pregnant and nursing women and on the development of the newborns. So far, immediately stopping the drug is advised and may contribute to decreasing the potential risks.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Calcitonin Gene-Related Peptide , Female , Humans , Infant, Newborn , Pregnancy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Treatment Outcome
11.
Cell Rep ; 39(5): 110754, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-2113939

ABSTRACT

Rapid spread of SARS-CoV-2 variants C.1.2 and B.1.621 (Mu variant) in Africa and the Americas, respectively, as well as a high number of mutations in the viral spike proteins raised concerns that these variants might pose an elevated threat to human health. Here, we show that C.1.2 and B.1.621 spike proteins mediate increased entry into certain cell lines but do not exhibit increased ACE2 binding. Further, we demonstrate that C.1.2 and B.1.621 are resistant to neutralization by bamlanivimab but remain sensitive to inhibition by antibody cocktails used for COVID-19 therapy. Finally, we show that C.1.2 and B.1.621 partially escape neutralization by antibodies induced upon infection and vaccination, with escape of vaccine-induced antibodies being as potent as that measured for B.1.351 (Beta variant), which is known to be highly neutralization resistant. Collectively, C.1.2 and B.1.621 partially evade control by vaccine-induced antibodies, suggesting that close monitoring of these variants is warranted.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Humans , Spike Glycoprotein, Coronavirus , Vaccination
12.
Infect Dis Clin North Am ; 36(4): 735-748, 2022 12.
Article in English | MEDLINE | ID: covidwho-2095433

ABSTRACT

Both cytokine release syndrome (CRS) and sepsis are clinical syndromes rather than distinct diseases and share considerable overlap. It can often be challenging to distinguish between the two, but it is important given the availability of targeted treatment options. In addition, several other clinical syndromes overlap with CRS and sepsis, further making it difficult to differentiate them. This has particularly been highlighted in the recent coronavirus disease-2019 pandemic. As we start to understand the differences in the inflammatory markers and presentations in these syndromes, hopefully we will be able to enhance treatment and improve outcomes.


Subject(s)
COVID-19 , Sepsis , Humans , Cytokine Release Syndrome/etiology , Antibodies, Monoclonal, Humanized/therapeutic use , Interleukin-6 , Sepsis/drug therapy
13.
JAMA Netw Open ; 5(10): e2238961, 2022 Oct 03.
Article in English | MEDLINE | ID: covidwho-2094120

ABSTRACT

This case series describes the kinetics of humoral deficiency in patients with relapsed refractory multiple myeloma treated with bispecific antibodies, the infectious complications, and response to COVID-19 immunization.


Subject(s)
Antibodies, Bispecific , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Kinetics , Neoplasm Recurrence, Local , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized
14.
Ter Arkh ; 94(8): 1028-1035, 2022 Oct 12.
Article in Russian | MEDLINE | ID: covidwho-2091506

ABSTRACT

The Advisory Board chaired by the chief specialist in infectious diseases of the Ministry of Health of Russian Federation, Professor V.P. Chulanov was held on June 18, 2022 in Saint Petersburg. Aim. The main purpose of the Board was following discussion: the analysis of the real-world data of levilimab as an anticipatory therapy for COVID-19 in hospitalized patients; the review of the experience and perspectives of levilimab as an anticipatory anti-inflammatory option for outpatient patients who meet defined clinical and laboratory criteria. Results. The analyzed data on clinical efficacy and safety formed the basis of recommendations proposed by experts for the use of levilimab in the inpatient and outpatient medical care for COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Anti-Inflammatory Agents , Receptors, Interleukin-6
15.
Ter Arkh ; 94(5): 675-682, 2022 Jun 17.
Article in Russian | MEDLINE | ID: covidwho-2091501

ABSTRACT

BACKGROUND: The use of virus-neutralizing monoclonal antibodies is an effective method of etiotropic therapy for SARS-CoV-2 in patients of high-risk groups of severe COVID-19. Regdanvimab is a single-component monoclonal antibodies immunoglobulin G1, whose mechanism of action is aimed at binding SARS-CoV-2 virus at the RBD site of the spike protein S1 domain. In the Russian Federation, regdanvimab is approved for emergency administration in COVID-19 for adult patients not requiring respiratory therapy who are at high risk of developing a severe course of the disease. AIM: To evaluate the efficacy and safety of therapy with regdanvimab in patients with mild/moderate COVID-19 in a short-term hospital unit. MATERIALS AND METHODS: Virus-neutralizing therapy with regdanvimab was performed at the short-term hospital unit of the Moscow City Clinic. An open retrospective observational single-center study included 92 adult patients with mild/moderate coronavirus infection. All patients had comorbid chronic diseases and belonged to the high-risk group for the development of a severe COVID-19. INCLUSION CRITERIA: age 18 to 75 years; presence of a verified diagnosis of COVID-19 of mild/moderate COVID-19, polymerase chain reaction (PCR) confirmed; one or more chronic diseases; first 7 days from the onset of the first symptoms of COVID-19 (including day 7). EXCLUSION CRITERIA: need for oxygen support. Clinical efficacy was assessed according to the World Health Organization Сlinical Progression Scale and supplemented with laboratory markers at baseline and in dynamics, as well as with monitoring of virus elimination by PCR. STATISTICS: Calculations were performed using the statistical computing environment R 4.1.3 (R Foundation for Statistical Computing, Austria). For quantitative indices the median (1; 3 quartiles) was indicated. For binomial signs we calculated 95% confidence intervals according to Wilson's method. Time interval analysis was performed according to the KaplanMeier method. The significance level was determined at p0.05. RESULTS: A significant decrease in the severity of clinical manifestations according to the World Health Organization Clinical Progression Scale was noted by patients by day 4 after regdanvimab administration. All 92 patients in the cohort were discharged from the hospital l on average on day 5 after regdanvimab administration and on day 9 of the disease. On day 4 after drug administration 82% of patients was being PCR negative. No adverse events related to the administration of regdanvimab were reported during the study. CONCLUSION: In real clinical practice, the efficacy and safety of regdanvimab in patients at high risk of severe COVID-19 was confirmed once again, with a positive clinical result observed in a mixed cohort by the causative agent omicron and delta strain.


Subject(s)
COVID-19 , Adult , Humans , Adolescent , Young Adult , Middle Aged , Aged , COVID-19/drug therapy , COVID-19/epidemiology , SARS-CoV-2 , Retrospective Studies , Spike Glycoprotein, Coronavirus , Time Factors , Antibodies, Monoclonal, Humanized/adverse effects , Treatment Outcome , Oxygen
16.
Nat Microbiol ; 7(11): 1906-1917, 2022 11.
Article in English | MEDLINE | ID: covidwho-2087227

ABSTRACT

SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , COVID-19/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Mutation , Antibodies, Monoclonal
18.
Front Immunol ; 13: 980079, 2022.
Article in English | MEDLINE | ID: covidwho-2065514

ABSTRACT

Treatment of systemic lupus erythematosus (SLE) currently employs agents with relatively unselective immunosuppressive properties. However, two target-specific biological drugs have been approved: belimumab (anti-B-cell-activating factor/BAFF) and anifrolumab (anti-interferon alpha receptor-1/IFNAR1). Here, we performed a comparative risk-benefit assessment for both drugs based on the role of BAFF and IFNAR1 in host defense and the pathogenesis of SLE and by considering the available data on safety and efficacy. Due to differences in target expression sites, anti-IFNAR1, but not anti-BAFF, might elicit organ-specific effects, consistent with clinical efficacy data. The IFNAR1 is specifically involved in innate and adaptive antiviral immunity in most cells of the body. Consistent with this observation, the available safety data obtained from patients negatively selected for LN and neuropsychiatric SLE, primary immunodeficiencies, splenectomy and chronic HIV, HBV, HCV infections suggest an increased risk for some viral infections such as varicella zoster and perhaps influenza. In contrast, BAFF is mainly involved in adaptive immune responses in lymphoid tissues, thus anti-BAFF therapy modulates SLE activity and prevents SLE flares without interfering with local innate host defense mechanisms and should only marginally affect immune memory to previous pathogen exposures consistent with the available safety data from SLE patients without chronic HIV, HBV or HCV infections. When using belimumab and anifrolumab, careful patient stratification and specific precautions may minimize risks and maximize beneficial treatment effects for patients with SLE.


Subject(s)
Biological Products , HIV Infections , Hepatitis C , Lupus Erythematosus, Systemic , Antibodies, Monoclonal, Humanized , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , HIV Infections/drug therapy , Hepatitis C/drug therapy , Humans , Risk Assessment
19.
Future Oncol ; 18(10): 1185-1198, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-2065335

ABSTRACT

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.


Subject(s)
Adenocarcinoma/drug therapy , Anilides/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyridines/therapeutic use , Adenocarcinoma/pathology , Androstenes/therapeutic use , Benzamides/therapeutic use , Humans , Male , Neoplasm Metastasis , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/pathology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
20.
Crit Care Med ; 50(12): 1788-1798, 2022 12 01.
Article in English | MEDLINE | ID: covidwho-2063013

ABSTRACT

OBJECTIVES: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. DESIGN: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. SETTING: Twelve clinical sites in France (ICU and general hospitals). PATIENTS: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. MEASUREMENTS AND MAIN RESULTS: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. CONCLUSIONS: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/therapeutic use , Oxygen , Treatment Outcome
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