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4.
BMC Infect Dis ; 23(1): 258, 2023 Apr 26.
Article in English | MEDLINE | ID: covidwho-2304946

ABSTRACT

BACKGROUND: Sotrovimab, a monoclonal antibody with efficacy against SARS-CoV-2 including certain Omicron variants, has been used in treatment of mild-moderate COVID-19. Limited data exists regarding its use in pregnant women. METHODS: Electronic medical record review of pregnant COVID-19 patients treated with sotrovimab from 12/30/21 - 1/31/22 (Yale New Haven Health Hospital System [YNHHS]) was performed. Included were pregnant individuals ≥ 12 years, weighing ≥ 40 kg, with positive SARS-CoV-2 test (within 10 days). Those receiving care outside YNHHS or receiving other SARS-CoV-2 treatment were excluded. We assessed demographics, medical history, and Monoclonal Antibody Screening Score (MASS). The primary composite clinical outcome assessed included emergency department (ED) visit < 24 h, hospitalization, intensive care unit (ICU) admission, and/or death within 29 days of sotrovimab. Secondarily, adverse feto-maternal outcomes and events for neonates were assessed at birth or through the end of the study period, which was 8/15/22. RESULTS: Among 22 subjects, median age was 32 years and body mass index was 27 kg/m2. 63% were Caucasian, 9% Hispanic, 14% African-American, and 9% Asian. 9% had diabetes and sickle cell disease. 5% had well-controlled HIV. 18%, 46%, and 36% received sotrovimab in trimester 1, 2, and 3, respectively. No infusion/allergic reactions occurred. MASS values were < 4. Only 12/22 (55%) received complete primary vaccination (46% mRNA-1273; 46% BNT162b2; 8% JNJ-78,436,735); none received a booster. CONCLUSIONS: Pregnant COVID-19 patients receiving sotrovimab at our center tolerated it well with good clinical outcomes. Pregnancy and neonatal complications did not appear sotrovimab-related. Though a limited sample, our data helps elucidate the safety and tolerability of sotrovimab in pregnant women.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Pregnancy , Infant, Newborn , Humans , Female , Adult , SARS-CoV-2 , Pregnant Women , BNT162 Vaccine , Antibodies, Monoclonal, Humanized/adverse effects , Pregnancy Complications, Infectious/drug therapy
5.
Clin Neurol Neurosurg ; 228: 107675, 2023 05.
Article in English | MEDLINE | ID: covidwho-2301290

ABSTRACT

Alemtuzumab is a humanized monoclonal antibody indicated for treatment of highly active relapsing-remitting multiple sclerosis (HA-RRMS). It binds to CD52 antigen and produces a rapid and prolonged lymphocyte depletion followed by a different pattern of T and B cell repopulation. Among others, its adverse events are autoimmune diseases.In this article, we present a patient with HA-RRMS, who was subsequently treated with alemtuzumab and afterwards developed hemophagocytic lymphohistiocytosis (HLH). Albeit rarely, HLH can be triggered by alemtuzumab treatment.HLH can favourably respond to prompt immunosuppressant therapy.Multidisciplinary approach by a team consisting of a neurology, hematology and rheumatology specialist is needed to treat this potentially lethal condition.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Alemtuzumab/adverse effects , Multiple Sclerosis/chemically induced , Lymphohistiocytosis, Hemophagocytic/chemically induced , Antibodies, Monoclonal, Humanized/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy
6.
Trials ; 23(1): 1042, 2022 Dec 22.
Article in English | MEDLINE | ID: covidwho-2274174

ABSTRACT

BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. DISCUSSION: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.


Subject(s)
Kidney Transplantation , Humans , Kidney Transplantation/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Double-Blind Method , Glomerular Filtration Rate , Graft Rejection/drug therapy , Graft Rejection/prevention & control , Isoantibodies , Graft Survival
8.
J Investig Med High Impact Case Rep ; 11: 23247096231154640, 2023.
Article in English | MEDLINE | ID: covidwho-2274549

ABSTRACT

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used in the treatment of solid and hematologic malignancies. Immune checkpoint inhibitors target the T-cell deactivation system via the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor, programmed cell death protein 1 (PD-1) receptor, and programmed cell death ligand 1 (PD-L1). As a result, the activated T-cell enhances the host tumor response. However, even with their essential clinical benefits, ICIs are associated with a broad spectrum of adverse effects that can be generalized or tissue-specific inflammatory responses known as immune-related adverse events (irAEs). The most common dermatologic toxicity manifests mainly as maculopapular rash and pruritus. Understanding the complexity of immune-mediated response and the importance of clinical histopathologic correlation in recognizing irAEs allows for appropriate intervention and patient care due. We present the case of a 71-year-old African American male diagnosed with a large-cell poorly differentiated neuroendocrine tumor in the gastroesophageal junction of the stomach with mediastinal lymphadenopathy. He was treated with carboplatin, etoposide, and atezolizumab for 4 cycles. However, he developed vitiligo while on maintenance atezolizumab, which is rarely seen with atezolizumab use. Despite the improving clinical outcomes in oncology with ICIs, their adverse effects should not be ignored. When promptly recognized and treated, patients on ICI monotherapy may not need treatment interruption or discontinuation.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Immunological , Vitiligo , Aged , Humans , Male , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Immune Checkpoint Inhibitors/adverse effects , Vitiligo/chemically induced , Vitiligo/drug therapy
9.
Obstet Gynecol ; 139(3): 368-372, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-2222779

ABSTRACT

OBJECTIVE: To describe outcomes associated with monoclonal antibody use in pregnant persons with mild-to-moderate coronavirus disease 2019 (COVID-19). METHODS: We present a retrospective case series of pregnant patients who received anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibody infusions at a single center from April 1, 2021, through October 16, 2021. Pregnant patients who had a positive SARS-CoV-2 polymerase chain reaction (PCR) test result and mild-to-moderate COVID-19 symptoms were eligible for monoclonal antibody infusion. Exclusion criteria for administration included need for supplemental oxygen, hospitalization due to COVID-19, and positive SARS-CoV-2 PCR test result more than 7 days before screening. All patients received either bamlanivimab plus etesevimab or casirivimab plus imdevimab based on availability and dosing instructions of the product and emerging resistance patterns in the community. RESULTS: During the study period, monoclonal antibody infusions were administered to 450 individuals at our institution, of whom 15 were pregnant. Of the 15 pregnant persons receiving monoclonal antibody, six (40%) had full-vaccination status at the time of infusion. Two individuals (13%, CI 0-31%) experienced systemic reactions during the infusion, both resulting in temporary changes in the fetal heart rate tracing that recovered with maternal and intrauterine resuscitative efforts. One patient delivered after infusion for worsening maternal and fetal status; the remainder of the patients did not require admission for COVID-19. CONCLUSION: In this case series, pregnant persons who received anti-SARS-CoV-2 monoclonal antibody infusions had generally favorable outcomes.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal/adverse effects , Antibodies, Neutralizing/adverse effects , COVID-19 Drug Treatment , Pregnancy Complications, Infectious/drug therapy , Drug Combinations , Female , Fetal Heart/drug effects , Humans , Overtreatment , Pregnancy , Retrospective Studies
10.
J Neurol Neurosurg Psychiatry ; 94(6): 487-493, 2023 06.
Article in English | MEDLINE | ID: covidwho-2213987

ABSTRACT

BACKGROUND: The majority of patients with multiple sclerosis on ocrelizumab have B-cell depletion after standard interval dosing of 26 weeks. With B-cell-guided dosing patients receive their next dose when B-cell repopulation occurs. Prediction of B-cell repopulation using ocrelizumab concentrations could aid in personalising treatment regimes. The objectives of this study were to evaluate the association between ocrelizumab drug concentration, antidrug antibodies (ADAs) and CD19 B-cell count, and to define a cut-off ocrelizumab concentration for start of B-cell repopulation (defined by ≥10 CD19+ B cells/µL). METHODS: In this investigator-initiated prospective study, blood samples at various time points during ocrelizumab treatment were collected from a biobank. Serum ocrelizumab concentrations and ADAs were measured with two different assays developed for this study. Data were analysed using linear mixed effect models. An receiver operating characteristic (ROC) curve was used to determine a cut-off ocrelizumab concentration for start of B-cell repopulation (defined by ≥10 cells/µL). RESULTS: A total of 452 blood samples from 72 patients were analysed. Ocrelizumab concentrations were detectable up until 53.3 weeks after last infusion and ranged between <0.0025 and 204 µg/mL after 1-67 weeks. Ocrelizumab concentration was negatively associated with B-cell count, with body mass index identified as effect modifier. We found a cut-off value of 0.06 µg/mL for start of B-cell repopulation of ≥10 cells/µL. Ocrelizumab ADAs were detectable in four patients (5.7%) with corresponding low ocrelizumab concentrations and start of B-cell repopulation. CONCLUSIONS: Serum ocrelizumab concentration was strongly associated with B-cell count. Measurement of ocrelizumab drug concentrations and ADAs could play an important role to further personalise treatment and predict the start of B-cell repopulation.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis/drug therapy , Immunologic Factors/adverse effects , Prospective Studies , Antibodies, Monoclonal, Humanized/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy
11.
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
12.
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
14.
BMC Infect Dis ; 22(1): 902, 2022 Dec 03.
Article in English | MEDLINE | ID: covidwho-2153524

ABSTRACT

BACKGROUND: Sotrovimab neutralizing SARS-CoV-2 remained effective at the advent of B.1 lineage of the Omicron variant in outpatients. Primarily for hospitalized patients, however, the Japanese government regulated to administer this antibody agent. As this regulation enabled close monitoring in inpatients to investigate post-infusion adverse events (AEs) and efficacy, we attempted a retrospective study while the Omicron BA.1 lineage was dominant regionally. METHODS: Subjects were inpatients with COVID-19 who received infusion of sotrovimab in our institute. In line with previous clinical trials, we included patients at risk of COVID-19 worsening and SARS-CoV-2 vaccinees, who were hospitalized as directed by the government. For statistical analyses, we reviewed background factors of demographics, imaging, and laboratory findings for the outcome infusion-related reactions including post-infusion pyrexia over 38 degrees Celsius and/or pulse oximetry below 94%. RESULTS: In a total of 139 patients, the follow-up period had a median of 200 days (range, 154-248 days). Among 119 patients (85.6%) fully vaccinated for SARS-CoV-2, 86 (61.9% of all) underwent 2 doses while 33 (23.7% of all) received 3 doses. For the outcome of pyrexia and/or dyspnea (N = 40, 28.8%), multivariate analysis showed that significant risk factors were pre-infusion lowered oximetry below 96.5% (Odds Ratio [OR] 0.344, 95% Confidence Interval [CI] 0.139-0.851, P = 0.021) and pre-infusion temperature more than 36.7 degrees Celsius (OR 4.056, 95% CI 1.696-9.701, P = 0.002). Infusion-related reactions included vomiting immediately after infusion, chill/shivering, dizziness, rash, pruritus, pyrexia, and dyspnea. The number of patients with any of these events was 44 (31.6%). Three patients (2.2%) showed worsening of COVID-19; one developed hypoxia and two died. Limitations for this study included no genome typing whether BA.1 or BA.2 lineage of the Omicron variant but the local epidemiology indicated the prevalence of BA.1. Another was sotrovimab administration for inpatients that allow precise detection of post-infusion events, confounding previous exacerbation definition including hospitalization. CONCLUSIONS: For 24 h after infusion of sotrovimab, COVID-19 patients showing pre-infusion lowered oximetry below 96.5% and/or temperature more than 36.7 degrees Celsius may have temperature elevation or dyspnea, warranting close monitoring for these risk factors.


Subject(s)
COVID-19 Drug Treatment , Drug-Related Side Effects and Adverse Reactions , Humans , SARS-CoV-2 , Inpatients , Retrospective Studies , Japan/epidemiology , Antibodies, Monoclonal, Humanized/adverse effects , Fever/etiology , Dyspnea
16.
Headache ; 62(9): 1218-1221, 2022 10.
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
17.
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 Drug Treatment , COVID-19 , Adult , Humans , Adolescent , Young Adult , Middle Aged , Aged , COVID-19/epidemiology , SARS-CoV-2 , Retrospective Studies , Spike Glycoprotein, Coronavirus , Time Factors , Antibodies, Monoclonal, Humanized/adverse effects , Treatment Outcome , Oxygen
19.
Lancet Respir Med ; 10(3): 237-246, 2022 03.
Article in English | MEDLINE | ID: covidwho-2036653

ABSTRACT

BACKGROUND: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. METHODS: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. FINDINGS: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41-137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79-89) participants in the lenzilumab group and in 190 (78%; 72-83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02-2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. INTERPRETATION: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. FUNDING: Humanigen.


Subject(s)
COVID-19 Drug Treatment , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Double-Blind Method , Humans , Male , Middle Aged , SARS-CoV-2 , Treatment Outcome
20.
N Engl J Med ; 387(6): 495-505, 2022 08 11.
Article in English | MEDLINE | ID: covidwho-2031919

ABSTRACT

BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).


Subject(s)
Antibodies, Bispecific , Antineoplastic Agents, Immunological , B-Cell Maturation Antigen , CD3 Complex , Multiple Myeloma , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Cell Maturation Antigen/antagonists & inhibitors , CD3 Complex/antagonists & inhibitors , Humans , Injections, Subcutaneous , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/drug therapy , Recurrence , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
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