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Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. Case Description: A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient's DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient's oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. Discussion(s): This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.Copyright © 2023
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Background: Bimekizumab (BKZ) is a monoclonal IgG1 antibody used in the treatment of psoriasis which selectively inhibits interleukin (IL)-17F in addition to IL-17A.1,2 Data pooled over two years have indicated that BKZ is generally well-tolerated.3 We report three-year BKZ pooled safety data in patients with moderate-to-severe plaque psoriasis. Method(s): Safety data were evaluated for all patients who received one or more dose BKZ in four Phase 3 trials (BE SURE [NCT03412747], BE VIVID [NCT03370133], BE READY [NCT03410992], and their ongoing open-label extension BE BRIGHT open-label extension [NCT03598790;data cut-off : 10/23/2021]) and four Phase 2 trials (BE ABLE 1 [NCT02905006], BE ABLE 2 [NCT03010527], PS0016 [NCT03025542], PS0018 [NCT03230292]). Safety data were evaluated separately for patients receiving BKZ dosed 320mg every four weeks (Q4W) or every eight weeks (Q8W). Exposureadjusted incidence rates (EAIRs) for treatmentemergent adverse events (TEAEs) are the incidence of new cases per 100 patient-years (PY). Result(s): Total BKZ exposure was 4,245.3 PY (N=1,789) across Phase 2/3 trials, and 3,876.4 PY (N=1,495) in Phase 3 trials. TEAEs occurred at a rate of 186.1 across Phase 2/3 trials, serious TEAEs at 5.6, and TEAEs leading to discontinuation at 3.5. Eighteen deaths occurred (0.4/100 PY), all unrelated to study treatment except one (relationship unknown). TEAEs occurred less frequently in Q8W- than Q4W-treated patients in Phase 3 trials. Consistent with previous reports, most common TEAEs (EAIR) in Phase 2/3 trials were nasopharyngitis (15.3), oral candidiasis (10.2), and upper respiratory tract infection (7.1).3 EAIR of serious infections was 1.2. Most frequently reported were serious coronavirus infections (0.2). There were no cases of active tuberculosis. EAIR of oral candidiasis was 10.2, decreased vs two-year data (12.6),3 and was less common with BKZ Q8W vs Q4W. The vast majority of oral candidiasis events were mild or moderate (99.4%);none were serious. EAIRs of hepatic events (4.0) and elevated liver enzymes (3.4) were decreased vs. two-year data (4.3 and 3.6, respectively).3 EAIRs for inflammatory bowel disease (0.1), adjudicated major adverse cardiac events (0.6), and adjudicated suicidal ideation and behavior (0.1) were low. EAIRs for other safety topics of interest were also low and were similar to or lower than two-year EAIRs.3 Conclusion(s): BKZ was well-tolerated over three years. No safety signals were identified;EAIRs of TEAEs did not increase compared with data from two years.3.
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Background: Viral dynamics models provide mechanistic insights into viral disease and therapeutic interventions. A detailed, mechanistic model of COVID-19 was developed and fit to data from molnupiravir (MOV) trials to characterize the SARS-CoV-2 viral dynamics in MOV-treated and untreated participants and describe the basis for variation across individuals. Method(s): An Immune-Viral Dynamics Model (IVDM) incorporating mechanisms of viral infection, viral replication, and induced innate and adaptive immune response described the dynamics of viral load (VL) from pooled data from MOV Phase 2 and 3 trials (N=1958). Population approaches were incorporated to estimate variation across individuals and to conduct an extensive covariate analysis. Nineteen parameters in a system of five differential equations described SARS-CoV-2 viral dynamics in humans. Six population parameters were successfully informed through fitting to observed trial data while the remaining parameters were fixed based on literature values or calibrated via sensitivity analysis. Result(s): Final viral dynamics and immune response parameters were all estimated with high certainty and reasonable inter-individual variabilities. The model captured the viral load profiles across a wide range of subpopulations and predicted lymphocyte dynamics without using this data to inform the parameters, suggesting inferred immune response curves from this model were accurate. This mechanistic representation of COVID-19 disease indicated that the processes of cellular infection, viral production, and immune response are in a time-varying, non-equilibrium state throughout the course of infection. MOV mechanism of action was best described as an inhibitory process on the infectivity term with estimated AUC50 of 10.5 muM*hr. Covariates identified included baseline viral load on infectivity and age, baseline disease severity, viral clade, baseline viral load, and diabetes on immune response parameters. Greater variation was identified for immune parameters than viral kinetic parameters. Conclusion(s): These findings show that the variation in the human response (e.g., immune response) is more influential in COVID-19 disease than variations in the virus kinetics. The model indicates that immunocompromised patients (due to HIV, organ transplant, active cancer, immunosuppressive therapies) develop an immune response to SARS-CoV-2, albeit more slowly than in immunocompetent, and MOV is effective in further reducing viral loads in the immunocompromised.
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Background: During the eleven months of the novel SARS-CoV-2 disease (COVID-19) outbreak in China and its global spread, there is a remarkable understanding of its epidemiology, pathobiol-ogy, and clinical management strategies. While countering a heavy toll on health and the economy, world's regional authorities are enforcing safety guidelines and providing patient care. Currently, there is no globally approved treatment or intervention for COVID-19. Method(s): A structured online literature search for peer-reviewed articles was conducted on PubMed, Europe PMC, Google, WHO, CDC, FDA, and ClinicalTrials portals, using phrases such as COVID-19 treatment and intervention, COVID-19 drugs and COVID-19 vaccines. Result(s): Analysis of the retrieved data showed that as a part of 'Solidarity Clinical Trials', hundreds of treatment and intervention strategies, including antiviral drugs, cytokine antagonists, convalescent plasma therapy, and vaccine candidates, have been registered worldwide. While remdesivir, the anti-Ebola virus drug, has been approved as an 'emergency use' drug in the USA, favipiravir, the anti-flu drug, has been recently approved in Russia. Tocilizumab and sarilumab, the cytokine (IL-6) antagonists, have entered Phase-II/III clinical trials in hospitalized COVID-19 patients. Among the leading vaccine candidates, Phase-III clinical trial results of Moderna, Pfizer and Oxford vaccines seem to be game changers for COVID19. Conclusion(s): The world health authorities have strongly and quickly responded to the COVID-19 pan-demic. Nonetheless, world bodies must unite in combating this health crisis by developing cost-effective drugs and vaccines and making them accessible to resource-poor countries.Copyright © 2021 Bentham Science Publishers.
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Coronavirus disease 2019 (COVID-19) outbreak started in Wuhan, China when people started with the symptoms of respiratory disorder. The onset of this disease have symptoms like fever, dry cough, fatigue, and difficulty in breathing. The nature of SARS-CoV-2 seems highly contagious as it also can be spread with asymptomatically infected individuals. It has been more than a year which this outbreak have been announced as a pandemic by World Health Organization (WHO) due to major public health crisis and uncontrollable around the globe. Some countries have taken initiatives in inventing vaccines and step up in the clinical trial process since a vaccine is an all-powerful tool which it always been a saviour in fighting infectious disease. In searching for the vaccine, researchers had studied the previously published article of SARS-CoV or MERS as in the beginning, in light, there will be a suitable vaccine to fight this pandemic situation. Recent research on the vaccine has been tested to seek the right vaccine for COVID-19. This study is to focus on the current vaccine development against COVID-19 and to explore the potential vaccines' characteristics that have been studied by the previous proven research findings. This review was done based on the research articles and reviews published until the end of April 2021 through established scientific search engines and related scientific platforms based on the inclusion criteria with its related keywords like coronavirus, SARS-CoV-2, COVID-19 Vaccine, clinical trials, and COVID-19 vaccine development. This review summarized a few vaccine candidates that have entered clinical trials and some supported evidence from Phase I until Phase III clinical trial studies that have been published and reported. In this review, 12 vaccine candidates have the potential to against SARS-CoV-2. Thus, their vaccine platform, characteristic as well as its efficacy studies have been discussed.Copyright © RJPT All right reserved.
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A more focused approach is needed to understand the SARS-CoV-2 virulence, structure, and genomics to devise more effective diagnostic and treatment interventions as this virus can evade the immune attack and causes life-threatening complications such as cytokine storm. The spread of the virus is still amplifying and causing thousands of new cases worldwide. It is essential to review current diagnostics and treatment approaches to pave the way to correct or modify our current practices to make more effective interventions against COVID-19. COVID-19 vaccine development has moved at a breakneck pace since the outbreak began, utilizing practically all possible platforms or tactics to ensure the success of vaccines. A total of 42 vaccine candidates have already entered clinical trials, including promising results from numerous vaccine candidates in phase 1 or phase 2 trials. Further, many existing drugs are being explored on broad-spectrum antiviral medications for their use in clinical recovery against COVID-19. The present review attempts to re-examine the SARS-CoV-2 structure, its viral life cycle, clinical symptoms and pathogenesis, mode of transmission, diagnostics, and treatment strategies that may be useful for resorting to more effective approaches for controlling COVID-19. Various antiviral drugs and vaccination strategies with their strengths and weaknesses are also discussed in the paper to augment our understanding of COVID-19 management.Copyright © 2022 Bentham Science Publishers.
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Despite the measures taken and the molecular advances for the development of new agents for the control of SARS-CoV-2 infection, there is still insufficient development of an effective treatment. The objective of the review was to de-scribe the clinical studies and reported articles on drugs used as possible therapeutic agents for COVID-19 and the main conclusions on their reuse. A non-systematic review through PubMed, ScienceDirect, and clinical trials at ClinicalTrials. gov on original articles and case report in English and Span-ish that will report information on COVID-19 treatment and its main conclusions. Articles that were not relevant or that did not mention updated information to that reported in other articles were excluded. A total of 99 bibliographic references were included. COVID-19 appears as a multisystemic disease with variable clinical symptoms. Since no specific treatment is yet known, multiple drugs have been proposed that attack the different pathways of SARS-CoV-2. For severe disease in patients who require hospitalization and oxygen support, the use of remdesivir, dexamethasone, or tocilizumab is recommended if there are patient conditions that apply to use them. The use of ivermectin, colchicine, lopinavir/ritonavir, hydroxy-chloroquine, and chloroquine have not reported benefits that surpass adverse effects.
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The 32nd European Respiratory Society (ERS) International Congress was held again in person at the FIRA Barcelona Gran Via Conference Center in Spain, as well as online. On-site attendance was limited to 10,000 delegates, with the spaces selling out before the conference began. The program included live streamed presentations, thematic poster discussion sessions, oral presentations, mini-symposia, industry exhibitors and skills workshops to discuss major respiratory fields that included thoracic oncology, respiratory infections, interstitial lung diseases, respiratory critical care, sleep and breathing disorders and pulmonary vascular diseases. This report will cover some of the most interesting presentations related to respiratory disease treatment. Copyright © 2022 Clarivate.
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Context: CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. Objective(s): To present updated results from CARTITUDE-2 Cohort A. Design(s): Phase 2, multicohort study. Patient(s): Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Intervention(s): Single cilta-cel infusion (target dose 0.75x106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measure(s): Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. Result(s): As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male;median age 60 years;median 2 prior LOT;95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% >=complete response;95% >=very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%);median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2;1 gr3/4) and ICANS in 15% (all 3 gr1/2);1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5;median persistence was 153.5 days. Conclusion(s): At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population. Copyright © 2022 Elsevier Inc.
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The availability of COVID-19 vaccines and mass vaccination programmes in adults have significantly reduced the case attack rates and disease burden. COVID-19 vaccination successfully decreases the population at risk of infection, allowing for the safer re-opening of economies and reducing the pandemic’s crippling impact on healthcare systems. However, the rapidly mutating severe acute respiratory syndrome-coronavirus-2 poses challenges in diminishing vaccine-induced immunity and vaccinating a significant proportion of adults to achieve herd immunity. These challenges necessitated adolescent vaccination. With the recent emergence of the highly transmissible Omicron variant and the increasing COVID-19 hospitalisation rates of children below 12 years old, many countries opted to also vaccinate younger children. Phase II/III clinical trials and real-world experience demonstrate that COVID-19 vaccinations are effective and safe for younger children and adolescents. Before Malaysia introduced its national COVID-19 vaccination programme for children 5-11 years old (which ran between March and June 2022), an expert advisory statement was issued by the College of Paediatrics, Academy of Medicine of Malaysia, to highlight the benefits and importance of vaccinating children. The advisory statement included clarifications about vaccine-related side effects such as post-vaccination myocarditis and allergic reactions to encourage informed decision making by healthcare providers and parents. This paper, which was prepared based on the critical appraisal of the current evidence, evaluation of the international experiences and the positive impact of COVID-19 vaccination in children, collectively sums up the rationale to support and ensure the success of the nationwide vaccination programme for children. Hence, the College recommends COVID-19 vaccination for children in Malaysia.
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The immunogenicity and efficacy of RNA-based vaccine platforms has been abundantly shown through their application in prophylactic SARS-CoV2 vaccines. Contrasting to mRNA based vectors, self amplifying mRNA platforms may offer dose-sparing and superior induction of T cell responses, and may also trigger distinct innate immune pathways, which may exert adjuvanting or inhibiting effects on vaccine-induced immunity. Optimal dosing for a novel self-amplifying mRNA (SAM) in a heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and SAM boosts was evaluated in two first-in-human phase 1/2 clinical trials assessing personalized neoantigen vaccines in patients with metastatic cancer (NCT03639714, NCT03953235). SAM vaccine dose escalation was performed to assess safety, tolerability, and immunogenicity, including administration of up to 8 SAM doses at 30, 100, or 300μg following a fixed dose of ChAd (1012 vp) over the course of a year. SAM was safe and well tolerated at all 3 dose levels, with no evidence of increasing reactogenicity with sequential doses. However, while immune monitoring via IFNγ ELISpot revealed that the 30μg SAM dose boosted T cell responses induced by the ChAd prime, the 100μg and 300μg SAM doses resulted in maintenance of T cell levels, without a clear T cell boost, suggesting a non-linear and likely bell-shaped dose-response curve to SAM in humans. Follow-up studies in non-human primates (NHPs) using a model antigen revealed dose-dependent increases in serum IFNa levels following administration of increasing SAM doses. Similarly, while multiple inflammatory cytokines were transiently increased following both ChAd and SAM administration in patients, serum IFNa levels were only increased 24h post SAM administration and correlated positively with SAM dose. Increased IFNa levels post SAM dosing suggested activation of mRNA-sensing innate immune pathways that may reduce the amplification of, and/or antigen expression by, the SAM vector and thus blunt T cell boosting at higher SAM doses. In addition, analysis of T cell responses in patients and NHPs showed increased boosting of T cell responses with longer intervals. These data lead to a reduction of the SAM dose to 30μg and adjusting SAM dosing intervals to 8 weeks in the Phase 2 portion of these clinical studies. Multiple patients have been dosed with the adjusted vaccine regimen, and preliminary data suggest robust boosting of ChAd-induced neoantigen-specific T cell responses with the selected SAM dosing regimen and the 30μg dose. We anticipate that this translational approach of adjusting clinical vaccine regimens based on strong translational immune data will increase the potency of our heterologous neoantigen vaccine, and subsequently provide more durable clinical benefit to patients with cancer.
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The 70th annual meeting of the American Society of Tropical Medicine and Hygiene was kicked off by Dr. Tedros Ghebreyesus, the Director-General of the World Health Organization (WHO). The virtual gathering format included plenary sessions, science and clinical sessions, E-poster sessions, and an exhibit hall featuring the latest products and services for tropical diseases and global health. This report provides highlights from the oral and poster sessions, focusing on developments in the treatment of tropical diseases.
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Introduction: More than 200 treatments have been tested for COVID-19 in over 7000 clinical trials. Most of these treatments are repurposed generic drugs, many of which have been studied extensively for the treatment of cancer. As cancer patients are particularly vulnerable, there is a need to understand how COVID-19 treatments might affect a patient's cancer. As part of the Reboot: COVID-Cancer Project, a living and freely available resource of clinical studies that report outcomes for cancer patients, we have developed a semi-automated pipeline to identify all relevant published clinical studies and registered clinical trials where COVID-19 drugs were tested for the treatment of cancer. Methods: Published clinical studies were assembled using targeted search queries in PubMed, rule-based approaches, and machine learning models. Machine learning models applied to natural language processing tasks were used to predict the drug, cancer type, study type, and therapeutic association. We used domain-specific rules and post-processing steps to further refine results, including determining whether a drug was used alone or in combination. Registered clinical trials were compiled from clinicaltrials.gov using targeted search queries, automated mapping, and rule-based screening. We extracted key information about each trial, such as the drug, cancer type, phase, location, trial status, age, gender, and availability of results. We applied our pipeline to a curated set of 202 drugs being tested for the treatment of COVID-19 in at least two interventional clinical trials worldwide, of which 27 are FDA-approved drugs that are standard of care for cancer, and 115 are FDA-approved drugs primarily used for non-cancer indications. Results: We found 28,138 published clinical studies and 9,118 registered clinical trials where the 202 drugs were tested for cancer. The published clinical studies include 5,286 case studies, 2,559 randomized controlled trials (RCTs), and 20,294 non-RCT clinical trials or observational studies. In 37% of the cases, the drug was used alone and not in combination. Lymphoid cancers were the most commonly tested, comprising 30% of studies. Possible benefit of the drug was found in 64% of publications. Of the 115 FDA-approved non-cancer drugs being tested for COVID-19, there is at least one published clinical study for 84 (73%) drugs. An additional 12 FDA-approved non-cancer drugs have been tested for the treatment of cancer in clinical trials, but have no results reported. Of the registered clinical trials, 39% are currently active, 66% are Phase 2 or later, and lymphoid cancers are again the most common, representing 29% of the trials. Discussion: Given the interconnection between COVID-19 and cancer, it is essential to understand how drugs used for COVID-19 might impact a patient's cancer. We have created a living resource for rapid review of information. The datasets are updated monthly and are freely available via an interactive dashboard.