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2021 ◽  
Vol 10 (2) ◽  
pp. 103-105
Author(s):  
Jared Robinson ◽  
Indrajit Banerjee

The novel SARS-CoV-2 infection has ripped through international health systems and protocols causing unprecedented mortality, morbidity and global trade deficits amounting to billions. Various monoclonal antibodies have been proposed for use in the treatment of COVID-19 infections. One such drug is LY-CoV555 which in an ongoing phase two trial study conducted by Chen P et al, showed to have an elimination of 99.97% of the viral RNA. The monoclonal antibody 47D11 discovered by Wang et al, binds to SARS-CoV-2. The 47D11 has been reconfigured into a human IgG1 isotope. It has shown that the 47D11 mAb effectively neutralizes the SARS-COV-2 virus. The stance and development however for the treatment of COVID-19 with monoclonal antibodies has shifted from a monotherapy to a so-called monoclonal antibody “cocktail” therapy. REGN-COV2 is such a cocktail developed with the use of two monoclonal antibodies REGN10987 and REGN10933 which have subsequently been named Imdevimab and Casirivimab. REGN-COV2 is currently under study in four phase 2 and 3 trial studies. These studies are multicentric in nature and are being conducted to evaluate the drug’s efficacy, dosing and clinical use as compared to the placebo. The mechanism of action of such monoclonal antibodies is related chiefly to the inhibition of the virus’s ability to perform its invasion and multiplication within the human body. The severity coupled with the sheer novelty of the SARSCoV-2 virus demands the use of newer therapies to both decrease the mortality and morbidity in patients suffering from the infection. The use of a combination of monoclonal antibodies is thereby well established and evident to both decrease the viral infection load, but is also useful in disrupting the virus’s life cycle and thus decreases the replication and viral shedding. It is therefore poignant that a combination of monoclonal antibodies, a “cocktail” therapy is employed so as to attack the virus at its various stages and thus this multifaceted approach may enhance the patient’s prognosis.


Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 592-599
Author(s):  
Paulina Horvei ◽  
Tippi MacKenzie ◽  
Sandhya Kharbanda

Abstract α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.


Author(s):  
Michael A. Lyons

Bedaquiline is a diarylquinoline antimycobacterial drug and a key component of several regimens in clinical development for treatment of tuberculosis (TB), but with ongoing phase 3 trials that include assessment of simplified dosing. A pharmacokinetic-pharmacodynamic model of bedaquiline Mycobacterium tuberculosis killing kinetics in adults with pulmonary TB was developed to inform dose selection of bedaquiline-containing regimens. The model parameters were estimated with data from the 14-day early bactericidal activity (EBA) study TMC207-CL001 conducted in Cape Town, South Africa. The study included 60 adult males and females with drug-susceptible pulmonary TB, who were administered bedaquiline with loading doses on the first two days followed by once daily 100 mg, 200 mg, 300 mg, or 400 mg. The modeling results included expected values (mean±SD) for a maximum drug kill rate constant equal to 0.23±0.03 log 10 CFU/mL sputum/day, a half-maximum effect plasma concentration equal to 1.6±0.3 mg/L, and an average time to onset of activity equal to 40±7 h. Model simulations showed once daily 200 mg, 300 mg, and 400 mg (without loading doses) attained 40%, 50%, and 60%, respectively, of an expected maximum 14-day EBA equal to 0.18 log 10 CFU/mL/day, or 10 h/day assessed by liquid culture time to positivity (TTP). Additional simulations illustrated efficacy outcomes during eight weeks of treatment with the recommended and alternative dosages. The results demonstrate a general mathematical and statistical approach to analysis of EBA studies with broad application to TB regimen development.


Author(s):  
Govindaraj Ganesan ◽  
Sasipriya Ponniah ◽  
Vivek Sundaram ◽  
Praveen Kumar Marimuthu ◽  
Venkatraman Pitchaikannu ◽  
...  

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Miwa Haranaka ◽  
James Baber ◽  
Yoichiro Ogama ◽  
Masako Yamaji ◽  
Masakazu Aizawa ◽  
...  

AbstractWe report interim safety and immunogenicity findings from an ongoing phase 1/2 study of BNT162b2 in healthy Japanese adults. Participants were randomized 3:1 to receive 2 intramuscular injections of 30 μg BNT162b2 or placebo 21 days apart. Overall, 160 individuals were randomized: 119 received BNT162b2, and 41 received placebo. Participants were stratified by age: 20–64 years (n = 130) and 65–85 years (n = 30). More than 97% of BNT162b2 recipients received 2 doses. Local reactions and systemic events were generally transient and mild to moderate. Severe adverse events were uncommon; there were no serious adverse events. One month after dose 2, SARS-CoV-2 50% serum neutralizing geometric mean titers were 571 and 366, and geometric mean fold rises were 55.8 and 36.6, in the younger and older age groups, respectively. In summary, BNT162b2 has an acceptable safety profile and produces a robust immune response, regardless of age, in Japanese adults. (ClinicalTrials.gov, NCT04588480).


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi79
Author(s):  
Tobias Weiss ◽  
Thomas Look ◽  
Emanuele Puca ◽  
Roberto De Luca ◽  
Teresa Hemmerle ◽  
...  

Abstract Treatment options for recurrent glioblastoma are limited and except from regorafenib (potentially), no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. We investigated the combination of lomustine or bevacizumab that are frequently used for recurrent glioblastoma with L19TNF (onfekafusp alfa), a systemically administered tumor-stroma targeting antibody-cytokine fusion protein that enables a targeted delivery of tumor-necrosis factor (TNF)a to the tumor. In immunocompetent orthotopic glioma mouse models, the combination of lomustine and L19TNF demonstrated the strongest anti-tumor activity, acted in synergy and cured a majority of tumor-bearing mice, whereas lomustine or L19TNF monotherapy only had only very limited anti-tumor activity. Ex vivo profiling of the tumors and tumor-infiltrating immune cells from immunocompetent or immunodeficient hosts demonstrated immune-dependent cytotoxic and cytostatic effects on the glioma cells, and a strong increase of tumor-infiltrating immune cells upon combination therapy in immunocompetent models. Based on these encouraging results, we translate this combinatorial therapy to patients with recurrent glioblastoma. For the first patients, the treatment with lomustine and L19TNF was well tolerated and led to stable disease with a reduction in tumor perfusion. More patients are recruited in an ongoing phase I/II clinical trial with lomustine and L19TNF for patients with recurrent glioblastoma (NCT04573192).


2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S420-S420
Author(s):  
Helen Paguntalan ◽  
Zoltán Magyarics ◽  
Lynn E Connolly ◽  
Ellie Hershberger ◽  
Kristin Narayan ◽  
...  

Abstract Background ADG20 is a fully human IgG1 monoclonal antibody engineered to have high potency and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential by binding to a highly conserved epitope in the receptor-binding domain (RBD) of the spike protein. The Fc region of ADG20 has been modified to provide an extended half-life. ADG20 is in clinical development for the treatment and prevention of COVID-19. Methods This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of ADG20 administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18–50 years with no evidence of prior or current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 cohorts (N=10/cohort: n=8 ADG20, n=2 PBO): ADG20 300 mg IM, 500 mg IV, and 600 mg IM. Safety, tolerability, PK, and sVNA titers were assessed up to 3 months post dose. Serum ADG20 concentrations were measured with a validated hybrid ligand binding liquid chromatography–mass spectrometry (MS)/MS assay. sVNA titers against authentic SARS-CoV-2 were determined by a plaque reduction neutralization assay. Results Overall, 30 participants received ADG20 (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK/sVNA titer data for the 300 mg IM cohort are reported. Through a minimum of 10 weeks post dose, no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions were reported. The observed preliminary PK profile was dose proportional, consistent with an extended half-life monoclonal antibody, and well predicted by translational physiologically-based PK modeling. The measured 50% sVNA titer (MN50; geometric mean [coefficient of variation, %]) was 1382 (32.7%) 13 days after a single 300 mg IM dose. These values are within the range of peak serum neutralizing antibody titers reported for COVID-19 mRNA vaccines. Conclusion A single dose of ADG20, up to 600 mg IM, was well tolerated. Preliminary PK and sVNA titer profiles support the ongoing Phase 2/3 trials of ADG20 at a 300 mg IM dose for the prevention of COVID-19 (EVADE: NCT04859517) and treatment of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Disclosures Helen Paguntalan, MD, Adagio Therapeutics, Inc. (Scientific Research Study Investigator) Zoltán Magyarics, MD, PhD, Adagio Therapeutics, Inc. (Consultant) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Ellie Hershberger, PharmD, Adagio Therapeutics, Inc. (Employee) Kristin Narayan, PhD, Adagio Therapeutics, Inc. (Employee) Deepali Gupta, BS, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee) Frank Engler, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Ed Campanaro, BSN, MSHS, Adagio Therapeutics, Inc. (Employee) Anita F. Das, PhD, Adagio Therapeutics, Inc. (Consultant) Pete Schmidt, MD, Adagio Therapeutics, Inc. (Employee)


2021 ◽  
Vol 37 (11) ◽  
pp. 1062-1065
Author(s):  
Bertrand Jordan

The elimination of some senescent cells by « senolytic » compounds can greatly improve the health of aged mice and in some cases reverse the effects of aging. Using a microbial exposure system that closely models coronavirus infection, it is possible to largely protect old mice from the effects of viral infection. This immediately suggests clinical application of the approach, and is the aim of ongoing phase II clinical trials in Covid-19 patients.


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