scholarly journals Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus

2021 ◽  
Author(s):  
Sumathi Sivapalasingam ◽  
George A Saviolakis ◽  
Kirsten Kulcsar ◽  
Aya Nakamura ◽  
Thomas Conrad ◽  
...  
Keyword(s):  
Middle East ◽  
Adverse Events ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Preclinical Study ◽  
Middle East Respiratory Syndrome ◽  
Lung Pathology ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Dipeptidyl Peptidase 4

Abstract Background REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. Methods Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. Results Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. Conclusions REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

Phase 1 study of intra-arterial hepatic (IAH) delivery of doxorubicin-transdrug (DT) for patients with advanced hepatocellular carcinoma (HCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14094-14094 ◽  
Author(s):  
P. Merle ◽  
S. Si Ahmed ◽  
F. Habersetzer ◽  
A. Abergel ◽  
J. Taieb ◽  
...  
Keyword(s):  
Adverse Events ◽  
Distress Syndrome ◽  
Phase 1 ◽  
Advanced Hepatocellular Carcinoma ◽  
Contrast Injection ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Advanced Hcc ◽  
Arterial Perfusion ◽  
Cirrhotic Patients

14094 Background: HCC is a highly chemoresistant due to MDR efflux pumps. DT is a newly cytotoxic chemotherapy composed of doxorubicin-loadded polyisohexylcyanoacrylate nanoparticles, allowing doxorubicin to overcome MDR pumps [Barraud, J Hepatol 2005; 42: 736]. Methods: 16 cirrhotic patients (pts) of Child-Pugh A with advanced HCC, transaminases/GGT <5N, platelets >100000/mm3, neutrophiles >1500/mm3, were enrolled in a multicentric noncontrolled study. A single IAH injection of 10, 20, 30, 35, or 40mg/m2 DT (respectively 3,3,4, and 3 pts) was performed, tolerance and efficacy being assessed 4 weeks later. Results: Grade 4 neutropenia (2pts at 40mg/m2) gave the Maximal Tolerated Dose. Grade 2–3 hypertransaminasemia (transient) occurred dose-independently. Two serious adverse events (SAE) were hypotension and acute respiratory distress syndrome. All adverse events (AE) (90% grade 1–2) occurring during injection were dose-independent, and completely and fastly recovered : cough (6pts), dyspnea (2pts), SaO2 decrease (2pts), tachycardia (2pts), bradycardia (2pts), hypotension (2pts). Anti-tumor efficacy of DT was evaluated by helicoidal CT-scan with contrast injection 4 weeks after injection : 3pts (20%) showed partial response with frank decrease of contrast enhancement at arterial perfusion, 8pts (50%) remained stable, and 5pts (30%) had progression. Conclusions: This phase 1 showed that a single IAH injection of DT was safe until 35 mg/m2 for Child-Pugh A patients with advanced HCC. This dosage will be retained for the phase 2 step comprising 3 injections at 4-week intervals which will aim at confirming the antitumour efficacy of DT for HCC. [Table: see text]

scholarly journals Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD protein vaccine against COVID-19 in adults: pooled analysis of two randomized, double-blind, placebo-controlled, phase 1 and 2 trials

2020 ◽  
Author(s):  
Shilong Yang ◽  
Yan Li ◽  
Lianpan Dai ◽  
Jianfeng Wang ◽  
Peng He ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Phase 1 ◽  
Phase 2 ◽  
Protein Subunit ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Phase 2 Study ◽  
To Receive

SummaryBackgroundA safe and effective coronavirus disease 2019 (COVID-19) vaccine is urgently needed to control the ongoing pandemic. Although progress has been made recently with several candidates reporting positive efficacy results, COVID-19 vaccines developed so far cannot meet the global vaccine demand. We developed a protein subunit vaccine against COVID-19, using dimeric form of receptor-binding domain (RBD) as the antigen. We aimed to assess the safety and immunogenicity of this vaccine in humans and determine the appropriate dose and schedule for an efficacy study.MethodsWe did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults aged 18-59 years were enrolled and randomly allocated to three groups to receive three doses of vaccine (25 μg or 50 μg RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 years were enrolled and randomly allocated to six groups to receive vaccine (25 μg or 50 μg RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the former 3 groups given two doses and the latter 3 groups given three doses, 30 days apart. For phase 1 trial, the primary outcome was safety, as measured by the occurrence of adverse events and serious adverse events. The secondary outcome was immunogenicity as measured by the seroconversion rate and magnitude of antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For phase 2 trial, the primary outcome included both safety and immunogenicity. These trials are registered with ClinicaTrials.gov, NCT04445194 and NCT04466085.FindingsBetween June 22 and September 15, 2020, 50 participants were enrolled to the phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-dose schedule. For both trials, local and systemic adverse reactions were absent or mild in most participants. There were no serious adverse events related to vaccine in either trial. After three doses, neutralizing antibodies were detected in all participants receiving either 25 μg or 50 μg dose of vaccine in phase 1 study, and in 97% (the 25 μg group) and 93% (the 50 μg group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 μg group and 117.8 for the 50 μg group in phase 1, and 102.5 for the 25 μg group and 69.1 for the 50 μg group in phase 2, exceeding the level of a panel of COVID-19 convalescent samples (GMT, 51). Vaccine induced balanced TH1 and TH2 responses. The 50 μg group did not show enhanced immunogenicity compared with the 25 μg group.InterpretationThe protein subunit vaccine ZF2001 is well-tolerated and immunogenic. The safety and immunogenicity data from phase 1 and 2 trials for ZF2001 support the use of 25 μg vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy.FundingNational Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical.

scholarly journals P05.03 OptimalTTF-1: Final results of a phase 1 study at first glioblastoma recurrence examining targeted craniotomy to enhance Tumor Treating Fields intensity

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii34-iii34
Author(s):  
A R Korshøj ◽  
N Mikic ◽  
S Lukacova ◽  
J C H Sørensen ◽  
F L Hansen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Electric Field ◽  
Phase 1 ◽  
Treatment Compliance ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Tumor Treating Fields ◽  
Secondary Endpoints ◽  
Glioblastoma Recurrence

Abstract BACKGROUND OptimalTTF-1 is an open-label phase-1 study on the combination of Tumor Treating Fields (TTFields) treatment together with targeted skull remodeling surgery aiming to enhance the electric field intensity in the brain (NCT02893137). Skull-remodeling surgery (SR-surgery) in this trial aims to reduce the electrical impedance of the skull. Pre-clinical modeling experiments indicate that these procedures may increase the intensity of the applied electric field. The final analysis this trial examined primarily toxicity of (TTFields) in combination with SR-surgery and best-choice chemotherapy in first glioblastoma recurrence (rGBM). MATERIAL AND METHODS 15 patients (4 female and 11 male) were enrolled into the trial, which was active from December 2016 to March 2019. The primary endpoint was frequency of serious adverse events (CTCAEv4.0) and among the secondary endpoints were overall survival (OS) and progression-free survival (PFS).Eligible patients were ≥18 years of age, had focal supratentorial rGBM, a KPS ≥60, and a minimum increase in TTFields i by ≥25% after SR-surgery, which was afterwards verified by computation field calculations. At the time-of-analysis patients were censored for time-to-event endpoints. RESULTS The baseline data (median (range)) demonstrated a patient age of 57 (39;67), skull defect area= 10.6 cm2 (7;37), and an increase in the TTFields intensity by 43% (25;59). All of the examined GBM tumors were IDH-wt and 4 of them carried an MGMT-Promoter methylation. In total, 4 patients were excluded from the study because of the following reasons: withdraw of consent, radionecrosis/non-recurrence, postoperative infection and neurodeficit, prior to treatment start. 11 patients (2 female/9 male) were treated with the study procedure.Headache 60% CI95%= [32; 84], fatigue 53%, CI95%= [27; 79], skin rash 47%, CI95%= [21; 73], and nausea 40%, CI95%= [16; 68] were found to be the most common AE of grade 1–2. With respect to grade 3 SAE, 6 seizures, 1 headache, 1 fatigue, 1 TIA, 1 post-op infection, 1 diarrhea and 1 DVT were observed. However, no device- related serious adverse events (SAEs) or grade 4–5 were reported. With respect to the secondary endpoints of OS and PFS, the study revealed that the PFS6 was 64%, CI95%= [35; 85], PFS= 8.8 months, CI95%= [6.2; 13.2], OS= 15.0 months, CI95%= [9.6;16.2], and OS12= 64%, CI95%= [35;85].The treatment compliance was 90% (48; 98) and the mean treatment duration was 6.8 months (2.3; 20.4). CONCLUSION The results of this study demonstrate that targeted craniotomy combined with TTFields is safe and does not induce additional toxicity. Therefore, this treatment regimen, by increasing the intensity of the electric field, could potentially result in significant improvement of overall survival in patients suffering from recurrent glioblastoma. Further evaluation of this concept in a phase 2 clinical trial is currently being planned.

scholarly journals A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Biapenem in Healthy Adult Subjects

2021 ◽  
Author(s):  
David C. Griffith ◽  
Elizabeth E. Morgan ◽  
Michael N. Dudley ◽  
Jeffery S. Loutit
Keyword(s):  
Adverse Events ◽  
Healthy Adult ◽  
Phase 1 ◽  
Urinary Recovery ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Multiple Doses ◽  
Dose Study ◽  
Dose Proportional

The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

scholarly journals Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

2021 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Boris Julg ◽  
C. Sabrina Tan ◽  
Rebecca Zash ◽  
Stephen R. Walsh ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Adverse Events ◽  
Antiviral Activity ◽  
Controlled Trial ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Cell Counts ◽  
Hiv 1

AbstractHuman immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

Abstract 14387: Dose-Related Reductions in Blood Pressure With a RNA Interference (RNAi) Therapeutic Targeting Angiotensinogen in Hypertensive Patients: Interim Results From a First-In-Human Phase 1 Study of ALN-AGT01

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Stephen A Huang ◽  
Jorg Taubel ◽  
Giuseppe Fiore ◽  
Peter Dewland ◽  
George L Bakris ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Single Dose ◽  
Adverse Events ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Therapeutic Targeting ◽  
Dose Administration ◽  
Hypertensive Patients ◽  
Single Dose Administration ◽  
Angiotensin Peptides

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

scholarly journals A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 296
Author(s):  
Irina Kiseleva ◽  
Irina Isakova-Sivak ◽  
Marina Stukova ◽  
Marianna Erofeeva ◽  
Svetlana Donina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Influenza Vaccine ◽  
Phase 1 ◽  
Healthy Adults ◽  
Controlled Study ◽  
Temperature Sensitive ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Human Influenza Virus ◽  
Live Attenuated Influenza Vaccine

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

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