Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program

Cephalalgia ◽  
2013 ◽  
Vol 34 (7) ◽  
pp. 483-492 ◽  
Author(s):  
Marcelo E Bigal ◽  
Rafael Escandon ◽  
Michele Bronson ◽  
Sarah Walter ◽  
Maria Sudworth ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase 1 ◽  
Vital Signs ◽  
Laboratory Findings ◽  
Ehlers Danlos Syndrome ◽  
Humanized Monoclonal Antibody ◽  
Calcitonin Gene ◽  
History Of ◽  
Danlos Syndrome

Background LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide. Objective The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program. Methods LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14). Results Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of “thoracic aortic aneurysm” in a participant later found to have an unreported history of Ehlers-Danlos syndrome. Conclusion Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified.

scholarly journals Chylomicronemia from GPIHBP1 autoantibodies

2020 ◽  
Vol 61 (11) ◽  
pp. 1365-1376
Author(s):  
Kazuya Miyashita ◽  
Jens Lutz ◽  
Lisa C. Hudgins ◽  
Dana Toib ◽  
Ambika P. Ashraf ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cell ◽  
Autoimmune Disease ◽  
Plasma Levels ◽  
Plasma Triglyceride ◽  
Cell Protein ◽  
Serological Evidence ◽  
Laboratory Findings ◽  
History Of ◽  
Very High

Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the “GPIHBP1 autoantibody syndrome” and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody–based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

scholarly journals Safety and Pharmacokinetics of Single Intravenous Dose of MGAWN1, a Novel Monoclonal Antibody to West Nile Virus

2010 ◽  
Vol 54 (6) ◽  
pp. 2431-2436 ◽  
Author(s):  
John H. Beigel ◽  
Jeffrey L. Nordstrom ◽  
Stanley R. Pillemer ◽  
Cory Roncal ◽  
D. Ronald Goldwater ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
West Nile Virus ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Study Drug ◽  
Virus Infections ◽  
West Nile ◽  
Humanized Monoclonal Antibody ◽  
Grade 3 ◽  
Immunogenicity Assays

ABSTRACT West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C max) of 953 μg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C max of 953 μg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.

scholarly journals Phase 1/2 Double-Blind, Placebo-Controlled, Dose Escalation, Safety, and Pharmacokinetic Study of Pagibaximab (BSYX-A110), an Antistaphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections, in Very-Low-Birth-Weight Neonates

2009 ◽  
Vol 53 (7) ◽  
pp. 2879-2886 ◽  
Author(s):  
Leonard E. Weisman ◽  
Helen M. Thackray ◽  
Joseph A. Garcia-Prats ◽  
Mirjana Nesin ◽  
Joseph H. Schneider ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Birth Weight ◽  
High Risk ◽  
Adverse Events ◽  
Dose Escalation ◽  
Very Low Birth Weight ◽  
Phase 1 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Vlbw Infants

ABSTRACT Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 ± 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

Ehlers-Danlos Syndrome in a bitch – case report

2021 ◽  
Vol XXVI (155) ◽  
pp. 26-30
Author(s):  
Naima J. dos S. Marciano ◽  
Camila Sabaudo Alves ◽  
Paulo Sérgio Salzo ◽  
Marcelo B. Contieri
Keyword(s):  
Quality Of Life ◽  
Environmental Management ◽  
Genetic Disorder ◽  
Ehlers Danlos Syndrome ◽  
History Of ◽  
Histopathological Studies ◽  
Index Value ◽  
Danlos Syndrome ◽  
Skin Samples

Ehlers-Danlos syndrome, cutaneous asthenia or dermatosparaxis, is a rare genetic disorder that causes alterations in the synthesis of collagen fibers, resulting in hyperextensibility and dermal fragility. This paper reports the case of a nine-year-old bitch, of no defined breed. The diagnosis was obtained by the history of the animal and clinical examination. The cutaneous extensibility test resulted in an index value of 23.5% extensibility, higher than the normal value for canines (14.5%). To confirm the diagnosis, skin samples were taken for histopathological studies. For this syndrome, treatment is palliative, prioritizing the quality of life of the animal and environmental management.

Peritoneal Ultrafiltration and Serum Icodextrin Concentration during Dialysis with 7.5% Icodextrin Solution in Japanese Patients

2003 ◽  
Vol 23 (4) ◽  
pp. 356-361
Author(s):  
◽  
Kazuo Ota ◽  
Takashi Akiba ◽  
Toshiaki Nakao ◽  
Masaaki Nakayama ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Period ◽  
Negative Impact ◽  
Vital Signs ◽  
Major Change ◽  
Japanese Patients ◽  
Baseline Period ◽  
Serious Adverse Events ◽  
Laboratory Findings ◽  
Serum Osmolarity

♦ Objectives To assess the efficacy and safety of icodextrin in Japanese patients and to investigate the relationship between net ultrafiltration (UF) during the long dwell and plasma oligosaccharides. ♦ Design Open-labeled clinical trial involving patients on continuous ambulatory peritoneal dialysis (CAPD) receiving icodextrin during the 12-hour long dwell for 6 weeks, preceded by and followed by a 2-week baseline period and a follow-up period during which 1.36% glucose was used for the 8-hour long dwell. ♦ Setting A prospective, randomized multicenter study done in tertiary medical centers. ♦ Patients 18 stable patients on CAPD for 3 months or longer. ♦ Main Outcomes Measures Net UF (in milliliters), UF rate (in milliliters per hour), plasma oligosaccharides, serum osmolarity (in milliosmoles per liter), peritoneal absorption of icodextrin, and peritoneal clearances of icodextrin, creatinine, and urea were assessed. Adverse events, laboratory findings, and vital signs were also monitored. ♦ Results Long-dwell net UF (544.4 ± 96.7 mL at day 3, p < 0.001; 309.4 ± 60.7 mL at week 4, p < 0.001; and 391.7 ± 61.1 mL at week 6, p< 0.001) and UF rate (48.2 ± 38.8 mL/hour at day 3, p < 0.001; 26.9 ± 22.1 mL/hr at week 4, p < 0.002; and 35.3 ± 22.9 mL/hr at week 6, p = 0.0002) were significantly greater during the icodextrin period than at baseline (-25.9 ± 46.0 mL and -2.2 ± 22.1 mL/hr, respectively). Plasma oligosaccharides reached steady state within 2 weeks, remained stable during the treatment period, and returned to baseline level 2 weeks after discontinuation of icodextrin. Serum osmolarity increased during the use of icodextrin by approximately 5 mOsm/L. No statistically significant relationship was found between plasma oligosaccharides and net UF. Peritoneal absorption of icodextrin (36.3% ± 5.1% at day 3,42.2% ± 5.9% at week 4, and 38.0% ± 6.3% at week 6) and peritoneal clearance of icodextrin (10.1 mL/minute at day 3,10.1 mL/min at week 4, and 10.3 mL/min at week 6) showed no major change over time. Serum sodium and serum chloride both decreased by 5 mEq/L with icodextrin but remained within the normal range during the treatment period and returned to baseline levels immediately after discontinuation. No serious adverse events were observed during the study. ♦ Conclusion The results of this study do not support the hypothesis that an increased blood oligosaccharide level and the concomitant elevation in serum osmolarity have a negative impact on peritoneal UF. Therefore, the increase in plasma oligosaccharides appears to be too small to be of clinical significance.

Fremanezumab autoinjector pen for the prevention of migraine

2021 ◽  
Author(s):  
Mark W Weatherall
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Calcitonin Gene Related Peptide ◽  
Phase Iii ◽  
Tolerability Profile ◽  
Related Peptide ◽  
Phase Iii Clinical Trials ◽  
Humanized Monoclonal Antibody ◽  
Calcitonin Gene ◽  
Favorable Tolerability Profile

Ajovy (fremanezumab, Teva Pharmaceuticals, Israel) is a fully humanized monoclonal antibody that selectively binds both isoforms of the calcitonin gene-related peptide. Calcitonin gene-related peptide is a 37-amino acid neuropeptide involved in central and peripheral pathophysiological events in migraine. It is indicated for prophylaxis of migraine in adults who have at least four migraine days per month, and can be administered as a subcutaneous injection using an autoinjector device, with two dosing options: 225 mg once a month or 675 mg quarterly. In this article, I present data from Phase III clinical trials of fremanezumab in episodic and chronic migraine, in which fremanezumab demonstrated efficacy and had a favorable tolerability profile, with no serious treatment-related adverse events.

Sign in / Sign up

Export Citation Format

Share Document