scholarly journals 631. Preliminary safety and pharmacokinetic profile of VIR-2482: a monoclonal antibody for the prevention of influenza A illness

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S376-S376
Author(s):  
Jennifer Sager ◽  
David K Hong ◽  
Aurelio Bonavia ◽  
Lynn Connolly ◽  
Deborah Cebrik ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Half Life ◽  
Influenza A ◽  
Phase 1 ◽  
Safety Data ◽  
Phase 2 ◽  
Independent Contractor ◽  
Post Dose ◽  
Phase 2 Study

Abstract Background VIR-2482 is a fully human immunoglobulin G1(IgG) monoclonal antibody (mAb) directed against a highly-conserved epitope in the influenza A hemagglutinin stem region and is in clinical development for the prevention of influenza A illness. The Fc region of VIR-2482 has been modified to provide an extended half-life. Methods This is a randomized, placebo-controlled, Phase 1/2 study of VIR-2482 administered intramuscularly (IM) to healthy adult volunteers aged 18-64 years old who have not received a current influenza vaccine. The Phase 1 portion of the study will evaluate the safety, tolerability, pharmacokinetic (PK), and immunogenicity profile of VIR-2482 following single (Part A) or multiple doses (Part B). The Phase 2 study will evaluate the efficacy of VIR-2482 in the prevention of influenza A illness as well as safety, tolerability, and PK. Part A is ongoing and consists of four single dose cohorts (N=25/cohort) randomized (4:1) to a single dose of VIR-2482 or placebo at 60, 300, 1200, or 1800 mg. Safety, tolerability, PK and immunogenicity will be evaluated for at least 52 weeks post-dose. Results In Part A, all 100 subjects received a single dose of VIR-2482 (N=80) or placebo (N=20). Preliminary blinded safety data for all cohorts and PK data for the 300 and 1200 mg cohorts are reported here. Dosing was well tolerated; 6% (6/100) of subjects experienced mild injection site reactions, which generally resolved within 48 hrs. Through 12 weeks post-dosing, the majority (124/126; 98.4%) of adverse events (AEs) were mild to moderate in nature, no serious AEs were reported, and no subjects discontinued due to an AE. Based on available data, exposure (Cmax and AUC) between 300 and 1200 mg of VIR-2482 increased in a dose proportional manner. The PK profile of VIR-2482 is consistent with a half-life extended IgG. Conclusion Based on available data, VIR-2482 has been well tolerated following single IM doses of up to 1800 mg in healthy subjects. The preliminary PK profile of VIR-2482 enables once per season dosing. Overall, these data support initiation of a Phase 2 study to evaluate efficacy of VIR-2482 for the prevention of influenza A illness. Disclosures Jennifer Sager, PharmD, Vir Biotechnology (Employee) David K. Hong, MD, Vir Biotechnology (Employee) Aurelio Bonavia, PhD, Vir Biotechnology (Employee) Lynn Connolly, MD, PhD, Vir Biotechnology (Employee) Deborah Cebrik, PhD, Vir Biotechnology (Independent Contractor) Marie Christine Fanget, MS, Vir Biotechnology (Employee) Erik Mogalian, PharmD, PhD, Vir Biotechnology (Employee)

scholarly journals 633. Preliminary Results from a Phase 1 Single Ascending-Dose Study Assessing Safety, Serum Viral Neutralizing Antibody Titers (sVNA), and Pharmacokinetic (PK) Profile of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Treatment and Prevention of Coronavirus Disease (COVID-19)

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S420-S420
Author(s):  
Helen Paguntalan ◽  
Zoltán Magyarics ◽  
Lynn E Connolly ◽  
Ellie Hershberger ◽  
Kristin Narayan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Half Life ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Post Dose ◽  
Treatment And Prevention ◽  
Dose Study ◽  
Antibody Titers ◽  
Single Ascending Dose Study ◽  
Ongoing Phase

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)

Safety and Pharmacokinetics of Ruxolitinib (INC424) in Healthy Japanese Volunteers: Placebo-Controlled, Double-Blind, Dose-Escalation Phase 1 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5162-5162
Author(s):  
Yoichiro Ogama ◽  
Tomoko Mineyame ◽  
Asuka Yamamoto ◽  
Naomi Shimada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Half Life ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Maximum Plasma ◽  
Post Dose ◽  
To Receive ◽  
Dose Reductions

Abstract Abstract 5162 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been evaluated in non-Asian healthy subjects. However, its ethnic sensitivity has not been investigated. This is the first study in Japan to evaluate the safety, tolerability, and PK of ruxolitinib in healthy Japanese volunteers. Methods: There were 4 dose cohorts with 10 male subjects in each, 8 randomized to receive ruxolitinib and 2 randomized to receive placebo. In cohort 1 (10 mg) and cohort 2 (25 mg), each subject received a single dose (QD) of ruxolitinib or placebo on day 1 and received twice daily (bid) doses on days 4 through 10. In cohorts 3 and 4, subjects received a single dose of ruxolitinib (50 and 100 mg, respectively) or placebo on day 1. Serial blood samples for PK analysis were collected up to 48 hours post-dose, and ruxolitinib concentrations were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters were derived from individual plasma concentration time data using non-compartmental analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Results: The median age of the 40 enrolled healthy subjects was 27 years. Ruxolitinib was rapidly absorbed (Cmax achieved 0.5 hours after dosing), and exposure increased dose proportionally between 10 and 100 mg (Table). Consistent with the half-life of 2–3 hours and a 12-hour dosing interval, drug accumulation was not observed after repeated dosing. These results are similar to those obtained in non-Japanese healthy volunteers (Shi JG, et al. J Clin Pharmacol, May 20, 2011 [epub ahead of print]). AUC(0–¥), area under the curve from zero to infinity; Cmax, maximum plasma concentration; t1/2, half-life; CL/F, apparent total body clearance. Consistent with ruxolitinib's inhibition of the JAK pathway, grade 2 decreases in absolute neutrophil counts were observed in 5 subjects (3 in the 10-mg bid cohort, 1 in the 25-mg bid cohort, and 1 in the 100-mg QD cohort). However, these neutrophil decreases were managed with dose reductions in 2 subjects (1 each in the 10- and 25-mg bid cohorts) or without dose reductions in 3 subjects and rapidly recovered after the last administration of the study drug. Laboratory values showed that a similar decrease in neutrophils was also observed in subjects randomized to placebo. One subject (25-mg bid cohort) experienced a grade 1 increase in alanine aminotransferase 3 days following the last dose. All AEs resolved during the study without any treatment and were not dose dependent. Conclusions: Orally administered ruxolitinib has a predictable PK and is well tolerated in healthy Japanese volunteers. There are no apparent ethnic differences in the PK of ruxolitinib between Japanese and non-Japanese subjects. Disclosures: Shimada: Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Natsume:Novartis Pharma K.K.: Employment.

scholarly journals Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
M. Pamela Griffin ◽  
Anis A. Khan ◽  
Mark T. Esser ◽  
Kathryn Jensen ◽  
Therese Takas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Respiratory Syncytial Virus ◽  
Half Life ◽  
Phase 1 ◽  
Target Population ◽  
Healthy Adults ◽  
Controlled Study ◽  
Similar Proportion ◽  
Syncytial Virus

ABSTRACT Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (n = 102) or placebo (n = 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.)

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)

A phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE): Results of the phase 1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17020-e17020
Author(s):  
Rana R. McKay ◽  
Wanling Xie ◽  
Archana Ajmera ◽  
Biren Saraiya ◽  
Mamta Parikh ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Bone Metastases ◽  
Phase 1 ◽  
Safety Data ◽  
Fixed Dose ◽  
Phase 2 ◽  
Evaluation Period ◽  
Radium 223 ◽  
Psa Response ◽  
Dose Reductions

e17020 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has improved survival in mCRPC. In preclinical models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the hypothesis that radium-223 + olaparib will demonstrate anti-tumor activity in mCRPC irrespective of homologous recombination repair deficiency (HRD) status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of radium-223 + olaparib. Eligible patients (pts) had mCRPC with ≥2 bone metastases without visceral metastases or lymphadenopathy > 4 cm. There was no limit on prior therapy. All pts had a baseline biopsy. The phase 1 used a 3+3 dose escalation design with fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). Dose level 1 (DL1) was olaparib 200 mg PO BID; DL2 was olaparib 300 mg PO BID. The primary objective was to determine the recommended phase 2 dose (RP2D) and safety. The dose limiting toxicities (DLT) evaluation period was 2 cycles (1 cycle=28 days). Secondary endpoints included radiographic progression-free survival (rPFS) defined by PCWG3 criteria, PSA response (50% decline from baseline), and alkaline phosphatase response (30% decline from baseline). Results: 12 pts were enrolled on the phase 1. Median age was 68 (range 59-81) years. Median prior lines of CRPC therapies was 2 (1-5), including 3 (25%) who had received prior chemotherapy and 100% a prior novel hormone therapy. 6 pts were enrolled at DL1. 1 patient experienced a DLT outside the DLT evaluation period. 3 pts had grade (G) 3-4 treatment-related adverse events (TrAE) including G3 anemia (n=2) and G3 thrombocytopenia (n=1). No patient underwent dose reductions at DL1. 6 pts were enrolled at DL2. 1 patient experienced a DLT outside the DLT evaluation period. 2 pts had G3-4 TrAE including G3 anemia and G4 lymphocytopenia (n=1) and G3 stroke (n=1). 5 underwent dose reductions at DL2. There were no G5 events. Reason for treatment discontinuation is in the table below. After review of safety data, the safety monitoring committee deemed the RP2D of olaparib at 200 mg BID when combined with radium-223. Overall, PSA response and alkaline phosphatase response were 16.7% (n=2, 1 at DL1, 1 at DL2) and 67% (n=8, 3 at DL1, 5 at DL2), respectively. Median follow-up was 6.5 (range 2.8, 11.8) months, and 6-month rPFS was 57% (95% CI: 25%, 80%). Conclusions: We demonstrate that olaparib can be safety combined with radium-223 with RP2 dose of 200 mg BID. The phase 2 study of radium-223 +/- olaparib is accruing (target 120 pts). Outcomes by HRD status will be presented. Clinical trial information: NCT03317392. [Table: see text]

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