scholarly journals Safety, Tolerability, and Clinical Pharmacology of ANX009, an Inhibitory Antibody Fab Fragment Against C1q, Administered Subcutaneously to Healthy Volunteers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3166-3166
Author(s):  
Anita Grover ◽  
Jeffrey Teigler ◽  
Emily Radomile ◽  
Shawn Rose ◽  
Ted Yednock ◽  
...  
Keyword(s):  
Clinical Pharmacology ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Complement Activation ◽  
Ex Vivo ◽  
Phase 1 ◽  
Complement Cascade ◽  
Publicly Traded ◽  
Full Reduction ◽  
Classical Complement

Abstract Certain autoantibodies that bind to tissue antigens or that deposit in tissues as a component of immune complexes can activate the classical complement cascade, leading to inflammation and tissue damage. As the initiating molecule of the classical complement cascade, C1q is an attractive target for preventing complement activation and its multiple tissue-damaging effects. ANX009 is an antigen binding fragment (Fab) of a humanized antibody against C1q that inhibits C1q substrate interactions and fully blocks activation of all downstream classical complement components. While inhibiting the classical cascade, ANX009 leaves the lectin and alternative complement pathways intact for their normal immune functions. ANX009 is formulated for subcutaneous (SC) administration and is designed for treatment of blood-based and vascular antibody-mediated autoimmune diseases, such as autoimmune hemolytic anemia (AIHA) and lupus nephritis, where complement activation is a key component of disease pathology. A phase 1 first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study of ANX009 with subcutaneous administration was conducted in 48 healthy volunteers (NCT04535752). Four SAD cohorts were enrolled followed by two MAD cohorts evaluating daily dosing for 7 days or twice weekly dosing x 4 doses. Each cohort had eight participants randomized in a 6:2 active:placebo ratio. Safety and tolerability were assessed, along with serum pharmacokinetics (unbound drug), pharmacodynamics (unbound C1q target), and an ex vivo measure of C1q activity (CH 50 hemolysis of antibody-sensitized sheep red blood cells). All dose levels were well-tolerated. No drug-related safety signals, dose-limiting toxicities, serious adverse events, or adverse events leading to discontinuations were observed. Mild, transient, local injection site reactions were observed. A clear dose-response relationship was observed in SAD cohorts. Negligible reduction in free C1q was observed in the two lowest dose cohorts. A maximum mean reduction in free C1q of 80% was observed at 48 hours post-dose at the third dose level, and full reduction of free C1q through 72 hours was observed at the highest dose level. Similarly, full reduction of free C1q was observed in the MAD cohort with daily dosing as well as in the second MAD cohort with twice weekly dosing. Full reduction of C1q was maintained for 4 days following the last dose in the second MAD cohort. Ex vivo functional activity of C1q was completely inhibited in close correspondence with free C1q levels. Combined safety, tolerability, and clinical pharmacology results from this phase 1 study support advancement of ANX009 to studies in patients with complement-mediated autoimmune disorders. Disclosures Grover: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Teigler: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Radomile: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Rose: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Yednock: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Keswani: Annexon Inc: Current Employment, Current equity holder in publicly-traded company.

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 Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

2016 ◽  
Vol 45 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Julia Cordelia Hempel ◽  
Felix Poppelaars ◽  
Mariana Gaya da Costa ◽  
Casper F.M. Franssen ◽  
Thomas P.G. de Vlaam ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Complement Activation ◽  
Ex Vivo ◽  
Ferric Carboxymaltose ◽  
Hypersensitivity Reactions ◽  
Iron Dextran ◽  
Iv Iron ◽  
Ex Vivo Assay

Background: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA). Methods: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients. Results: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation. Conclusion: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

scholarly journals Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2186-2186
Author(s):  
David C. Dale ◽  
Steven P. Treon ◽  
David F. McDermott ◽  
Diego Cadavid ◽  
Xia Luo ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Publicly Traded ◽  
Whim Syndrome ◽  
Phase 2 Trial ◽  
Phase 1B ◽  
Wbc Count

Abstract Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM). Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs. Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.

scholarly journals Nonclinical Development of ANX005: A Humanized Anti-C1q Antibody for Treatment of Autoimmune and Neurodegenerative Diseases

2017 ◽  
Vol 36 (6) ◽  
pp. 449-462 ◽  
Author(s):  
Janice A. Lansita ◽  
Kirsten M. Mease ◽  
Haiyan Qiu ◽  
Ted Yednock ◽  
Sethu Sankaranarayanan ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Recombinant Antibody ◽  
Serum Levels ◽  
Repeat Dose ◽  
Complement Cascade ◽  
Immunoglobulin G4 ◽  
Adverse Effect Level ◽  
Classical Complement

ANX005 is a humanized immunoglobulin G4 recombinant antibody against C1q that inhibits its function as the initiating molecule of the classical complement cascade. The safety and tolerability of ANX005 are currently being evaluated in a phase I trial in healthy volunteers ( www.clinicaltrials.gov Identifier: NCT03010046). Inhibition of C1q can be applied therapeutically in a broad spectrum of diseases, including acute antibody-mediated autoimmune disease, such as Guillain-Barré syndrome (GBS), and in chronic diseases of the central nervous system involving complement-mediated neurodegeneration, such as Alzheimer's disease (AD). To support the clinical development of ANX005, several studies were conducted to assess the pharmacology, pharmacokinetics, and potential toxicity of ANX005. ANX-M1, the murine precursor of ANX005, functionally inhibits the classical complement cascade both in vitro and in vivo, to protect against disease pathology in mouse models of GBS and AD. Toxicology studies with ANX005, itself, showed that intravenous administration once weekly for 4 weeks was well tolerated in rats and monkeys, with no treatment-related adverse findings. Serum levels of ANX005 in monkeys correlate with a reduction in free C1q levels both in the serum and in the cerebrospinal fluid. In summary, ANX005 has shown proof of concept in in vitro and in vivo nonclinical pharmacology models, with no toxicity in the 4-week repeat-dose studies in rats and monkeys. The no observed adverse effect level was 200 mg/kg/dose, which is 200-fold higher than the first-in-human starting dose of 1 mg/kg in healthy volunteers.

GMI-1070, a Pan-Selectin Inhibitor: Safety and PK In a Phase 1/2 Study In Adults with Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1632-1632 ◽  
Author(s):  
Lori Styles ◽  
Ted Wun ◽  
Laura M. De Castro ◽  
Marilyn J. Telen ◽  
William Kramer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Steady State ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Study Drug ◽  
Cell Disease ◽  
Employment Equity ◽  
The Past ◽  
Equity Ownership

Abstract Abstract 1632 GMI-1070 is a pan-selectin inhibitor that targets E-, P-, and L-selectins and has shown activity in multiple animal models of disease. Sickle cell disease (SCD) is characterized by periodic vaso-occlusive (VOC) episodes in which cell adhesion and aggregation play a crucial role. GMI-1070 has previously been shown to restore blood flow and improve survival in a mouse model of VOC, and safety and PK have been evaluated in normal, healthy volunteers in phase 1. Here we report clinical, safety, and PK results from the first study of GMI-1070 in individuals with SCD. Methods: An open-label phase 1/2 study was performed, enrolling adults with SCD at steady state. GMI-1070 was administered in two IV doses given on the same day: 20 mg/kg in the first dose, followed 10 hours later by 10 mg/kg. Patients were evaluated for safety on days 0, 1, 2, 7 and 28, including adverse events (AEs), routine clinical labs, and clinical exam. Plasma and urine concentrations of GMI-1070 were measured on days 0, 1, and 2, and PK parameters calculated and compared with those from healthy volunteers. Results: Fifteen adults were enrolled at three centers; 13 with HbSS, 2 with HbSB0thal. All were African-American, 9 were male, mean age was 32 years (range 18–50), mean weight was 64.7 kg; 4 were on hydroxyurea. In the past year, 6 had experienced VOC requiring medical care; 2 had ACS; 2 required transfusions; and 1 had an episode of priapism. Five were hospitalized in the past year; 12 were hospitalized in the past 5 years. All subjects received both doses of study drug; all but one were followed for 28 days. The PK in adults with SCD was in good agreement with that in the controls. The elimination half-life of GMI-1070 averaged 7.73 ± 2.45 hours (Figure). Renal clearance averaged 18.0 ± 7.93 mL/min and accounted for essentially all elimination. Physical exam parameters after dosing were unchanged, and all infusions were well tolerated. Four subjects reported headache within 24 hours of dosing, all of which were mild or moderate and resolved within 24 hours. Two subjects experienced VOC not requiring hospitalization, at 2 and 4 weeks after dosing. One subject had worsening anemia requiring transfusion 5 days after dosing. Other adverse events typical of SCD were reported without apparent association with study drug; none were serious adverse events. Routine labs demonstrated no changes from baseline (Hb, reticulocytes, platelets, electrolytes, glucose, ALT, LDH, BUN, Cr, bilirubin, urinalysis) with the exception of white blood cell counts (WBC) and absolute neutrophil counts (ANC). At 24 hours, mean WBC change from baseline was 1.9K/mm3, or 20% (p=0.076, using parametric test with mixed model); mean ANC change was 2.7, or 67% (p=0.019); all returned to baseline by 7 days. One individual had marked leukocytosis 24 hours after dosing (from 10.4 to 28K/mm3), returning to baseline by day 7; no other effects were observed in this subject. Mean C-reactive protein (CRP) increased at 24 and 48 hours, returning to baseline by day 7. Two subjects had marked increases in CRP: one exhibited leukocytosis with dosing and the other had a high baseline WBC count. There was otherwise no apparent correlation between PK, WBC/ANC, hydroxyurea use, or adverse events. In conclusion, GMI-1070, a pan-selectin inhibitor, when administered to adults with SCD at steady state, has a similar safety and PK profile to that in healthy volunteers. However, SCD patients had moderate WBC and ANC increases at 24–48 hours after dosing, which return to baseline without other observed symptomatic adverse events. This study supports further evaluation of GMI-1070 for the treatment of vaso-occlusive crisis. Disclosures: Styles: GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics: Consultancy, clinical trial sponsorship. De Castro:GlycoMimetics: clinical trial sponsorship. Telen:GlycoMimetics: Consultancy, clinical trial sponsorship. Kramer:GlycoMimetics: Consultancy. Flanner:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Thackray:GlycoMimetics: Employment, Equity Ownership. Off Label Use: This drug (GMI-1070) has not been approved for any clinical indication.

scholarly journals 674. Pre-Clinical and Phase I Safety Data for Anti-Pseudomonas aeruginosa Human Monoclonal Antibody AR-105

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S307-S308
Author(s):  
Andreas Loos ◽  
Nadine Weich ◽  
Jennifer Woo ◽  
Guy Lalonde ◽  
Luisa Yee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Pseudomonas Aeruginosa ◽  
Animal Models ◽  
Adverse Events ◽  
Phase I ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Safety Data ◽  
Igg1 Mabs ◽  
Human Igg1

Abstract Background Anti-bacterial monoclonal antibodies can serve as a new treatment modality for difficult to treat infections. AR-105 is a fully human IgG1 monoclonal antibody (mAb) that binds to an extracellular polysaccharide epitope of Pseudomonas aeruginosa (PA) and was shown to mediate in vitro complement-dependent opsonophagocytic killing. AR-105 is currently being tested in a global Phase 2 clinical trial as an adjunctive treatment to standard of care antibiotics in ventilator-associated pneumonia patients. Here we present pre-clinical efficacy and clinical safety data for AR-105. Methods Efficacy in nonclinical studies against PA pneumonia was tested in prophylactic and therapeutic mouse models, either as a stand-alone therapy or in combination with antibiotics. Mice were dosed intranasally or by intravenous infusion with AR-105 post or prior to infection with PA and survival or lung bacteriology were monitored. In a clinical Phase 1 open-label study, 16 healthy volunteers received 2, 8, or 20 mg/kg of AR-105. Adverse events, immunogenicity, and pharmacokinetic (PK) profiles were evaluated for up to 84 days following administration. Results In the animal models, AR-105 reduced lung bacterial counts in a dose-dependent manner, and improved survival (80% in the treated group vs. 0% in the control group). Combination of AR-105 with antibiotics was more effective than monotherapy. In the Phase I study, no serious adverse events (AE) were observed in any cohort. Few AE were deemed related to the investigational drug, and all were mild and transient. AR-105 was found to be well tolerated in healthy volunteers with no anti-drug antibodies (ADA) detected. The PK profile was comparable with other human IgG1 mAbs, exhibiting a serum half-life of approximately 20 days. Conclusion AR-105 was confirmed to be effective in PA pneumonia animal models, either as stand-alone therapeutic or in combination with antibiotics. In the Phase 1 clinical study, AR-105 was shown to be safe and well-tolerated, with a PK profile similar to that of other IgG1 mAbs. AR-105 is a promising drug candidate for therapy of PA pneumonia. Disclosures All authors: No reported disclosures.

scholarly journals The Pharmacokinetics, Pharmacodynamics, and Safety of Intravenous Pegcetacoplan Treatment in Healthy Subjects

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4304-4304
Author(s):  
Federico Grossi ◽  
Michael Yeh ◽  
Raymond Xu ◽  
Pascal Deschatelets
Keyword(s):  
Adverse Events ◽  
Hemolytic Activity ◽  
Healthy Subjects ◽  
Sodium Acetate Solution ◽  
Complement Cascade ◽  
Acetate Solution ◽  
Publicly Traded ◽  
Post Dose ◽  
Complement Activity ◽  
Saline Treatment

Abstract Background: The complement cascade is part of innate immunity and is involved in multiple inflammatory processes and implicated in several diseases. Pegcetacoplan (PEG) is a pegylated, cyclic peptide that binds to complement protein C3 and is a broad inhibitor of the complement cascade. Subcutaneous (SC) dosing of PEG has demonstrated efficacy in the treatment of chronic conditions, such as paroxysmal nocturnal hemoglobinuria (PNH) and was recently approved by the FDA for the treatment of PNH in adults. Intravenous (IV) PEG administration may allow for more rapid and robust reduction of uncontrolled complement activation, especially in an acute setting, such as an acute hemolytic episode in PNH. Aims: To determine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IV PEG in acetate-buffered saline treatment in a Phase 1 single ascending dose study (ACTRN12616000700437) in healthy subjects. Methods: On Day 1, four cohorts with PEG doses (200mg, 600mg, 1500mg, 2300mg) received a single bolus of PEG IV (or matching placebo) administered over 30min. Blood samples for PK analyses of PEG concentration and PD analyses of alternative complement pathway hemolytic activity (AH50), total complement hemolytic activity (CH50), C3 and C3a levels were collected at 15, 30, and 60min, 4, 8, 12, and 24hrs, and Days 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43. Subjects were monitored during a safety period from Day 2 to 8 by physical examination, ECG, hematology, serum chemistry, monitoring for injection site reaction and treatment emergent adverse events (TEAEs). Follow-up safety assessments were performed on Days 15, 22, 29, and 43. Results: Twenty subjects were enrolled and allocated 4:1 to PEG or placebo per cohort (PEG-200mg, n=4; PEG-600mg, n=4; PEG-1500mg, n=4; PEG-2300mg, n=4; pooled placebo, n=4). Following a single IV dose, peak concentration (C max) of PEG was observed at 1hr post-dose (infusion start) for most cohorts (mean serum concentration: PEG-200mg, 61μg/mL; PEG-600mg, 193μg/mL; PEG-2300mg, 708μg/mL) except PEG-1500mg (occurred at 4hrs, 542μg/mL). PEG concentration at the end of infusion was similar to the observed C max. PEG concentration declined in a mono-exponential manner, with a terminal elimination half-life ranging from 200 to 285 hrs (Figure). Total body clearance of PEG after IV administration was similar across cohorts. Early, immediate decreases in mean AH50 values were detected within 1hr in all PEG cohorts, with 1500 and 2300mg doses decreasing AH50 to undetectable levels (Figure). Decreases in mean AH50 values were maintained for at least 12, 72, 144 and 168hrs after single doses of 200, 600, 1500 and 2300mg PEG, respectively. All PEG groups had an initial rapid decrease within 1hr in mean C3a levels, with all dose groups having trough mean C3a levels within 24hrs of dosing. Dose related decreases in mean C3a were not observed, all doses recorded a max mean decrease of 47% to 57%. No changes seen with placebo for C3a. C3 and CH50 results will be forthcoming. Of the twenty subjects included in the study, 11 (55.0%) experienced a treatment-related adverse event (TEAE). The most common TEAEs in the PEG group were headache, (n=6, 37.5%); upper respiratory infections attributed to seasonal viral infection (n=2, 12.5%); diarrhea (n=2, 12.5%). No serious adverse events, deaths, or severe TEAEs occurred. One subject (5.0%) in the PEG-2300mg cohort experienced a moderate TEAE (infusion-related reaction, dizziness, clamminess, nausea) that led to study discontinuation. Conclusions: These results suggest that administration of IV PEG in a sodium acetate solution has a favorable safety profile and effectively increases PEG serum concentrations while decreasing complement activity within the first hour post-dose in healthy subjects. Although the safety and efficacy of SC PEG treatment has been demonstrated in patients with PNH, IV PEG administration could serve as a useful therapeutic option for patients with a need for rapid control of complement activity. While this formulation is different than the commercially available PEG (EMPAVELI), which is administered SC and is suspended in sorbitol, the results suggest that IV PEG is well tolerated and provides the grounds for future investigations of IV PEG administration. Figure 1 Figure 1. Disclosures Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Xu: Apellis Pharmaceuticals: Current Employment. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: Pegcetacoplan, a subcutaneously administered C3-inhibitor that was recently approved by the US FDA for the treatment of PNH, controls IVH and prevents EVH. While subcutaneous pegcetacoplan is safe and effective, the aim of this study was to determine the safety, pharmacokinetics, and pharmacodynamics of IV pegcetacoplan in acetate-buffered saline treatment, different from current FDA approved formulation.

Safety Profile of AMG 531 in Healthy Volunteers and in Thrombocytopenic Patients with Immune Thromobocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1240-1240 ◽  
Author(s):  
Daniel E. Stepan ◽  
Elaine Sergis-Deavenport ◽  
Reggie Kelly ◽  
Jenny Christal ◽  
Chien-Feng Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Safety Profile ◽  
Phase 1 ◽  
Phase 2 ◽  
Platelet Response ◽  
Open Label ◽  
Two Phase ◽  
Open Label Extension

Abstract AMG 531 is a novel platelet-stimulating peptibody that targets the thrombopoietin (TPO) receptor, resulting in an increased production of platelets. AMG 531 lacks sequence homology to native TPO. To date, AMG 531 has been administered in two phase 1 studies in a total of 56 healthy volunteers and in three phase 2 studies, with the option to continue in an open-label extension study, in a total of 57 patients with immune thrombocytopenic purpura (ITP). In general, no deaths or detectable neutralizing antibodies have occurred across the AMG 531 development program. In the two phase 1 studies, AMG 531 increased platelet counts in a dose-response manner when administered as a single subcutaneous (SC) or intravenous (IV) dose of ≥ 1.0 μg/kg. The dynamics of the platelet response were as expected based on experience with other Mpl ligands. Single doses of AMG 531 ≤ 10.0 μg/kg were well tolerated. No deaths, serious or severe adverse events, or other events of clinical importance were reported at any dose administered (0.1, 0.3, 1.0, and 2.0 μg/kg SC; 0.3, 1.0, and 10.0 μg/kg IV). Commonly reported adverse events in healthy subjects receiving AMG 531 were mild to moderate headache (13% incidence in both studies), malaise/fatigue (4% and 6%), and various flu-like reactions. In the phase 2 studies in patients with ITP, AMG 531 was administered SC using weight-based dosing in all but one study. The maximum dose administered (in the extension study) was 23 μg/kg; most patients received doses of 3 to 9 μg/kg. AMG 531 has been administered as frequently as weekly for > 24 weeks. To date, three studies have been completed: two studies of two administrations on day 1 and 15, administered as unit (μg) doses in one study (N=16 and N=24, respectively), one placebo-controlled study of 6 weeks’ duration with weekly dosing (AMG 531 N=17; placebo N=4). One open-label extension (N=26) is ongoing. AMG 531 has been generally well tolerated in ITP patients. Most of the reported adverse events have been mild to moderate in severity; no dose-related trends have been observed. Across the four studies, the most commonly reported adverse events in patients receiving AMG 531 were headache (29%–54% incidence), contusion (15%–53%), and epistaxis (13%–41%). In the 6-week, weekly-dosing study, contusion and epistaxis were each reported for 50% and 41% of placebo-treated patients, respectively. Across the phase 2 studies, five patients treated with AMG 531 have experienced serious adverse events deemed as serious, unexpected, and reported as related to study drug. These include worsening of thrombocytopenia in three patients after completing treatment, headache and elevated LDH in one patient, and diffuse reticulin formation in the bone marrow reported as myelofibrosis in one patient. The reticulin formation is hypothesized to be due to an excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a follow-up bone marrow (after 3 months) showed improvement in reticulin. In summary, AMG 531 has been generally well tolerated and able to stimulate platelet production in a dose-response manner in healthy volunteers and ITP patients. Results suggest that both unit dosing and weight-based dosing provide a predictable platelet response. AMG 531 may represent a new treatment option for thrombocytopenic patients with ITP. Safety surveillance is ongoing to further establish the safety profile of AMG 531.

scholarly journals SAT0143 A PHASE 1 STUDY IN HEALTHY VOLUNTEERS EXPLORING THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ATI-450: A NOVEL ORAL MK2 INHIBITOR

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1010.2-1010
Author(s):  
J. Schnyder ◽  
J. Monahan ◽  
W. Smith ◽  
H. Hope ◽  
D. Kelly ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Small Molecule ◽  
Ex Vivo ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Post Dose ◽  
Dose Cohort ◽  
Drug Levels ◽  
Dose Proportional

Background:ATI-450, is an investigational small molecule inhibitor of the MAPK-activated protein kinase 2 (MK2) signaling pathway. This pathway drives the expression of multiple cytokines including TNFα, IL-1α and β, and IL-6.Objectives:We evaluated the safety and tolerability of ATI-450 in healthy volunteers as well as pharmacokinetics (PK) and pharmacodynamics (PD). Here we present data from single and multiple ascending dose cohorts. The aim was to select a dose for evaluation in phase 2 in patients with rheumatoid arthritis.Methods:Safety, PK and PD were assessed in a randomized, observer-blind, placebo-controlled, phase 1 study in male and female healthy subjects aged 18-55 (n=77).Part A: Single Ascending Dose (SAD) (n=32, 8 subjects per dose cohort - 2 placebo, 6 active). A single dose of 10mg, 30mg, 50mg and 100mg was tested.Part B: Multiple Ascending Dose (MAD) (n=30, 10 subjects per dose cohort - 2 placebo, 8 active). 10mg BID, 30mg BID and 50mg BID doses were tested over 7 days of administration.Safety and tolerability of ATI-450 was evaluated based on adverse events, clinical laboratory, vital signs, 12-lead ECG, Holter monitoring, and physical examination. Blood was drawn for PK analysis at 0.5, 1, 2, 4, 6, 8, 12 hours, 24, 36, and 48 hours post dose in the SAD cohort and on day 7 of the MAD cohort. PD of ATI-450 were explored by investigating the inhibition of a target biomarker, phospho-HSP27 (pHSP27) and proinflammatory cytokines, TNFα, IL1β, IL6 and IL8 inex-vivoLPS-stimulated blood samples collected 4 and 12 hours post dose on day 7 from subjects in the MAD cohorts.Results:ATI-450 was generally well tolerated. No serious adverse events or severe adverse events were reported, and no adverse events led to discontinuation of the study medication. The most common adverse events (reported by 2 or more subjects who received ATI-450) observed during the trial were dizziness, headache, upper respiratory tract infection, constipation, nausea, and abdominal pain. All adverse events were mild. A trend of a decrease in absolute neutrophil count (ANC) was observed without correlated clinical sequelae.ATI-450 had dose proportional PK with a terminal half-life (t½) of 9-12 hours in the MAD cohort on day 7. A dose and concentration dependent inhibition ofex vivostimulated cytokines and target biomarker was observed. On day 7, patients in the 50mg BID dose (the dose with the highest degree of inhibition) recorded mean trough drug levels (12 hours post dose) that were 1.4, 2.5, 2.5 and 2.4 times greater than the IC80for TNFα, IL1β, IL8 and pHSP27 respectively. Mean Cmax drug levels (4 hours post dose) were 3.6, 6.4, 6.2 and 6.0 times greater than the IC80for TNFα, IL1β, IL8 and pHSP27 respectively. IL6 levels were inhibited by more than 50% for part of the dosing interval.Conclusion:Oral ATI-450 was generally well tolerated at all doses with dose proportional PK. The t½ suggests that once or twice daily oral dosing may be possible. At the 50mg BID dose, marked inhibition of TNFα, IL1β and IL8, IL6 and pHSP27 was observed. ATI-450 has the potential to be an oral, small molecule drug which can target multiple cytokines. Exploration of its benefit to risk profile in patients with rheumatoid arthritis is warranted.Disclosure of Interests:Judy Schnyder Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, Joe Monahan Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, Walter Smith Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, Heidi Hope Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, Deborah Kelly Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, David Burt Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, E Huff Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, A Kaul Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, A Hildebrand Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, B Burnette Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, N Klug Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics, M Bangs Shareholder of: Aclaris Therapeutics, Employee of: Aclaris Therapeutics, David Gordon Shareholder of: aclaris therapeutics, Employee of: aclaris therapeutics

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