A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers
Abstract Background Inhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity...
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | BMC Pulmonary Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12890-018-0763-9 |
| _version_ | 1819111382645211136 |
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| author | Tracy L. Staton Kun Peng Ryan Owen David F. Choy Christopher R. Cabanski Alice Fong Flavia Brunstein Kathila R. Alatsis Hubert Chen |
| author_facet | Tracy L. Staton Kun Peng Ryan Owen David F. Choy Christopher R. Cabanski Alice Fong Flavia Brunstein Kathila R. Alatsis Hubert Chen |
| author_sort | Tracy L. Staton |
| collection | DOAJ |
| description | Abstract Background Inhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity, neutrophilic inflammation, and steroid resistance. BITS7201A is a novel, humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17. Methods Safety, pharmacokinetics, and immunogenicity of BITS7201A were evaluated in a phase 1 study. Part A was a single ascending-dose design with 5 cohorts: 30-, 90-, and 300-mg subcutaneous (SC), and 300- and 750-mg intravenous (IV). Part B was a multiple ascending-dose design with 3 cohorts: 150-, 300-, and 600-mg SC every 4 weeks × 3 doses. Both parts enrolled approximately 8 healthy volunteers into each cohort (6 active: 2 placebo). Part B included an additional cohort of patients with mild asthma (600-mg SC). Results Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. The cohort with mild asthma patients was terminated after enrollment of a single patient. No deaths, serious adverse events, or dose-limiting adverse events occurred. In Part A, 12 active (39%) and 5 placebo subjects (50%), and in Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common AEs were fatigue (n = 3) and influenza-like illness (n = 2). One injection-site reaction was reported. Two subjects with elevated blood eosinophil counts at baseline had transient elevations in blood eosinophils (≥Grade 2, > 1500 cells/μL). In Parts A and B, 16 of 30 (53%) and 16 of 17 (94%) active subjects, respectively, tested positive for anti-drug antibodies (ADAs). No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with an IgG monoclonal antibody; exposure generally increased dose-proportionally. Postdose elevations of the serum pharmacodynamic biomarkers, IL-17AA and IL-17FF, occurred, confirming target engagement. Conclusions BITS7201A was well tolerated, but was associated with a high incidence of ADA formation. Trial registration ClinicalTrials.gov, NCT02748642; registered April 6, 2016 (retrospectively registered). |
| first_indexed | 2024-12-22T03:56:44Z |
| format | Article |
| id | doaj.art-a7047a62425c46428a3a3ea92002c7fd |
| institution | Directory Open Access Journal |
| issn | 1471-2466 |
| language | English |
| last_indexed | 2024-12-22T03:56:44Z |
| publishDate | 2019-01-01 |
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| series | BMC Pulmonary Medicine |
| spelling | doaj.art-a7047a62425c46428a3a3ea92002c7fd2022-12-21T18:39:51ZengBMCBMC Pulmonary Medicine1471-24662019-01-0119111610.1186/s12890-018-0763-9A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteersTracy L. Staton0Kun Peng1Ryan Owen2David F. Choy3Christopher R. Cabanski4Alice Fong5Flavia Brunstein6Kathila R. Alatsis7Hubert Chen8Genentech, Inc.Genentech, Inc.Genentech, Inc.Genentech, Inc.Genentech, Inc.Genentech, Inc.Genentech, Inc.Genentech, Inc.Genentech, Inc.Abstract Background Inhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity, neutrophilic inflammation, and steroid resistance. BITS7201A is a novel, humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17. Methods Safety, pharmacokinetics, and immunogenicity of BITS7201A were evaluated in a phase 1 study. Part A was a single ascending-dose design with 5 cohorts: 30-, 90-, and 300-mg subcutaneous (SC), and 300- and 750-mg intravenous (IV). Part B was a multiple ascending-dose design with 3 cohorts: 150-, 300-, and 600-mg SC every 4 weeks × 3 doses. Both parts enrolled approximately 8 healthy volunteers into each cohort (6 active: 2 placebo). Part B included an additional cohort of patients with mild asthma (600-mg SC). Results Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. The cohort with mild asthma patients was terminated after enrollment of a single patient. No deaths, serious adverse events, or dose-limiting adverse events occurred. In Part A, 12 active (39%) and 5 placebo subjects (50%), and in Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common AEs were fatigue (n = 3) and influenza-like illness (n = 2). One injection-site reaction was reported. Two subjects with elevated blood eosinophil counts at baseline had transient elevations in blood eosinophils (≥Grade 2, > 1500 cells/μL). In Parts A and B, 16 of 30 (53%) and 16 of 17 (94%) active subjects, respectively, tested positive for anti-drug antibodies (ADAs). No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with an IgG monoclonal antibody; exposure generally increased dose-proportionally. Postdose elevations of the serum pharmacodynamic biomarkers, IL-17AA and IL-17FF, occurred, confirming target engagement. Conclusions BITS7201A was well tolerated, but was associated with a high incidence of ADA formation. Trial registration ClinicalTrials.gov, NCT02748642; registered April 6, 2016 (retrospectively registered).http://link.springer.com/article/10.1186/s12890-018-0763-9IL-13IL-17AsthmaAnti-drug antibodiesImmunogenicityPhase 1 |
| spellingShingle | Tracy L. Staton Kun Peng Ryan Owen David F. Choy Christopher R. Cabanski Alice Fong Flavia Brunstein Kathila R. Alatsis Hubert Chen A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers BMC Pulmonary Medicine IL-13 IL-17 Asthma Anti-drug antibodies Immunogenicity Phase 1 |
| title | A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers |
| title_full | A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers |
| title_fullStr | A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers |
| title_full_unstemmed | A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers |
| title_short | A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers |
| title_sort | phase i randomized observer blinded single and multiple ascending dose study to investigate the safety pharmacokinetics and immunogenicity of bits7201a a bispecific antibody targeting il 13 and il 17 in healthy volunteers |
| topic | IL-13 IL-17 Asthma Anti-drug antibodies Immunogenicity Phase 1 |
| url | http://link.springer.com/article/10.1186/s12890-018-0763-9 |
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