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A Phase I, Randomized, Observer-Blinded, Placebo-Controlled, Single and Multiple Ascending-Dose Study to Investigate the Safety, Pharmacokinetics, and Immunogenicity of BITS7201A in Healthy Volunteers
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A1365 - A Phase I, Randomized, Observer-Blinded, Placebo-Controlled, Single and Multiple Ascending-Dose Study to Investigate the Safety, Pharmacokinetics, and Immunogenicity of BITS7201A in Healthy Volunteers
Author Block: H. Chen, K. Peng, D. F. Choy, C. Cabanski, A. Fong, F. Brunstein, K. Rajapaksa, I. Templeton, T. Staton; Genentech, Inc., South San Francisco, CA, United States.
Rationale: 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 humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17.
Methods: The safety, pharmacokinetics, and immunogenicity of BITS7201A was 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. Part B was a multiple ascending-dose design with 3 cohorts: 150, 300, and 600 mg SC Q4 weeks x3 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 at the top dose, which was terminated after enrollment of a single patient.
Results: Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. Age, sex, and race were roughly similar between active and placebo groups: mean age, 32 years; 46% female; and 72% white. No deaths, serious adverse events, or dose-limiting toxicities occurred. For Part A, 12 active subjects (39%) and 5 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). For Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 TEAE. The most common AEs were fatigue (n=3) and influenza-like illness (n=2). One injection site reaction was reported. Two subjects had elevated blood eosinophils (≥Grade 2, >1500 cells/μL); both subjects had elevated counts at baseline. For Part A, 16 of 30 (53%) active subjects tested positive for anti-drug antibodies (ADAs) compared with 1 of 10 (10%) placebo subjects. For Part B, 16 of 17 (94%) active subjects and 1 of 5 (20%) placebo subjects were ADA-positive. No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with those of an IgG monoclonal antibody; exposure increased in a generally dose-proportional manner. Serum IL-17AA and IL-17FF were measured as pharmacodynamic biomarkers; elevation of these cytokines was observed post dose, confirming target engagement.
Conclusions: BITS7201A, a novel bispecific antibody, demonstrated acceptable safety and tolerability, but was associated with a high incidence of ADA formation. The potential for immunogenic consequences cannot be excluded.
Author Block: H. Chen, K. Peng, D. F. Choy, C. Cabanski, A. Fong, F. Brunstein, K. Rajapaksa, I. Templeton, T. Staton; Genentech, Inc., South San Francisco, CA, United States.
Rationale: 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 humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17.
Methods: The safety, pharmacokinetics, and immunogenicity of BITS7201A was 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. Part B was a multiple ascending-dose design with 3 cohorts: 150, 300, and 600 mg SC Q4 weeks x3 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 at the top dose, which was terminated after enrollment of a single patient.
Results: Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. Age, sex, and race were roughly similar between active and placebo groups: mean age, 32 years; 46% female; and 72% white. No deaths, serious adverse events, or dose-limiting toxicities occurred. For Part A, 12 active subjects (39%) and 5 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). For Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 TEAE. The most common AEs were fatigue (n=3) and influenza-like illness (n=2). One injection site reaction was reported. Two subjects had elevated blood eosinophils (≥Grade 2, >1500 cells/μL); both subjects had elevated counts at baseline. For Part A, 16 of 30 (53%) active subjects tested positive for anti-drug antibodies (ADAs) compared with 1 of 10 (10%) placebo subjects. For Part B, 16 of 17 (94%) active subjects and 1 of 5 (20%) placebo subjects were ADA-positive. No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with those of an IgG monoclonal antibody; exposure increased in a generally dose-proportional manner. Serum IL-17AA and IL-17FF were measured as pharmacodynamic biomarkers; elevation of these cytokines was observed post dose, confirming target engagement.
Conclusions: BITS7201A, a novel bispecific antibody, demonstrated acceptable safety and tolerability, but was associated with a high incidence of ADA formation. The potential for immunogenic consequences cannot be excluded.
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