Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers

Barbara White, Francisco Leon, Wendy White, Gabriel Robbie

Research output: Contribution to journalArticle

Abstract

Background: Interleukin-9 (IL-9) is involved in pathogenic aspects of the asthmatic response, including induction of the proliferation of T-helper type 2 lymphocytes, mucus production, and mast-cell differentiation, proliferation, and recruitment to the lung. In preclinical studies in mice, inhibition of IL-9 through neutralizing monoclonal antibody (mAb) treatment partially reduced airway hyperresponsive-ness and mast-cell progenitor migration to the lung. Objective: The goal of the present studies was to determine the safety and pharmacokinetic profiles and im-munogenicity of MEDI-528, a humanized immunoglobulin G1k anti-IL-9 mAb, in healthy adult volunteers. Methods: In separate open-label, Phase I dose-escalation studies, single doses of MEDI-528 0.3, 1.0, 3.0, or 9.0 mg/kg were administered as an intravenous infusion (20 mg/min administered over 1-40 minutes, depending on dose) and by subcutaneous injection. All subjects were followed for 84 days. Any laboratory test value outside the normal reference range was considered an adverse event (AE). Results: Twenty-four subjects were enrolled in the intravenous study, and 29 subjects were enrolled in the subcutaneous study. No deaths or serious or severe AEs occurred in either study. The most frequently reported AEs in the intravenous study were laboratory test abnormalities; the most frequently reported AEs in the subcutaneous study were pharyngolaryngeal pain, palpable lymph nodes, and laboratory test abnormalities. The single-dose pharmacokinetics of MEDI-528 were linear and dose proportional over the dose range studied with both routes of administration. The mean t1/2 after intravenous administration was ~26 days (range, 25-28 days); the mean t1/2 after subcutaneous administration ranged from 33 to 87 days across doses. A low titer (1:80) of antibodies to MEDI-528 was detected on day 84 in a single volun- teer receiving intravenous MEDI-528 3.0 mg/kg. No antibody titers were detected in any of the volunteers receiving subcutaneous MEDI-528. Conclusions: Administered intravenously or subcu-taneously, MEDI-528 had an acceptable safety profile and exhibited linear pharmacokinetics over the dose range studied in healthy adults in these Phase I studies. The findings support further investigation of MEDI-528 in multiple-dose trials in patients with asthma. ClinicalTrials.gov Identification numbers: NCT00192296 (intravenous study); NCT00116168 (subcutaneous study).

Original languageEnglish (US)
Pages (from-to)728-740
Number of pages13
JournalClinical Therapeutics
Volume31
Issue number4
DOIs
StatePublished - Apr 2009
Externally publishedYes

Fingerprint

Interleukin-9
Healthy Volunteers
Monoclonal Antibodies
Safety
Pharmacokinetics
Mast Cells
Volunteers
Reference Values
Lung
MEDI-528
Antibodies
Subcutaneous Injections
Mucus
Helper-Inducer T-Lymphocytes
Neutralizing Antibodies
Intravenous Infusions
Intravenous Administration
Cell Movement
Immunoglobulins
Cell Differentiation

Keywords

  • asthma
  • interleukin-9
  • MEDI-528
  • monoclonal antibody
  • pharmacokinetics
  • safety

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. / White, Barbara; Leon, Francisco; White, Wendy; Robbie, Gabriel.

In: Clinical Therapeutics, Vol. 31, No. 4, 04.2009, p. 728-740.

Research output: Contribution to journalArticle

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T1 - Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers

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AU - Robbie, Gabriel

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N2 - Background: Interleukin-9 (IL-9) is involved in pathogenic aspects of the asthmatic response, including induction of the proliferation of T-helper type 2 lymphocytes, mucus production, and mast-cell differentiation, proliferation, and recruitment to the lung. In preclinical studies in mice, inhibition of IL-9 through neutralizing monoclonal antibody (mAb) treatment partially reduced airway hyperresponsive-ness and mast-cell progenitor migration to the lung. Objective: The goal of the present studies was to determine the safety and pharmacokinetic profiles and im-munogenicity of MEDI-528, a humanized immunoglobulin G1k anti-IL-9 mAb, in healthy adult volunteers. Methods: In separate open-label, Phase I dose-escalation studies, single doses of MEDI-528 0.3, 1.0, 3.0, or 9.0 mg/kg were administered as an intravenous infusion (20 mg/min administered over 1-40 minutes, depending on dose) and by subcutaneous injection. All subjects were followed for 84 days. Any laboratory test value outside the normal reference range was considered an adverse event (AE). Results: Twenty-four subjects were enrolled in the intravenous study, and 29 subjects were enrolled in the subcutaneous study. No deaths or serious or severe AEs occurred in either study. The most frequently reported AEs in the intravenous study were laboratory test abnormalities; the most frequently reported AEs in the subcutaneous study were pharyngolaryngeal pain, palpable lymph nodes, and laboratory test abnormalities. The single-dose pharmacokinetics of MEDI-528 were linear and dose proportional over the dose range studied with both routes of administration. The mean t1/2 after intravenous administration was ~26 days (range, 25-28 days); the mean t1/2 after subcutaneous administration ranged from 33 to 87 days across doses. A low titer (1:80) of antibodies to MEDI-528 was detected on day 84 in a single volun- teer receiving intravenous MEDI-528 3.0 mg/kg. No antibody titers were detected in any of the volunteers receiving subcutaneous MEDI-528. Conclusions: Administered intravenously or subcu-taneously, MEDI-528 had an acceptable safety profile and exhibited linear pharmacokinetics over the dose range studied in healthy adults in these Phase I studies. The findings support further investigation of MEDI-528 in multiple-dose trials in patients with asthma. ClinicalTrials.gov Identification numbers: NCT00192296 (intravenous study); NCT00116168 (subcutaneous study).

AB - Background: Interleukin-9 (IL-9) is involved in pathogenic aspects of the asthmatic response, including induction of the proliferation of T-helper type 2 lymphocytes, mucus production, and mast-cell differentiation, proliferation, and recruitment to the lung. In preclinical studies in mice, inhibition of IL-9 through neutralizing monoclonal antibody (mAb) treatment partially reduced airway hyperresponsive-ness and mast-cell progenitor migration to the lung. Objective: The goal of the present studies was to determine the safety and pharmacokinetic profiles and im-munogenicity of MEDI-528, a humanized immunoglobulin G1k anti-IL-9 mAb, in healthy adult volunteers. Methods: In separate open-label, Phase I dose-escalation studies, single doses of MEDI-528 0.3, 1.0, 3.0, or 9.0 mg/kg were administered as an intravenous infusion (20 mg/min administered over 1-40 minutes, depending on dose) and by subcutaneous injection. All subjects were followed for 84 days. Any laboratory test value outside the normal reference range was considered an adverse event (AE). Results: Twenty-four subjects were enrolled in the intravenous study, and 29 subjects were enrolled in the subcutaneous study. No deaths or serious or severe AEs occurred in either study. The most frequently reported AEs in the intravenous study were laboratory test abnormalities; the most frequently reported AEs in the subcutaneous study were pharyngolaryngeal pain, palpable lymph nodes, and laboratory test abnormalities. The single-dose pharmacokinetics of MEDI-528 were linear and dose proportional over the dose range studied with both routes of administration. The mean t1/2 after intravenous administration was ~26 days (range, 25-28 days); the mean t1/2 after subcutaneous administration ranged from 33 to 87 days across doses. A low titer (1:80) of antibodies to MEDI-528 was detected on day 84 in a single volun- teer receiving intravenous MEDI-528 3.0 mg/kg. No antibody titers were detected in any of the volunteers receiving subcutaneous MEDI-528. Conclusions: Administered intravenously or subcu-taneously, MEDI-528 had an acceptable safety profile and exhibited linear pharmacokinetics over the dose range studied in healthy adults in these Phase I studies. The findings support further investigation of MEDI-528 in multiple-dose trials in patients with asthma. ClinicalTrials.gov Identification numbers: NCT00192296 (intravenous study); NCT00116168 (subcutaneous study).

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KW - interleukin-9

KW - MEDI-528

KW - monoclonal antibody

KW - pharmacokinetics

KW - safety

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