Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study

S. X. Wang, S. B. Abramson, M. Attur, M. A. Karsdal, Richard A Preston, Carlos Lozada, M. P. Kosloski, F. Hong, P. Jiang, M. J. Saltarelli, B. A. Hendrickson, J. K. Medema

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA). Method This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. Results A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. Conclusion ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.

Original languageEnglish (US)
Pages (from-to)1952-1961
Number of pages10
JournalOsteoarthritis and Cartilage
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Pharmacodynamics
Knee Osteoarthritis
Interleukin-1
Placebos
Safety
Collagen
Subcutaneous Injections
Proteins
Pharmacokinetics
Biomarkers
Matrix Metalloproteinases
Antibodies
C-Reactive Protein
Serum
Tissue
Inflammation
Degradation
Matrix Metalloproteinase 1
Collagen Type III
Erythema

Keywords

  • ABT-981
  • Clinical study
  • Interleukin-1
  • Osteoarthritis
  • Pharmacokinetic
  • Safety

ASJC Scopus subject areas

  • Rheumatology
  • Biomedical Engineering
  • Orthopedics and Sports Medicine

Cite this

Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee : a randomized phase 1 study. / Wang, S. X.; Abramson, S. B.; Attur, M.; Karsdal, M. A.; Preston, Richard A; Lozada, Carlos; Kosloski, M. P.; Hong, F.; Jiang, P.; Saltarelli, M. J.; Hendrickson, B. A.; Medema, J. K.

In: Osteoarthritis and Cartilage, Vol. 25, No. 12, 01.12.2017, p. 1952-1961.

Research output: Contribution to journalArticle

Wang, S. X. ; Abramson, S. B. ; Attur, M. ; Karsdal, M. A. ; Preston, Richard A ; Lozada, Carlos ; Kosloski, M. P. ; Hong, F. ; Jiang, P. ; Saltarelli, M. J. ; Hendrickson, B. A. ; Medema, J. K. / Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee : a randomized phase 1 study. In: Osteoarthritis and Cartilage. 2017 ; Vol. 25, No. 12. pp. 1952-1961.
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abstract = "Objective To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA). Method This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. Results A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86{\%}) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54{\%} vs 63{\%}). The most common AE reported with ABT-981 vs placebo was injection site erythema (14{\%} vs 0{\%}). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37{\%} of patients but were not associated with the incidence or severity of AEs. Conclusion ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.",
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T1 - Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee

T2 - a randomized phase 1 study

AU - Wang, S. X.

AU - Abramson, S. B.

AU - Attur, M.

AU - Karsdal, M. A.

AU - Preston, Richard A

AU - Lozada, Carlos

AU - Kosloski, M. P.

AU - Hong, F.

AU - Jiang, P.

AU - Saltarelli, M. J.

AU - Hendrickson, B. A.

AU - Medema, J. K.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Objective To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA). Method This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. Results A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. Conclusion ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.

AB - Objective To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA). Method This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. Results A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. Conclusion ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.

KW - ABT-981

KW - Clinical study

KW - Interleukin-1

KW - Osteoarthritis

KW - Pharmacokinetic

KW - Safety

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