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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

Open AccessPublished:September 27, 2017DOI:https://doi.org/10.1016/j.joca.2017.09.007

      Summary

      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.

      Keywords

      Introduction

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      .
      The objective of this phase 1 randomized trial was to investigate the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of ABT-981 in patients with mild-to-moderate knee OA.

      Methods

      Study conduct

      The procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1975, as revised in 2000. The ethics committee that approved the study was the University of Miami Human Subjects Research Office (Miami, FL, USA). All participants provided informed consent before initiation of study treatment or any study procedures.

      Study design

      This randomized, double-blind, multiple ascending dose, placebo-controlled phase 1 study in patients with OA of the knee was conducted in one center in Florida, United States, between September 2012 and October 2013 (ClinicalTrials.gov identifier: NCT01668511). Thirty-six patients were equally randomized to four dose cohorts. Cohorts 1–3 received four SC injections of ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week (EOW) on days 1, 15, 29, and 43; cohort 4 received three SC injections of ABT-981 (3 mg/kg) or placebo every 4 weeks (E4W) on days 1, 29, and 57. Dose escalation for subsequent cohorts took place a minimum of 2 weeks after the last dose of study drug and after safety, tolerability, and PK assessments were reviewed for the preceding cohort. Patients were confined to the study site starting 1 day before dosing and supervised for approximately 48 h for each study drug administration. Patients were asked to return for assessments throughout the study until day 113 (cohorts 1–3) or day 127 (cohort 4).
      During confinement, participants received a standardized diet and water. Over-the-counter or prescription medications and nutritional supplements were to be safely discontinued for ≥5 half-lives or 14 days (whichever was longer) before the first ABT-981 or placebo dose. Patients could take acetaminophen for acute episodes of pain during the study (≤3 days per week, ≤3000 mg/day).

      Study participants

      Eligible patients were 40–70 years old and had a body mass index (BMI) of 18–35 kg/m2 at screening; they were required to have symptomatic OA of the knee for ≥3 months (with pain intensity of the study joint between 40 and 80 mm on a 100-mm visual analog scale [VAS]) and radiographic OA of the knee (Kellgren–Lawrence [K–L] grade 1, 2, or 3 confirmed by a radiologist). Patients were to be in general good health other than OA of the knee. Exclusion criteria included prior exposure to anti-IL-1 treatment or other investigational drug within 30 days or five half-lives of the drug (whichever was longer), history of persistent chronic or active infection(s), and absolute neutrophil count (ANC) < 2000 cells/mm3, K–L grade 4 radiographic OA, inflammatory arthritis, and arthritis other than OA involving the knee joint.
      Randomization was via computer-assigned unique consecutive numbers for each of the four cohorts generated at AbbVie before study initiation. Patients within a cohort were randomized 7:2 to receive ABT-981 or matching placebo. Except an unblinded pharmacist, all study site personnel and patients remained blinded to the treatment.

      Endpoints

      The primary objectives were to evaluate safety, tolerability, and PK of ABT-981 (detailed PK results reported elsewhere
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      Pharmacokinetics and tolerability of a dual variable domain immunoglobulin ABT-981 against IL-1α and IL-1β in healthy subjects and patients with osteoarthritis of the knee.
      ). Secondary and exploratory objectives included assessment of immunogenicity, PD variables and biomarkers, and patient-reported outcomes (PROs).
      Safety and tolerability were assessed through day 113 in the EOW groups and through day 127 in the E4W group. Adverse events (AEs) were coded using the current Medical Dictionary for Regulatory Activities v16.0. If applicable, severity of AEs was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.
      Biomarkers examined in this study included ANC and the following in serum: target engagement biomarkers (IL-1α/β), inflammation biomarkers (high-sensitivity C-reactive protein [hsCRP], vascular endothelial growth factor [VEGF], matrix metalloproteinase [MMP]-9, and IL-1Ra), and bone/cartilage biomarkers (aggrecan [AGN] x1, MMP-derived type 1 collagen [C1M], type 2 collagen [C2M], and type 3 collagen [C3M], MMP-degraded CRP [CRPM], collagen C-telopeptide [CTX]-I, cartilage oligomeric matrix protein [COMP], and MMP-degraded and citrullinated vimentin [VICM]). A urine bone/cartilage biomarker panel included CTX-I, CTX-II, type II collagen neoepitope (TIINE-5OH), and creatinine (all values normalized to creatinine). Serum protein concentrations of IL-1α/β were analyzed using validated immuno-polymerase chain reaction assays (Chimera Biotec GmbH, Dortmund, Germany). Biomarkers were measured by BioClinica Molecular Marker Lab (Lyon, France), AbbVie Deutschland GmbH & Co. KG (Ludwigshafen, Germany), AbbVie ABR (Redwood City, CA, USA), and Chimera Biotec (Dortmund, Germany). The bone/cartilage biomarker panel was analyzed using validated enzyme-linked immunosorbent assays (Nordic Bioscience, Herlev, Denmark, or Roche Diagnostics, Indianapolis, IN, USA) performed under standard conditions according to manufacturer specifications. A panel of peripheral blood mRNA biomarkers were examined (Asuragen, Austin, TX, USA). Total ribonucleic acid (widely understood) (RNA) isolated from PAXgene was converted to complementary deoxyribonucleic acid (widely understood) (DNA) for quantitative polymerase chain reaction (PCR) detection of a panel of mRNAs, including IL-1α, IL-1β, and IL-1Ra.
      Whole blood (after a minimum 12-h fast) and urine samples were collected (pre-dose on dosing days) from EOW-group patients on days 1, 5, 15, 19, 29, 33, 43, 47, 57, and 113 and E4W-group patients on days 1, 8, 15, 29, 43, 57, 66, 85, and 127. Peripheral blood was collected in PAXgene RNA tubes (Qiagen, Venlo, Netherlands) on days 1, 5, 57, and 113 (EOW groups only).
      Immunogenicity was assessed via measurement of serum antidrug antibodies (ADAs) using a validated bridging electrochemiluminescent immunoassay. Samples were considered positive for ADA when the mean signal was greater than the calculated screening cut point and the suppression in the confirmatory assay was ≥19.13% when spiked with 10 μg/mL of ABT-981.
      Although the study was not designed to assess efficacy, PROs were measured for an exploratory analysis of the patients' OA symptoms and response to treatment. Patient's assessment of pain in the study joint was evaluated using a 100-mm VAS (0 = no pain; 100 = the worst pain). In addition, the Western Ontario and McMaster Universities Arthritis Index
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      The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation.
      , which measures changes in physical functioning, were assessed.

      Statistical analysis

      With a planned enrollment of seven patients treated with ABT-981 in each group, the probability of not observing a given AE with a true incidence rate of 0.5 was 0.008.
      Demographic and PD variables were summarized using descriptive statistics with a breakdown by regimen defined by dose level (with placebo considered as a dose level) and dosing frequency. The number and percentage (with Clopper–Pearson 95% exact confidence intervals (CIs)) of participants reporting treatment-emergent AEs were tabulated. Placebo data from EOW groups were pooled.
      Patients who received ≥1 dose of ABT-981 or placebo were included in the biomarker analyses. When nearly all levels were quantifiable (e.g., for hsCRP), a repeated-measures analysis using a linear mixed effect model was performed after the start of dosing on day 1 (days 1–113 for the pooled placebo EOW and ABT-981 EOW groups; days 1–127 for the ABT-981 E4W group). The pooled placebo group did not include the two E4W placebo patients because of their small sample size. Changes in logarithm-transformed biomarker measurements from the baseline (day 1) were analyzed as the response variable in the repeated-measures model, which included the log-transformed baseline measurement as a covariate, the time effect, the treatment group effect, and the interaction effect between time and treatment groups. The compound symmetry structure for the variance/covariance matrix for the measurements from each patient was used, based on the selection among possible structures using the Akaike information criterion. Based on the least-square means obtained from the repeated-measures model, differences between each ABT-981 treatment group and the placebo group were averaged over time and compared. Two time spans were assessed: (1) the whole period after the start of dosing (days 5–113 for EOW groups and days 5–127 for the E4W group) and (2) during the treatment window (days 5–57 for all groups). All tests were performed at a significance level of 0.05 (Bonferroni adjusted P values). The Bonferroni multiplicity adjustment was assessed for comparisons of multiple treatment groups vs placebo. Multiplicity adjustment was not made on multiple biomarkers because they were considered exploratory endpoints; and adjustment was not necessary for multiple visits because comparisons were made on differences averaged over the visits. Mean percentage changes from baseline for each treatment group and visit were calculated after transforming the least-square means from the mixed model back to the original scale and were visualized in figures.
      To evaluate the relationship between ABT-981 serum concentrations and baseline-normalized changes in ANC, data were pooled from all study participants and fit to an inhibitory effect model defined by maximum inhibition potential (Imax) and half-maximal inhibitory concentration (IC50) using Phoenix WinNonlin v6.3 (Certara, Princeton, NJ, USA). Individual ANC was normalized to levels before study drug administration on day 1 and reported as percentage change from baseline.
      For efficacy endpoints, the least-squares mean change from baseline in patient's assessment of VAS pain was analyzed for the EOW groups. The statistical analyses were conducted using SAS® v9.1 (SAS Institute Inc., Cary, NC, USA) and the repeated-measures analyses were conducted using SAS PROC GLIMMIX. The degrees of freedom for the repeated-measures mixed model were calculated by the Kenwood and Roger approximation (in SAS PROC GLIMMIX, option DDFM = KR).

      Results

      A total of 36 patients with OA of the knee were dosed (ABT-981, n = 28; placebo, n = 8) and 31 patients (86%) completed the study (Fig. 1). Most patients were female and all were white (Table I). There were no significant differences between groups in baseline biomarkers; the mean baseline serum concentrations of hsCRP indicated normal levels (<3 mg/dL) to weak systemic inflammation in this study population, similar to levels reported previously in OA patients (Table II).
      Fig. 1
      Fig. 1Disposition of patients. Study enrolled 36 patients with OA of the knee. Four patients discontinued the study drug (after one or two doses of ABT-981 or three doses of placebo) but continued study visits; one patient discontinued the study after one dose of ABT-981.
      Table IBaseline demographic characteristics
      Pooled placebo EOW (n = 6)ABT-981 0.3 mg/kg EOW (n = 7)ABT-981 1 mg/kg EOW (n = 7)ABT-981 3 mg/kg EOW (n = 7)Placebo E4W (n = 2)ABT-981 3 mg/kg E4W (n = 7)
      Age, years60.0 ± 5.961.3 ± 5.162.6 ± 3.661.4 ± 5.055.0 ± 1.460.0 ± 6.1
      BMI, kg/m228.4 ± 2.327.6 ± 4.426.4 ± 1.127.3 ± 2.928.7 ± 0.529.3 ± 3.0
      Weight, kg73.3 ± 5.974.4 ± 13.971.2 ± 9.966.2 ± 8.667.2 ± 1.270.6 ± 6.0
      Height, cm161 ± 4164 ± 7164 ± 9156 ± 4153 ± 0155 ± 3
      Female5 (83.3)5 (71.4)5 (71.4)7 (100)2 (100)7 (100)
      White6 (100)7 (100)7 (100)7 (100)2 (100)7 (100)
      Data presented as mean ± SD or n (%).
      Table IIBaseline biomarker values: geometric mean and coefficient of variation (CV) (%)
      Biomarker, geometric mean
      The geometric mean is obtained by transforming the arithmetic mean of log-transformed values back to the original scale. It is appropriate to use the geometric mean as an average metric for the measurements of biomarkers such as protein and mRNA, which are log-normally distributed.
      (CV%)
      Placebo EOW (n = 6)ABT-981 0.3 mg/kg EOW (n = 7)ABT-981 1 mg/kg EOW (n = 7)ABT-981 3 mg/kg EOW (n = 7)Placebo E4W (n = 2)ABT-981 3 mg/kg E4W (n = 7)All patients (n = 36)
      AGNx1, ng/mL4.9 (116)3.1 (179)2.2 (184)2.0 (74)2.2 (206)3.4 (202)2.9 (165)
      C1M, ng/mL59.2 (39)58.4 (91)52.9 (32)70.8 (77)49.6 (30)73.2 (45)61.7 (54)
      C2M, ng/mL0.20 (40)0.20 (48)0.17 (52)0.18 (65)0.15 (190)0.28 (75)0.18 (59)
      C3M, ng/mL35.6 (34)35.8 (21)36 (18)33.9 (31)37.2 (15)33.1 (10)35 (22)
      COMP, U/L10.2 (15)8.5 (20)10.2 (23)11.2 (19)9.9 (21)10.8 (14)10.1 (19)
      CRPM, ng/mL12.5 (32)14.3 (19)13.9 (14)11.6 (54)14.2 (6)11.9 (21)12.9 (28)
      CTX-I, ng/mL0.39 (46)0.33 (60)0.30 (65)0.33 (71)0.54 (1)0.35 (65)0.35 (56)
      hsCRP, mg/L2.7 (145)2.7 (127)2.8 (123)5 (162)0.95 (48)2.6 (158)2.8 (148)
      IL-1α, pg/mL6.3 (111)4.4 (104)9.9 (203)7.6 (58)14.9 (54)12.1 (68)7.9 (113)
      IL-1β, pg/mL0.69 (203)0.31 (97)0.60 (113)0.42 (31)0.19 (59)0.51 (128)0.48 (117)
      IL-1RA, pg/mL485 (29)469 (41)434 (30)413 (87)445 (18)389 (25)436 (41)
      MMP-9, ng/mL309 (25)413 (19)391 (37)335 (28)480 (15)445 (49)383 (33)
      Urine creatinine, mg/L487 (42)612 (35)593 (42)627 (35)773 (18)599 (26)593 (33)
      Urine CTX-I, ng/mL2.1 (61)1.9 (104)2.2 (106)2.3 (109)7.2 (22)2.3 (122)2.3 (99)
      Urine CTX-II, ng/mL1.0 (36)1.0 (34)1.3 (76)1.6 (41)1.9 (57)1.1 (43)1.2 (48)
      Urine TIINE-5OH, ng/mL0.37 (56)0.43 (52)0.46 (53)0.41 (74)0.56 (95)0.44 (44)0.43 (52)
      VEGF, pg/mL32.4 (88)22.8 (44)35.3 (145)42.5 (111)19.0 (33)24.6 (52)29.8 (88)
      VICM, ng/mL1.8 (79)2.9 (65)2.2 (69)2.6 (53)18.6 (110)3.0 (89)2.8 (90)
      IL-1RA, IL-1 receptor agonist.
      The geometric mean is obtained by transforming the arithmetic mean of log-transformed values back to the original scale. It is appropriate to use the geometric mean as an average metric for the measurements of biomarkers such as protein and mRNA, which are log-normally distributed.

      Safety

      Fifteen patients receiving ABT-981 (54%) and five receiving placebo (63%) had ≥1 treatment-emergent AE during the study (Table III). The most common AE reported in patients who received ABT-981 vs placebo was injection site erythema (n = 4 [14%] vs n = 0), reported in two patients each in the 3.0-mg/kg EOW and E4W groups. The only other AE that occurred in >1 patient was headache (one patient each in the 0.3-mg/kg and 3.0-mg/kg EOW groups). Four patients receiving ABT-981 discontinued the study because of AEs (Table III). Six of 28 patients receiving ABT-981 and one of eight patients receiving placebo had an AE considered by the investigator to have a reasonable possibility of being study drug related. All AEs were mild or moderate in severity with the exception of the one serious grade 3 AE of bronchitis and viral infection. No difference was noted between the incidence of total infections among ABT-981- and placebo-treated patients (Table III). No other serious AEs (SAEs) or deaths were reported, and no clinically significant values for hematology, serum chemistry, urinalysis, vital signs, or electrocardiograms ECGs) occurred in this study.
      Table IIIIncidence of treatment-emergent adverse events
      AE, n (%[95% CI])EOW dosingE4W dosingABT-981 total (n = 28)Placebo total (n = 8)
      ABT-981 (n = 21)Placebo (n = 6)ABT-981 (n = 7)Placebo (n = 2)
      Any AE11 (52.4 [29.8–74.3])4 (66.7 [22.3–95.7])4 (57.1 [18.4–90.1])1 (50.0 [1.3–98.7])15 (53.6 [33.9–72.5])5 (62.5 [24.5–91.5])
      Any SAE
      Includes one event each of bronchitis and viral infection in a woman aged 55 years in the ABT-981 3 mg/kg EOW dose group on day 5 after the initial dose of study drug. The patient was hospitalized from day 15 to day 17, and the event was considered resolved on day 20. The patient discontinued study drug after the initial dose. A transient grade 2 AE of neutropenia was also reported for this patient. The neutrophil count was 3000/mm3 at baseline and 1000/mm3 on day 10; the neutrophil count returned to normal (5800/mm3) by day 13.
      1 (4.8 [0.1–23.8])0 (0 [0–45.9])0 (0 [0–41.0])0 (0 [0–84.2])1 (3.6 [0.1–18.3])0 (0 [0–36.9])
      AEs leading to discontinuation
      For ABT-981, includes nonserious events of hypertension (0.3 mg/kg EOW), atrial fibrillation (1 mg/kg EOW), and diarrhea (3 mg/kg EOW), all assessed as unrelated to ABT-981, and one serious event of bronchitis/viral infection (3 mg/kg EOW), assessed as reasonably possibly related to ABT-981. For placebo (EOW), includes infected insect bite.
      4 (19.0 [5.4–41.9])1 (16.7 [0.4–64.1])0 (0 [0–41.0])0 (0 [0–84.2])4 (14.3 [4.0–32.7])1 (12.5 [0.3–52.7])
      Any infection
      By system organ class; includes one event each of bronchitis, nasopharyngitis, urinary tract infection and viral infection in the ABT-981 group and one event each of infected bite and upper respiratory tract infection in the placebo group.
      3 (14.3 [3.0–36.3])2 (33.3 [4.3–77.7])0 (0 [0–41.0])0 (0 [0–84.2])3 (10.7 [2.3–28.2])2 (25.0 [3.2–65.1])
      AEs in ≥2 participants in overall ABT-981 or placebo groups
       Injection site erythema2 (9.5 [1.2–30.4])0 (0 [0–45.9])2 (28.6 [3.7–71.0])0 (0 [0–84.2])4 (14.3 [4.0–32.7])0 (0 [0–36.9])
       Headache2 (9.5 [1.2–30.4])0 (0 [0–45.9])0 (0 [0–41.0])0 (0 [0–84.2])2 (7.1 [0.9–23.5])0 (0 [0–36.9])
      Includes one event each of bronchitis and viral infection in a woman aged 55 years in the ABT-981 3 mg/kg EOW dose group on day 5 after the initial dose of study drug. The patient was hospitalized from day 15 to day 17, and the event was considered resolved on day 20. The patient discontinued study drug after the initial dose. A transient grade 2 AE of neutropenia was also reported for this patient. The neutrophil count was 3000/mm3 at baseline and 1000/mm3 on day 10; the neutrophil count returned to normal (5800/mm3) by day 13.
      For ABT-981, includes nonserious events of hypertension (0.3 mg/kg EOW), atrial fibrillation (1 mg/kg EOW), and diarrhea (3 mg/kg EOW), all assessed as unrelated to ABT-981, and one serious event of bronchitis/viral infection (3 mg/kg EOW), assessed as reasonably possibly related to ABT-981. For placebo (EOW), includes infected insect bite.
      By system organ class; includes one event each of bronchitis, nasopharyngitis, urinary tract infection and viral infection in the ABT-981 group and one event each of infected bite and upper respiratory tract infection in the placebo group.

      Neutropenia adverse events

      Two patients (placebo, n = 1; ABT-981, n = 1) had postbaseline ANC < 1500 (but ≥1000) cells/mm3. The patient on ABT-981 (3 mg/kg EOW) had transient grade 2 neutropenia (ANC of 1000 cells/mm3) reported as an AE on day 10 after one dose of ABT-981; ANC returned to normal at day 13. This patient was hospitalized on day 15 due to grade 3 serious bronchitis/viral infection.

      Immunogenicity

      Measurable ADA titers were found 37% (13/35) of patients (ABT-981, n = 12; placebo, n = 1). The magnitude of ADA response was low, with most patients having titers below 90; only two patients had titer values ≥ 270. There was no apparent effect of ADAs on ABT-981 exposure
      • Kosloski M.P.
      • Goss S.
      • Wang S.X.
      • Liu J.
      • Loebbert R.
      • Medema J.K.
      • et al.
      Pharmacokinetics and tolerability of a dual variable domain immunoglobulin ABT-981 against IL-1α and IL-1β in healthy subjects and patients with osteoarthritis of the knee.
      and there was no association observed between incidence of ADA and the incidence or severity of any reported AEs.

      Target engagement markers

      The average serum IL-1α level was 7.1 pg/mL at baseline. In all four ABT-981 treatment groups, mean serum IL-1α levels significantly decreased by 71–93% from baseline to day 57 [P < 0.001; Fig. 2(A)]. These decreases were maintained until day 113 in the 1-mg/kg (P < 0.001, −70%) and 3-mg/kg groups (P < 0.05, −61%) and day 127 in the 3-mg/kg E4W group (P < 0.01, −62%); the IL-1α level in the 0.3-mg/kg group, however, recovered to a near-baseline level by day 113. Compared with the placebo group, mean percentage change from baseline in serum IL-1α levels in all three ABT-981 EOW groups were significantly decreased through days 57 and 113 (all P < 0.0001) and in the E4W group through days 57 and 127 (both P < 0.001).
      Fig. 2
      Fig. 2Mean percentage change from baseline in IL-1α (A) and IL-1β (B). Arrows indicate the days of ABT-981 injection; apatients received four injections of ABT-981 (0.3, 1, or 3 mg/kg) or placebo EOW on days 1, 15, 29, and 43 in cohorts 1–3, and bthree injections of ABT-981 (3 mg/kg) E4W on days 1, 29, and 57 in cohort 4. Patients who received placebo E4W (n = 2) were excluded from the analysis. Follow-up period was until day 113 (cohorts 1–3) or day 127 (cohort 4). Error bars represent standard error.
      The average serum IL-1β level was 0.46 pg/mL at baseline. In all the ABT-981 groups, serum IL-1β levels decreased from baseline to day 57 (between 39% and 87%); this was significant in the 3-mg/kg group at day 57 [P < 0.0001; Fig. 2(B)]. Significant decreases were maintained until day 47 in the 1-mg/kg group (−66%; P < 0.05) and day 113 in the 3-mg/kg group (−82%, P < 0.0001). At day 127 in the 3-mg/kg E4W group, the decrease from baseline was −48%; at day 113 in the 0.3-mg/kg group, IL-1β levels were closest to baseline levels (−25%). Compared with the placebo group, mean percentage change from baseline in serum IL-1β levels were significantly decreased through days 57 and 113 in the 1- and 3-mg/kg EOW groups (all P < 0.05). IL-1Ra levels showed no significant trends in response to ABT-981 treatment.
      Peripheral blood cell IL-1α mRNA was undetectable by quantitative PCR (cycle threshold > 35) in all dose groups and at all time points tested. At day 5, there was a significant decrease in IL-1β mRNA expression in the 3-mg/kg group (P < 0.001) and a downward trend in the 1-mg/kg group (P = 0.092). IL-1Ra mRNA expression levels did not show dose-dependent changes in the treatment groups.

      Anti-inflammatory markers

      There was a significant mean percentage decrease in ANC in the ABT-981 3-mg/kg EOW (P < 0.001) and 3-mg/kg E4W (P < 0.0001) groups compared with pooled placebo through day 57; these differences were maintained through day 113 (3-mg/kg EOW group; P < 0.01) and day 127 (3-mg/kg E4W group; P < 0.0001; Fig. 3). Across participants, decreases in ANC demonstrated a clear ABT-981 concentration-dependent response (data not shown). Model fitted parameters estimates (standard error (±SE)) for Imax were 33.6% ± 8.1% and for IC50, 3.74 ± 2.25 μg/mL.
      Fig. 3
      Fig. 3Mean percentage change from baseline in ANC vs study day. Arrows indicate the days of ABT-981 injection, as described for . Error bars represent standard error.
      Following treatment with ABT-981, mean absolute serum concentrations of hsCRP decreased continuously through week 2 irrespective of dose level or dosage interval [Fig. 4(A)]. Although the hsCRP values were highly variable across the ABT-981 groups (e.g., percentage change from baseline ranged from −90% to 48% at day 15), the percentage change from baseline in the ABT-981 groups compared with the pooled placebo group were significant through days 57 and 113 in the 3-mg/kg EOW group (P < 0.01 and P < 0.05, respectively) and through days 57 and 127 in the 3-mg/kg E4W group (both P < 0.0001). Mean hsCRP levels remained below baseline at the final assessment on day 113 (EOW group) or day 127 (E4W group).
      Fig. 4
      Fig. 4Mean percentage change from baseline in (A) hsCRP, (B) C1M, (C) C3M, and (D) CRPM. Arrows indicate the days of ABT-981 injection, as described for . Error bars represent standard error.
      Clear, dose-dependent decreases following ABT-981 treatment were observed in the mean percentage changes from baseline in C1M [Fig. 4(B)], C3M [Fig. 4(C)], and CRPM [Fig. 4(D)] in all groups. Generally, decreases in C1M, C3M, and CRPM concentrations were observed as soon as 5–8 days after the first ABT-981 dose, continued to decrease up to day 15, and then remained steady during the remainder of the dosing period. Following the end of dosing, concentrations remained below baseline levels through approximately five half-lives of ABT-981. Compared with the pooled EOW placebo group, the percentage changes with ABT-981 were significant through days 57 and 113 for C1M (both P < 0.05) in the 3-mg/kg EOW group and through days 57 and 127 in the 3-mg E4W group (both P < 0.01), through days 57 and 127 for C3M in the 3-mg E4W group (both P < 0.05), and through day 127 for CRPM in the 3-mg E4W group (P < 0.05). C2M did not exhibit a clear trend of change from baseline after ABT-981 treatment (data not shown). Other markers, including VEGF, MMP-9, AGNx1, serum CTX-I, COMP, VICM, urine CTX-I, urine CTX-II, and TIINE-5OH, exhibited no clear trend of change with ABT-981 treatment.

      Efficacy assessments

      Patient's assessment of pain (Fig. 5) and other PROs (data not shown) improved, reflected as decreases from baseline, throughout the duration of the study for all dose groups, including placebo. No significant differences were observed between any of the ABT-981 dose groups and placebo.
      Fig. 5
      Fig. 5Least-squares mean change from baseline in the VAS patient's assessment of pain. Arrows indicate the days of ABT-981 injection, as described for . Cohort 4 data (E4W dosing) are not shown due to the different assessment schedule.

      Discussion

      This phase 1 multiple ascending dose trial demonstrated that ABT-981 was well tolerated and induced significant, dose-dependent decreases in serum concentrations of target engagement markers (IL-1α and IL-1β) and other biomarkers of inflammation and joint degradation, including hsCRP, C1M, C3M, and CRPM, compared with placebo. These findings suggest that, through simultaneous inhibition of IL-1α and IL-1β, ABT-981 significantly reduces serum hsCRP levels (indicating a reduction in systemic inflammation) and C1M levels (indicating a dampening of inflammation-mediated joint destruction). Additionally, the observed serum C3M and CRPM decreases suggest that ABT-981 may ameliorate inflammation-mediated tissue destruction and chronic tissue inflammation with long-term administration in patients with inflammation-driven OA.
      Overall, ABT-981 was well tolerated with no observed dose-limiting toxicities. Injection site erythema was the most common AE in patients who received SC injection of ABT-981. Other molecules targeting the IL-1 pathway have reported safety information, including canakinumab, a human anti-IL-1β monoclonal antibody, and anakinra, a recombinant IL-1R antagonist
      • Chevalier X.
      • Goupille P.
      • Beaulieu A.D.
      • Burch F.X.
      • Bensen W.G.
      • Conrozier T.
      • et al.
      Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.
      • Chakraborty A.
      • Tannenbaum S.
      • Rordorf C.
      • Lowe P.J.
      • Floch D.
      • Gram H.
      • et al.
      Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1beta monoclonal antibody.
      • Cohen S.B.
      • Moreland L.W.
      • Cush J.J.
      • Greenwald M.W.
      • Block S.
      • Shergy W.J.
      • et al.
      A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.
      . The use of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS) was associated with more frequent infections. Similarly, an increased rate of infection was observed for patients with systemic juvenile idiopathic arthritis treated with canakinumab
      • Ruperto N.
      • Brunner H.I.
      • Quartier P.
      • Constantin T.
      • Wulffraat N.
      • Horneff G.
      • et al.
      Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.
      . Anakinra was evaluated in patients with OA and rheumatoid arthritis (RA)
      • Chevalier X.
      • Goupille P.
      • Beaulieu A.D.
      • Burch F.X.
      • Bensen W.G.
      • Conrozier T.
      • et al.
      Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.
      • Cohen S.B.
      • Moreland L.W.
      • Cush J.J.
      • Greenwald M.W.
      • Block S.
      • Shergy W.J.
      • et al.
      A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.
      . In patients with OA, after a single intraarticular injection of anakinra, approximately 13% of patients reported infections, largely with the higher 150-mg dose, compared with only 6% of placebo-treated patients
      • Chevalier X.
      • Goupille P.
      • Beaulieu A.D.
      • Burch F.X.
      • Bensen W.G.
      • Conrozier T.
      • et al.
      Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.
      . In patients with RA who received single daily SC injections of anakinra (100 mg) and concurrent methotrexate (10–25 mg weekly) for 24 weeks, there were no differences in the rate of total infectious events between anakinra and placebo
      • Cohen S.B.
      • Moreland L.W.
      • Cush J.J.
      • Greenwald M.W.
      • Block S.
      • Shergy W.J.
      • et al.
      A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.
      ; however, an increased incidence of serious infections (2%) vs placebo (1%) was observed
      • KINERET® (anakinra)
      Prescribing Information.
      • KINERET® (anakinra)
      Summary of Product Characteristics.
      . In this study, no difference in the incidence of infections in the ABT-981 vs placebo groups was observed (Table III); however, the sample size and duration of exposure were limited.
      Administration of ABT-981 was associated with decreases in ANC as early as 3 days after dosing, with the greatest changes from baseline observed with 3-mg/kg dosing. Decreased neutrophil counts have been previously reported with administration of products targeting the IL-1 pathway
      • Cohen S.B.
      • Proudman S.
      • Kivitz A.J.
      • Burch F.X.
      • Donohue J.P.
      • Burstein D.
      • et al.
      A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee.
      • Emsley H.C.
      • Smith C.J.
      • Georgiou R.F.
      • Vail A.
      • Hopkins S.J.
      • Rothwell N.J.
      • et al.
      A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients.
      . IL-1 may inhibit neutrophil apoptosis through IL-6 induction
      • Dinarello C.A.
      Biologic basis for interleukin-1 in disease.
      • Asensi V.
      • Valle E.
      • Meana A.
      • Fierer J.
      • Celada A.
      • Alvarez V.
      • et al.
      In vivo interleukin-6 protects neutrophils from apoptosis in osteomyelitis.
      and stimulate bone marrow granulopoiesis through induction of granulocyte colony stimulating factor (G-CSF)
      • Lawlor K.E.
      • Campbell I.K.
      • Metcalf D.
      • O'Donnell K.
      • van Nieuwenhuijze A.
      • Roberts A.W.
      • et al.
      Critical role for granulocyte colony-stimulating factor in inflammatory arthritis.
      and granulocyte-macrophage CSF
      • Manz M.G.
      • Boettcher S.
      Emergency granulopoiesis.
      . In the placebo-controlled RA studies, 8% of patients receiving anakinra had decreases in neutrophil counts of at least one toxicity grade compared with 2% in the placebo group
      • KINERET® (anakinra)
      Prescribing Information.
      . The effect of ABT-981 administration on ANC will continue to be closely monitored in future studies, including assessing risk factors for neutropenia (e.g., low baseline ANC).
      Decreased levels of hsCRP, C1M, C3M, and CRPM occurred within 4 days of the first ABT-981 dose and, once a nadir was reached, remained suppressed throughout the duration of ABT-981 dosing. The final observations took place 70 days after the last dose of ABT-981 for all groups, when ABT-981 serum concentrations were ≤5% of maximum levels
      • Kosloski M.P.
      • Goss S.
      • Wang S.X.
      • Liu J.
      • Loebbert R.
      • Medema J.K.
      • et al.
      Pharmacokinetics and tolerability of a dual variable domain immunoglobulin ABT-981 against IL-1α and IL-1β in healthy subjects and patients with osteoarthritis of the knee.
      , yet many of the biomarkers among groups had not returned to pre-dose baseline levels. This slow rebound of biomarker levels after termination of ABT-981 treatment suggests that alleviation of proinflammatory cytokines, such as IL-1α and IL-1β, has acute and prolonged beneficial effects on tissue turnover.
      No difference between ABT-981 and placebo was noted in PROs of pain and physical function; longer studies in larger populations are needed. Other limitations of this phase 1 study included low patient numbers with limited disease activity, which decreases the ability to see substantial changes detectable by biomarkers (a “ceiling effect”), as well as the exploratory nature of the biomarkers investigation. Current phase 2 studies will address these limitations and later studies will address whether ABT-981 treatment also results in symptomatic and/or structural benefit for patients with OA. The current exploratory analysis of biomarkers may aid the identification of patients with a high response profile, enabling a personalized health care approach for a subpopulation of patients with inflammatory-driven OA.
      For patients with OA, therapeutic choices are limited and there is a specific need for disease-modifying treatments that are safe to administer for long-term management in an older patient population
      • Hochberg M.C.
      • Altman R.D.
      • April K.T.
      • Benkhalti M.
      • Guyatt G.
      • McGowan J.
      • et al.
      American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee.
      . Targeting the IL-1 pathway is appropriate because of the key role IL-1 plays in the pathophysiology of OA
      • Jotanovic Z.
      • Mihelic R.
      • Sestan B.
      • Dembic Z.
      Role of interleukin-1 inhibitors in osteoarthritis: an evidence-based review.
      . Based on our findings, ABT-981 is a viable candidate for further research into the treatment of OA; patients presenting with significant inflammation and/or rapid disease progression may be the most appropriate candidates for treatment. Subsequent phase 2 studies of ABT-981 in knee OA and erosive hand OA focused on patients with clinical or imaging evidence of synovitis/effusion
      • Kloppenburg M.
      • Peterfy C.
      • Haugen I.K.
      • Kroon F.
      • Chen S.
      • Wang L.
      • et al.
      OP0168 A phase 2a, placebo-controlled, randomized study of ABT-981, an anti-interleukin-1ALPHA and -1BETA dual variable domain immunoglobulin, to treat erosive hand osteoarthritis (EHOA).
      • Fleischmann R.
      • Bliddal H.
      • Blanco F.J.
      • Schnitzer T.J.
      • Peterfy C.
      • Chen S.
      • et al.
      Safety and efficacy of ABT-981, an anti-interleukin-1α/β dual variable domain (DVD) immunoglobulin, in subjects with knee osteoarthritis: results from the randomized, double-blind, placebo-controlled, parallel-group phase 2 trial.
      .
      In conclusion, treatment of patients with knee OA with ABT-981 reduced serum IL-1α and IL-1β concentrations and was associated with sustained and significant suppression of tissue turnover markers that are associated with an inflammatory phenotype in OA. The safety and tolerability profile in conjunction with its effects on inflammatory biomarkers supports further investigation of ABT-981 in patients with OA.

      Authors' contribution

      The authors and AbbVie scientists designed the studies and analyzed and interpreted the data. All authors have made substantial contributions: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be submitted. JKM (email: [email protected] ) takes responsibility for the integrity of the work as whole, from inception to finished article.

      Conflict of interest

      SXW is a former AbbVie employee and may own stock/options in AbbVie. SBA and MA have received research funding from AbbVie and have filed a patent for the use of IL-1 and tumor necrosis factor as markers for symptomatic knee OA progression. MAK is a full-time employee of Nordic Bioscience, a company engaged in biomarker research, development, and commercialization. RAP has received research grants from AbbVie to the University of Miami. CJL is a consultant for Heel Pharmacy and Pfizer and has received research grants from AbbVie to the University of Miami. MPK, FH, PJ, MJS, BAH, and JKM are employed by AbbVie and may own stock/options in AbbVie.

      Role of the funding source

      AbbVie was involved in the study design and in collection, analysis, and interpretation of data. AbbVie funded the research and medical writing support. AbbVie reviewed and approved the manuscript; the authors maintained control over the final content.

      Acknowledgments

      The authors would like to thank Martin Okun (Fort Healthcare, Fort Atkinson, WI, USA) for his contribution to the development of the manuscript content and Jia Liu, PhD, AbbVie Inc., for her contributions to the statistical analysis and manuscript. Editorial and medical writing support was provided by Maria Hovenden, PhD, of Complete Publication Solutions, LLC (North Wales, PA, USA), which was funded by AbbVie. AbbVie and the authors thank the patients who participated in the clinical trial and all study investigators for their contributions.

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