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)

Abstract

BackgroundNo approved OA therapies reduce pain and slow joint damage. Mouse data suggested that inhibiting IL-1α and -1β with ABT-981 would reduce pain and slow structural progression in EHOA.ObjectivesTo test the efficacy and safety of ABT-981 in EHOA.MethodsSubjects with HOA per ACR criteria, ≥3 inflamed IP joints (tender, swollen, or both), hand pain ≥6 (scale 0–10), and ≥1 erosive IP joint on X-ray (Verbruggen-Veys) were randomized to placebo (PBO) or ABT-981 200 mg SC every 2 wk for 26 wk. The primary outcome was AUSCAN hand pain at 16 wk. Subjects had radiographs of both hands and MRI of the index hand at baseline and 26 wk. Both radiographs (Verbruggen-Veys, GUSS™, OARSI, Kellgren-Lawrence [KL]) and MRIs (HOAMRIS) were read by 2 independent central readers. A modified intent-to-treat population (ie, randomized and treated) was analyzed. Continuous efficacy endpoints were assessed using ANCOVA models with treatment and country as main factors and baseline measurements as covariates with LOCF imputation for the primary endpoint.ResultsOf 131 treated subjects (85% women; mean age 66 y), 61/67 randomized to PBO and 49/64 to ABT-981 completed the study; subject characteristics were well matched. AUSCAN pain was not significantly different vs PBO at wk 16 (P=0.39; Table 1, Figure); X-ray data and other endpoints also were not statistically different vs PBO (Table 1). ABT-981 significantly decreased hsCRP, neutrophils, IL-1α, and IL-1β. Immunogenicity had no impact on ABT-981 pharmacokinetics. Besides injection site reactions and neutropenia, ABT-981 was well tolerated and safety was similar vs PBO, with no serious infections (Table 2).Table 1PBOABT-981PBOABT-981 P 1° Endpoint Baseline, mean±SDLS, mean change±SE at Wk 16AUSCAN pain (0–50)39±738±6−10.7±2.4−9.2±2.30.39 2° Endpoints Baseline, mean±SDLS, mean change±SE at Wk 26AUSCAN function (0–90)69±1571±13−14.3±4.2−16.4±4.00.49Tender joints (0–30)12±612±7−4.7±1.2−5.8±1.20.32Swollen joints (0–30)6±66±5−1.8±0.8−2.2±0.90.64X-ray erosive joints (0–16)2±2*3±2*0.26±0.08†0.18±0.08†0.33KL score (0–80)41±1346±130.13±0.190.10±0.190.87OARSI JSN (0–58)28±1032±90.14±0.190.03±0.190.51OARSI osteophytes (0–58)23±1126±100.25±0.150.14±0.160.45HOAMRIS synovitis (sum score; 0–52.5)11±410±40.92±0.480.85±0.510.89HOAMRIS erosive damage (sum score; 0–105)18±917±100.26±0.640.10±0.670.80HOAMRIS BML (sum score, 0–105)7±55±40.11±0.640.44±0.660.60*Verbruggen-Veys, erosive phase (E) + erosive with remodeling (E/R) or†new E or E/R or R.Table 2PBO (n=67)ABT-981 (n=64) Any AE/serious AE, %88/391/3Death, %00Infection/serious infection, %51/041/0Injection site reaction, %1636Neutropenia by NCI CTCAE grade, n G2 (1000 to <1500/mm3)09 G3 (500 to <1000/mm3)03 G4 (<500/mm3)00ConclusionsDespite adequate pharmacodynamics results, targeting IL-1 may be ineffective in EHOA, as ABT-981 did not improve outcomes.AcknowledgementsAbbVie funded the study (NCT02384538); participated in study design, data collection, analysis, and interpretation and in abstract writing, review, and approval; and funded writing ...

2018 update of the EULAR recommendations for the management of hand osteoarthritis

“…However, the 2007 recommendations did not include advice on the use of these drugs, and no evidence was available at that time. Trials investigating the efficacy of hydroxychloroquine,53 69 70 different TNF-inhibitors71–74 and anti-interleukin-1,75 could not demonstrate efficacy of these antirheumatic drugs in patients with hand OA. Trials investigating methotrexate, sulfasalazine or colchicine have not been performed.…”

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

“…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 43,44 .…”

“…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-1a, IL-1b, 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 days1,5,15,19,29,33,43, 47, 57, and 113 and E4W-group patients on days1, 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).…”

Influence of Disease Activity in Rheumatoid Arthritis on Radiographic Progression of Concomitant Interphalangeal Joint Osteoarthritis

“…Similar to findings in RA, bone marrow edema and synovitis are also associated with the radiographic progression of hand OA , indicating that inflammation may participate in its pathogenesis. However, antiinflammatory biologics such as tumor necrosis factor inhibitors or interleukin‐1 inhibitors have demonstrated only minimal effectiveness in treating DIP joint OA . Thus, the role of inflammation on osseous changes in OA of the hand remains unclear.…”