Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Results From a 2-Part, Proof-of-Concept, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Sirukumab, a Human Anti-Interleukin-6 Monoclonal Antibody, in Active Rheumatoid Arthritis Patients Despite Methotrexate Therapy.
Hsu1, Benjamin, Sheng2, Shihong, Smolen3, Josef, Weinblatt4, Michael
Centocor R&D, a division of J&J Pharmaceutical R& D, LLC/Univ. of Pennsylvania, Malvern/Philadelphia, PA
Centocor R&D, a division of Johnson & Johnson Pharmaceutical Research & Development, LLC, Malvern
Medical University of Vienna and Hietzing Hospital, Vienna, Austria
Brigham & Women's Hospital, Boston, MA
IL-6 overproduction is believed to be involved in RA pathogenesis. Sirukumab(formerly CNTO 136) is a human mAb that binds with high affinity to cytokine IL-6. In the proof of concept part (Part A) of a multicenter, randomized, double blind, pbo controlled, ph 2 study, 100mg sirukumab SC q2w were generally well tolerated & efficacious compared with pbo in pts with active RA despite MTX.
The ph2 dose ranging Part B was initiated to determine efficacious & safe sirukumab dose regimens and to describe SC sirukumab PK and PD in active RA pts. In Part B, pts with active RA despite MTX were randomized equally to: (1)pbo q2w at wks 010, then sirukumab 100mg q2w at wks1224; (2)sirukumab 100mg q2w at wks 024; (3)sirukumab 100mg q4w at wks024; (4)sirukumab 50mg q4w at wks024;or (5)sirukumab 25mg q4w at wks024. Primary endpoint was ACR50 response at wk12, compared between each active grp vs pbo. Key secondary endpoints were change from baseline(bsl) in DAS28(CRP) at wk12, serum sirukumab PK and % change from bsl in serum CRP at wk2.
In Part B, 151pts were randomized & treated(table). 85% pts were female, 60% Caucasian, 21% Japanese. At bsl, mean age: 53±11yrs, mean weight: 69±15kg, mean DAS28(CRP): 5.9±0.9, and median serum CRP: 1.7mg/dL. 26(87%) pbo pts crossed over to sirukumab 100mg q2w at wk12. At wk12, sirukumab significantly improved ACR50 response (overall p=0.010) and significantly reduced DAS28 scores (p<0.001, table). Sirukumab PK were linear over the SC dose range of 25100mg. PK parameters were generally consistent between Caucasians& Japanese. Mean serum CRP levels decreased >80% from bsl with sirukumab at wk2 and remained suppressed thru wk24 (table). Thru wk38, AEs occurred more often with sirukumab than pbo (81 vs 67%), including mostly minor infections/infestations (31 vs 13%), GI disorders (19 vs 10%), and injection site reactions (16 vs 3%). AEs of leukopenia (9,13%[1 NCI Grade 3]), neutropenia (5,3%[3 Gr 3]), thrombocytopenia (3,2%[1 Gr 3, 1 Gr 4]), and lymphopenia (2,1%, [1 Gr 3, 1 Gr 4]) were reported with sirukumab. ALT(8 Gr 3, 7%) and AST(1 Gr 3, 1%) elevations not associated with increased bilirubin; and sustained increases from bsl starting at wk2 in total cholesterol (mean sirukumab vs pbo: 19%± 17% vs -5%± 12%) and LDL (20%± 20% vs -4%± 22%) were seen with sirukumab. These lab abnormalities occurred without dose relationship or short term clinical sequelae. SAEs were more common with pbo(4, 13%) than sirukumab(13, 9%); the majority were infections. 1 pt died of unrelated brain aneurysm. 4/136 (3%; 2 100mg q4w, 2 pbo®100mg q2w) evaluable pts had antibodies to sirukumab thru wk38; 3 of these pts were ACR50 responders at wk24, 0 had injection site reactions.
Sirukumab was efficacious & generally well tolerated in pts wi expected to incur 6,475,642 incident cases of symptomatic knee OA over the next decade, with those ages 4564 accounting for 59% of these cases (Figure). Among Americans who were ages 4554 at the beginning of the 1990s, an estimated 412,214 incident cases of knee OA were expected over the subsequent 10 years, resulting in a 10-year cumulative incidence of 1.5%. Among people in the same baseline age group in the 2010s, 2,108,881 incident cases of symptomatic knee OA are expected over the next 10 years, a cumulative incidence of 4.8%. The projected number of 10-year incident cases among those ages 6574 at baseline decreased slightly between the 1990s (1,169,615 cases) and the 2010s (882,997 cases).
Since the early 1990s, the age of onset of physician-diagnosed symptomatic knee OA has shifted dramatically, occurring on average 16 years earlier in life. This trend may reflect temporal changes in the prevalence of OA risk factors, as well as thresholds for patient care-seeking and physician diagnosis of OA. If the current OA incidence trend continues, nearly 6.5 million Americans between the ages of 35 and 84 will be diagnosed with symptomatic knee OA in the next 10 years, with those ages 4564 accounting for more than half of these incident cases. A resulting spike in the utilization of healthcare, specifically total knee replacements, could have a dramatic economic impact and place additional burden on the healthcare system.
To cite this abstract, please use the following information:
Hsu, Benjamin, Sheng, Shihong, Smolen, Josef, Weinblatt, Michael; Results From a 2-Part, Proof-of-Concept, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Sirukumab, a Human Anti-Interleukin-6 Monoclonal Antibody, in Active Rheumatoid Arthritis Patients Despite Methotrexate Therapy. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2631