Richard Newmark

Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: A twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial†

OBJECTIVE RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. METHODS RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. RESULTS At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. CONCLUSION Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass : A Randomized, Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ −2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.

Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.

BACKGROUND We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis. METHODS We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12. RESULTS Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group. CONCLUSIONS Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).

Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates

Objectives To report results of subgroup analyses of bone mineral density (BMD) and bone turnover markers from a randomised, double-blind, placebo-controlled, phase II study of denosumab, an investigational RANKL inhibitor, in patients with rheumatoid arthritis (RA) concurrently receiving treatment with bisphosphonates or glucocorticoids. Methods Patients received subcutaneous placebo (n=75), denosumab 60 mg (n=71) or denosumab 180 mg (n=72) at baseline and 6 months. Assessments included dual x-ray absorptiometry scans of the lumbar spine and hip, and determination of levels of serum type I C-telopeptide (sCTx-I) and serum procollagen 1N-terminal peptide (P1NP). Results Denosumab treatment increased mean lumbar spine and hip BMD and reduced sCTx-I and P1NP compared with placebo through 12 months, regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use. Conclusions This study extends evidence that denosumab increases BMD and reduces bone turnover in patients with RA and may provide a new therapeutic option for reducing systemic bone loss in patients with RA.

Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients

Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores.

The influence of the resolution and contrast on measuring the articular cartilage volume in magnetic resonance images

The progression of OA in patients may be followed by measuring the volume of articular cartilage from MR images. We attempted to determine the reproducibility of volume measurements of articular cartilage made from magnetic resonance images of the knees and the dependence of the reproducibility on image resolution and contrast-to-noise. A fat-suppressed 3D technique was used to generate four image sets with different image resolution. Each patient was imaged twice to obtain image pairs at each resolution. To assess the dependence of reproducibility on noise we generated six image sets for each patient by adding noise to the original images and repeating the comparison. On each image set, the femoral, tibial, and patellar cartilage were outlined by a combination of computer and manual methods, and the images were used to calculate the volume of each cartilage plate. Comparing the coefficient of variance between the volume measurements made from the two visits, the volume measurements made from images with the highest resolution (0.275 x 0.275 x 1.0 mm) had the highest reproducibility. The high resolution images of the tibia and femur had the least partial-volume averaging and, as a result, better defined the boundaries between cartilage and adjacent tissues. A different trend was evident for the patella. For studies of osteoarthritis therapies, we recommend using MR images with the highest possible in-plane spatial resolution to provide the most reproducible volume measurements of knee cartilage.

Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis

Osteoclast‐mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer‐based technique, digital x‐ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA.

A Study to Evaluate the Safety, Tolerability, and Efficacy of Brodalumab in Subjects with Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Objective. To evaluate the efficacy and safety of brodalumab, a human monoclonal antibody inhibitor of the interleukin 17 receptor, in subjects with rheumatoid arthritis (RA). Methods. Patients (n = 252) with inadequate response to methotrexate (MTX) were randomized to receive subcutaneous injections of brodalumab (70 mg, 140 mg, or 210 mg) or placebo. The primary endpoint was the American College of Rheumatology 50% response (ACR50) at Week 12. Results. Demographics and baseline characteristics were generally balanced among treatment groups. At Week 12, ACR50 occurred in 16% (70 mg), 16% (140 mg), 10% (210 mg), and 13% (placebo; all nonsignificant vs placebo) of subjects. No significant treatment effects were observed for the secondary endpoints, including ACR20, ACR70, and Disease Activity Score in 28 joints. Incidences of all adverse events (AE), including serious AE (SAE), were similar across treatment groups. A total of 7 subjects reported SAE during the study (2 in the placebo group and 5 in the brodalumab groups), none of which was treatment related. There was 1 death (cardiopulmonary failure) ∼1 week after the last dose in the 140 mg group. Conclusion. Our study failed to find evidence of meaningful clinical efficacy with brodalumab treatment in subjects with RA who had an inadequate response to MTX. These preliminary results do not support further evaluation of brodalumab as a treatment for RA. Clinicaltrials.gov number: NCT00950989.

OP0175 Two-Year Clinical Response to Brodalumab, An Anti-IL-17 Receptor Antibody, in Patients with Psoriatic Arthritis

Background The interleukin-17 (IL-17) cytokine family plays a key role in the pathogenesis of psoriatic diseases of skin and joint. Brodalumab is a fully human anti–IL-17 receptor monoclonal antibody that blocks the activity of IL-17A, IL-17F, and IL-17A/F. Objectives To evaluate the long-term safety and efficacy of brodalumab in patients with psoriatic arthritis (PsA) in an open-label extension (OLE) of a phase 2 study. Methods In a phase 2 study (NCT01516957), adults (18–75 years) with active PsA were randomized to brodalumab (140 or 280 mg) or placebo at weeks 0, 1, 2, 4, 6, 8, and 10. At week 12, patients could enter an OLE and receive brodalumab 280 mg every 2 weeks (Q2W); a protocol amendment in November 2013 resulted in dosage reduction to 210 mg Q2W for all patients. Outcome measures based on observed data through week 108 included percentages of patients with 20% and 50% improvement in American College of Rheumatology criteria (ACR20 and ACR50) and changes in ACR components and Psoriasis Symptom Inventory (PSI) score. Safety was assessed by adverse events (AEs). Results At baseline, patients were 64% female, 94% white, with mean age and weight of 52 years and 91 kg, respectively. Mean PsA duration was 9 years, 92% were rheumatoid factor negative, and mean PSI score was 12.7. Of 168 patients randomized at baseline, 156 (52 placebo, 53 brodalumab 140 mg, and 51 brodalumab 280 mg) entered the OLE and 109 (70%) remained at week 108. Through week 108, 149 (96%) patients reported an AE and 23 (15%) reported a serious AE (SAE). The most frequent SAEs (n=2 each) were coronary artery disease, cholelithiasis, and cellulitis; the most frequent AEs (≥10% of all patients) were nasopharyngitis, upper respiratory tract infection, psoriatic arthropathy, urinary tract infection, arthralgia, diarrhea, sinusitis, and bronchitis. Exposure-adjusted AE rate (per 100 patient-years) for all patients was 526; exposure-adjusted SAE rate was 14. There were no deaths, 1 laboratory report of neutropenia, 1 case of suicidal ideation, and 11 cases of oral candidiasis. At week 12 of the study (double-blind phase), percentages of patients with ACR20 and ACR50 (non-responder imputation [NRI] analysis) were significantly greater in each brodalumab group than placebo: ACR20 37% (140 mg) and 39% (280 mg) vs 18% (placebo); ACR50 14% and 14% vs 4%. Through week 108 of the OLE, we continued to observe meaningful clinical benefit in ACR20 and ACR50 (Figure 1, as observed). Continued clinical benefit was also demonstrated by NRI analysis. Responses for other outcome measures were also sustained from week 12 to 108 in patients remaining in the OLE. Figure 1 Conclusions Treatment with brodalumab resulted in an acceptable safety profile and meaningful clinical benefit that was maintained through week 108 in patients with PsA in this ongoing OLE. Acknowledgements Jessica Ma (Amgen Inc) provided medical writing support. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen Inc, Biogen Idec, BMS, Celgene, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen Inc, Biogen Idec, BMS, Celgene, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen Inc, Biogen Idec, BMS, Celgene, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, M. Genovese Grant/research support from: Amgen Inc, M. Greenwald Grant/research support from: Amgen Inc, C. Ritchlin Grant/research support from: Amgen Inc, A. Beaulieu Grant/research support from: Amgen Inc, A. Deodhar Grant/research support from: Amgen Inc, R. Newmark Shareholder of: Amgen Inc, Employee of: Amgen Inc, J. Feng Shareholder of: Amgen Inc, Employee of: Amgen Inc, N. Erondu Shareholder of: Amgen Inc, Employee of: Amgen Inc, A. Nirula Shareholder of: Amgen Inc, Employee of: Amgen Inc

AB0752 Efficacy and Safety of Brodalumab over One Year in Patients with Psoriatic Arthritis with and without Prior Exposure to A Biologic

Background New agents with novel mechanisms of action are needed to treat the growing pool of patients with psoriatic arthritis (PsA) who do not respond to, lose response to, or do not tolerate biologics. Patients with PsA who fail one tumor necrosis factor inhibitor (TNFi) often demonstrate reduced treatment response to subsequent TNFis. Objectives To compare the long-term efficacy at weeks 12, 24, and 52 and safety of brodalumab in biologic-naïve vs. biologic-experienced patients with PsA. Methods Patients between 18 – 75 years with active PsA (Classification of Psoriatic Arthritis criteria with ≥3 tender and ≥3 swollen joints) for ≥6 months were randomly assigned (1:1:1) to receive double-blind placebo or brodalumab (140 or 280 mg Q2W); at week 12, patients could enter an open-label extension to receive 280 mg Q2W brodalumab. As observed American College of Rheumatology (ACR) response rates, and changes from baseline in Disease Activity Score (28 joint count C-reactive Protein [DAS28CRP]) and enthesitis and dactylitis counts were analyzed. Results A total of 168 patients were randomized (naïve N=82; experienced N=86); 156 entered the open-label phase. Patients were similar in baseline demographics, disease characteristics, and mean baseline doses of methotrexate (19 vs. 18 mg/wk), although PsA duration was slightly less in the naïve group (7 vs. 10 years). Approximately 97% of the experienced patients had used a TNFi; based on medication history, 54% were primary failures, 6% secondary failures, while the rest discontinued due to intolerance (10%) or other non-specified reasons (30%). ACR response rates were comparable between naïve and experienced patients at weeks 12, 24, and 52 (Table). The groups were also comparable in mean change from baseline in DAS28-CRP, enthesitis, and dactylitis. There was no difference in tolerability of brodalumab between the groups, with 91% (n/N=71/78) of both naïve and experienced patients reporting an adverse event, and 9% (n/N=7/78) and 4% (n/N=3/78) of patients experiencing a serious adverse event in the open-label phase. Conclusions Prior exposure to a biologic does not seem to affect the efficacy or tolerability of brodalumab over one year in the treatment of PsA. Acknowledgements This study was funded by Amgen, Inc. Disclosure of Interest M. Genovese Grant/research support: Amgen, Inc, Consultant for: Amgen, Inc, P. Mease Grant/research support: (Abbott) AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB Pharma, Vertex, Consultant for: (Abbott) AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB Pharma, Vertex, Speakers bureau: (Abbott) AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Genentech, Janssen, Lilly, Pfizer, and UCB Pharma, M. Greenwald Grant/research support: Amgen, Genentech, Roche, C. Ritchlin Grant/research support: Amgen, UCB, Janssen, Consultant for: Amgen, Abbvie, Laboratories, Janssen, UCB, Regeneron, A. Beaulieu Consultant for: Amgen, A. Deodhar Grant/research support: Amgen, Abbvie, UCB, Pfizer, Novartis, Consultant for: Abbvie, Novartis, Pfizer, MSD, UCB, R. Newmark Employee of: Amgen, J. Feng Employee of: Amgen, N. Erondu Employee of: Amgen, A. Nirula Employee of: Amgen DOI 10.1136/annrheumdis-2014-eular.1499