Ajay Nirula

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

BACKGROUND Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physicians global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

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 .).

A prospective phase III, randomized, double‐blind, placebo‐controlled study of brodalumab in patients with moderate‐to‐severe plaque psoriasis

The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.

Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment

BACKGROUND Brodalumab (anti-interleukin-17-receptor antibody) was effective in treating moderate to severe psoriasis in a 12-week, dose-ranging, placebo-controlled trial. OBJECTIVE We sought to evaluate efficacy and safety of long-term brodalumab treatment. METHODS In this interim analysis at week 120 of an open-label extension study, patients received brodalumab 210 mg every 2 weeks. Protocol amendments reduced the dose (140 mg) in patients weighing 100 kg or less and subsequently increased the dose (210 mg) in patients with inadequate responses. Efficacy was measured by static physician global assessment and 75% or greater, 90% or greater, or 100% improvement in Psoriasis Area and Severity Index score (PASI-75, PASI-90, and PASI-100, respectively). RESULTS Of 181 patients, 144 completed week 120. Static physician global assessment scores of clear/almost clear and clear were achieved by 90% and 63% of patients, respectively, at week 12 and by 72% and 51% at week 120. The PASI-75, PASI-90, and PASI-100 response rates at week 12 (95%/85%/63%) were sustained through week 120 (86%/70%/51%). Most commonly reported adverse events were nasopharyngitis (26.5%), upper respiratory tract infection (19.9%), arthralgia (16.0%), and back pain (11.0%). Four patients had grade-2 absolute neutrophil count. LIMITATIONS There was no control group in this open-label extension. CONCLUSION Brodalumab demonstrated sustained clinical response and an acceptable safety profile through 120 weeks in patients with moderate to severe psoriasis.

Efficacy and safety of brodalumab in subpopulations of patients with difficult-to-treat moderate-to-severe plaque psoriasis.

BACKGROUND Novel therapies are needed for difficult-to-treat populations of patients with psoriasis. OBJECTIVE We sought to assess the efficacy and safety of the interleukin-17 Receptor A inhibitor brodalumab in patients with psoriasis with or without a self-reported history of psoriatic arthritis (PsA) and with or without a history of biologic use. METHODS Subset analyses of a phase II, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis were performed. Improvement from baseline in Psoriasis Area and Severity Index score of 75%, 90%, and 100% at week 12; static Physician Global Assessment (0/1) score; Dermatology Life Quality Index response; and Psoriasis Symptom Inventory response were evaluated within subgroups. RESULTS Efficacy and quality-of-life measures were generally similar between subgroups of patients with or without a history of PsA and with or without a history of biologic use across brodalumab doses and were significantly higher among patients who received brodalumab 140 mg every 2 weeks or 210 mg every 2 weeks versus placebo. LIMITATIONS Differences between subgroups were not compared statistically, PsA was self-reported, only skin involvement/symptoms were reported, and reasons for discontinuation of prior biologic were not captured. CONCLUSION Brodalumab is efficacious in patients with psoriasis with or without a history of PsA or biologic use.

Improvement in Psoriasis Signs and Symptoms Assessed by the Psoriasis Symptom Inventory with Brodalumab Treatment in Patients with Psoriatic Arthritis

Objective. To evaluate the effect of brodalumab on psoriasis signs and symptoms assessed by the Psoriasis Symptom Inventory (PSI) in patients with psoriatic arthritis (PsA). Methods. This prespecified analysis of a phase II study (NCT01516957) evaluated patients with active PsA and psoriasis-affected body surface area ≥ 3%, randomized to brodalumab (140 or 280 mg) or placebo every 2 weeks (Q2W) for 12 weeks with loading dose at Week 1. At Week 12, patients entering an open-label extension received brodalumab 280 mg Q2W. The PSI measures 8 psoriasis signs and symptoms: itch, redness, scaling, burning, stinging, cracking, flaking, and pain. PSI response is defined as total PSI ≤ 8 (range 0–32), each item ≤ 1 (range 0–4). PSI scores were assessed at weeks 12 and 24. Results. There were 107 eligible patients. At Week 12, mean improvement in PSI scores was 7.8, 11.2, and 1.5 in brodalumab 140 mg, 280 mg, and placebo groups, respectively; by Week 24, improvement was 10.2, 12.4, and 11.7. At Week 12, 75.0%, 81.8%, and 16.7% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI response; improvement was sustained through Week 24, when 83.9% of prior placebo recipients achieved response. At Week 12, 25.0%, 36.4%, and 2.8% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI 0. Percentages improved through Week 24: 40.0% brodalumab 140 mg, 42.9% brodalumab 280 mg, and 48.4% placebo. Conclusion. Significantly more brodalumab-treated patients with PsA achieved patient-reported improvements in psoriasis signs and symptoms than did those receiving placebo. Improvements were comparable between brodalumab groups.

Biomarker Profiles in Asthma With High vs Low Airway Reversibility and Poor Disease Control

BACKGROUND High bronchodilator reversibility in adult asthma is associated with distinct clinical characteristics. This analysis compares lung function, biomarker profiles, and disease control in patients with high reversibility (HR) and low reversibility (LR) asthma. METHODS A retrospective analysis was performed with data from two completed clinical trials of similar design. Patients were divided into HR and LR subgroups based on their response to bronchodilators (HR = ΔFEV1 postbronchodilator ≥ 20%). Blood eosinophil count, serum IgE level, and fraction of exhaled nitric oxide concentration, biomarkers commonly used to stratify patients into T-helper (Th)-2-high vs Th2-low phenotypes, were measured in patients with not well controlled (1.5 ≤ Asthma Control Questionnaire [ACQ] ≤ 2.143) and very poorly controlled (ACQ > 2.143) disease. RESULTS The majority of patients in the HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarker profiles (40.1% vs 29.4%, P = .006), lower lung function (FEV1, 63.5 ± 7.7% predicted vs 67.9 ± 8.4% predicted; P < .001), and atopy (93.7% vs 86.5%, P = .005). CONCLUSIONS HR is a physiologic indicator of reduced lung function and is more often associated with elevations in Th2 biomarkers than LR in moderate to severe asthma. However, the majority of patients with HR and LR asthma in this analysis had a Th2-low biomarker profile. Moreover, a Th2-high biomarker profile was not associated with worse disease control.

Population pharmacokinetics of brodalumab in healthy adults and adults with psoriasis from single and multiple dose studies.

Brodalumab, a human monoclonal IgG2‐antibody, acts as a potent antagonist at the interleukin‐17 receptor A, which is important in the pathogenesis of psoriasis. To characterize the pharmacokinetics of brodalumab and assess the effects of covariates, brodalumab concentrations from Phase 1a and Phase 2 clinical studies in healthy adults and subjects with psoriasis were used to construct a population PK model. The final two‐compartment model with parallel linear and non‐linear elimination pathways fit the data well. The population typical values for PK parameters CL, V, and Vmax were 0.223 L/day, 4.62 L, and 5.40 mg/day with between‐subject‐variability of 69.2, 69.6, and 25.9%CV, respectively. Body weight (BW) was an important covariate on CL (and Q), V (and V2) and Vmax, with estimated effect exponents of 0.598, 0.849, and 1.12, respectively. Based on simulations from the final model, for doses between 140 and 210 mg, AUC was predicted to be greater than two fold higher in subjects weighing less than 75 kg compared to reference subjects. Age and diagnosis had smaller influence on exposure and was not clinically significant. These data suggest that BW is an important covariate explaining some of the variability in population PK observed in human clinical trials with brodalumab.

Reliability and Validity of the Psoriasis Symptom Inventory in Patients With Psoriatic Arthritis.

To evaluate the measurement properties of the Psoriasis Symptom Inventory (PSI) in psoriatic arthritis (PsA).

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