A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn's Disease.

OBJECTIVES: To assess the safety and efficacy of brodalumab, a human anti-interleukin-17 receptor monoclonal antibody, in patients with moderate-to-severe Crohn's disease (CD). METHODS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in patients with moderate-to-severe CD and evidence of active inflammation. Patients were randomized 1:1:1:1 to receive brodalumab (210, 350, or 700 mg at baseline and week 4) or placebo. The primary end point was proportion of patients achieving Crohn's disease activity index (CDAI) remission (≤150) at week 6. Secondary end points included proportion of patients with CDAI response (reduction from baseline of ≥100) at week 6 and change from baseline in CDAI at week 6. RESULTS: The study was terminated early based on an imbalance in worsening CD in active treatment groups. At the time of termination, 130 patients had been randomized. At week 6, remission rates were 3% (210 mg), 15% (350 mg), 9% (700 mg), and 3% (placebo) and CDAI response occurred in 16% (210 mg), 27% (350 mg), 15% (700 mg), and 13% (placebo) of patients. Mean change in CDAI at week 6 was -8.7 (95.3) (210 mg), -35.4 (105.6) (350 mg), -0.6 (105.9) (700 mg), and -28.2 (86.0) (placebo). Besides worsening of CD, overall incidences of adverse events were similar across treatment groups. CONCLUSIONS: Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD.

Time trends in 30 day case-fatality following hospitalisation for asthma in adults in Scotland: a retrospective cohort study from 1981 to 2009.

BACKGROUND: The risk of case-fatality following hospitalisation for asthma has not been well characterised. We describe trends in 30 day case-fatality following hospitalisation for asthma in adults in Scotland from 1981 to 2009. METHODS: Using the Scottish Morbidity Record Scheme (SMR01) with all asthma hospitalisations for adults (≥18 years) with ICD9 493 and ICD10 J45-J46 in the principal diagnostic position at discharge (1981-2009). These data were linked to mortality data from the General Register Office for Scotland (GROS), with asthma case-fatality defined as death within 30 days of asthma admission (in or out of hospital). Logistic regression was used to explore the impact of age, sex, previous asthma admission (in the 12 months prior to hospitalisation), socioeconomic deprivation, year of admission and co-morbidity on 30-day case-fatality. RESULTS: There were a total of 116,457 asthma hospitalisations; a total of 1000 (0.9%) hospitalisations resulted in a post-admission death (within 30 days of admission). Odds ratios for unadjusted and adjusted case-fatality showed a decreased risk of case-fatality from the mid-1990s onwards when compared to case-fatality in 1981. Advancing age and co-morbid diagnoses of respiratory failure, cancer, renal failure, cor pulmonale, coronary heart disease and respiratory infection were associated with increased likelihood of death. CONCLUSIONS: 30 day case-fatality has declined over the last three decades, comparable to case-fatality reported in other parts of the U.K. This decline may be in part due to improved guidelines, protocols and disease management for asthma over the last 30 years. The likelihood of death 30 days following an asthma admission increased with age group and was associated with respiratory failure, renal failure and cancer.

Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor.

PURPOSE: For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. METHODS: Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. RESULTS: The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. CONCLUSION: The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications.

OBJECTIVES: Assessment of associations between etanercept treatment and rare adverse events has been limited by the size of clinical trial populations. The authors examined the collective safety of etanercept in clinical trials across approved indications. PATIENTS AND METHODS: Forty-nine U.S. and non-U.S. trials of etanercept, involving up to 13,977 patients for approved indications, with final trial reports as of May 2006, were selected from the Amgen Inc. clinical trials database. Exposure-adjusted rates of serious infections, opportunistic infections, malignancies, and deaths were reported by trial, indication, and dosage. RESULTS: Rates of serious infections were generally similar between etanercept and controls. Overall rates of opportunistic infections and tuberculosis were low. The standardized incidence ratio (SIR) (95% CI) for malignancy was 1.00 (0.83-1.19) for all etanercept patients across all indications. The SIR for lymphoma for patients with rheumatoid arthritis was 3.45 (1.83-5.89); all other indications reported SIRs similar to those observed in the general population. The SIRs for cutaneous squamous cell carcinoma in patients with psoriasis relative to the general population with high or low sun exposure were 2.09 (1.27-3.22) and 4.96 (3.03-7.66), respectively. SIRs were less than 1.0 for all other indications regardless of sun exposure. Rates of melanoma and basal cell carcinoma were not significantly different from those in the general population. There was no increase in mortality associated with etanercept use relative to control populations. CONCLUSION: These data support the overall tolerability of etanercept across approved indications.

Patient-derived joint counts are a potential alternative for determining Disease Activity Score.

OBJECTIVE: To investigate the correlation between the Disease Activity Score using a 28-joint count (DAS28) based on physician-derived joint counts and the DAS28 based on patient-derived joint counts (Pt-DAS28) in rheumatoid arthritis (RA). METHODS: Data from a multicenter, open-label study investigating the immunogenicity of etanercept (ETN) were analyzed. ETN-naive patients with active RA received ETN 50 mg once weekly alone or with methotrexate (MTX). Joint counts were performed at baseline, Week 12, and Week 24 by the physician and patient independently. Patients received instruction in performing joint assessments. RESULTS: Of 447 patients enrolled (ETN, n = 218; ETN + MTX, n = 229), most were women (79%) and the mean age was 54.5 years. Correlation coefficients between DAS28 and Pt-DAS28 were > or = 0.57 at baseline, Week 12, and Week 24. At Week 24, 48%, 39%, and 12% of patients could be classified as having low, moderate, or high disease activity, respectively, using DAS28. Using Pt-DAS28, 43%, 39%, and 18% were similarly classified. Agreement in the category of disease activity classification occurred in 72% of patients (kappa = 0.55). At Week 24, 78% of patients using DAS28 and 72% of patients using Pt-DAS28 were classified as moderate or good European League Against Rheumatism responders. CONCLUSION: These results support the possible use of patient-derived tender and swollen joint counts to aid in the assessment of disease activity and clinical response in patients with RA.

Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis.

OBJECTIVE: To evaluate the safety and efficacy of up to 8 years of etanercept treatment in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). METHODS: Patients with JRA who previously participated in a randomized controlled trial (RCT) of etanercept were eligible to receive etanercept in a long-term open-label extension (OLE) trial. Safety end points included the incidences of serious adverse events (SAEs), medically important infections (MIIs), and death. Efficacy end points included the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement. RESULTS: Of the 69 patients originally enrolled in the RCT, 58 (84%) participated in the OLE, for a total of 318 patient-years of etanercept exposure. A total of 42 of the 58 patients (72%) entered the fourth year of continuous etanercept treatment, and 26 patients (45%) entered the eighth year. Sixteen patients (23% of those entering the RCT) reported 39 SAEs. The overall rate of SAEs (0.12 per patient-year) did not increase with long-term exposure to etanercept. The rate of MIIs (0.03 per patient-year) remained low; 1 new MII was reported in patients with > or =5 years of etanercept exposure. No cases of tuberculosis, opportunistic infections, malignancies, lymphomas, lupus, demyelinating disorders, or deaths were reported. An ACR Pedi 70 response or higher was achieved by 100% of patients with 8 years of data (11 of 11) and by 61% of patients according to the last observation carried forward data (28 of 46). CONCLUSION: These data suggest that the acceptable safety profile of etanercept therapy is maintained for up to 8 years in this population of JRA patients. Improvements in the signs and symptoms of JRA were also maintained for up to 8 years.

Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a).

We find that CD11c(+) cells with many markers of dendritic cells (DCs) are a major cell type in the skin lesions of psoriasis. These CD11c(+) cells, which are evident in both epidermis and dermis, are the sites for the expression of two mediators of inflammation, inducible nitric oxide synthase (iNOS) and TNF-alpha in diseased skin. These cells express HLA-DR, CD40, and CD86, lack the Langerin and CD14 markers of Langerhans cells and monocytes, respectively, and to a significant extent express the DC maturation markers DC-LAMP and CD83. Treatment of psoriasis with efalizumab (anti-CD11a, Raptiva) strongly reduces infiltration by these DCs in patients responding to this agent. Disease activity after therapy was more related to DC infiltrates and iNOS mRNA levels than T cell infiltrates, and CD11c(+) cells responded more quickly to therapy than epidermal keratinocytes. Our results suggest that a type of DC, which resembles murine "Tip-DCs" that can accumulate during infection, has proinflammatory effects in psoriasis through nitric oxide and TNF-alpha production, and can be an important target for suppressive therapies.

Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris.

Psoriasis vulgaris, a skin disease that is considered to be the result of a type 1 autoimmune response, provides an opportunity for studying the changes that occur in a target-diseased tissue during innovative immunotherapies. To gain a more comprehensive picture of the response to an approved biological therapy, we studied alfacept, which is a CD2 binding fusion protein. We examined T cells, dendritic cells (DCs), and expression of a number of inflammatory genes. In 22 patients, 55% demonstrated a clear histological remission of the disease, with a 73% reduction in lesional lymphocytes and a 79% decrease in infiltrating CD8+ cells. Only histological responders showed marked reductions in the tissue expression of inflammatory genes IFN-gamma, signal transducer and activator of transcription 1, monokine induced by IFN-gamma, inducible NO synthase, IL-8, and IL-23 subunits. Parallel decreases in CD83+ and CD11c+ DCs also were measured by immunohistochemistry. Because we observed that alefacept binds primarily to T cells and not DCs, we suggest that T cells are the primary target for therapy, but that DCs and a spectrum of type 1 inflammatory genes are coordinately suppressed.

The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.

Natural killer cells are important cytolytic cells in innate immunity. We have characterized human NK cells of spleen, lymph nodes, and tonsils. More than 95% of peripheral blood and 85% of spleen NK cells are CD56(dim)CD16(+) and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs). In contrast, NK cells in lymph nodes have mainly a CD56(bright)CD16(-) phenotype and lack perforin. In addition, they lack KIRs and all NCR expression, except low levels of NKp46. The NK cells of tonsils also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 and NKp46. Upon IL-2 stimulation, however, lymph node and tonsilar NK cells up-regulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL-2 activation, and therefore display a phenotype similar to peripheral blood NK cells. We hypothesize that IL-2 can mobilize the NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. Because lymph nodes harbor 40% and peripheral blood only 2% of all lymphocytes in humans, this newly characterized perforin(-) NK cell compartment in lymph nodes and related tissues probably outnumbers perforin(+) NK cells. These results also suggest secondary lymphoid organs as a possible site of NK cell differentiation and self-tolerance acquisition.