Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study

OBJECTIVE Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568

Safety and clinical activity of atacicept in the long-term extension of the Phase IIb ADDRESS II study in systemic lupus erythematosus

Objectives: Atacicept reduced SLE disease activity in the Phase IIb ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods: In the 24-week, randomised, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary end point. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results: 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%). 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy

Amyloid-β Inhibits No-cGMP Signaling in a CD36- and CD47-Dependent Manner

Amyloid-β interacts with two cell surface receptors, CD36 and CD47, through which the matricellular protein thrombospondin-1 inhibits soluble guanylate cyclase activation. Here we examine whether amyloid-β shares this inhibitory activity. Amyloid-β inhibited both drug and nitric oxide-mediated activation of soluble guanylate cyclase in several cell types. Known cGMP-dependent functional responses to nitric oxide in platelets and vascular smooth muscle cells were correspondingly inhibited by amyloid-β. Functional interaction of amyloid-β with the scavenger receptor CD36 was indicated by inhibition of free fatty acid uptake via this receptor. Both soluble oligomer and fibrillar forms of amyloid-β were active. In contrast, amyloid-β did not compete with the known ligand SIRPα for binding to CD47. However, both receptors were necessary for amyloid-β to inhibit cGMP accumulation. These data suggest that amyloid-β interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation. Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-β can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease

Efficacy and Safety of Atacicept in Patients With Systemic Lupus Erythematosus: Results of a Twenty‐Four–Week, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Arm, Phase IIb Study

OBJECTIVE: To evaluate the efficacy and safety of atacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE). METHODS: ADDRESS II was a phase IIb, multicentre study (NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to atacicept (75 or 150 mg) or placebo for 24 weeks. The primary endpoint was the SLE responder index (SRI)-4 at Week 24. RESULTS: The ITT population included 306 patients. There was a trend towards improved SRI-4 response rate with atacicept 75 mg (57.8% [adjusted OR 1.78], P = 0.045) and 150 mg (53.8% [adjusted OR 1.56], P = 0.121) versus placebo (44.0%) at Week 24 (primary analysis; screening visit as baseline). In a pre-specified sensitivity analysis using study Day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg (55.9% [adjusted OR 1.88], P = 0.029) and 150 mg (55.8% [adjusted OR 1.96], P = 0.020) achieved SRI-4 response at Week 24 versus placebo (41%). In pre-defined subpopulations with baseline high disease activity (HDA), serologically active disease (SA), or both, statistically significant improvements in SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. Severe flare risk was reduced with atacicept in both the ITT and HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept versus placebo. CONCLUSION: Atacicept showed evidence of efficacy in SLE, particularly in HDA and SA patients. Reductions in disease activity and severe flare were observed with atacicept treatment, along with an acceptable safety profile

8 Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a 24-week randomisedrandomized, placebo-controlled, phase iib study

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A manifesto for researching entrepreneurial ecosystems

Entrepreneurial ecosystems are the focus of government economic policies around the world for their potential to generate entrepreneur-led economic development. The paper identifies key research questions and challenges to building effective public policy: (i) the limitations of existing data sources, (ii) the need to balance findings from quantitative and qualitative studies, (iii) the danger that entrepreneurial ecosystems will be just a policy fad, (iv) the narrow focus of policy and research on high tech firms and scale-ups, and (v) the need to balance research approaches between simplified models and a complex systems approach. There is a need for a better understanding of the diversity of policy contexts (level of government, country context) and model of ecosystem governance. A more granulated understanding of ecosystem thinking is required, with greater consideration of the diversity of actors and the institutional context, with more attention given to the heterogeneous nature of places and complex interactions between actors and networks. Looking to the future, the potential of new data sources and methodologies is identified. Future research should give greater consideration to the institutional context to understand how policy can better support entrepreneurial activity and the extent to which specific policies can be replicated elsewhere

16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends

Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index

s7a 4 reduction of systemic lupus flares by atacicept in a randomised placebo controlled phase iib study address ii and its extension study

Purpose Atacicept targets the B-cell stimulating factors, BLyS and APRIL, and has shown evidence of clinical response in patients with SLE. The 24 week Phase II ADDRESS II (NCT01972568) Study and its long-term extension (LTE; NCT02070978) provided data on disease activity with up to 48 weeks of atacicept treatment. Methods In ADDRESS II, patients were randomised (1:1:1) to receive weekly atacicept (75 or 150 mg SC injection) or placebo (PBO) for 24 weeks. Those who completed treatment were eligible to enter the LTE, to either continue on the same atacicept dose (atacicept groups), or switch from PBO to atacicept 150 mg (PBO/150 mg). The SLE flare analysis from both studies are reported here. Results The ITT population of ADDRESS II included 306 patients; 158 of whom met the predefined high disease activity (HDA) criterion (SLEDAI-2K≥10 at Screening). Of the 262 patients who completed the ADDRESS II, 253 entered the LTE. At 24 weeks in the PBO-controlled trial, cumulative incidence of severe flare was significantly reduced with atacicept 75 mg vs PBO by BILAG A (HR 0.24; p=0.0186), and with atacicept 150 mg vs PBO by SFI (HR 0.18; p=0.002). There was no difference in moderate-to-severe flare by BILAG A/2B. In the HDA subpopulation, incidence of severe flare at 24 weeks was significantly reduced with both atacicept doses vs PBO by BILAG A (75 mg HR 0.08, p=0.002; 150 mg HR 0.32, p=0.038) and SFI (75 mg HR 0.33, p=0.029; 150 mg HR 0.19, p=0.004). Incidence of moderate-to-severe flare by BILAG A/2B was significantly reduced with atacicept 150 mg vs PBO (HR 0.34, p=0.032). At 48 weeks, risk of severe flare by SFI was significantly lower with atacicept 150 mg vs the PBO/150 mg in both the ITT and HDA populations (figure 1); significant flare reductions were seen with atacicept 75 mg by BILAG A, and with both atacicept doses by BILAG A/2B vs PBO/150 mg, in the HDA subpopulation. Conclusions In this 24 week, double-blind, PBO-controlled trial, atacicept treatment was associated with significant flare reductions compared with PBO. Rates of flare continued to be low in atacicept-treated patients between weeks 24–48. Most flares occurred in HDA patients in the PBO group

s7a 5 sri response attainment of low disease activity and safety in patients with systemic lupus treated with atacicept in a phase iib study address ii

Purpose Atacicept targets B-cell stimulating factors, BLyS and APRIL. ADDRESS II (NCT01972568) investigates the efficacy and safety of atacicept in SLE. Methods In this Phase IIb multicenter study, patients with active (SLEDAI-2K≥6), autoantibody-positive SLE on standard of care therapy received weekly SC injections of atacicept (75 or 150 mg) or placebo (PBO) for 24 weeks. The primary endpoint was proportion of patients achieving SLE responder index (SRI)−4 response at week 24. Other endpoints included SRI-5 through SRI-8 response and low disease activity (LDA) attainment, defined as LDA-1 (SLEDAI-2K≤2), LDA-2 (SLEDAI-2K≤2 and prednisone-equivalent ≤7.5 mg/day), or LLDAS (SLEDAI–2K≤4 without major organ activity, no new disease activity vs previous visit, Physician's Global Assessment≤1, prednisone-equivalent ≤7.5 mg/day, and stable maintenance doses of immunosuppressants). A pre-defined subset of patients was also evaluated, with high disease activity (HDA: SLEDAI-2K≥10 at Screening). Differences in clinical response between patients treated with atacicept and PBO at Week 24 were analysed using odds ratio estimated from logistic regression. Results The ITT population included 306 patients, and 158 had HDA. There was a trend towards improved SRI-4 response with atacicept vs PBO at Week 24 (p=ns in primary analysis; screening visit as baseline, BL). In a pre-specified sensitivity analysis using study day 1 as BL, a significantly larger proportion of patients on atacicept achieved SRI-4 response at week 24. In the HDA subpopulation, there were significant improvements in SRI-4,–5, −6,–7 and −8 response rates and attainment of LDA with atacicept 150 mg vs PBO (table 1). Atacicept was associated with increased serum C3 and C4, and decreased IgG, IgA, IgM and anti-dsDNA antibodies over time. Rates of treatment emergent adverse event (TEAE) and serious TEAEs were similar among groups. The most frequent serious TEAEs were infections but the incidence was not increased in the atacicept groups vs PBO. Conclusions Atacicept showed evidence of efficacy in SLE with a dose-dependent reduction of SLE disease activity in patients with HDA. Atacicept was associated with an acceptable safety profile. These results also suggest that more discriminatory endpoints will be useful for future SLE clinical trials

Dysplasia of the Upper Aerodigestive Tract Squamous Epithelium

Dysplasia of the oral, laryngeal and oropharyngeal stratified squamous epithelia is a microscopically defined change that may occur in clinically identifiable lesions including erythroplakia, leukoplakia and erythroleukoplakia, lesions that convey a heightened risk for carcinomatous progression. Dysplastic lesions have been classified microscopically according to degree of cytologic atypia and changes in architectural patterns, usually on a three part or four part gradation scale. Vocal cord epithelial lesions are graded according to either the Ljubljana or the World Health Organization (WHO) system whereas oral dysplasias are generally classified according to WHO criteria. Cytologically atypical cells are considered to represent precancerous changes predicting an increase risk for carcinomatous transformation. Inter- and intra-rater reliability studies among pathologists have disclosed low correlation coefficients for four part grading systems, whereas improved agreement is achieved (kappa correlation values) using the Ljubljana systems. Evidence forwarded by some studies supports the prognostic value of progressively severe dysplastic changes for carcinomatous transformation; however, some studies indicate that the presence of a clinically defined lesion without microscopic evidence of dysplasia also connotes increased risk for carcinomatous transformation. Loss of heterozygosity (LOH) at 3p and 9p microsatellite domains, DNA ploidy analysis and nuclear image analyses may have predictive value as molecular and histomorphological biomarkers