Safety and Efficacy of Different Doses and Regimens of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial.

Importance: Faricimab, the first bispecific antibody designed for intraocular use, simultaneously and independently binds and neutralizes angiopoietin 2 (Ang-2) and vascular endothelial growth factor A (VEGF-A). Objective: To assess the efficacy and safety of different doses and regimens of faricimab vs ranibizumab in patients with neovascular age-related macular degeneration (nAMD). Design, Setting, and Participants: AVENUE was a 36-week, multiple-dose-regimen, active comparator-controlled, double-masked, phase 2 randomized clinical study performed at 58 sites in the United States. Eligible participants were anti-VEGF treatment naive with choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 73 (Snellen equivalent, 20/40) to 24 (Snellen equivalent, 20/320). Data were collected from August 11, 2015, to January 12, 2017, with the final patient visit completed September 26, 2017. Data were analyzed from August 11, 2015, to October 4, 2019. Interventions: Patients were randomized 3:2:2:2:3 to receive ranibizumab, 0.5 mg every 4 weeks (arm A [n = 68]); faricimab, 1.5 mg every 4 weeks (arm B [n = 47]); faricimab, 6.0 mg every 4 weeks (arm C [n = 42]); faricimab, 6.0 mg every 4 weeks until week 12, then faricimab, 6.0 mg every 8 weeks (arm D [n = 47]); and ranibizumab, 0.5 mg every 4 weeks until week 8, then faricimab, 6.0 mg every 4 weeks (arm E [n = 69]). Main Outcomes and Measures: Mean change in BCVA from baseline to week 36, proportion of participants gaining at least 15 letters, BCVA of 20/40 or better or 20/200 or worse, and ocular coherence tomographic outcomes in anti-VEGF treatment-naive participants (arms A, B, C, D) and from weeks 12 to 36 in those with incomplete response (participants in arms A and E with week 12 BCVA ETDRS letter score of ≤68 [Snellen equivalent, 20/50 or worse]). Results: A total of 263 participants were included in the analysis (172 [65.4%] female; 258 [98.1%] white; mean [SD] age, 78.3 [8.7] years). At week 36, adjusted mean change in BCVA vs ranibizumab was 1.6 (80% CI, -1.6 to 4.7) letters for arm B (P = .52), -1.6 (80% CI, -4.9 to 1.7) letters for arm C (P = .53), and -1.5 (80% CI, -4.6 to 1.6) letters for arm D (P = .53). For arm E, adjusted mean change from week 12 was -1.7 (80% CI, -3.8 to 0.4) letters (P = .30). Conclusions and Relevance: AVENUE did not meet its primary end point of superiority of faricimab over ranibizumab in BCVA at week 36. Although not superior to monthly ranibizumab as given in this trial, overall visual and anatomical gains noted with faricimab support pursuing phase 3 trials for a potential alternative to monthly anti-VEGF therapy. Faricimab showed no new or unexpected safety signals. Trial Registration: ClinicalTrials.gov Identifier: NCT02484690.

Correction to: Exploring Social Biomarkers in High­Functioning Adults with Autism and Asperger's Versus Healthy Controls: A Cross­Sectional Analysis.

The original version of this article unfortunately contained a mistake in CI values in Table 2.

Exploring Social Biomarkers in High-Functioning Adults with Autism and Asperger's Versus Healthy Controls: A Cross-Sectional Analysis.

Biomarkers for autism spectrum disorder (ASD) are lacking but would facilitate drug development for the core deficits of the disorder. We evaluated markers proposed for characterization of differences in social communication and interaction in adults with ASD versus healthy controls (HC) for utility as biomarkers. Data pooled from an observational study and baseline data from a placebo-controlled study were analyzed. Between-group differences were observed in eye-tracking tasks for activity monitoring, biomotion, human activity preference, composite score (p = 0.0001-0.037) and pupillometry (various tasks, p = 0.017-0.05). Impaired olfaction was more common in the ASD sample versus HC (p = 0.018). Our preliminary results suggest the potential use for stratification and response sub-analyses outcome-prediction of specific eye-tracking tasks, pupillometry and olfaction tests in ASD trials.

Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial.

PURPOSE: The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME). DESIGN: The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States. PARTICIPANTS: The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 µm or more. METHODS: Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability. MAIN OUTCOME MEASURES: The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment. RESULTS: The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P = 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals. CONCLUSIONS: The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.

In Search of Biomarkers for Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) lacks validated measures of core social functions across development stages suitable for clinical trials. We assessed the concurrent validity between ASD clinical measures and putative biomarkers of core deficits, and their feasibility of implementation in human studies. Datasets from two adult ASD studies were combined (observational study [n = 19] and interventional study baseline data [n = 19]). Potential biomarkers included eye-tracking, olfaction, and auditory and visual emotion recognition assessed via the Affective Speech Recognition test (ASR) and Reading-the-Mind-in-the-Eyes Test (RMET). Current functioning was assessed with intelligence quotient (IQ), adaptive skill testing, and behavioral ratings. Autism severity was determined by the Autism Diagnostic Observation Scale-2 and Social Communication Interaction Test (SCIT). Exploratory measures showed varying significant associations across ASD severity, adaptive skills, and behavior. Eye tracking endpoints showed little relationship to adaptive ability but correlated with severity and behavior. ASR scores significantly correlated with most adaptive behavior domains, as well as severity. Olfaction predicted visual and auditory emotion recognition. SCIT scores related moderately to multiple severity domains, and was the only measure not related with IQ. RMET accuracy was less related to ASD features. Eye tracking, SCIT, and ASR showed high test-retest reliability. We documented associations of proximal biomarkers of social functioning with multiple ASD dimensions. With the exception of SCIT, most correlations were modest, limiting utility as proxy measures of social communication. Feasibility and reliability were high for eye-tracking, ASR, and SCIT. Overall, several novel experimental paradigms showed potential as social biomarkers or surrogate markers in ASD. Autism Research 2018, 11: 1567-1579. © 2018 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: More accurate measurements of treatment effects are needed to help the development of new drug treatments for autism spectrum disorders (ASD). This study evaluates the relationship between assessments designed to measure behaviors associated with social communication and cognition in ASD with clinical and diagnostic assessments of symptom severity as well as their implementation. The assessments including eye-tracking, auditory and visual social stimuli recognition, and olfaction identification showed potential for use in the evaluation of treatments for social difficulties in ASD.

Validation of disease states in schizophrenia: comparison of cluster analysis between US and European populations.

BACKGROUND: There is controversy as to whether use of statistical clustering methods to identify common disease patterns in schizophrenia identifies patterns generalizable across countries. OBJECTIVE: The goal of this study was to compare disease states identified in a published study (Mohr/Lenert, 2004) considering US patients to disease states in a European cohort (EuroSC) considering English, French, and German patients. METHODS: Using methods paralleling those in Mohr/Lenert, we conducted a principal component analysis (PCA) on Positive and Negative Syndrome Scale items in the EuroSC data set (n=1,208), followed by k-means cluster analyses and a search for an optimal k. The optimal model structure was compared to Mohr/Lenert by assigning discrete severity levels to each cluster in each factor based on the cluster center. A harmonized model was created and patients were assigned to health states using both approaches; agreement rates in state assignment were then calculated. RESULTS: Five factors accounting for 56% of total variance were obtained from PCA. These factors corresponded to positive symptoms (Factor 1), negative symptoms (Factor 2), cognitive impairment (Factor 3), hostility/aggression (Factor 4), and mood disorder (Factor 5) (as in Mohr/Lenert). The optimal number of cluster states was six. The kappa statistic (95% confidence interval) for agreement in state assignment was 0.686 (0.670-0.703). CONCLUSION: The patterns of schizophrenia effects identified using clustering in two different data sets were reasonably similar. Results suggest the Mohr/Lenert health state model is potentially generalizable to other populations.