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.

The Impact of Inherited Retinal Diseases in the Republic of Ireland (ROI) and the United Kingdom (UK) from a Cost-of-Illness Perspective.

To date, there has been a global lack of data regarding the prevalence of conditions falling under the Inherited Retinal Diseases (IRD) classification, the impact on the individuals and families affected, and the cost burden to economies. The absence of an international patient registry, and equitable access to genetic testing, compounds this matter. The resulting incomplete knowledge of the impact of IRDs hinders the development and commissioning of clinical services, provision of treatments, and planning and implementation of clinical trials. Thus, there is a need for stronger evidence to support value for money to regulatory bodies for treatments approved, and progressing through clinical trials. To ensure a strategic approach to future research and service provision, it is necessary to learn more about the IRD landscape. This review highlights two recent cost-of-illness reports on the socio-economic impact of 10 IRDs in the Republic of Ireland (ROI) and the United Kingdom (UK), which demonstrate the comprehensive impact of IRDs on individuals affected, their families, friends and society. Total costs attributable to IRDs in the ROI were estimated to be £42.6 million in 2019, comprising economic (£28.8 million) and wellbeing costs (£13.8 million). Wellbeing costs were estimated using the World Health Organization (WHO) burden of disease methodology, a non-financial approach, where pain, suffering and premature mortality are measured in terms of disability-adjusted-life-years (DALYs). In the UK, wellbeing costs attributable to IRDs were £196.1 million, and economic costs were £327.2 million amounting to £523.3 million total costs in 2019. Accounting for over one-third of total costs, the wellbeing burden of persons affected by IRDs should be emphasized and factored into reimbursement processes for therapies and care pathways. This targeted review presents the most current and relevant data on IRD prevalence in the ROI and the UK, and the impacts (financial and non-financial) of IRDs in terms of diagnosis, wellbeing, employment, formal and informal care, health system costs, deadweight losses and issues surrounding payers and reimbursement. This review demonstrates IRD patients and their families have common issues including, the need for timely equitable access to genetic testing and counselling, equality in accessing employment, and a revision of the assessment process for reimbursement of therapies currently focused on the cost-of-illness to the healthcare system. This review reveals that IRD patients do not frequently engage the healthcare system and as such suggests a cost-of-illness model from a societal perspective may be a better format.

A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder.

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo (n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD.

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.

A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder.

This corrects the article DOI: 10.1038/npp.2016.232.

A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder.

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278.