A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the FDA for the treatment of schizophrenia and bipolar I disorder. To improve communication of the OLZ/SAM benefit-risk profile, a structured framework was utilized.

The Benefit-Risk Action Team framework was used to evaluate OLZ/SAM, with analyses completed for each pivotal study. ENLIGHTEN-1 evaluated antipsychotic efficacy and safety. ENLIGHTEN-2 evaluated the weight profile of OLZ/SAM vs olanzapine. Benefit-risk outcomes were selected based on study outcome parameters, known risks of olanzapine and samidorphan, and public health importance. A subset of opioid antagonist risks was not assessed due to clinical trial exclusions; however, they were factored into the overall evaluation. Risk differences and confidence intervals were analyzed.

In ENLIGHTEN-1, OLZ/SAM had a lower risk of psychiatric discontinuation and nonresponse to treatment compared with placebo; higher risks of hyperprolactinemia, weight gain (≥7%), sedation, and worsening of fasting triglycerides and glucose, and no difference for fasting total and LDL cholesterol, neutropenia, orthostatic hypotension, and movement disorders. In ENLIGHTEN-2, OLZ/SAM had reduced risks of weight gain and waist circumference increase compared to olanzapine along with similar risks of relapse and psychiatric discontinuation and no difference in metabolic worsening, neutropenia, hyperprolactinemia, orthostatic hypotension, sedation, and movement disorders.

Based on this assessment, OLZ/SAM has comparable efficacy and a safety profile consistent with olanzapine, with reduced weight gain. A structured approach to assessing the benefit-risk profile of a product facilitates transparent evaluation and communication.

Alkermes, Inc.

We aimed to investigate the coronavirus disease 2019 (COVID-19)-related knowledge and practices of cancer patients and to assess their anxiety- and depression-related to COVID-19 during the early surge phase of the pandemic.

An online questionnaire survey of cancer patients was conducted from February 10-29, 2020. Knowledge and practices related to COVID-19 were assessed using a custom-made questionnaire. The Hospital Anxiety and Depression Scale was used to assess the presence of anxiety and depression, with scores beyond 7 indicating anxiety or depressive disorder. Univariate and multiple linear regression analyses were used to identify the high-risk groups according to the level of knowledge, practices, anxiety, and depression scores.

A total of 341 patients were included. The rate of lower level of knowledge and practices was 49.9% and 18.8%, respectively. Education level of junior high school degree or lower showed a significant association with lower knowledge score (β: −3.503; P < 0.001) and lower practices score (β: −2.210; P < 0.001) compared to the education level of college degree and above. The prevalence of anxiety and depression among the respondents was 17.6% and 23.2%, respectively. A higher depression score was associated with older age, marital status of the widowed, and lower level of education, knowledge score, and practices score (P < 0.05).

Targeted COVID-19-related education interventions are required for cancer patients with a lower level of knowledge to help improve their practices. Interventions are also required to address the anxiety and depression of cancer patients.

The aim of this study was to present the clinical characteristics and dynamic changes in laboratory parameters of the coronavirus disease 2019 (COVID-19) in Guangzhou, and explore the probable early warning indicators of disease progression.

We enrolled all the patients diagnosed with COVID-19 in the Guangzhou No. 8 People’s Hospital. The patients’ demographic and epidemiologic data were collected, including chief complaints, lab results, and imaging examination findings.

The characteristics of the patients in Guangzhou are different from those in Wuhan. The patients were younger in age, predominately female, and their condition was not commonly combined with other diseases. A total of 75% of patients suffered fever on admission, followed by cough occurring in 62% patients. Comparing the mild/normal and severe/critical patients, being male, of older age, combined with hypertension, abnormal blood routine test results, raised creatine kinase, glutamic oxaloacetic transaminase, lactate dehydrogenase, C-reactive protein, procalcitonin, D-dimer, fibrinogen, activated partial thromboplastin time, and positive proteinuria were early warning indicators of severe disease.

The patients outside epidemic areas showed different characteristics from those in Wuhan. The abnormal laboratory parameters were markedly changed 4 weeks after admission, and also were different between the mild and severe patients. More evidence is needed to confirm highly specific and sensitive potential early warning indicators of severe disease.

Combination olanzapine and samidorphan (OLZ/SAM) is in development for treatment of schizophrenia and bipolar I disorder and is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This 52-week open-label extension study (NCT02873208; ENLIGHTEN-2-EXT) in schizophrenia assessed the safety and tolerability of OLZ/SAM. Methods: Patients completing the 24-week, randomized, double-blind, phase 3 ENLIGHTEN−2 study comparing weight gain with OLZ/SAM vs olanzapine were eligible for ENLIGHTEN-2-EXT enrollment. Initial OLZ/SAM doses were based on olanzapine dose (10 or 20 mg) received at the conclusion of ENLIGHTEN-2; subsequent olanzapine dose adjustments were allowed. The samidorphan dose (10 mg) remained fixed throughout. Assessments included adverse events (AEs), weight, waist circumference, metabolic laboratory parameters, and Positive and Negative Syndrome Scale (PANSS) scores. Analyses were based on observed results using descriptive statistics. Baseline was relative to the first OLZ/SAM dose in the extension study.

265 patients received OLZ/SAM; 167 (63.0%) completed the extension study. Common AEs (= 5%) were weight decreased (n=23; 8.7%), extra dose administered (n=21; 7.9%), headache (n=18; 6.8%), and weight increased (n=16; 6.0%). At week 52, mean (SD) change from baseline for weight and waist circumference was −0.03 (6.216) kg and −0.35 (6.115) cm, respectively. Changes in fasting lipid and glycemic parameters were generally small and remained stable over 52 weeks. PANSS total scores remained stable during the extension.

OLZ/SAM was generally well tolerated over 52 weeks. Weight, waist circumference, metabolic laboratory parameters, and schizophrenia symptoms remained stable throughout the study.

Alkermes, Inc.

Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data.

The OLZ/SAM development program consists of 18 phase 1–3 clinical studies evaluating antipsychotic and weight mitigation efficacy of OLZ/SAM, along with pharmacokinetics, safety, and tolerability. Safety evaluation also included metabolic laboratory assessments.

OLZ/SAM significantly improved psychotic symptoms (measured by Positive and Negative Syndrome Scale); improvements were similar to that observed with olanzapine vs placebo. OLZ/SAM resulted in significantly less weight gain than olanzapine. Additionally, 2 long-term phase 3 extension studies confirmed the durability of antipsychotic effect, as well as stabilization of weight and metabolic parameters in those continuing treatment. Supporting the potential use of OLZ/SAM in BD-I, OLZ/SAM or olanzapine resulted in bioequivalent olanzapine plasma concentrations, and OLZ/SAM did not affect lithium or valproate pharmacokinetics. OLZ/SAM treatment had no clinically relevant effects on ECG parameters (including QTc interval). OLZ/SAM and olanzapine safety were similar, except for reduced weight gain with OLZ/SAM; no additional safety risks were identified.

Data across 18 OLZ/SAM studies in >1600 subjects support an antipsychotic efficacy and safety profile for OLZ/SAM that is similar to olanzapine, with significantly less weight gain than olanzapine. OLZ/SAM is a potential new treatment for schizophrenia and BD-I patients needing efficacious long-term treatment with reduced risk of weight gain.

Alkermes, Inc.

Combination olanzapine and samidorphan (OLZ/SAM), in development for schizophrenia and bipolar I disorder, is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. OLZ/SAM safety, tolerability, and efficacy from a 52-week open-label extension study in patients with schizophrenia are reported.

Patients previously completing the 4-week, double-blind ENLIGHTEN-1 study switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Assessments included adverse events (AEs), weight, vital signs, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression-Severity (CGI-S) scores. Baseline was prior to first dose of OLZ/SAM in the extension study.

In total, 281 patients enrolled, 277 received ≥1 OLZ/SAM dose, and 183 (66.1%) completed 52 weeks. Reasons for discontinuation included patient withdrawal (15.5%), loss to follow-up (6.9%), AEs (5.8%), and lack of efficacy (1.8%). AEs were reported in 136 (49.1%) patients; increased weight (13%) and somnolence (8%) were most common. Ten serious AEs were reported in eight patients (2.9%); none were considered treatment related. There were no deaths. Mean (SD) baseline weight was 79.1 (17.8) kg. Mean weight change from baseline to week 52 was 1.86 kg (2.79% increase). PANSS total and CGI-S scores continued to decline over 52 weeks (mean [95% CI] changes from baseline to week 52: −16.2 [−18.5, −14.0] and −0.9 [−1.0, −0.8], respectively).

OLZ/SAM was generally well tolerated in this extension study; most patients completed the 52-week treatment period with sustained improvement in schizophrenia symptoms. Mean increases in weight stabilized by week 6 with limited subsequent change through end of treatment.

To determine whether ambient air pollutants and meteorological variables are associated with daily COVID-19 incidence.

A retrospective cohort from January 25 to February 29, 2020.

Cities of Wuhan, Xiaogan, and Huanggang, China.

The COVID-19 cases detected each day.

We collected daily data of COVID-19 incidence, 8 ambient air pollutants (particulate matter of ≤2.5 µm [PM2.5], particulate matter ≤10 µm [PM10], sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], and maximum 8-h moving average concentrations for ozone [O3-8h]) and 3 meteorological variables (temperature, relative humidity, and wind) in China’s 3 worst COVID-19–stricken cities during the study period. The multivariate Poisson regression was performed to understand their correlation.

Daily COVID-19 incidence was positively associated with PM2.5 and humidity in all cities. Specifically, the relative risk (RR) of PM2.5 for daily COVID-19 incidences were 1.036 (95% confidence interval [CI], 1.032–1.039) in Wuhan, 1.059 (95% CI, 1.046–1.072) in Xiaogan, and 1.144 (95% CI, 1.12–1.169) in Huanggang. The RR of humidity for daily COVID-19 incidence was consistently lower than that of PM2.5, and this difference ranged from 0.027 to 0.111. Moreover, PM10 and temperature also exhibited a notable correlation with daily COVID-19 incidence, but in a negative pattern The RR of PM10 for daily COVID-19 incidence ranged from 0.915 (95% CI, 0.896–0.934) to 0.961 (95% CI, 0.95–0.972, while that of temperature ranged from 0.738 (95% CI, 0.717–0.759) to 0.969 (95% CI, 0.966–0.973).

Our data show that PM2.5 and humidity are substantially associated with an increased risk of COVID-19 and that PM10 and temperature are substantially associated with a decreased risk of COVID-19.

To estimate the current evidence regarding the association between gestational acrylamide (AA) exposure and offspring’s growth.

Systematic review and meta-analysis.

A systematic literature search for relevant publications was conducted using PubMed, Medline, Embase, Web of Science databases from inception to 26 April 2019. The standardised mean difference (SMD) or OR with 95 % CI was selected as the effect sizes and was calculated using a random effects model.

Five cohort studies including 54 728 participants were identified. Offspring’s birth weight was significantly lower in high AA exposure group than in low AA exposure group (SMD –0·05, 95 % CI –0·09, –0·02, P = 0·005). There was also an association between maternal AA exposure and small for gestational age (OR 1·14, 95 % CI 1·06, 1·23, P < 0·001). In addition, pooled ORs suggested that children had a high risk of developing overweight/obesity in the future in maternal high AA exposure group (OR 1·14, 95 % CI 1·08, 1·21, P < 0·001 at age 3; OR 1·13, 95 % CI 1·07, 1·19, P < 0·001 at age 5; OR 1·09, 95 % CI 1·02, 1·16, P = 0·020 at age 8).

These findings have important implications for conducting health education, providing guidance on maternal diet and developing an appropriate dietary strategy for pregnant women to reduce dietary AA exposure.

Dietary salt intake may vary depending on different lifestyles. We aimed to estimate the different salt intakes and evaluate the knowledge and self-awareness about salt among people speaking the Teochew, Teochew–Hakka and Hakka dialects in the Chaoshan region of southern China.

The study followed a cluster sampling of residents in Chaoshan region. General characteristics, lifestyles, health status as well as knowledge and self-awareness related to salt intake were investigated using a questionnaire. Anthropometric variables as well as Na and K excretion in a 24-h urine collection were measured.

Chaoshan region of China.

Four hundred fifteen adults who spoke only one of these three dialects.

The salt intake of adults who spoke the Teochew, Teochew–Hakka and Hakka dialects was 7·19 (interquartile range (IQR) 5·29–10·17), 9·03 (IQR 6·62–11·54) and 10·12 (IQR 7·61–12·82) g/d, respectively, with significant differences between Teochew and Teochew–Hakka speakers and between Teochew and Hakka speakers (both P < 0·05). The Na:K ratio for adults who spoke the three dialects was 3·00 (IQR 2·00–4·11), 3·50 (IQR 2·64–4·82) and 4·52 (IQR 3·35–5·97), respectively, and differed significantly among the groups (all P < 0·05). Multiple linear regression analysis showed increased Na:K ratio associated with hypertension (β = 0·71, P = 0·043) in Hakka speakers. Knowledge and self-awareness about salt intake were poor in this population.

Salt intake was closely related to lifestyles and was higher than the upper limit (5 g/d) recommended by the WHO in adults of Chaoshan, especially those speaking the Hakka dialect.

Opioid antagonists may mitigate medication-associated weight gain and/or metabolic dysregulation. ENLIGHTEN-2 evaluated a combination of olanzapine and the opioid antagonist samidorphan (OLZ/SAM) vs olanzapine for effects on weight gain and metabolic parameters over 24 weeks in adults with stable schizophrenia.

This phase 3, double-blind study (ClinicalTrials.gov: NCT02694328) enrolled adults 18–55 yo with stable schizophrenia, randomized 1:1 to once-daily OLZ/SAM or olanzapine. Co-primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. Waist circumference and fasting metabolic parameters were also measured. Completers could enter a 52-week open-label safety extension.

561 patients were randomized: 550 were dosed, 538 had ≥1 post-baseline weight assessment, and 352 (64%) completed; 10.9% discontinued due to AEs. At week 24, least squares mean (SE) percent weight change from baseline was 4.21 (0.68)% with OLZ/SAM and 6.59 (0.67)% with olanzapine (difference, −2.38 [0.76]%; P=0.003). Fewer patients treated with OLZ/SAM (17.8%) had ≥10% weight gain vs olanzapine (29.8%; odds ratio=0.50; P=0.003). The change from baseline in waist circumference was significantly smaller with OLZ/SAM (P<0.001). Common AEs (≥10%) with OLZ/SAM and olanzapine were weight increased (24.8%, 36.2%), somnolence (21.2%, 18.1%), dry mouth (12.8%, 8.0%), and increased appetite (10.9%, 12.3%), respectively. Metabolic parameter changes were generally small and remained stable with long-term OLZ/SAM treatment.

OLZ/SAM treatment limited weight gain associated with olanzapine. Metabolic parameter changes were generally small, similar between groups over 24 weeks, and remained stable over an additional 52 weeks of open-label OLZ/SAM treatment.

This study was funded by Alkermes, Inc.

A combination of olanzapine and samidorphan (OLZ/SAM) is in development for schizophrenia to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The objective of this phase 1 exploratory study was to assess metabolic treatment effects of OLZ/SAM.

Healthy, non-obese adults (18–40 years) were randomized 2:2:1 to once-daily OLZ/SAM, olanzapine, or placebo for 21 days. Assessments included oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, weight gain, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance.

Sixty subjects were randomized (OLZ/SAM, n=24; olanzapine, n=24; placebo, n=12); 19 (79.2%), 22 (91.7%), and 11 (91.7%), respectively, completed the study. In the OGTT, olanzapine led to significant hyperinsulinemia (P<0.0001) and significantly reduced insulin sensitivity (2-hour Matsuda index) at day 19 vs baseline (P=0.0012), changes not observed with OLZ/SAM. No significant between-group differences were observed for change from baseline in clamp-derived insulin sensitivity index at day 21. Least squares mean weight change from baseline was similar with OLZ/SAM (3.16 kg) and olanzapine (2.87 kg); both were significantly higher than placebo (0.57 kg; both P<0.01). Caloric intake significantly decreased from baseline to day 22 with OLZ/SAM (P=0.015) but not with olanzapine or placebo. Forty-nine subjects (81.7%) experienced ≥1 AE (OLZ/SAM, 87.5%; olanzapine, 79.2%; placebo, 75.0%).

In this exploratory study, hyperinsulinemia and decreased insulin sensitivity were observed in the OGTT with olanzapine but not with OLZ/SAM or placebo. Clamp-derived insulin sensitivity index and weight changes were similar with OLZ/SAM and olanzapine in healthy subjects during the 3-week study.

This study was funded by Alkermes, Inc.

Social attention ability is crucial for human adaptive social behaviors and interpersonal communications, and the malfunction of which has been implicated in autism spectrum disorder (ASD), a highly genetic neurodevelopmental disorder marked by striking social deficits.

Using a classical twin design, the current study investigated the genetic contribution to individual variation in social and non-social attention abilities, and further probed their potential genetic linkage. Moreover, individual autistic traits were further measured in an independent group of non-twin participants to examine the hypothetical link between the core social attention ability and ASD.

We found reliable genetic influences on the social attentional effects induced by two distinct cues (eye gaze and walking direction), with 91% of their covariance accounted for by common genetic effects. However, no evidence of heritability or shared genetic effects was observed for the attentional effect directed by a non-social cue (i.e. arrow direction) and its correlation with the social attention ability. Remarkably, one's autistic traits could well predict his/her heritable core social attention ability extracted from the conventional social attentional effect.

These findings together suggest that human social attention ability is supported by unique genetic mechanisms that can be shared across different social, but not non-social, processing. Moreover, they also encourage the identification of ‘social attention genes’ and highlight the critical role of the core human social attention ability in seeking the endophenotypes of social cognitive disorders including ASD.

ALKS 3831, currently under development for the treatment of schizophrenia, is composed of olanzapine (OLZ) and a fixed dose of 10mg of samidorphan. In a Phase 2 study in stable patients with schizophrenia, ALKS 3831mitigated OLZ-associated weight gain while maintaining an antipsychotic efficacy profile similar to OLZ.

To assess the efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia.

This was a Phase 3, 4-week, randomized, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomized 1:1:1 to receive ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2weeks of the study and could be treated as inpatients or outpatients for the remaining 2weeks. Patients were excluded if they received OLZ within 6months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression–Severity (CGI-S) and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs).

Of 401 randomized patients who received ALKS 3831, OLZ, or PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean±standard deviation scores were 101.7±11.9 for PANSS total score and 5.1±0.7 for CGI-S scale score. The mean OLZ dose was 18.4mg/day in both active treatment arms. Least squares (LS) mean difference±standard error (SE) vs PBO from baseline to Week 4 in PANSS total score was –6.4±1.8 (P<.001) for the ALKS 3831 group and –5.3±1.8 (P=.004) for the OLZ group. LS mean difference±SE vs PBO from baseline to Week 4 in CGI-S scale score was −0.4±0.1 (P=.002) for the ALKS3831 group and −0.4±0.1 (P<.001) for the OLZ group. The percentage of patients with improvement in PANSS response (≥30% from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I scale response (score of ≤2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (≥5% in any group) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia.

Treatment with ALKS 3831 was more effective than PBO, as measured by the PANSS and CGI-S scale, and its antipsychotic efficacy was similar to the active control OLZ. The safety profile of ALKS 3831 was similar toOLZ.

Funding Acknowledgements: This study was funded by Alkermes, Inc.