Phase 2 Dose-Finding Study in Patients with Gout Using SEL-212, a Novel PEGylated Uricase (SEL-037) Combined with Tolerogenic Nanoparticles (SEL-110).

INTRODUCTION: SEL-212 is a developmental treatment for uncontrolled gout characterized by serum uric acid (sUA) levels ≥ 6 mg/dl despite treatment. It comprises a novel PEGylated uricase (SEL-037; also called pegadricase) co-administered with tolerogenic nanoparticles containing sirolimus (rapamycin) (SEL-110; also called ImmTOR®), which mitigates the formation of anti-drug antibodies (ADAs) against uricase and SEL-037 (PEGylated uricase), thereby enabling sustained sUA control (sUA < 6 mg/dl). The aim of this study was to identify appropriate dosing for SEL-037 and SEL-110 for use in phase 3 clinical trials. METHODS: This open-label phase 2 study was conducted in adults with symptomatic gout and sUA ≥ 6 mg/dl. Participants received five monthly infusions of SEL-037 (0.2 or 0.4 mg/kg) alone or in combination with three or five monthly infusions of SEL-110 (0.05-0.15 mg/kg). Safety, tolerability, sUA, ADAs, and tophi were monitored for 6 months. RESULTS: A total of 152 adults completed the study. SEL-037 alone resulted in rapid sUA reductions that were not sustained beyond 30 days in most participants due to ADA formation and loss of uricase activity. Levels of ADAs decreased with increasing doses of SEL-110 up to 0.1 mg/kg, with anti-uricase titers < 1080 correlating with sustained sUA control and reductions in tophi. Overall, 66% of evaluable participants achieved sUA control at week 20 following five monthly doses of SEL-037 0.2 mg/kg + SEL-110 0.1-0.15 mg/kg, whereas only 26% achieved sUA control at week 20 when SEL-110 was withdrawn after week 12. Compared to other dose combinations, SEL-037 0.2 mg/kg + SEL-110 0.15 mg/kg achieved the greatest sUA control at week 12 and was well-tolerated with no safety concerns. CONCLUSION: Results provide continued support for the use of multiple monthly administrations of SEL-037 0.2 mg/kg + SEL-110 0.1-0.15 mg/kg in clinical trials for SEL-212. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02959918.

Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia.

Biologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.

Building on a Sequential Mixed-Mode Research Design in the Monitoring the Future Study.

Given the promise of the web push plus e-mail survey design for providing cost-effective and high-quality data (Patrick et al. 2018, 2019) as an alternative to a paper-and-pencil mailed survey design for the longitudinal Monitoring the Future (MTF) study, the current study sought to further enhance the web push condition. The MTF sample is based on US nationally representative samples of 12th grade students surveyed annually. The MTF control group for the current study included participants who completed the in-school baseline survey in the 12th grade and were selected to participate in their first follow-up survey in 2017 via mailed surveys (N = 1,222). A supplementary sample (N = ∼2,450) was assigned to one of the two sequential mixed-mode conditions. Those in condition 1 (N = 1,198), or mail push, were invited to complete mailed surveys and later given a web survey option. Those in condition 2 (N = 1,173), or enhanced web push, were invited to complete a web survey (the same as in the 2014 study, but with the addition of text messages and quick response (QR) codes and the web survey was optimized for mobile devices) and then later given a mailed survey option. Research aims were to examine response rates across conditions, as well as how responses were distributed across mode (paper, web), devices (computer, smartphone, table), and method of accessing the web survey (hand-entered URL, QR code, e-mail link, SMS link). Response rates differed significantly: the MTF control group was 34.2 percent, mail push was 35.4 percent, and enhanced web push was 42.05 percent. The higher response rate in the enhanced web push condition suggests that the additional strategies were effective at bringing in more respondents. Key estimates produced by the enhanced web push condition did not differ from those of the MTF control group.

Self-reported perceived negative consequences of marijuana use among U.S. young adult users, 2008-2019.

PURPOSE: This study estimated self-reported perceived negative marijuana use consequences among a national sample of U.S. young adults, examining consequence prevalence differences by use frequency, college attendance, living situation, employment, sex, and race/ethnicity; and use frequency/sociodemographic characteristic interactions. METHODS: A subsample of 1,212 respondents from the 2004-2018 class cohorts of 12th grade students participating in the nationally-representative Monitoring the Future study was surveyed up to two times from modal ages 19 through 22 (in 2008-2019). Respondents self-reported negative consequences related to their own past 12-month marijuana use. Bivariate and multivariable models examined subgroup differences in consequence prevalence. RESULTS: Approximately 60% of those using frequently (20+ use occasions in the past 30 days) and 35% of those using non-frequently reported negative consequences. Among all young adult marijuana users, 31.1% reported emotional/physical consequences, 12.9% performance/financial consequences, and 12.3% relational consequences. Use frequency was positively associated with consequence likelihood, excluding regret and unsafe driving. Among college students, frequent use was more strongly associated with any and performance/financial consequences. Controlling for use frequency, men reported more performance/financial consequences; relational consequences were higher among Hispanic (vs. White) respondents, and those living with parents, employed full-time, and not attending 4-year colleges. CONCLUSION: Young adults using marijuana reported a wide range of negative use consequences; likelihood of most consequences increased with higher use frequency. Perceived consequences varied by college attendance, living situation, employment, sex, and race/ethnicity. Efforts to reduce negative marijuana consequences may be strengthened by recognizing and addressing the different types of negative consequences users perceive.

ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia.

A major barrier to adeno-associated virus (AAV) gene therapy is the inability to re-dose patients due to formation of vector-induced neutralizing antibodies (Nabs). Tolerogenic nanoparticles encapsulating rapamycin (ImmTOR) provide long-term and specific suppression of adaptive immune responses, allowing for vector re-dosing. Moreover, co-administration of hepatotropic AAV vectors and ImmTOR leads to an increase of transgene expression even after the first dose. ImmTOR and AAV Anc80 encoding the methylmalonyl-coenzyme A (CoA) mutase (MMUT) combination was tested in a mouse model of methylmalonic acidemia, a disease caused by mutations in the MMUT gene. Repeated co-administration of Anc80 and ImmTOR was well tolerated and led to nearly complete inhibition of immunoglobulin (Ig)G antibodies to the Anc80 capsid. A more profound decrease of plasma levels of the key toxic metabolite, plasma methylmalonic acid (pMMA), and disease biomarker, fibroblast growth factor 21 (FGF21), was observed after treatment with the ImmTOR and Anc80-MMUT combination. In addition, there were higher numbers of viral genomes per cell (vg/cell) and increased transgene expression when ImmTOR was co-administered with Anc80-MMUT. These effects were dose-dependent, with the higher doses of ImmTOR providing higher vg/cell and mRNA levels, and an improved biomarker response. Combining of ImmTOR and AAV can not only block the IgG response against capsid, but it also appears to potentiate transduction and enhance therapeutic transgene expression in the mouse model.

Adolescent drug use before and during U.S. national COVID-19 social distancing policies.

BACKGROUND: How adolescent substance use and perceived availability of substances have changed during the COVID-19 pandemic remain largely unknown. Substantial reduction in availability of substances would present a unique opportunity to consider the supply-side hypothesis that reductions in drug availability will lead to reductions in drug prevalence. METHODS: Longitudinal data come from Monitoring the Future and are based on responses from 582 adolescents who were originally surveyed as part of a national sample of 12th grade students in early 2020, one month before social distancing policies began. They were surveyed again after social distancing policies were implemented, in the summer of 2020. RESULTS: Perceived availability of marijuana and alcohol declined across the two survey waves at the largest levels ever recorded in the 46 years of the project, by an absolute 17 %, p < .01 and 24 %, p < .01, respectively. Despite these declines, prevalence levels did not significantly change across the two waves for marijuana use in the past 30 days or for binge drinking in the past two weeks. Perceived availability of vaping devices significantly declined, from 73 % to 63 %, as did nicotine vaping prevalence in the past 30 days, from 24 % to 17 %. CONCLUSIONS: Perceived availability of marijuana, alcohol, and vaping devices declined at historic rates during the pandemic of 2020. Lack of accompanying reductions in prevalence for marijuana and binge drinking demonstrates the substantial challenges facing a supply-side approach to the reduction of adolescent use of these substances.

Trends in Use and Perceptions of Nicotine Vaping Among US Youth From 2017 to 2020.

Importance: US adolescent nicotine vaping increased at a record pace from 2017 to 2019, prompting new national policies to reduce access to flavors of vaping products preferred by youth. Objective: To estimate prevalence, perceived harm, and accessibility of nicotine vaping products among US adolescents from 2017 to 2020. Design, Setting, and Participants: This survey study includes data from Monitoring the Future, which conducted annual, cross-sectional, school-based, nationally representative surveys from 2017 to 2020 of 10th- and 12th-grade students (results pooled grades, n = 94 320) about vaping and other topics. Main Outcomes and Measures: Prevalence of self-reported nicotine vaping; vaping brand and flavor used most often; perceived risk of nicotine vaping; and perceived ease of getting vaping devices, nicotine solutions for vaping, and flavored solutions. Results: In 2020, Monitoring the Future surveyed 8660 students in 10th and 12th grade, of whom 50.6% (95% CI, 47%-54%) were female, 13% (95% CI, 8%-21%) were non-Hispanic Black, 29% (95% CI, 21%-40%) were Hispanic, and 53% (95% CI, 42%-63%) were non-Hispanic White. Nicotine vaping prevalence in 2020 was 22% (95% CI, 19%-25%) for past 30-day use, 32% (95% CI, 28%-37%) for past 12-month use, and 41% (95% CI, 37%-46%) for lifetime use; these levels did not significantly change from 2019. Daily nicotine vaping (use on ≥20 days of the last 30 days) significantly declined from 9% (95% CI, 8%-10%) to 7% (95% CI, 6%-9%) over 2019 to 2020. JUUL brand prevalence in the past 30 days decreased from 20% (95% CI, 18%-22%) in 2019 to 13% (95% CI, 11%-15%) in 2020, while use of other brands increased. Among youth who vaped in the past 30 days in 2020, the most often used flavor was fruit at 59% (95% CI, 55%-63%), followed by mint at 27% (95% CI, 24%-30%) and menthol at 7% (95% CI, 5%-9%); significantly fewer reported easy access to vaping devices and nicotine solutions compared with 2019; and 80% (95% CI, 75%-84%) reported they could easily get a vaping flavor other than tobacco or menthol. Among all youth, perceived risk of both occasional and regular nicotine vaping increased from 2019 to 2020. Conclusions and Relevance: Increasing US adolescent nicotine vaping trends from 2017 to 2019 halted in 2020, including a decline in daily vaping. Decreases in perceived accessibility of some vaping products, as well as increases in perceived risk of nicotine vaping, occurred from 2019 to 2020. Yet, adolescent nicotine vaping remains highly prevalent, flavors remain highly accessible, and declines in JUUL use were countered by increased use of other brands.

Diversion of Medical Marijuana to Unintended Users Among U.S. Adults Age 35 and 55, 2013-2018.

OBJECTIVE: This study estimated the percentage of age 35 and 55 adults reporting using medical marijuana intended for someone else (diverted use) and compared demographics and health status of such users with respondents reporting recommended use (i.e., individuals with a medical marijuana recommendation for their own health conditions) and to respondents using marijuana not intended for medical use (nonmedical marijuana [NMM] use). METHOD: Cross-sectional analyses were conducted using complex sample survey data collected from 2013 to 2018 from 12,138 adults (6,998 women) at modal ages 35 or 55 participating in the U.S. national Monitoring the Future study. RESULTS: Diverted use was reported by 72.9% [95% CI, 66.4, 79.4] and 64.3% [56.0, 72.7] of age 35 and 55 past-12-month medical marijuana users, respectively. Age 35 diverted users were more likely than recommended users to not work full time and have no postsecondary education. Age 55 recommended users were more likely than NMM users to be retired. Age 35 diverted users were less likely than recommended users to report poor physical health (odds ratio [OR] = 0.40 [0.17, 0.94]). Age 55 diverted users were less likely than recommended users to report three or more poor health conditions (OR = 0.22 [0.09, 0.55]) and any qualifying conditions (OR = 0.21 [0.08, 0.58]). Prevalence of these conditions was similar between diverted and NMM users. CONCLUSIONS: Results indicated a substantial degree of nonmedical (i.e., recreational) marijuana use. Diverted and NMM users reported generally similar levels of health conditions, whereas diverted users had fewer indicators of poor health than recommended users.

Changes in the Order of Cigarette and Marijuana Initiation and Associations with Cigarette Use, Nicotine Vaping, and Marijuana Use: U.S. 12th Grade Students, 2000-2019.

This study (a) examined changes in marijuana and cigarette initiation sequencing and (b) considered implications of such changes for prevention efforts by examining associations between initiation sequencing and current adolescent substance use. Analyses used 2000-2019 cross-sectional data from the national Monitoring the Future (MTF) study (78,252 U.S. 12th grade students). Models examined trends in six distinct patterns of initiation order, and multivariable associations between order of initiation and 30-day cigarette and marijuana use prevalence, cigarette and marijuana use frequency among users, and nicotine and marijuana vaping prevalence. While the percentage of students initiating neither cigarettes nor marijuana increased, increases also were observed in marijuana-only initiation (the fastest-growing pattern) and initiation of marijuana before cigarettes; these increases were accompanied by a significant decrease in cigarette-only initiation. Cigarette use prevalence and frequency were highest among students initiating cigarettes before marijuana; marijuana use prevalence and frequency were highest among students initiating marijuana before cigarettes. Cigarette and marijuana prevalence, as well as marijuana frequency, were lowest among students initiating only a single substance. Nicotine vaping was less prevalent among students initiating a single substance versus both substances, but no significant differences were observed in nicotine vaping prevalence between those initiating only cigarettes versus only marijuana. Implications of these findings for prevention efforts are discussed in the frameworks of both the common liability model and route of administration model.

The growing transition from lifetime marijuana use to frequent use among 12th grade students: U.S. National data from 1976 to 2019.

BACKGROUND: More United States adolescents now report high-frequency marijuana use than similar use levels of alcohol or tobacco. Increased high-frequency use raises questions such as (a) is frequent use likelihood growing among adolescents who experiment with use? (b) Is such change observed equally across sex and racial/ethnic subgroups? (c) Have sociodemographic and other covariate associations with frequent use changed over time? METHODS: Data were obtained from 649,505 12th grade students participating in the cross-sectional, nationally-representative Monitoring the Future study from 1976 to 2019. Historical trends were modeled for any and frequent (20+ occasions) past 30-day marijuana use among all students and lifetime users, and lifetime user sex and racial/ethnic subgroups. Multivariable logistic regression estimates from 1989 to 1993 (lowest prevalence years) versus 2015-2019 (most recent years) were compared to examine covariate association changes with frequent use. RESULTS: Among all students, recent linear trends in any and frequent marijuana use were not significantly different from zero (0.023 [SE 0.156] and 0.036 [0.073], respectively); frequent use among lifetime users increased (0.233 [0.107], p = 0.048). Among lifetime users, the increase was stronger for male than female students, and for minority versus White students. Significant association changes with race/ethnicity, parental education, and perceived risk were observed. CONCLUSIONS: The proportion of adolescent lifetime marijuana users reporting current frequent marijuana use increased, and is now at near-record levels. Increases were particularly strong among males and minority students. There appears to be an increasing likelihood that adolescents who experiment with marijuana use may progress to frequent use.

The great decline in adolescent cigarette smoking since 2000: consequences for drug use among US adolescents.

OBJECTIVE: Adolescent cigarette smoking declined steadily and substantially from 2000 to 2018. This paper considers the potential consequences of this 'great decline' for the prevalence of other drug use among adolescents. METHODS: Data are annual, cross-sectional, nationally representative Monitoring the Future surveys of more than 1.2 million US students in 12th, 10th and 8th grades from 2000 to 2018. Analyses include trends in the past 12 months' non-medical amphetamine, tranquillisers and opioid use overall, among ever and never cigarette smokers, and projected if adolescent cigarette smoking levels had remained at 2000 levels. RESULTS: Within groups of ever and never cigarette smokers, the prevalence for each of the three substances has either changed little or overall increased in 2018 as compared with 2000. When the two groups were combined into one pool, the overall prevalence for each of the drugs declined by about half. The decline resulted from the growing group of never smokers, whose levels of non-medical drug use over the study period were at least four times lower than the levels of ever smokers. CONCLUSIONS: The results support the 'gateway' prediction that declines in cigarette smoking among adolescents pull downward their non-medical use of amphetamines, tranquillisers and opioids. Continuing to reduce adolescent smoking through policy and programmatic prevention efforts should have further positive spillover effects on adolescent drug use.

Two-Year Follow-up of a Sequential Mixed-Mode Experiment in the U.S. National Monitoring the Future Study.

This study examines the two-year follow up (data collected in 2016 at modal age 21/22) of an original mixed-mode longitudinal survey experiment (data collected at modal age 19/20 in 2014). The study compares participant retention in the experimental conditions to retention in the standard Monitoring the Future (MTF) control condition (participants who completed an in-school baseline survey in 12th grade in 2012 or 2013 and were selected to participate in the first follow-up survey by mail in 2014, N=2,451). A supplementary sample who completed the 12th grade baseline survey in 2012 or 2013 but were not selected to participate in the main MTF follow-up (N=4,950) were recruited and randomly assigned to one of three experimental conditions: 1: Mail Push, 2: Web Push, 3: Web Push + Email in 2014 and again in 2016. Results from the first experiment indicated that Condition 3 (Web Push + Email) was promising based on similar response rates and lower costs (Patrick et al. 2018). The current study examines how experimental condition and type of 2014 response were associated with response in 2016, the extent to which response mode and device type changed from 2014 to 2016, and cumulative cost comparisons across conditions. Results indicated that responding via web in 2014 was associated with greater odds of participation again in 2016 regardless of condition; respondents tended to respond in the same mode although the "push" condition did move respondents toward web over paper; device type varied between waves; and the cumulative cost savings of Web Push + Email grew larger compared to the MTF Control. The web push strategy is therefore promising for maintaining respondent engagement while reducing cost.

The national prevalence of adolescent nicotine use in 2017: Estimates taking into account student reports of substances vaped.

INTRODUCTION: This study presents the first nationally-representative estimates of adolescent nicotine prevalence that take into account adolescent reports of substances vaped. These reports allow nicotine estimates that consider the impact of the newly-emerged group of adolescents who report vaping only non-nicotine substances such as flavoring and/or marijuana and do not use nicotine in any form - a group typically treated as nicotine users. METHODS: Data come from Monitoring the Future and are a randomly-selected subsample of 2231 U.S. 12th grade students who answered surveys with detailed questions on tobacco use and vaping in 2017. RESULTS: Among 12th grade students 24.7% used nicotine in the last 30 days. This estimate does not include the 3.8% of students who vaped only non-nicotine substances and did not use nicotine in any other form. These students more closely resemble their peers who do not use nicotine than those who do, in terms of perceived risk and disapproval of cigarettes, as well as percentage of friends who use cigarettes. CONCLUSIONS: A decline in nicotine prevalence was statistically significant, but not strikingly large, after taking into account students who vape non-nicotine substances and do not use nicotine in any form. These students are largely similar to their peers who do not use nicotine, which underscores the importance of efforts to alert youth that they may be vaping nicotine unknowingly, and prevent them from doing so.

Increasing marijuana use for black adolescents in the United States: A test of competing explanations.

AIMS: In the last decade the relatively lower levels of marijuana use for black relative to non-black high school seniors has grown smaller and disappeared, drawing to a close a unique disparity that actually favored a disadvantaged group for at least thirty years. In this study we test trends in cigarette smoking and religiosity as possible explanations for this closing disparity. The study also examines whether increasing marijuana levels for black adolescents is better characterized as a cohort effect or an historical period effect. DESIGN: Analyses use relative risk regression and focus on data from yearly, cross-sectional surveys from the time period 2008-2017. SETTING AND PARTICIPANTS: Data comes from the nationally-representative Monitoring the Future survey, which conducts in-school surveys of secondary school students. The analysis uses data from 114,552 high school seniors (in 12th grade), 123,594 in 10th grade, and 136,741 in 8th grade. FINDINGS: Past 12-month marijuana prevalence significantly increased for black as compared to non-black adolescents from 2008 to 2017 in 12th grade, 10th grade, and 8th grade. The increase attenuated by more than half and was not statistically significant after adjusting for cigarette smoking. In contrast, the increase was little changed after adjusting adolescent levels of religiosity. The increase is better characterized as a cohort effect than a period effect. CONCLUSIONS: These results support the increase in marijuana use for black relative to non-black adolescents as an unexpected consequence of the great decline in adolescent cigarette smoking, which has occurred slower for black adolescents.

Young adult longitudinal patterns of marijuana use among US National samples of 12th grade frequent marijuana users: a repeated-measures latent class analysis.

BACKGROUND AND AIMS: Long-term frequent marijuana use is associated with significant negative outcomes, yet little is known about the longitudinal course of marijuana use among those who start frequent use during adolescence. Objectives are (a) to identify latent patterns of within-person marijuana use from ages 19-30 years among 12th graders reporting frequent marijuana use, (b) to examine if membership in identified patterns has changed across historical time and (c) to examine if key covariates differentiate class membership. DESIGN, SETTING, PARTICIPANTS: Longitudinal, national US panel data from 4423 individuals [53.4% of the eligible sample; 2744 (62%) males] who reported frequent marijuana use in 12th grade (modal age 18 years; senior year cohorts 1976-2006) followed biennially from ages 19/20 to 29/30. MEASUREMENTS: Self-reported past 30-day marijuana use (frequent use defined as use on 20+ occasions), demographics, college graduation, marriage and parenthood. FINDINGS: Repeated-measures latent class analysis (RMLCA) identified five latent classes of past 30-day marijuana use from ages 19/20 to 29/30: continued frequent users (estimated membership 23.4%); frequent to non-frequent users (15.5%); consistent non-frequent users (18.4%); non-frequent users to discontinuers (19.5%); and discontinuers (23.2%). In multivariable models, membership in the highest-risk latent class (continued frequent users) versus one or more of the lower-risk latent classes was more likely for recent cohorts (P = 0.038 to <0.001), as well as those who did not marry (P = 0.039 to < 0.001) or become parents (P = 0.001) by modal age 29/30. CONCLUSIONS: Nearly one in four 12th grade (modal age 18 years) frequent marijuana users in the US continues to report high frequency use to age 30; the proportion continuing high frequency use across young adulthood has increased among more recent cohorts.