Abstract: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Abstract: Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract: The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

Abstract: Drowning is a leading cause of injury-related mortality globally. Unintentional drowning (International Classification of Diseases (ICD) 10 codes W65-74 and ICD9 E910) is one of the 30 mutually exclusive and collectively exhaustive causes of injury-related mortality in the Global Burden of Disease (GBD) study. This study’s objective is to describe unintentional drowning using GBD estimates from 1990 to 2017. Methods Unintentional drowning from GBD 2017 was estimated for cause-specific mortality and years of life lost (YLLs), age, sex, country, region, Socio-demographic Index (SDI) quintile, and trends from 1990 to 2017. GBD 2017 used standard GBD methods for estimating mortality from drowning. Results Globally, unintentional drowning mortality decreased by 44.5% between 1990 and 2017, from 531 956 (uncertainty interval (UI): 484 107 to 572 854) to 295 210 (284 493 to 306 187) deaths. Global age-standardised mortality rates decreased 57.4%, from 9.3 (8.5 to 10.0) in 1990 to 4.0 (3.8 to 4.1) per 100 000 per annum in 2017. Unintentional drowning-associated mortality was generally higher in children, males and in low-SDI to middle-SDI countries. China, India, Pakistan and Bangladesh accounted for 51.2% of all drowning deaths in 2017. Oceania was the region with the highest rate of age-standardised YLLs in 2017, with 45 434 (40 850 to 50 539) YLLs per 100 000 across both sexes. Conclusions There has been a decline in global drowning rates. This study shows that the decline was not consistent across countries. The results reinforce the need for continued and improved policy, prevention and research efforts, with a focus on low- and middle-income countries.

Abstract: BAFF and APRIL are TNF superfamily members that bind both TACI and BCMA on B cells; BAFF also binds BAFF-R. Together, BAFF and APRIL support B cell development, differentiation, and survival. Their co-neutralization dramatically reduces B cell function, including antibody production, whereas inhibition of either BAFF or APRIL alone mediates relatively modest effects. Objectives: While CTLA-4-based therapeutics that block T cell costimulation provide safe and moderately effective T cell inhibition in many disease settings, and while B cell targeting therapies have demonstrated promising therapeutic potential, we postulate that improved, combined BAFF and APRIL inhibition, either alone or coupled with inhibition of T cell costimulation, will provide more effective and durable relief from severe B cell-related autoimmune diseases like SLE. Methods: We used our directed evolution platform to identify variant domains of the TNF family receptors TACI or BCMA that exhibit enhanced affinity for BAFF and APRIL as compared to their wild-type (WT) counterparts. These variant TACI or BCMA domains (vTD), alone or together with platform-derived CTLA-4 domains (vIgD), were fused to a modified human IgG1 Fc lacking effector function, yielding a panel of immunomodulatory molecules: TACI vTD-Fc, BCMA vTD-Fc, TACI vTD/CTLA-4 vIgD-Fc, & BCMA vTD/CTLA-4 vIgD-Fc. All were evaluated for functional activity: 1) in vitro in primary human B cell & MLR assays and in a Jurkat/NF-kB reporter cell line expressing TACI, and 2) in vivo in standard immunization models, and in the bm12-induced and NZB/NZW spontaneous mouse models of lupus. Results: The novel engineered TACI vTD-Fc or BCMA vTD-Fc fusion proteins significantly inhibited BAFF- and APRIL-mediated signaling in vitro in TACI + Jurkat cells. TACI (or BCMA) vTD/CTLA-4 vIgD-Fc proteins also attenuated T cell activation in primary human lymphocyte assays. When administered to mice, these molecules rapidly and potently reduced key B and T cell subsets, including plasma cells, follicular T helper cells, germinal center cells, & memory T cells. Treatment with TACI vTD-Fc or TACI vTD/CTLA-4 vIgD-Fc proteins also significantly reduced titers of antigen-specific antibodies in immunized mice more so than abatacept or WT TACI-Fc, and potently suppressed anti-dsDNA autoantibodies, blood urea nitrogen levels, proteinuria, and renal immune complex deposition in the bm12 & NZB/W lupus models. Conclusion: Directed evolution of TNFR and IgSF domains has successfully facilitated the development of Fc fusion proteins containing TACI or BCMA vTDs, with or without fusion to CTLA-4 vIgDs. These novel immunomodulators consistently demonstrate potent immunosuppressive activity and efficacy in vitro and in vivo , appearing superior to existing and/or approved immunomodulators like belimumab, abatacept, or atacicept. Such biologics may therefore be attractive candidates for the treatment of serious autoimmune diseases, particularly B cell-related diseases such as SLE, Sjogren’s syndrome, etc. Disclosure of Interests: : Stacey R. Dillon Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Lawrence S. Evans Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Mark W. Rixon Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Joe Kuijper Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Dan Demonte Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Katherine E. Lewis Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Steve Levin Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Kayla Kleist Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Sherri Mudri Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Susan Bort Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Janhavi Bhandari Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Fariha Ahmed-Qadri Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Jing Yang Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Michelle A. Seaberg Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Rachel Wang Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Russell Sanderson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Martin F. Wolfson Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Jan Hillson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Stanford L. Peng Shareholder of: Alpine Immune Sciences, Inc., Employee of: CMO and President of Alpine Immune Sciences, Inc., Kristine M. Swiderek Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc.

Abstract: B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are tumor necrosis factor (TNF) superfamily members that bind TACI (transmembrane activator and CAML interactor), BCMA (B-cell maturation antigen), and/or BAFF-R on B cells and together support B cell development, differentiation, and survival. ALPN-303 is an Fc fusion protein of a human TACI variant TNFR domain engineered by directed evolution 1,2 . It mediates significantly improved combined BAFF and APRIL inhibition in vitro and enhanced pharmacokinetic and immunomodulatory properties in preclinical studies, as compared to wild-type (WT) TACI-Fc molecules. B-cell targeting therapies like the WT TACI-Fc fusions atacicept and telitacicept have demonstrated promising clinical potential in B cell-related diseases like systemic lupus erythematosus (SLE). ALPN-303, with enhanced inhibitory activity against BAFF and APRIL, has previously been shown to demonstrate promising efficacy in an (NZB/NZW)F 1 mouse model of lupus, and may therefore further improve clinical outcomes in such diseases. Objectives To further characterize the comparative activity of ALPN-303 versus an Fc matched control, a WT TACI-Fc comparator (telitacicept), and/or a B cell-depleting therapy (anti-mouse CD20 [anti-mCD20] monoclonal antibody [mAb] ), in antibody-related preclinical models. Methods The functional activity of ALPN-303, as compared to telitacicept or a depleting anti-mCD20 mAb, was evaluated in a sheep red blood cell (SRBC) immunization mouse model. Mice immunized intraperitoneally with SRBC on Study Day 0 were administered 200 µg ALPN-303 or a molar-matched amount (240 µg) of telitacicept on Days 1 and 6 or were treated with 200 µg anti-mCD20 (rat IgG2b) on Day 1. At study termination on Day 15, serum was collected to measure levels of test article and anti-SRBC immunoglobulin (Ig) titers, and spleens and bone marrow (BM) were collected for immunophenotyping by flow cytometry. A study in the inducible bm12 mouse model of lupus was also conducted, with mice treated twice weekly with 200 µg ALPN-303 or a molar-matched dose of Fc control, starting on Day 5 after splenocyte transfer and continuing through Week 13. Results ALPN-303 administration rapidly and potently reduced BM plasma cells, splenic germinal center B cells, follicular T helper cells, and plasmablasts in SRBC-immunized mice, often significantly more so than telitacicept and/or anti-mCD20 mAb. ALPN-303 also significantly reduced serum titers of anti-SRBC IgM, IgG1, IgG2a, and IgG2b as compared to all other treatment groups. In the bm12 model, ALPN-303 treatment significantly impacted the same key lymphocyte subsets affected in the SRBC model, and significantly reduced circulating anti-dsDNA antibodies (Figure 1) and total IgA, IgM, IgG1, IgG2b, and IgG3, and inhibited renal IgG deposits (Figure 1). Figure 1. ALPN-303 treatment significantly reduces serum autoantibody titers and renal immune complex deposition in the inducible bm12 mouse model of lupus. * p 〈 0.05, ** p 〈 0.01, **** p 〈 0.0001 by the Kruskal-Wallis test. Conclusion ALPN-303 is an engineered, potent BAFF/APRIL antagonist that continues to consistently demonstrate encouraging immunomodulatory activity and efficacy in vitro and in vivo, as further demonstrated in the SRBC immunization and bm12 lupus models, with superiority to WT TACI-Fc and anti-CD20 comparators. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell- and/or autoantibody-related diseases such as SLE, Sjögren’s syndrome, and other connective tissue diseases. A Phase 1 study of ALPN-303 in adult healthy volunteers ( NCT05034484 ) is ongoing. References [1]Dillon SR, Evans LS, Lewis KE, et al. Annals of the Rheumatic Diseases 2021;80:21. [2]Dillon SR, Evans LS, Lewis KE, et al. Arthritis Rheumatol. 2021; 73 (suppl 10). Disclosure of Interests Stacey R. Dillon Employee of: Alpine Immune Sciences, Katherine E. Lewis Employee of: Alpine Immune Sciences Inc, Sherri Mudri Employee of: Alpine Immune Sciences Inc, Kayla Kleist Employee of: Alpine Immune Sciences Inc, Luana Griffin Employee of: Alpine Immune Sciences Inc, Lawrence S. Evans Employee of: Alpine Immune Sciences Inc, Janhavi Bhandari Shareholder of: Amgen, Novo Nordisk, Employee of: Alpine Immune Sciences Inc, Logan Garrett Employee of: Alpine Immune Sciences Inc, Michelle A. Seaberg Employee of: Alpine Immune Sciences Inc, NingXin Wang Employee of: Alpine Immune Sciences Inc, Allison Chunyk Employee of: Alpine Immune Sciences Inc, Daniel Ardourel Employee of: Alpine Immune Sciences Inc, LuAnne Hebb Employee of: Alpine Immune Sciences Inc, Martin F. Wolfson Employee of: Alpine Immune Sciences Inc, Mark W. Rixon Employee of: Alpine Immune Sciences Inc, Pamela Holland Employee of: Alpine Immune Sciences Inc, Stanford L. Peng Employee of: Alpine Immune Sciences Inc