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Background & Aims: A common genetic variant (rs738409) encoding isoleucine to methionine at position 148 in the PNPLA3 protein is a determinant of hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver-related mortality. AZD2693 is a liver-targeted antisense oligonucleotide against PNPLA3 mRNA. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics in single ascending dose (SAD) and multiple ascending dose (MAD) studies., Methods: AZD2693 was assessed in 3D cultures of homozygous PNPLA3 148M primary human hepatocytes and mice expressing human PNPLA3. The SAD study investigated 2-110 mg doses in overweight/mildly obese but otherwise healthy volunteers. The MAD study investigated three monthly doses (25 mg, 50 mg and 80 mg) in participants with magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥ 7%. Changes in liver fat content were assessed at baseline, weeks 8 and 12 by MRI-PDFF. PNPLA3 mRNA and protein knockdown levels were evaluated for the 80 mg dose., Results: AZD2693 potently reduced PNPLA3 expression in human hepatocytes and livers of mice. Clinically, AZD2693 was generally well tolerated (no adverse events leading to discontinuation or treatment related serious adverse events). Half-life was 14-33 days across investigated doses. A least-square (LS) mean liver PNPLA3 mRNA knockdown of 89% and reduction of protein levels demonstrated target engagement. Changes in hepatic steatosis at week 12 were -7.6% and -12.2% (placebo-corrected LS means) for the 25 mg and 50 mg doses, respectively. There was a dose-dependent increase of polyunsaturated fatty acids in serum triglycerides and decreases vs placebo in high-sensitivity C-reactive protein and interleukin 6., Conclusions: AZD2693 reduced liver PNPLA3 with an acceptable safety and tolerability profile. These findings support the continued development of AZD2693., Clinical Trial Number: NCT04142424, NCT04483947 IMPACT AND IMPLICATIONS: Clinical treatment options for MASH are limited. The genetic risk factor with the largest effect size for progressing to poor liver-related outcomes in MASH is a single-nucleotide polymorphism in the gene PNPLA3 (p.I148M). In Phase 1 SAD and MAD studies, AZD2693, a liver-targeted antisense oligonucleotide was well tolerated, reduced liver PNPLA3 mRNA and protein levels, and dose dependently reduced liver fat content in homozygous PNPLA3 148M risk allele carriers. These data support continued development of AZD2693 as a potential precision medicine treatment for MASH. The Phase 2b FORTUNA study is now ongoing., Competing Interests: Declaration of Competing Interest JA, MR, JS, ML, LW, MN, OE, TS, JS, LB, SH, SW, PK, MB, IM, YW, OF, DL, JEB are employees and stockholders of AstraZeneca. RGL, SB and SG are employees and stockholders of Ionis Pharmaceuticals. SR has served as a consultant for AstraZeneca, Celgene, Sanofi, Amgen, Akcea Therapeutics, Camp4, Medacorp and Ambys, and has received research grants from AstraZeneca. EL serves as consultant for 89Bio, AstraZeneca, Akero, Boehringer Ingelheim, BMS, Corcept, Intercept, Novo Nordisk, Merck, Sagimet, Takeda, and Terns, and as speaker for Abbvie, Gilead Sciences, Intercept, and Madrigal. In addition, his institution received research funding from 89Bio Inc., Akero Therapeutics, Altimmune, Amgen, Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, DSM, Corcept, Eli Lilly and Company, Enanta Pharmaceuticals, Enyo Pharma, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, , Gilead Sciences, GlaxoSmithKline, Hanmi Pharmaceuticals, Hightide Biopharma, Intercept Pharmaceuticals, Inventiva, Janssen Pharmaceuticals, Madrigal Pharmaceuticals, Merck & Co., NeuroBio, NGM Biopharmaceuticals Inc., Northsea Therapeutics, Novartis, Novo Nordisk Inc., Poxel Co., Regeneron, Rivus, Sagimet Biosciences, Takeda, Terns Pharmaceuticals, Viking Therapeutics, Zydus Pharmaceuticals. RL serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. RL has stock options in Sagimet Biosciences. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc, (Copyright © 2025. Published by Elsevier B.V.)

Introduction: Global disparities in HIV prevalence among transgender women are well documented. However, current epidemiological literature on HIV disparities demonstrates gaps in research that include the diversity within transgender populations-for example, transgender men and non-binary trans people across global regions. This systematic review and meta-analysis protocol aims to summarise global HIV inequities among all transgender and non-binary (trans) populations. The objectives of this review are to estimate pooled HIV prevalence and prevention outcomes (pre-exposure prophylaxis and antiretroviral therapy) and differences by gender identity, global regions and self-report versus lab-confirmed findings among trans adults worldwide., Methods and Analysis: We will conduct a systematic review of all studies on HIV outcomes among trans youth and adults (aged 15+ years) published between 2000 and 2024, following the Preferred Reporting Items for Systematic Review and Meta-Analysis Prereporting guidelines. We will use Covidence software for the title and abstract screening, full-text review and data abstraction processes. We will summarise the study's descriptive statistics and conduct meta-analyses of extracted data points to calculate and synthesise pooled findings and effect size. Specifically, we will use the Mantel-Haenszel method with random effects to model our meta-analyses and the DerSimonian and Laird Q test for heterogeneity testing. We will conduct a narrative synthesis on the areas of research that have been conducted to improve HIV prevention and treatment among trans populations and summarise their findings. Subgroup analyses by gender identity, global regions and self-report versus lab-confirmed findings will be conducted., Ethics and Dissemination: Ethics approval is not applicable for this review since we will not be collecting primary data. The results will be disseminated through peer-reviewed publications and conference presentations., Prospero Registration Number: The protocol is registered in the International Prospective Register of Systematic Reviews database (PROSPERO ID: CRD42022357285)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)