AT-752 / Atea Pharma - LARVOL DELTA

Dual-channel fluorescent probe for simultaneously visualizing ONOO- and viscosity in epilepsy, non-alcoholic fatty liver and tumoral ferroptosis models. (PubMed, Biosens Bioelectron) - "QX-DP was highly sensitive to viscosity at 668 nm and ONOO- at 752 nm which exhibited significant "turn-on" fluorescence signals, respectively...Most importantly, the concurrent utilization of viscosity and ONOO- for visualizing tumor ferroptosis has been successfully achieved not only in cancer cells and zebrafish but also in tumor mice models. Undoubtedly, in comparison with detection of a single biomarker, monitoring dual biomarkers at the same time may offer a more sensitive and dependable strategy in the diagnosis and image-assisted surgery of oxidative stress and viscosity related diseases."

Journal • CNS Disorders • Epilepsy • Hepatology • Liver Failure • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology

Structural basis for broad-spectrum binding of AT-9010 to flaviviral methyltransferases. (PubMed, Arch Virol) - "AT-9010 (2'-methyl-2'-fluoro guanosine triphosphate) is a GTP analog whose prodrug, AT-752 is under consideration in human medicine as a potential antiviral drug against certain flaviviruses...Our analysis also suggested that the triphosphate part of AT-9010 is flexible. Despite minor variations, the overall binding mode of AT-9010 was found to be the same for all of the flaviviral MTases examined, suggesting a structural basis for the efficacy of AT-9010 against multiple orthoflavivirus MTases."

Journal • Infectious Disease

Directly Grown Polyimide Covalent Organic Framework Films with High Electrochromic and Energy-Storage Performance. (PubMed, ACS Appl Mater Interfaces) - "Their optical contrasts were 77.6% at 752 nm and 60.4% at 708 nm, respectively...Remarkably, the TAPA-PMDA PI COF film also demonstrated large specific capacitance and excellent charge-discharge rate capabilities. The directly grown polyimide 2D COF films are enormously promising for high-performance electrochromic and energy-storage materials."

Journal

Trends and insights in dengue virus research globally: a bibliometric analysis (1995-2023). (PubMed, J Transl Med) - "This bibliometric study underscores the critical role of interdisciplinary collaboration in advancing DENV research, identifying key trends and areas needing further exploration, including host-virus dynamics, the development and application of antiviral drugs and vaccines, and the use of artificial intelligence. It advocates for strengthened partnerships across various disciplines to effectively tackle the challenges posed by DENV."

Journal • Dengue Fever • DDX58 • IFNA1 • NFKB1 • STAT1

The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution. (PubMed, PLoS Biol) - "Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Crystal structures of human histidine triad nucleotide binding protein 1, adenosine deaminase-like protein 1, guanylate kinase 1, and nucleoside diphosphate kinase at 2.09, 2.44, 1.76, and 1.9 Å resolution, respectively, with cognate precursors of AT-9010 illuminate the activation pathway from the orally available bemnifosbuvir to AT-9010, pointing to key drug-protein contacts along the activation pathway. Our work provides a framework to integrate the design of antiviral nucleotide analogues, confronting requirements and constraints associated with activation enzymes along the 5'-triphosphate assembly line."

Journal • HINT1

First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus. (PubMed, Antimicrob Agents Chemother) - P1 | "The favorable safety and pharmacokinetic results support the evaluation of AT-752 as an antiviral for the treatment of dengue in future clinical studies. Registered at ClinicalTrials.gov (NCT04722627)."

Journal • P1 data • PK/PD data • Dengue Fever

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of AT-752, a Novel Nucleotide Prodrug with Pan-Serotype Activity, in Adult Patients with Dengue Virus Infection (ASTMH 2023) - "While pts. presented too late to show a drug effect on VL, positive trends for fever resolution were observed in the AT-752 arm, warranting further evaluation."

Clinical • Late-breaking abstract • P2 data • Dengue Fever • Hematological Disorders • Infectious Disease • Thrombocytopenia

Blood-based epigenome-wide analyses of 19 common disease states: A longitudinal, population-based linked cohort study of 18,413 Scottish individuals. (PubMed, PLoS Med) - "We discovered over 100 associations between blood methylation sites and common disease states, independently of major confounding risk factors, and a need for greater standardisation among EWAS on human disease."

Journal • Breast Cancer • Cardiovascular • Chronic Kidney Disease • Chronic Obstructive Pulmonary Disease • Coronary Artery Disease • Diabetes • Heart Failure • Immunology • Infectious Disease • Metabolic Disorders • Nephrology • Novel Coronavirus Disease • Oncology • Pain • Pulmonary Disease • Renal Disease • Respiratory Diseases • Solid Tumor • Type 2 Diabetes Mellitus

The Challenge of Multi-organism Lung Infection With Human Immunodeficiency Virus (ATS 2023) - "While the primary treatment and prophylaxis for PCP pneumonia is trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone, its concern of developing resistant organisms is increasing...Lactase Dehydrogenase (LDH) was elevated at 752...Patient was admitted and started on TMP-SMX IV, Fluconazole and steroids IV however patient continued with clinical deterioration...Patient was then treated with Pentamidine, Doxycycline, Fluconazole, Meropenem, Vancomycin as well as HIV therapy with Bictarvy...While the primary treatment and prophylaxis for PCP pneumonia is trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone, its concern of developing resistant organisms is increasing...Lactase Dehydrogenase (LDH) was elevated at 752...Patient was admitted and started on TMP-SMX IV, Fluconazole and steroids IV however patient continued with clinical deterioration...Patient was then treated with Pentamidine, Doxycycline, Fluconazole, Meropenem, Vancomycin as well as HIV therapy with..."

Anemia • Cardiovascular • Hematological Disorders • Human Immunodeficiency Virus • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • CD4

Bee venom: an unusual cause of acute kidney injury (PubMed, Nephrol Ther) - "Renal failure with serum creatinine level at 752,2 µmol/L was documented on day 3 in a context of total anuria...The renal prognosis depends on the number of stings, and especially on the delay and the quality of the treatment. Early initiation of dialysis treatment reduces mortality."

Journal • Acute Kidney Injury • Hematological Disorders • Nephrology • Renal Disease

Study of AT-752 in Healthy Subjects in a Dengue Human Challenge Model (clinicaltrials.gov) - P1 | N=5 | Terminated | Sponsor: Atea Pharmaceuticals, Inc. | N=12 ➔ 5 | Trial completion date: Nov 2022 ➔ Mar 2023 | Recruiting ➔ Terminated | Trial primary completion date: Nov 2022 ➔ Mar 2023; Sponsor decision to deprioritize the dengue program

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Dengue Fever

Bee venom: an unusual cause of acute kidney injury (PubMed, Nephrol Ther) - "Renal failure with serum creatinine level at 752,2 μmol/L was documented on day 3 in a context of total anuria...The renal prognosis depends on the number of stings, and especially on the delay and the quality of the treatment. Early initiation of dialysis treatment reduces mortality."

Journal • Acute Kidney Injury • Hematological Disorders • Nephrology • Renal Disease

AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus, does not effect cardiac repolarisation: results from a robust QT/QCc evaluation in healthy participants (ECCMID 2023) - No abstract available

Clinical • Dengue Fever

Study of AT-752 in Patients With Dengue Infection (clinicaltrials.gov) - P2 | N=21 | Terminated | Sponsor: Atea Pharmaceuticals, Inc. | N=60 ➔ 21 | Recruiting ➔ Terminated; Sponsor decision to deprioritize the dengue program

Enrollment change • Trial termination • Dengue Fever • Infectious Disease

AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5. (PubMed, Antiviral Res) - "AT-9010 is discriminated ∼10 to 14-fold against GTP at the NS5 active site of all four DENV1-4 NS5 RdRps, arguing for significant inhibition through viral RNA synthesis termination. In Huh-7 cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC ≈ 0.50 μM), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses."

Journal • Dengue Fever

Safety, tolerability, and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus: results from a first-in-human dose-escalation study (ASTMH 2022) - "No pharmacokinetic ethnic sensitivity was detected. The 750 mg TID dose led to a rapid increase in plasma AT-273 levels to exceed the 90% effective concentration of the drug in inhibiting dengue viral replication in vitro (0.64 uM) and maintained such levels over the treatment period.The overall safety and pharmacokinetic results obtained in this FIM study support further clinical development of AT-752 for the treatment and/or prophylaxis of dengue."

Clinical • P1 data • PK/PD data • Dengue Fever • Gastrointestinal Disorder • Infectious Disease

Study of AT-752 in Healthy Subjects (clinicaltrials.gov) - P1 | N=65 | Completed | Sponsor: Atea Pharmaceuticals, Inc. | Recruiting ➔ Completed | N=48 ➔ 65

Enrollment change • Trial completion • Dengue Fever

Study of AT-752 in Patients With Dengue Infection (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Atea Pharmaceuticals, Inc.

New P2 trial • Dengue Fever • Infectious Disease

Study of AT-752 in Healthy Subjects in a Dengue Human Challenge Model (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Atea Pharmaceuticals, Inc.

New P1 trial • Dengue Fever