CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusions: A single dose of NM5TFV sustained suppression of HBV DNA in mice for over two months without activating ISGs and inflammasome. These promising findings support further development of NM5TFV as an ultra-long acting formulation candidate.

transaminases which were also considered possibly related to recent passage of a gallstone. In M19-968, linear pharmacokinetics (PK) was observed from 400 to 1800 mg IV with terminal half-life ranging from approximately 12 to 25 days. The concentration required to achieve nearly complete (>90%) α4β7 receptor saturation in healthy volunteers was 3 µg/mL. Trosunilimab-mediated β7 internalization followed a U-shaped relationship with drug concentration. In M19-966 Part A, circulating HIV virions expressed α4β7 indicating potential for Fc-mediated immune responses. Expression of α4β7 on virion was found to be inversely correlated with internalization of the receptor. Conclusions: The phase 1 studies showed that trosunilimab was well-tolerated in healthy volunteers and in PWH. The safety, PK/PD, and immunogenicity data from phase 1 studies allowed dose selection for the ongoing phase 2 study, M19-965, evaluating combinations of trosunilimab and budigalimab in PWH undergoing analytic treatment interruption.

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Potent, Pan-Coronavirus Antiviral Activity of the Novel 3CLpro Inhibitor ALG-097558 Cheng Liu 1 , Ching-Wen Chang 2 , Dirk Jochmans 3 , Antitsa Stoycheva 1 , Sarah K. Stevens 1 , David McGowan 4 , Neelam Oswal 2 , David B. Smith 1 , Julian A. Symons 1 , Lawrence Blatt 1 , David Perlin 2 , Arnaud Marchand 5 , Johan Neyts 3 , Stanley Wang 1 , Andreas Jekle 1 1 Aligos Therapeutics, San Francisco, CA, USA, 2 Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ, 3 KU Leuven, Leuven, Belgium, 4 Aligos Therapeutics, Inc, Leuven, Belgium, 5 Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Leuven, Belgium Background: Despite widespread immunity from SARS-CoV-2 vaccination and/ or past infection, safe, effective, and convenient treatments for acute infection are still needed for individuals who remain at high risk for disease progression. Moreover, the risk of another coronavirus pandemic is an ongoing threat to global health. In this context, the development of pan-coronavirus therapeutics is a critical component of pandemic preparedness to avoid a repeat of the immense public health and societal costs caused by COVID-19. Methods: The 3-chymotrypsin like protease (3CLpro) from SARS-CoV-2 and other human and bat coronaviruses was used in enzymatic assays to assess the inhibitory activity of ALG‑097558. The antiviral activity was tested in cell-based assays with SARS-CoV-2, SARS-CoV-1, MERS-CoV and other α- and β-coronaviruses. Bioinformatics analysis was performed to assess sequence conservation in currently circulating SARS-CoV-2 strains and predict susceptibility to ALG-097558. Results: ALG-097558 is a potent inhibitor of the SARS-CoV-2 3CLpro (Wuhan strain) with an IC 50 of 0.22 nM in enzymatic assays. ALG-097558 retained strong inhibitory activity when tested against the 3CLpro derived from SARS-CoV-2 Omicron, MERS-CoV, human α- CoVs NL63 and 229E and β-CoV HKU-1 as well as 3CLpros derived from several bat CoVs with the potential to infect human cells. In cell-based experiments, ALG-097558 demonstrated pan-coronavirus activity with a narrow EC 50 range of 7-40 nM against 8 different SARS-CoV-2 isolates including the Omicron subvariants BA.2, BA.5, BQ.1 and XBB1.5, as well as other human coronaviruses including SARS-CoV-1, MERS-CoV, 229E, the human β-CoV OC43 and a feline CoV. Against Omicron subvariants, ALG-097558 is 3- to 9-fold more active than nirmatrelvir (the 3CLpro inhibitor in Paxlovid™). Other 3CLpro inhibitors in clinical development such as ensitrelvir and ibuzatrelvir demonstrated greatly reduced antiviral activity against α-CoVs. Bioinformatics analysis predicts that ALG-097558 will retain antiviral activity against currently circulating SARS-CoV-2 strains. Conclusions: ALG-097558 demonstrates potent, pan-coronaviral activity in preclinical experiments and is uniquely positioned as a treatment option for SARS-CoV-2 infection and potential future coronavirus pandemics. After having demonstrated a favorable clinical safety and PK profile in Phase I, including ritonavir-free dosing, ALG-097558 warrants further evaluation in patients with COVID-19. Novel Class of Small Molecules Inhibits SARS-CoV-2 PLpro Through Molecular Glue-Induced Dimerization Teresa Ng, Orville A. Pemberton, Thomas E. Frederick, Emily Nicholl, Myron Srikumaran, Jun Chen, Alla Korepanova, Vincent S. Stoll, Andrew M. Petros, Sujatha M. Gopalakrishnan, Justin D. Dietrich, Liliam Rios Cordero, David Hardee, Amanda M. Nevins, Chaohong C. Sun AbbVie, Inc, North Chicago, IL, USA Background: SARS-CoV-2 papain-like protease (PLpro) represents a promising target for novel COVID-19 therapeutics due to its essential roles in viral replication and dysregulation of host innate immunity. PLpro is a domain of SARS-CoV-2 non-structural protein 3 (Nsp3) and is one of two cysteine proteases encoded by the virus. Currently, there are no SARS-CoV-2 PLpro inhibitors in clinical development. Methods: A novel class of PLpro-binding small molecules containing a diarylmethanol substructure was identified from a DNA-encoded library (DEL) screen. The original PLpro DEL binders and their analogs were evaluated in biochemical assays to assess inhibition of PLpro enzymatic function, and in

Poster Abstracts

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Preclinical Evaluation of an Ultra-Long-Acting Tenofovir Prodrug Nanosuspension Samiksha S. Raut, Srijanee Das, Grace Bybee, Haritha Chava, Mojisola Ogunnaike, Weimin Wang, Anup Pathania, Nam Le, Howard Gendelman, Larisa Poluektova, Natalia Osna, Benson Edagwa University of Nebraska Medical Center, Omaha, NE, USA Background: Effective treatment of hepatitis B (CHBV) infection requires adherence to long-term daily antiviral therapies. These include oral tenofovir (TFV) prodrugs [TFV disoproxil-/TFV alafenamide-fumarate - TDF/TAF] or entecavir. Treatment cessation leads to HBV reactivation and disease progression. This underscores the need for long-acting formulations to improve treatment outcomes. Considering these needs, we developed a scalable amino acid-free hydrophobic and lipophilic crystalline phosphonate TFV prodrug (M5TFV). Surfactant-stabilized aqueous nanosuspensions (NM5TFV) were produced at a >300 mg/ml drug concentration. The formulation was stable at room temperature. We now report on possible mechanisms by which NM5TFV sustains suppression of HBV replication in hepatocytes. NM5TFV is well tolerated at the injection site. These promising data support further development and translation of NM5TFV formulation. Methods: Scalable M5TFV was formulated into aqueous nanosuspensions using Tween 20 and PEG 3350 as the stabilizing surfactants. In vivo efficacy was evaluated in transgenic (Tg05) mice administered a single intramuscular injection of NM5TFV at either 200 or 400 mg/kg TFV equivalents. NM1TFV, an injectable TFV prodrug shown to be longer acting than TAF (Sci Adv, 2023), was used as a control. HBV viral load in blood was tested biweekly until rebound. At the time of animal sacrifice, liver tissues were collected to evaluate treatment-mediated activation of interferon (IFN)-stimulated genes (ISG) and inflammasomes. For in vitro studies, HepAD38 cells were treated with NM5TFV for eight hours, followed by incubation in drug-free media for 48 hours. HBV DNA and cccDNA were determined by qPCR. Results: Treatment of HepAD38 cells with NM5TFV led to a two-fold reduction in HBV DNA and cccDNA levels. In HBV-infected mice, low and high-dose single injections of NM5TFV exhibited comparable and >2.5 logs 10 reductions in HBV DNA, lasting over two months ( Fig. A ). Similar observations were recorded for NM1TFV. However, unlike NM5TFV, NM1TFV induced the expression of APOBEG3G and activation of inflammasome receptors, including, NLRP3 and AIM2, and IL1β gene, suggesting divergent antiviral mechanisms of action ( Fig. B ).

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