A Phase 2/3, Open-Label Study to Evaluate the Pharmacokinetics, Safety, and Antiviral Activity of Bictegravir/Lenacapavir in Children and Adolescents With HIV-1

The goal of this clinical study is to learn about the safety and tolerability of bictegravir/lenacapavir (BIC/LEN) and to learn how the study drug interacts with the body in virologically suppressed (VS) children and adolescents with human immunodeficiency virus type 1 (HIV-1) on a stable and complex antiretroviral (ARV) regimen. The study will also assess the safe loading dose of LEN and pharmacokinetics (PK) of BIC/LEN.
The primary objectives of this study are:
* To evaluate the steady-state PK of BIC and LEN and confirm the dose of the LEN loading dose and BIC/LEN FDC in VS children and adolescents with HIV-1.
* To evaluate the safety and tolerability of BIC/LEN through Week 24 in VS children and adolescents with HIV-1.

Start Date01 Nov 2024

Sponsor / Collaborator

Gilead Sciences, Inc.

NCT06333808 / RecruitingPhase 3

Phase 3 Double-blind Multicenter Randomized Active-Controlled Study to Evaluate the Safety and Efficacy of Bictegravir/Lenacapavir Versus Biktarvy® (Bictegravir/Emtricitabine/Tenofovir Alafenamide) in Virologically Suppressed People With HIV-1

The goal of this clinical study is to learn more about the effects of switching to the study drugs, bictegravir (BIC)/lenacapavir (LEN), fixed-dose combination (FDC) versus current therapy bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) FDC in people living with HIV-1 (PWH).
The primary objective of this study is to learn how effective it is to switch to BIC/LEN FDC tablets versus continuing on B/F/TAF FDC tablets in virologically suppressed PWH.

Start Date25 Mar 2024

Sponsor / Collaborator

Gilead Sciences, Inc.

100 Clinical Results associated with HIV integrase x HIV-1 capsid

100 Translational Medicine associated with HIV integrase x HIV-1 capsid

0 Patents (Medical) associated with HIV integrase x HIV-1 capsid

Literatures (Medical) associated with HIV integrase x HIV-1 capsid

01 Oct 2018·Future Science OA

Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Review

Author: Lu, Dai ; Choi, Eungi ; Mallareddy, Jayapal Reddy ; Kolluru, Srikanth

AIDS caused by the infection of HIV is a prevalent problem today. Rapid development of drug resistance to existing drug classes has called for the discovery of new targets. Within the three major enzymes (i.e., HIV-1 protease, HIV-1 reverse transcriptase and HIV-1 integrase [IN]) of the viral replication cycle, HIV-1 IN has been of particular interest due to the absence of human cellular homolog. HIV-1 IN catalyzes the integration of viral genetic material with the host genome, a key step in the viral replication process. Several novel classes of HIV IN inhibitors have been explored by targeting different sites on the enzyme. This review strives to provide readers with updates on the recent developments of HIV-1 IN inhibitors.

01 Dec 2012·Journal of Molecular ModelingQ4 · CHEMISTRY

Identification of old drugs as potential inhibitors of HIV-1 integrase – human LEDGF/p75 interaction via molecular docking

Q4 · CHEMISTRY

Article

Author: Weiqiang Lu ; Xianqiang Sun ; Xu Shen ; Jin Huang ; Guixia Liu ; Xi Li ; Guoping Hu ; Yun Tang

Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, human protein Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. LEDGF/p75-HIV-1 IN interaction represents an attractive target for anti-HIV therapy. In this study, approved drugs were investigated for the finding of potential inhibitors on this target. Via molecular docking against the LEDGF/p75-binding pocket of HIV-1 IN, 26 old drugs were selected from the DrugBank and purchased for bioassays. Among them, eight, namely Atorvastatin, Bumetanide, Candesartan, Carbidopa, Diclofenac, Diflunisal, Eprosartan, and Sulindac, were identified as potential inhibitors of LEDGF/p75- HIV-1 IN interaction, whose IC(50) values ranged from 6.5 μM to 36.8 μM. In addition, Atorvastatin was previously reported to block HIV-1 replication and may have an important implication for the treatment of AIDS. Our results suggested a mechanism of action for the anti-HIV effects of Atorvastatin. This work provides a new example of inhibitors targeting protein-protein interaction and confirmed that old drugs were valuable sources for antiviral drug discovery.

01 Feb 2002·Journal of Medicinal ChemistryQ1 · MEDICINE

CoMFA and CoMSIA 3D QSAR and Docking Studies on Conformationally-Restrained Cinnamoyl HIV-1 Integrase Inhibitors: Exploration of a Binding Mode at the Active Site

Q1 · MEDICINE

Article

Author: Assefa, Haregewein ; Buolamwini, John K.

Anti-HIV (human immunodeficiency virus) drug discovery has been increasingly focusing on HIV integrase (IN) as a potential therapeutic target. This enzyme is required for the integration of reverse transcribed proviral DNA into the host cell's genome and is essential for the propagation of the HIV life cycle. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D QSAR) studies and docking simulations were conducted on a series of potent conformationally restrained cinnamoyl inhibitors of HIV-1 IN (Artico; et al. J. Med. Chem. 1998, 41, 3948-3960). Predictive 3D QSAR models were established using SYBYL multifit molecular alignment rule, which had conventional r(2) and cross-validated coeffiecient (q(2)) values up to 0.981 and 0.721 for CoMFA and 0.975 and 0.804 for CoMSIA, respectively. These models were validated by an external test set (Burke; et al. J. Med. Chem. 1995, 38, 4171-4178). CoMFA and CoMSIA 3D QSAR models were also derived using a molecular alignment obtained by docking the compounds into the active site of HIV IN. These latter models were comparable to multifit-derived models in terms of relative descriptor field contributions and the partial least squares (PLS) contour maps. The CoMSIA 3D QSAR models performed better than the CoMFA models. The superior performance of CoMSIA was attributed to the large contribution of hydrogen-bonding interactions to the inhibitory activity differences among the compounds. This was supported by FlexX binding energy scores that correlated well with the inhibitory activity differences between hydroxylated compounds and their corresponding methoxy or deoxy counterparts. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking results, were integrated to propose a binding mode for the cinnamoyl inhibitors at the active site of HIV-1 IN.

News (Medical) associated with HIV integrase x HIV-1 capsid

26 Apr 2023

·www.fiercebiotech.com

GSK drops one of 2 maturation inhibitors in HIV pipeline

GSK made the decision that its candidate was not differentiated enough in the daily oral HIV market. GSK’s weighty HIV pipeline just got slightly lighter as the British Big Pharma decided not to progress a once-promising candidate into late-stage trials. The asset in question, dubbed GSK3640254, was a so-called maturation inhibitor, a type of antiretroviral medicine designed to prevent the HIV replication process by blocking key enzyme activity and causing the formation of immature virus particles. The candidate had demonstrated antiviral activity, safety and tolerability in a phase 2a study back in 2021, but the anticipated phase 2b findings never appeared. The move to cull GSK3640254 was revealed in a presentation (PDF) to coincide with GSK’s first-quarter earnings results this morning. The company made the decision that the candidate was not differentiated enough in the daily oral HIV market, Fierce Biotech has learned. Another limit on the drug’s potential effectiveness was its food effect, a term for the reduced effectiveness of certain drugs if taken soon after a meal. All of GSK’s HIV assets are developed by ViiV Healthcare, its HIV unit that also lists Pfizer and Shionogi as shareholders. ViiV spoke positively about GSK3640254 back in 2021, describing phase 2a results as demonstrating the unit’s “commitment to researching and developing a broad range of innovative approaches to treating HIV.” “Because there are no treatments available that target this specific stage of the HIV life cycle, maturation inhibitors may help meet a critical need, particularly for individuals who are treatment-experienced,” ViiV head of R&D Kimberly Smith, M.D., said at the time. Still, Fierce Biotech understands that removing the candidate is not expected to have any wider impact on GSK’s HIV pipeline, which still includes a maturation inhibitor in the form of VH3739937, currently in phase 1. It’s joined by the HIV capsid protein inhibitors VH4004280 and VH4011499 as well as the HIV integrase inhibitor VH4524184. GSK also lists one HIV drug in phase 2 development: the broadly neutralizing antibody VH3810109, which showed promise in a midstage trial in October. GSK and ViiV can point to other recent successes on the HIV front, with Cabenuva, a combination of the approved drugs cabotegravir and rilpivirine that is administered monthly or every other month, approved in 2021.

Clinical ResultPhase 2Drug ApprovalPhase 1

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