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Investigational Antiviral Drugs
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
John Mills, Suzanne M. Crowe, Marianne Martinello
Fostemsavir (BMS-663068) is the prodrug of temsavir (BMS-626529). Temsavir prevents initial viral attachment and entry by binding to the host cell CD4, thereby preventing cellular entry of HIV; its method of action is a first for HIV drugs, and hence it may be useful in patients with highly resistant HIV strains. The drug is a P-glycoprotein substrate but does not induce CYP1A2, 2B6, or 3A4 enzymes in human hepatocytes. It has high (92%) plasma protein binding. EC50 values show considerable strain-dependent variation but are < 10 nM against the majority of HIV-1 strains and in the low picomolar range for the most susceptible HIV-1 strains. Mutations in gp120 (M426L or S375M and to a lesser extent M434I and M475I) were associated with reduced susceptibility in subtype B strains; class resistance in subtype AE viruses was mapped to 375H and 475I mutations. However, because gp120 is a highly conserved area of the virus, the drug is highly unlikely to promote resistance via generation of CD4-independent virus. In a phase IIb trial, subjects were randomized to receive either BMS-663068 (n = 52 for the 400 mg twice daily group, n = 50 for the 800 mg twice daily group, n = 51 for the 600 mg once daily group, and n = 50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n = 51). At week 24, 40/50 (80%) patients in the BMS-663068 400 mg twice daily group, 34/49 (69%) patients in the 800 mg twice daily group, 39/51 (76%) patients in the 600 mg once daily group, and 36/50 (72%) patients in the 1200 mg once daily group had virologic suppression (< 50 copies/ml), compared with 38/51 (75%) patients in the ritonavir-boosted atazanavir group. Serious adverse events were noted in 13/200 (7%) patients in the BMS-663068 groups and 5/51 (10%) patients in the ritonavir-boosted atazanavir group. A phase III study is actively recruiting as of July 2016 (NCT02362503) (Brinson et al., 2014; Lalezari et al., 2014; Lalezari et al., 2015; Landry et al., 2016; Zhu et al., 2015).
Investigational drugs for HIV: trends, opportunities and key players
Published in Expert Opinion on Investigational Drugs, 2023
Ronald J. Overmars, Zoë Krullaars, Thibault Mesplède
A few observations make fostemsavir an interesting drug beyond its clinical benefits for highly treatment-experienced individuals. First, viral suppression rates increased between weeks 24 and 96 in BRIGHTE [28]. This result is unusual since viral suppression rates typically decline over this period. However, a similar delayed viral suppression was observed previously for individuals treated with maraviroc [33]. For context, fostemsavir prevents HIV-1 entry into target cells, as do other antiretroviral drugs such as ibalizumab, maraviroc, and enfuvirtide. However, ibalizumab and maraviroc are post-attachment inhibitors, and enfuvirtide is a fusion inhibitor. Thus, among these four drugs, only fostemsavir acts before the engagement of HIV envelope protein with the target cells, potentially leaving cell-free viral particles in the extracellular space.
Fostemsavir for the treatment of HIV
Published in Expert Review of Anti-infective Therapy, 2021
Nikhil Seval, Cynthia Frank, Michael Kozal
Human Immunodeficiency virus 1 (HIV-1) drug resistance remains a significant barrier to widespread virologic suppression and reduction in both morbidity and mortality in persons living with HIV (PLWH) [1,2]. New drugs and drug classes are needed to provide therapeutic options for persons who are heavily treatment experienced (HTE) with virologic failure. Fostemsavir (FTR), trade name Rukobia, was approved 2 July 2020 by the FDA [3] – it is a first in its class attachment inhibitor with a unique mechanism of action involving direct attachment to the virus. Fostemsavir will be an important component of HIV-1 treatment regimens for persons with heavily treatment experienced virus and limited options. The following is a summary of pharmacology, efficacy, tolerability, and clinical role for this newly approved antiretroviral agent Table 1.
The piperazine scaffold for novel drug discovery efforts: the evidence to date
Published in Expert Opinion on Drug Discovery, 2022
Maria Novella Romanelli, Dina Manetti, Laura Braconi, Silvia Dei, Alessio Gabellini, Elisabetta Teodori
Fostemsavir (11) is an anti-HIV agent approved in 2020 by the FDA. It is the prodrug of temsavir, whose mechanism of action is unique among approved anti-HIV drugs: it inhibits the interaction of the surface envelope protein gp120 with the CD4 receptor. Compounds acting in this way are defined attachment inhibitors [39]. The development of this drug is shown in Figure 3A. A phenotyping screening identified the initial lead (29), which attracted the interest of researchers for its innovative mechanism of action. Optimization was carried out mainly on the indole ring, but extensive SAR was performed also on the piperazine moiety. A (R)-2-methyl group as in first clinical candidate 30, BMS-378806 (Figure 3A), was found to improve the potency, while the alkylation in position 3, the constraint into a 2,5-diazabicyclo[2.2.1]heptane, the increase of size to 1,4-diazepane, or the opening to an ethylenediamine derivative were all detrimental for activity [40]. Nevertheless, some concerns about the metabolic liability on this methyl group suggested removing it [41]. Further optimization led to temsavir (31) and then to its prodrug 11. The piperazine ring in 31 functions as scaffold, which allows the N-benzoyl group to establish π-stacking interactions with Phe382 and Trp427 of the envelope gp120 protein and the amide CO of the oxalyl residue to form an H-bond with the backbone NH of Trp427 (Figure 3B) [42]. Interestingly, the conformational flexibility of the piperazine ring has been proposed as an important factor to find the best shape of 30 to interact with the protein [43].