Fostemsavir 600mg modified-release tablets

Background: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4+ T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose–response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1–infected subjects. Methods: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) 3-fold increase). Results: 66/200 fostemsavir and 14/51 ATV/r subjects had resistance testing performed; 44/66 and 9/14 were successfully tested using the PhenoSense GT assay. No subjects had emergent tenofovir disoproxil fumarate or ATV resistance. Six fostemsavir-treated subjects developed emergent raltegravir resistance. 29/66 fostemsavir-treated subjects had an evaluable phenotype using PhenoSense Entry (which tests for viral susceptibility to temsavir) and 13/29 exhibited >3-fold increase in temsavir IC50 from BL. gp120 population sequencing was successful in 11/13 subjects and 7 had emergent substitutions in gp120 associated with reduced temsavir susceptibility (S375, M426, or M434). However, 5/13 fostemsavir-treated subjects achieved subsequent suppression to <50 copies/mL before the week 48 database lock, regardless of key gp120 substitutions. Conclusions: Response rates remained similar across study arms regardless of BL nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor resistance-associated mutations. Emergent changes in viral susceptibility occurred more frequently with fostemsavir compared with ATV/r. However, the full impact of temsavir IC50 changes and emergent HIV-1 gp120 substitutions, and thus appropriate clinical cutoffs, requires further study. Fostemsavir is being evaluated in a phase 3 trial in heavily treatment-experienced subjects.

Abstract licence: CC BY-NC-ND 4.0

Introduction The BRIGHTE study assessed the efficacy of fostemsavir tromethamine 600 mg with optimized background therapy in adults with multidrug-resistant HIV-1 and virological failure. Participants were divided into a randomized cohort, comparing fostemsavir with placebo, and an observational cohort. After eight days, all randomized participants switched to fostemsavir. This study evaluated the certainty of evidence from the BRIGHTE trial. Methods The GRADEpro tool was used to assess the quality of evidence. Five studies related to BRIGHTE were included, covering follow-up assessments at eight days (randomized phase) and 48, 96, and 240 weeks (observational phase). The outcomes assessed included changes in viral load, adverse events, virological response and failure, changes in CD4+ T cell count from baseline, mortality, quality of life, and treatment adherence. Differences between the randomized and observational phases were evaluated, focusing on the impact of this transition on evidence quality. Results Transition to the observational phase compromised methodological robustness, increasing the risk of bias. In the randomized phase, evidence quality was reduced by the lack of details on the randomization process and uncertainties regarding double blinding. In the observational phase, confounding bias arose mainly due to intervention classification and the absence of an active comparator, hampering the assessment of fostemsavir’s relative efficacy. Intervention status influenced outcomes. Despite these limitations, fostemsavir showed consistent virological responses, indicating potential benefit for highly treatment-experienced individuals. Overall, evidence certainty was rated low for most outcomes, reflecting the combined impact of bias risks and methodological limitations. Conclusions Although findings from the BRIGHTE study highlight fostemsavir’s clinical potential, the transition from a randomized controlled trial to an observational study reduced its evidence quality. The lack of comparators in the observational phase limited interpretations. However, a single-arm design is ethically justified for individuals with limited options to ensure access to interventions. Future studies should prioritize hybrid approaches and real-world data to improve clinical applicability.

Abstract licence: CC BY 4.0

Fostemsavir, a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated in combination with other antiretrovirals for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE). Temsavir binds to HIV-1 gp120, close to the CD4 binding site, preventing the initial interaction of HIV-1 with CD4 on the host cell. Amino acid substitutions at four positions in gp120 have been identified as important determinants of viral susceptibility to temsavir (S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I), with a fifth position (T202E) recently described. For most currently circulating group M HIV-1 subtypes, the prevalence of these resistance-associated polymorphisms (RAPs) is low. As with many other antiretrovirals, the impact of RAPs is modified by other changes in the target molecule. Different regions of gp120 interact to modify the temsavir binding pocket, with multiple amino acids playing a role in determining susceptibility. Extensive variability of HIV-1 gp120 means the susceptibility of clinical isolates to temsavir is also highly variable. Importantly, in vitro measurement of the susceptibility of clinical isolates to temsavir does not necessarily capture the range of susceptibilities of the heterogeneous mix of viruses generally present in each isolate. Due to these factors and limited phenotypic clinical data, thus far, no relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in individuals who are HTE; therefore, pre-treatment temsavir resistance testing may be of limited benefit. In the phase III BRIGHTE study, re-suppression after virologic failure was observed in some participants despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility, and substantial CD4+ T-cell count increases occurred even among participants with HIV-1 RNA ⩾40 copies/mL at Week 240. Clinical management of people who are HTE and experience virologic failure during treatment with fostemsavir-based regimens requires an individualized approach with consideration of potential benefits beyond virologic suppression.

Abstract licence: CC BY-NC 4.0

Abstract Background Patients with multidrug-resistant HIV (Human Immunodeficiency Virus) face limited treatment options, increasing their risk of virologic failure. Fostemsavir, a novel attachment inhibitor, has shown efficacy and safety in clinical trials, but real-world data is lacking. We aimed to evaluate virologic suppression, immunologic response, and safety outcomes in treatment-experienced individuals in a real-world clinical setting.Trends in CD4 Count and HIV Viral Load Over 12 Months in Patients Receiving Fostemsavir Methods We conducted a retrospective chart review of patients living with HIV >18 years old in a Ryan White funded HIV clinic in Newark , NJ who were treated with Fostemsavir for more than 6 months. Data on viral load, CD4 counts, adverse effects, and adherence were collected and descriptive statistics was used to analyze outcomes over 12 months. Primary outcomes were virologic suppression (HIV RNA < 20 copies/mL) and CD4 count change from baseline. Secondary outcomes assessed adherence, adverse effects, and reasons for discontinuation. Results 17 patients met the inclusion criteria, with a mean age of 57.2 years. The majority were male gender (70.6%). 58.8% were Black or African American, 17.6% White, and 23.5% identified as other races. At baseline, the mean viral load was 56,402 copies/mL, which declined to 400 copies/mL at month 3, 84 copies/mL at month 6, and 53 copies/mL at month 12. Mean CD4 count increased from 439 cells/mm³ at baseline to 492 cells/mm³ at month 3, remained stable at 491 cells/mm³ at month 6, and rose further to 619 cells/mm³ by month 12 as shown in Figure 1. Virologic suppression was achieved in most patients by month 12. Adherence was high with 82.4% fully compliant, 11.8% intermittently compliant, and 5.9% non-compliant. Adverse effects were minimal; 76% reported none, while 11.8% experienced muscle wasting, and 5.9% each reported insomnia or arthralgia. Fostemsavir was discontinued in two patients: due to virologic failure (5.9%), oral intolerance (5.9%). Conclusion Fostemsavir demonstrated effective virologic suppression and immune recovery, with a favorable safety profile, in a real-world cohort of treatment-experienced HIV patients. These findings support its clinical utility. Ongoing research in larger populations will build on these findings to further characterize long-term outcomes. Disclosures Jihad Slim, MD, FACP, gilead: Honoraria|merck: Honoraria|Thera: Honoraria|ViiV: Honoraria

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