temsavir (BMS-626529) / BMS - LARVOL DELTA

Population pharmacokinetics and exposure-response relationship for temsavir following fostemsavir administration in treatment-experienced HIV patients. (PubMed, Pharmacol Res Perspect) - "Both the population PK and E-R models support administration of FTR 600 mg BID to decrease virologic load in HIV-1 HTE patients, with no dose adjustments necessary for coadministration with moderate CYP3A inducers, strong CYP3A inhibitors, prandial status, or body weight. Results from this analysis supported the regulatory approval of the fostemsavir 600 mg dose and are applicable to clinical trial simulations in other scenarios and populations (e.g., pediatrics)."

Journal • PK/PD data • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease • Pediatrics

A gp41 HR2 residue modulates the susceptibility of HIV-1 envelope glycoproteins to small molecule inhibitors targeting gp120. (PubMed, J Virol) - "Since residue 629 within the HR2 region of gp41 has also been proposed to have co-evolved with residue 375, we explored its role in the susceptibility of HIV-1 Env to two classes of small molecule gp120 inhibitors: the conformational blocker temsavir and the CD4-mimetic (CD4mc) BNM-III-170...Here, we report that a residue of the gp41 HR2 region affects Env trimer stability and its susceptibility to gp120-directed small molecule inhibitors. This work adds to our understanding of HIV-1 Env resistance to small molecule inhibitors."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Fostemsavir resistance in clinical context: a narrative review. (PubMed, Ther Adv Infect Dis) - "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."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • CD4

Enhanced Recognition of V3 bNAb Epitopes Induced by Fostemsavir on Cell-Associated Primary HIV-1 Env (CROI 2025) - "It is the prodrug of its active form, temsavir (TMR). Additionally, enhancement of V3 directed bnAb binding after 15 mins of TMR treatment with the RS mutant (gp160), suggests that TMR may directly influence Env conformation rather than indirectly affecting it through processing or glycosylation inhibition. Conclusions These data indicate that FTR does not primarily affect all strains by decreasing Env expression, and may be used in combination with certain V3 bnAb treatments to potentially enhance the effectiveness of bnAb-based therapies."

Human Immunodeficiency Virus • Infectious Disease • CD4

Temsavir Treatment Improves Recognition of HIV-1 Infected Cells by Broadly Neutralizing Antibodies (CROI 2025) - "TMR is the active form of fostemsavir (FTR), a drug approved for use in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Conclusions Our results demonstrate that TMR treatment enhances antibody binding to the infected cells that maintain CD4 expression with a majority of bnAbs, at concentrations similar to the antiviral potency of TMR. These suggest that combining bnAbs with TMR can broaden the range of HIV-1 infected cells susceptible to antibody-mediated clearance, potentially increasing the likelihood of reservoir reduction in clinical settings."

Human Immunodeficiency Virus • Infectious Disease • CD4

Investigating the combination of Temsavir and entry inhibitors on HIV replication: Synergistic and antagonistic effects observed against various R5-tropic envelopes. (PubMed, Virology) - "Here, we investigated the effects of combining Temsavir with other HIV entry inhibitors, including CD4 mimetic BNM-III-170, T20 or enfuvirtide, Ibalizumab, and Maraviroc. These results are promising for the potential of co-administrating antiretrovirals for HIV treatment and highlights the importance of developing advanced antiviral strategies. On the other hand, the variable responses against different R5-tropic envelopes underscore the complexity of designing universally effective combination antiviral therapies."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

CD4 T‐cell, CD4/CD8 ratio improvement and a general reduction in inflammatory biomarkers with low‐ level viraemia (LLV) up to week 192 with fostemsavir (FTR)‐based regimens in individuals with multidrug‐resistant (MDR) HIV‐1 (HIV-Glasgow 2024) - "FTR (prodrug of the first-in-class attachment inhibitor temsavir) is indicated with other antiretrovirals (ARVs) for heavily treatment-experienced individuals with MDR HIV-1 unable to construct suppressive regimens. In participants with LLV, there is a persistent increase in CD4 T-cell count and improvement in CD4/CD8 ratio, with a general reduction in inflammatory markers up to week 192. Results highlight the value of FTR-based regimens for sustained improvement where there is incomplete virological suppression."

Biomarker • Clinical • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • CD8

No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches. (PubMed, Pharmacol Res Perspect) - "Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir."

Journal • Human Immunodeficiency Virus • Infectious Disease

Characterization of Clinical Envelopes With Lack of Sensitivity to the HIV-1 Inhibitors Temsavir and Ibalizumab. (PubMed, Antiviral Res) - "Previous data suggest a lack of cross-resistance between the gp120-directed attachment inhibitor temsavir (active moiety of fostemsavir) and the CD4-directed post-attachment inhibitor ibalizumab. Interestingly, introduction of the gp120 V5 region from a highly ibalizumab-susceptible envelope mitigated the E202 effect on ibalizumab but not temsavir. A rare HIV-1 gp120 E202 mutation reduced temsavir susceptibility, and depending on sequence context, could result in reduced susceptibility to ibalizumab."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

The Sensitivity of HIV-1 gp120 Polymorphs to Inhibition by Temsavir Correlates to Temsavir Binding On-rate. (PubMed, Antiviral Res) - "Loss of susceptibility to temsavir observed for gp120 polymorphisms strongly correlated with reductions in temsavir binding on-rate. Nonetheless, temsavir retained the ability to fully block CD4-gp120 engagement given sufficiently high concentrations."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Development of a physiologically based pharmacokinetic model of fostemsavir and its pivotal application to support dosing in pregnancy. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi-drug-resistant human immunodeficiency virus (HIV) infections. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug-drug interactions in pregnancy."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Temsavir Treatment Enhances bNAb Recognition and Subsequent Clearance of HIV-1–Infected Cells (CROI 2024) - "Temsavir (TMR), the active form of the HIV-1 attachment inhibitor fostemsavir, binds to and stabilizes Env in a 'closed' conformation that may allow better targeting by broadly neutralizing antibodies (bnAbs).To understand whether TMR can modulate bnAb binding to Env on the infected cells, we conducted experiments with primary CD4+T cells isolated from HIV negative donors infected with a broad panel of viruses that includes 26 clinical HIV isolates. We have demonstrated for the majority of viruses tested that TMR treatment leads to enhanced bnAb binding to the infected cells that maintain CD4 expression, and the reduced bnAb binding to the CD4 downregulated infected cells occurs at much higher concentrations than neutralization. These results suggest that combination of bnAb and TMR can expand the population of HIV-1 infected cells susceptible to bnAb mediated clearance and may increase the likelihood of reservoir reduction in the clinical setting."

Human Immunodeficiency Virus • Infectious Disease • CD4

Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir. (PubMed, Nat Commun) - "A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Clinical Data from the GP120 Inhibitor Temsavir and Its Potential Relevance to Immune Reconstitution and HIV Associated Inflammation (EACS 2023) - "Sponsored by Virology Education"

Clinical data • Human Immunodeficiency Virus • Infectious Disease

Model-Based Dose Selection of Fostemsavir for Pediatric Populations With Multidrug-Resistant HIV-1 and Relative Bioavailability Assessment in Healthy Adults. (PubMed, Clin Pharmacol Drug Dev) - "Fostemsavir, a prodrug of the first-in-class HIV-1 attachment inhibitor temsavir, is approved for the treatment of multidrug-resistant HIV-1 in adults; its use in pediatric populations is currently being studied. Temsavir maximum concentration for formulation B was similar in fed and fasted states, but area under the plasma concentration-time curve from time zero to infinity geometric mean ratio was increased under fed conditions, consistent with previous results in adults. These analyses demonstrated efficient pediatric dose selection using a model-based approach."

Journal • Human Immunodeficiency Virus • Infectious Disease • Pediatrics

Temsavir Modulates HIV-1 Envelope Conformation by Decreasing Its Proteolytic Cleavage. (PubMed, Viruses) - "Our results suggest that the effect of temsavir on Env conformation is associated with its capacity to decrease Env processing. Indeed, we found that the effect of temsavir on Env processing affects the recognition of HIV-1-infected cells by broadly neutralizing antibodies and correlates with their capacity to mediate antibody-dependent cellular cytotoxicity (ADCC)."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120. (PubMed, Cell Chem Biol) - "Mechanistically, this depends on temsavir's capacity to prevent soluble gp120-CD4 interaction, to reduce gp120 shedding, and to alter gp120 antigenicity. This suggests that the clinical benefits provided by temsavir could extend beyond blocking viral entry."

Immunomodulating • Journal • Human Immunodeficiency Virus • Immune Modulation • Infectious Disease • CD4

Development and validation of a liquid chromatography coupled to tandem mass spectrometry method for the monitoring of temsavir plasma concentrations in people living with HIV. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Fostemsavir (RUKOBIA®) is the prodrug of temsavir, a first-in-class oral attachment inhibitor approved for the treatment of heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The method achieves excellent performance in terms of trueness (99.7 - 105.3%), repeatability and intermediate precision (both from 1.6% to 5.8%). This LC-MS/MS method is now part of the routine analyses of the Laboratory of the Service of Clinical Pharmacology of Lausanne (CHUV), Switzerland, as an integrated part of our general TDM Service for antiretrovirals."

Journal • Cardiovascular • Diabetes • Heart Failure • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • Renal Disease

Fostemsavir and ethinyl estradiol drug interaction: Clinical recommendations for co-administration. (PubMed, HIV Med) - P1 | "Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 μg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected."

Journal • Cardiovascular • Human Immunodeficiency Virus • Infectious Disease

A multivariate analysis of the phase III BRIGHTE trial, through week 24, to identify predictors of virologic response to fostemsavir in heavily treatment-experienced people living with HIV (HIV-Glasgow 2022) - " In randomized participants, baseline CD4+ cell count, baseline log10HIV-1 RNA, presence of relevant gp120 substitutions (S375H/I/M/N/Y or M426L), and temsavir day 8 trough concentration (Ctau) were significantly associated (p < 0.05) with decrease in HIV-1 RNA >0.5log10 at day 8. Virologic response to FTR functional monotherapy or treatment with FTR plus OBT in randomized participants was significantly associated with well-established factors such as baseline CD4+ cell count, baseline log10HIV-1 RNA, and drug concentration. Relevant baseline gp120 substitutions were significantly associated with reduced response to FTR functional monotherapy but not with virologic outcome to FTR plus OBT over 24 weeks. Overall, the presence of baseline factors associated with virologic response to FTR was not predictive of PDVF in this patient population."

P3 data • Human Immunodeficiency Virus • Infectious Disease • CD4

Fostemsavir and QT prolongation: clinical applications for co-administration with other agents (HIV-Glasgow 2022) - "Background: Fostemsavir (FTR) is an oral prodrug of temsavir (TMR), a first-in-class attachment inhibitor approved for use with other antiretrovirals (ARVs) for the treatment of HIV-1 in heavily treatment-experienced (HTE) adults with multidrug-resistance. FTR does not require dose adjustment when combined with other ARVs or agents with a known TdP risk. Clinically significant interactions may occur with agents with known TdP risk and the combination of FTR + bPI or FTR + RPV. Evaluation of FTR-containing ARV regimen, pre-existing cardiac disease, and age must be considered when combining with agents with known TdP risk."

Clinical • Atrial Fibrillation • Cardiovascular • Heart Failure • Human Immunodeficiency Virus • Infectious Disease • Ventricular Tachycardia

Temsavir blocks HIV-1 soluble GP120-induced immunomodulatory activities (HIV-Glasgow 2022) - "Symposium organised by Virology Education"

Human Immunodeficiency Virus • Immune Modulation • Infectious Disease • Inflammation

Clinical data from the GP120 inhibitor temsavir and its relevance to immune reconstitution and HIV associated inflammation (HIV-Glasgow 2022) - "Symposium organised by Virology Education"

Clinical data • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation

Pharmacokinetics, Metabolism and Excretion of Radiolabeled Fostemsavir Administered with or without Ritonavir in Healthy Male Subjects. (PubMed, Xenobiotica) - "The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. Pretreatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • CYP3A4

Characterization of Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Variants Selected for Resistance to a CD4-Mimetic Compound. (PubMed, J Virol) - "Together, the S375N and I424T changes, but not the E64G change, conferred >100-fold and 33-fold resistance to BMS-806 and BMS-529 (temsavir), respectively, potent HIV-1 entry inhibitors that block Env conformational transitions...We relate the antiviral potency of a CD4mc against this panel of HIV-1 variants to the ability of the CD4mc to activate changes in Env conformation and to induce the shedding of the gp120 exterior Env from the spike. These findings will guide efforts to improve the potency and breadth of small-molecule HIV-1 entry inhibitors."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4 • CXCR4