Fostemsavir (FTR, GSK3684934; formerly BMS‐663068) is a human immunodeficiency virus type 1 (HIV‐1) attachment inhibitor approved for the treatment of multidrug‐resistant HIV‐1 infection in heavily treatment‐experienced (HTE) patients failing their current antiretroviral regimen. FTR is an extended‐release prodrug and is hydrolyzed by alkaline phosphatase in the gastrointestinal lumen to its active moiety, temsavir (TMR). TMR is primarily metabolized by esterase‐mediated hydrolysis with contributions from cytochrome P450 (CYP) 3A4. A population pharmacokinetic (PK) analysis was performed using TMR exposure data from seven clinical studies (Phases 1 through 3) to characterize the time course of TMR plasma concentrations and to evaluate covariate effects on TMR PK. This analysis showed TMR PK was adequately described using a two‐compartment model with dual zero and first‐order absorption and first‐order elimination with CYP3A inducers and inhibitors as covariates on CL/F and allometrically scaled body weight as a covariate on CL/F, V2/F, Q/F, and V3/F. Exposure metrics were derived from the final population PK model to assess relationships between TMR PK and efficacy at Day 8 and Week 24 and safety endpoints of interest, using exposure‐response (ER) models. 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).

Aim: Fostemsavir (FTR), an extended-release prodrug of temsavir (TMR), is a human immunodeficiency virus type 1 (HIV-1) attachment inhibitor approved for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced (HTE) patients failing current antiretroviral treatment. A population PK and exposure-response analysis was performed to assess the influence of intrinsic/extrinsic factors and support regulatory approval of 600 mg BID fostemsavir regimen. Methods: Analysis was conducted using TMR data from seven clinical studies (Phases 1-3). Models were assessed using standard goodness of fit and parameter precision (root mean square error (%RSE)). Model-estimated exposure metrics were used to assess TMR PK- efficacy and safety exposure response relationships. Results: TMR PK was adequately described using a two-compartment model with zero and first-order absorption and first-order elimination. Clearance, volume and absorption parameters were precisely estimated (CL/F 51.0 L/hr (2.1% RSE), V2/F 257 1/hr (3.18 %RSE), Ka 2.33 1/hr (13.3 %RSE)). Concomitant CYP3A inducers and inhibitors were covariates on CL/F, and body weight was a covariate on CL/F, V2/F, Q/F, and V3/F. An Emax model described the trough TMR concentration (Ctau) - day 8 plasma HIV-1 RNA relationship (Emax 1.00 log10 c/mL (17.1 %RSE), EC50 64.3 ng/mL (98% RSE)). No exposure-safety relationships were evident. Simulation showed virologic response was achieved irrespective of coadministration with moderate CYP3A inducers, strong CYP3A inhibitors, changes in prandial status, or body weight. Conclusion: Results support administration of FTR 600 mg BID to decrease virologic load in HIV-1 HTE patients, with no dose adjustments necessary for intrinsic or extrinsic factors.

In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).

Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4(+) T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes. Drugs that induce or inhibit CYP3A, P-glycoprotein, and BCRP may affect temsavir concentrations. Understanding potential drug-drug interactions (DDIs) following fostemsavir coadministration with antiretrovirals approved for HIV-1-infected treatment-experienced patients, including darunavir plus cobicistat (DRV/c) or DRV plus low-dose ritonavir (DRV/r) and etravirine, is clinically relevant. Open-label, single-sequence, multiple-dose, multicohort DDI studies were conducted in healthy participants (n = 46; n = 32). The primary objective was to assess the effects of DRV/r, etravirine, DRV/r plus etravirine, cobicistat, and DRV/c on temsavir systemic exposures; safety was a secondary objective. Compared with fostemsavir alone, coadministration with DRV/r increased the temsavir maximum observed plasma concentration (C-max), area under the concentration-time curve in one dosing interval (AUC(tau)), and plasma trough concentration (C-tau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir C-max, AUC(tau), and C-tau by similar to 50% each. DRV/r plus etravirine increased the temsavir C-max, AUC(tau), and C-tau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir C-max, AUC(tau), and C-tau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir C-max, AUC(tau), and C-tau by 79%, 97%, and 124%, respectively. Fostemsavir with all combinations was generally well tolerated. No dose adjustment is required for fostemsavir when coadministered with strong CYP3A inhibitors, P-glycoprotein inhibitors, and modest inducers, including regimens with DRV/r, DRV/c, cobicistat, etravirine, and DRV/r plus etravirine based on the therapeutic margin for temsavir.

OBJECTIVES:Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies.METHODS:Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration.RESULTS:Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect.CONCLUSIONS: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.

Background The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non–cross-resistant mechanisms for inhibiting HIV-1 entry. Methods A single-centre, Phase 1, double-blind, randomized, placebo-controlled study was conducted in healthy volunteers, using a 2-part adaptive study design: in Part 1, participants were randomized to receive subcutaneous injection of GSK3732394 or placebo (3:1) as single ascending doses (10-mg starting dose); in Part 2, participants were intended to receive multiple ascending doses. Primary and secondary objectives included safety, pharmacokinetics (PK) and pharmacodynamics (PD; cluster of differentiation four receptor occupancy [CD4 RO]) of GSK3732394 in healthy adults; PK/PD results in healthy volunteers were used to project HIV-1 treatment success. Results The most frequently reported adverse event was injection site reactions (ISRs; 8/18 [44%]). Most ISRs were mild (Grade 1–2; n = 7); one participant experienced a Grade 3 ISR (erythema ≥10 cm). All ISRs were delayed in onset (after Day 10). GSK3732394 demonstrated linear PK across all cohorts. Clearance was faster than expected, and PK/PD results were lower than expected, with the maximum dose investigated (80 mg) achieving mean trough CD4 RO of ∼25% on Day 7. The study was terminated as the PK/PD model linking PK and CD4 RO indicated that the maximum planned doses would not achieve the desired therapeutic profile. Conclusions This study demonstrated successful deployment of PK/PD dose relationships in the design and conduct of clinical trials by leveraging the findings toward predicting probability of success, resulting in appropriate early termination ( ClinicalTrials.gov , NCT03984812).

The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%-36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%.The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment 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.

BACKGROUND:Temsavir (TMR), the active agent of the gp120-directed attachment inhibitor fostemsavir (FTR), the CD4-directed attachment inhibitor ibalizumab (IBA), and the CCR5 antagonist maraviroc (MVC) are antiretroviral agents that target steps in HIV-1 viral entry. Although mechanisms of inhibition of the three agents are different, it is important to understand whether there is potential for cross-resistance between these agents, as all involve interactions with gp120.METHODS:Envelopes derived from plasma samples from participants in the BRIGHTE study who experienced protocol-derived virologic failure (PDVF) and were co-dosed with FTR and either IBA or MVC were analyzed for susceptibility to the agents. Also, CCR5-tropic MVC-resistant envelopes from the MOTIVATE trials were regenerated and studies were performed to understand whether susceptibility to multiple agents were linked.RESULTS:The cloned envelopes exhibited reduced susceptibility to TMR and resistance to the co-dosed agent. At PDVF, emergent or preexisting amino acid substitutions were present at TMR positions of interest. When amino acid substitutions at these positions were reverted to the consensus sequence, full susceptibility to TMR was restored without effecting resistance to the co-dosed agent. In addition, five envelopes from MOTIVATE were regenerated and exhibited R5-tropic-MVC-resistance. Only one exhibited reduced susceptibility to TMR and it contained an M426L polymorphism. When reverted to 426M, full sensitivity for TMR was restored, but it remained MVC resistant.CONCLUSION:The data confirm that decreased susceptibility to TMR and resistance to IBA or MVC are not linked and that there is no cross-resistance between either of these two agents and FTR.

Fostemsavir (Rukobia™, ViiV Healthcare, Research Triangle Park, NC), a prodrug of the first-in-class attachment inhibitor temsavir, was developed to provide a much-needed new therapeutic option for heavily treatment-experienced (HTE) people living with HIV-1 (PLWH)

The oral prodrug fostemsavir (GSK3684394, formerly BMS-663068) is an antiretroviral treatment for HIV-1. Fostemsavir is metabolized to its active moiety, temsavir, a first-in-class HIV-1 attachment inhibitor that binds to the viral envelope glycoprotein 120. Long-term antiretroviral therapy, the resulting longer life expectancy, and/or certain coinfections can increase the risk of chronic liver and kidney disease in HIV-1-infected individuals. Two studies were conducted to collectively evaluate the impact of renal and hepatic impairment on temsavir pharmacokinetics (PK) and safety following a single dose of a 600-mg extended-release fostemsavir tablet. There was no clinically meaningful effect of renal or hepatic impairment on temsavir PK, although renal clearance decreased with increasing renal impairment from moderate to severe, and exposure (maximum concentration and area under the plasma concentration-time curve from time 0 to infinity) tended to increase with increasing severity of hepatic impairment. No clinically meaningful effect of hemodialysis on temsavir PK parameters was observed. Fostemsavir was generally safe and well tolerated by treated subjects. Most adverse events (AEs) were mild, with the exception of 1 patient in the renal impairment study who discontinued due to 2 serious AEs unrelated to the study drug. No other treatment-emergent serious AEs occurred, and no other AEs leading to discontinuation were reported. Overall, these results suggest that fostemsavir can be used without dose modification in subjects with mild to severe renal impairment, including those with end-stage renal disease on hemodialysis, and in subjects with mild to severe hepatic impairment.

Abstract Background BRIGHTE is an ongoing global study evaluating the gp120 attachment inhibitor fostemsavir (FTR) in heavily treatment-experienced (HTE) adults with multidrug resistant (MDR) HIV-1 unable to form a viable antiretroviral (ARV) regimen. An estimated 2 million people living with HIV-1 have been infected with SARS-CoV-2. Those with HIV viremia and/or low CD4+ counts are at increased risk of serious adverse outcome. We describe the reported COVID cases in a clinical trial population of people living with MDR HIV and immune suppression. Methods At the start of the COVID pandemic, all ongoing BRIGHTE subjects had achieved ≥ 192 weeks on FTR and optimized background ARVs; results through Week 96 were presented previously. Investigators used WHO guidelines for COVID diagnosis and reported exposure, testing results and symptom presence. Figure 1. BRIGHTE Study Design Results 371 subjects [272 Randomized Cohort (RC), 99 Non-Randomized Cohort (NC)] were enrolled; 44% were ≥ 50 years of age and 86% had an AIDS history. Median CD4+ count at study start of was 80 cells/mm3 (IQR 11–202); 30% with ≤ 20 cells/mm3. 250 subjects remained in BRIGHTE at pandemic start. By April 2021, 17 subjects (14 RC, 3 NC) had confirmed COVID infection (positive PCR test). Severity was Grade 1-3, all cases resolved with no deaths. Six subjects were hospitalized (Table 1); most recent CD4+ count prior to COVID were 293-1641 cells/mm3 and 5/6 subjects were virologically suppressed. Treatments often included prophylactic anticoagulants and supplemental oxygen; no cART changes were made. The remaining 11/17 confirmed cases were managed outpatient. Five more subjects had suspect COVID not confirmed by PCR and 2 subjects had negative PCR tests. Table 1. Characterization of Participants with Serious AEs of Confirmed COVID-19 Infections – All Hospitalizations Conclusion A total of 22/250 COVID-19 cases (17 confirmed, 5 unconfirmed) have been reported in BRIGHTE. Outcomes were reassuring with no deaths or known persistent sequelae, despite having advanced HIV and comorbid diseases at baseline associated with poorer COVID outcomes. Outcomes may have benefitted from immunologic improvement during the trial. Disclosures Shiven Chabria, MD, Viiv Healthcare (Employee) Stephane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Amy Pierce, BS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Bronagh M. Shepherd, PhD, GlaxoSmithKline (Employee, Shareholder) Michael Warwick-Sanders, BM BSc DPM MFPM, GSK (Employee) Marcia Wang, PhD, GlaxoSmithKline (Employee, Shareholder) Andrew Clark, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Peter Ackerman, MD, GSK/ViiV Healthcare (Employee, Shareholder)

Objectives: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. Design: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). Methods: Virologic response rates (HIV-1 RNA <40 copies/ml, Snapshot analysis) and CD4 + T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4 + T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc). Results: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4 + T-cell count increases were comparable across subgroups. Participants with baseline CD4 + T-cell counts less than 20 cells/μl had a mean increase of 240 cells/μl. In the safety population, more participants with baseline CD4 + T-cell counts less than 20 vs. at least 200 cells/μl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups. Conclusion: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.

Background: Fostemsavir, a prodrug of the gp120-directed attachment inhibitor temsavir, is indicated for use in heavily treatment-experienced individuals with MDR HIV-1. Reduced susceptibility to temsavir in the clinic maps to discrete changes at amino acid positions in gp160: S375, M426, M434 and M475. Objectives: To query the Los Alamos National Laboratory (LANL) HIV Sequence Database for the prevalence of polymorphisms at gp160 positions of interest. Methods: Full-length gp160 sequences (N=7560) were queried for amino acid polymorphisms relative to the subtype B consensus at positions of interest; frequencies were reported for all sequences and among subtypes/circulating recombinant forms (CRFs) with >= 10 isolates in the database. Results: Among 239 subtypes in the database, the 5 most prevalent were B (n=2651, 35.1%), C (n=1626, 21.5%), CRF01_AE (n=674, 8.9%), A1 (n=273, 3.6%) and CRF02_AG (n=199, 2.6%). Among all 7560 sequences, the most prevalent amino acids at positions of interest (S375, 73.5%; M426, 82.1%; M434, 88.2%; M475, 89.9%) were the same as the subtype B consensus. Specific polymorphisms with the potential to decrease temsavir susceptibility (S375H/I/M/N/T/Y, M426L/P, M434I/K and M475I) were found in <10% of isolates of subtypes D, G, A6, BC, F1, CRF07_BC, CRF08_BC, 02A, CRF06_cpx, F2, 02G and 02B. S375H and M475I were predominant among CRF01_AE (S375H, 99.3%; M475I, 76.3%; consistent with previously reported low temsavir susceptibility of this CRF) and 01B (S375H, 71.7%; M475I, 49.5%). Conclusions: Analysis of the LANL HIV Sequence Database found a low prevalence of gp160 amino acid polymorphisms with the potential to reduce temsavir susceptibility overall and among most of the common subtypes.

Heavily treatment-experienced (HTE) people living with HIV-1 (PLWH) have limited viable antiretroviral regimens available because of multidrug resistance and safety concerns. The first-in-class HIV-1 attachment inhibitor fostemsavir demonstrated efficacy and safety in HTE participants in the ongoing phase III BRIGHTE trial. We describe patient-reported outcomes (PROs) through week 48. Eligible participants for whom their current regimen was failing were assigned to the randomized cohort (RC; one to two fully active agents remaining) or the nonrandomized cohort (NRC; no fully active agents remaining). PRO assessments included the EQ-5D-3L, EQ-VAS, and Functional Assessment of HIV Infection (FAHI) instruments. Both cohorts achieved increases in EQ-5D-3L US- and UK-referenced utility score from baseline at week 24. Mean visual analog scale (VAS) scores in the RC and NRC increased from baseline by 8.7 (95% CI 6.2–11.2) and 5.6 points (95% CI 1.5–9.7) at week 24 and increased from baseline by 9.8 (95% CI 7.0–12.6) and 4.9 points (95% CI 0.6–9.2) at week 48, respectively. Mean increases in FAHI total score from baseline to weeks 24 and 48 in the RC were 6.9 (95% CI 4.2–9.7) and 5.8 (95% CI 2.7–9.0), respectively, whereas mean increases in physical and emotional well-being subscale scores were 2.7 (95% CI 1.9–3.6) and 2.4 (95% CI 1.3–3.4) and 3.2 (95% CI 2.2–4.2) and 2.6 (95% CI 1.6–3.7), respectively, with little to no change in other subscales. Improvements in major domains of the EQ-VAS and FAHI through week 48, combined with efficacy and safety results, support the use of fostemsavir for HTE PLWH. NCT02362503; February 13, 2015.

Abstract Background Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies using a limited number of clinical isolates showed that there was intrinsic variability in their susceptibility to temsavir. Objectives Here, an analysis was performed using all clinical isolates analysed in the Monogram Biosciences PhenoSense® Entry assay as part of the development programme. Methods In total, 1337 individual envelopes encompassing 20 different HIV-1 subtypes were examined for their susceptibility to temsavir. However, only seven subtypes (B, C, F1, A, [B, F1], BF and A1) were present more than five times, with subtype B (881 isolates) and subtype C (156 isolates) having the largest numbers. Results As expected, variability in susceptibility was observed within all subtypes. However, for the great majority of these viruses, temsavir was highly potent, with most viruses exhibiting IC50s <10 nM. One exception was CRF01_AE viruses, where all five isolates exhibited IC50s >100 nM. For the 607 isolates where tropism data were available, geometric mean temsavir IC50 values were remarkably similar for CCR5-, CXCR4- and dual mixed-tropic envelopes from infected individuals. Conclusions These data show that HIV-1 viruses from most subtypes are highly susceptible to temsavir and that temsavir susceptibility is independent of tropism.

Background Fostemsavir is an oral prodrug of temsavir, a first‐in‐class attachment inhibitor that binds HIV‐1 gp120, preventing initial HIV attachment and entry into host immune cells. Objective The pharmacokinetic interaction was determined between temsavir and maraviroc, a CCR5 allosteric inhibitor indicated for CCR5-tropic HIV-1 that may be co-administered with fostemsavir as part of combination antiretroviral therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Methods This was a Phase 1, open-label, single-sequence, 3-period crossover study evaluating the effect of fostemsavir on maraviroc pharmacokinetics and the effect of maraviroc on temsavir pharmacokinetics (ClinicalTrials.gov, NCT02480894). Fourteen healthy participants received fostemsavir 600 mg twice daily (BID) for 4 days in Period 1 (followed by a 3-day washout), maraviroc 300 mg BID for 5 days in Period 2, and fostemsavir 600 mg BID with maraviroc 300 mg BID for 7 days in Period 3. Study drugs were administered orally with a standard meal. Results Following fostemsavir and maraviroc co-administration, maraviroc area under the plasma concentration-time curve over the dosing interval (AUCτ) increased 25% (from 1914 to 2382 ng.h/mL) and maraviroc plasma concentration at the end of the dosing interval (Ctrough) increased 37% (from 36.5 to 49.9 ng/mL), but there was no change in maximum observed concentration (Cmax). Following fostemsavir and maraviroc co-administration, temsavir AUCτ and Cmax increased 10-13% and Ctrough decreased 10%. Conclusions Co-administration of fostemsavir and maraviroc did not result in clinically relevant changes in maraviroc or temsavir exposure. Fostemsavir and maraviroc may be co-administered without dose adjustment of either antiretroviral agent.

Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV‐1) infection in heavily treatment‐experienced adults with multidrug‐resistant HIV‐1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure–response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline‐adjusted Fridericia‐corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two‐sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2‐fold higher than the geometric mean TMR peak plasma concentration (Cmax) of 1,770 ng/mL in heavily treatment‐experienced HIV‐1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study (NCT02362503).

BackgroundFostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96.MethodsBRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96.FindingsBetween Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per μL (SD 191) in the randomised cohort and 119 cells per μL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per μL.InterpretationIn heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population.FundingViiV Healthcare.