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Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study
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The Lancet Nov 2020
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IAS 2019: Week 96 safety and efficacy of the novel HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced participants infected with multi-drug-resistant HIV-1 (BRIGHTE Study)
Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study
Published: November, 2020 The Lancet - Max Lataillade, Jacob P Lalezari, Michael Kozal, Judith A Aberg, Gilles Pialoux, Pedro Cahn, Melanie Thompson, Jean-Michel Molina, Santiago Moreno, Beatriz Grinsztejn, Ricardo S Diaz, Antonella Castagna, Princy N Kumar, Gulam H Latiff, Edwin De Jesus, Marcia Wang, Shiven Chabria, Margaret Gartland, Amy Pierce, Peter Ackerman, Cyril Llamoso
Perhaps the most important and clinically impactful finding for the heavily treatment-experienced population is that participants in the randomised cohort, who were the most profoundly immunosuppressed at baseline with CD4 counts less than 20 cells per μL, achieved a life-changing mean increase of 240 cells per μL at week 96..
CD4 counts also increased steadily through week 96 in the randomised cohort (figure 3A): at week 96, the mean increase from baseline was 205 (SD 191) cells per μL and the median increase was 175 (IQR 89-288) cells per μL. Increases in CD4 counts were generally consistent across subgroups, including for participants with fewer than 20 cells per μL at baseline who had a mean increase from baseline of 240 cells per μL (median 212 cells per μL; table 2). Most participants either maintained or improved their CD4 count category from baseline to week 96 (appendix p 8): 56% (40 of 71) shifted from fewer than 50 cells per μL to 200 cells per μL or more, and 57% (31 of 54) from fewer than 20 cells per μL to 200 cells per μL or more. CD4/CD8 ratios also increased over time (figure 3B).
A ratio of more than 0·45 has been associated with a two-fold decrease in risk of progression to severe non-AIDS-defining event or death compared with a ratio less than 0·30.
Among the participants in the randomised cohort treated in our study, the mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 by observed analysis through week 96, suggesting improvement of immune function and overall health status and consistent with the observed decline in AIDS-defining events.
Figure 1: Most common antiretroviral agents in the initial optimised background therapy for randomised and non-randomised cohorts
Antiretrovirals included those that were in the initial optimised background therapy for at least 10% of study participants in either cohort. (A) The randomised cohort had 272 participants. (B) The non-randomised cohort had 99 participants. *Based on the screening criteria of activity (per screening and historical resistance measures) and availability (tolerability, contraindications, and, in the case of enfuvirtide only, willingness to receive an injectable).
Summary
Background
Fostemsavir, 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.
Methods
BRIGHTE (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.
Finding
Between 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.
Over an initial 8 days of functional monotherapy in the randomised cohort, fostemsavir added to the failing antiretroviral regimen showed superior antiviral efficacy compared with placebo added to failing antiretroviral regimen (primary study endpoint: mean HIV-1 RNA decrease from baseline 0·8 log10 copies per mL vs 0·2 log10 copies per mL; p<0·0001).
In the randomised cohort, the proportion of participants with a virological response (ie, HIV-1 RNA <40 copies per mL) by snapshot analysis increased over time from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96 (figure 2A; appendix p 7). By observed analysis (including only participants with observed HIV-1 RNA measures for each visit), the proportions of participants with a virological response increased from 57% (141 of 246) at week 24 to 79% (170 of 214) at week 96 (figure 2B). Rates of virological response by snapshot analysis at week 96 were similar across most baseline subgroups, including between participants with one or two fully active antiretrovirals in their initial optimised background therapy (table 2). The lowest virological response rates were seen among participants with baseline viral loads of 100 000 copies per mL or more or those with baseline CD4 cell counts of less than 20 cells per μL, whereas the highest virological response rates were among those with baseline viral loads of less than 1000 copies per mL or baseline CD4 cell counts of 200 cells per μL or more. Nevertheless, response rates by snapshot analysis in participants with high viral load (from 35% at week 24 to 49% at week 96) or low CD4 cell count (32% at week 24 to 46% at week 96) did increase over time.
CD4 counts also increased steadily through week 96 in the randomised cohort (figure 3A): at week 96, the mean increase from baseline was 205 (SD 191) cells per μL and the median increase was 175 (IQR 89-288) cells per μL. Increases in CD4 counts were generally consistent across subgroups, including for participants with fewer than 20 cells per μL at baseline who had a mean increase from baseline of 240 cells per μL (median 212 cells per μL; table 2). Most participants either maintained or improved their CD4 count category from baseline to week 96 (appendix p 8): 56% (40 of 71) shifted from fewer than 50 cells per μL to 200 cells per μL or more, and 57% (31 of 54) from fewer than 20 cells per μL to 200 cells per μL or more. CD4/CD8 ratios also increased over time (figure 3B).
In the non-randomised cohort, 37% (37 of 99) at week 24 and week 96 achieved virological response by snapshot analysis (figure 2A). Among the 15 participants who received ibalizumab in their initial optimised background therapy, response rate at week 24 was 53% (eight of 15) compared with 35% (29 of 84) for those who did not receive ibalizumab, and at week 96 was 33% (five of 15) compared with 38% (32 of 84) for those who did not receive ibalizumab. Three individuals receiving ibalizumab who were classified as virological failure at week 96 after previous virological response had died in the interim period (data not shown). The mean increase in CD4 count at week 96 in the non-randomised cohort was 119 cells per μL (SD 202); the median increase was 75 cells per μL (IQR −1 to 162; figure 3A). The mean increase in CD4/CD8 ratio was 0·08 (SD 0·13); the median increase was 0·10 (IQR 0·00-0·20). The 15 participants with ibalizumab in their initial optimised background therapy had mean baseline CD4 count of 114 cells per μL (SD 121) and median baseline count of 73 cells per μL (IQR 7-230). The mean CD4 count increase for this subgroup at week 96 (n=9) was 18 cells per μL (SD 95) compared with 135 cells per μL (210) for participants without ibalizumab in their initial optimised background therapy, and the median increase was 32 cells per μL (IQR −67 to 88) compared with 90 cells per μL (1 to 183) for those without ibalizumab in their initial optimised background therapy.
Up to week 96, 63 (23%) of 272 participants in the randomised cohort and 49 (49%) of 99 in the non-randomised cohort met the criteria for protocol-defined virological failure. On-treatment gp120 sequencing data were obtained for 50 (79%) of 63 participants in the randomised cohort and 44 (90%) of 49 in the non-randomised cohort, and phenotypic temsavir susceptibility data were obtained for 53 (84%) of 63 participants in the randomised cohort and 45 (92%) of 49 in the non-randomised cohort. In the randomised cohort, the incidence of protocol-defined virological failure at week 96 was similar regardless of the presence of gp120 substitutions of interest or elevated temsavir IC50 fold-change at baseline: 31 (22%) of 141 participants without gp120 substitutions at baseline, compared with 31 (25%) of 122 participants with relevant gp120 substitutions, had protocol-defined virological failure; and 29 (22%) of 132 participants with temsavir IC50 fold-change of one or less, compared with ten (29%) of 34 with IC50 fold-change of more than 100, had protocol-defined virological failure. In the protocol-defined virological failure population through week 96, treatment-emergent gp120 substitutions at one or more of the four amino acid positions previously associated with reduced phenotypic susceptibility to temsavir (most frequently Ser375Asn and Met426Leu) were found in 48% of participants in the randomised cohort and 75% in the non-randomised cohort (table 3). In the randomised cohort, the median increase in temsavir IC50 fold-change from baseline to protocol-defined virological failure in participants with emergent gp120 substitutions of interest (n=24) was 511-fold. In participants with no emergent gp120 substitutions of interest (n=26), the median increase in temsavir IC50 fold-change from baseline to protocol-defined virological failure was 0·9-fold, and 23 (88%) had a change in temsavir IC50 fold-change from baseline to protocol-defined virological failure of three-fold or less. In the non-randomised cohort, the median increase in temsavir IC50 fold-change from baseline to protocol-defined virological failure in participants with emergent gp120 substitutions of interest (n=32) was 2260-fold. In participants with no emergent gp120 substitutions of interest (n=11), the median change in temsavir IC50 fold-change from baseline to protocol-defined virological failure was 0·7-fold, and 82% (n=9) had a change in temsavir IC50 fold-change from baseline to protocol-defined virological failure of three-fold or less.
Analysis of nadir HIV-1 RNA values after protocol-defined virological failure showed that through the week 96 data cutoff date, virological suppression to less than 40 HIV-1 RNA copies per mL after protocol-defined virological failure was achieved for 17 (27%) of 63 participants in the randomised cohort and five (10%) of 49 in the non-randomised cohort.
Interpretation
In 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. Fostemsavir, a prodrug of the first-in-class attachment inhibitor temsavir, which was approved by the US Food and Drug Administration on July 2, 2020, is indicated for the treatment of heavily treatment-experienced people with multidrug-resistant HIV-1. Temsavir has a unique mechanism of action, binding directly to the viral envelope gp120, close to the CD4 binding site, locking gp120 into a closed state that prohibits the conformational change necessary for initial interaction between the virus and CD4 cell-surface receptors, thereby preventing attachment and subsequent entry into host T cells and other immune cells (appendix p 3). Fostemsavir has no in-vitro cross-resistance with other antiretroviral classes, and is active against CCR5-tropic, CXCR4-tropic, and dual-tropic strains of HIV-1. The in-vitro temsavir 50% inhibitory concentration (IC50) varies widely (10 pM to >10 μM), which might be linked to heterogeneity in HIV-1 gp120; however, for most laboratory and clinical isolates of temsavir-naive HIV-1, the IC50 is less than 10 nM.
In the ongoing BRIGHTE study, we are evaluating fostemsavir in heavily treatment-experienced individuals who have limited remaining approved fully active antiretrovirals available as treatment options to form a viable ART regimen (one or two fully active antiretrovirals in the randomised cohort and zero fully active antiretrovirals in the non-randomised cohort). Over an initial 8 days of functional monotherapy in the randomised cohort, fostemsavir added to the failing antiretroviral regimen showed superior antiviral efficacy compared with placebo added to failing antiretroviral regimen (primary study endpoint: mean HIV-1 RNA decrease from baseline 0·8 log10 copies per mL vs 0·2 log10 copies per mL; p<0·0001). Subsequent open-label treatment with fostemsavir in combination with optimised background therapy resulted in a virological response (HIV-1 RNA <40 copies per mL) at week 24 in 53% of participants in the randomised cohort and 37% in the non-randomised cohort, and at week 48 in 54% of participants in the randomised cohort and 38% in the non-randomised cohort, with mean increases in CD4 count from baseline to week 48 of 139 cells per μL in the randomised cohort and 63 cells per μL in the non-randomised cohort. We also saw improvements in patient-reported HRQoL measures (EQ visual analogue scale and the Functional Assessment of HIV Infection [FAHI]), with greater improvements in those with lower CD4 cell counts and higher viral loads at baseline.
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