Fostemsavir shows sustained virologic suppression in multidrug-resistant HIV
The investigational first-in-class attachment inhibitor prodrug fostemsavir (FTR) continues to improve virologic and immunologic response from weeks 48 to 96 in patients with multidrug-resistant HIV-1 who had been heavily treated, according to the BRIGHTE* study presented at IAS 2019.
Heavily treatment-experienced (HTE) patients harbouring multidrug resistant HIV-1 represent a difficult-to-treat population with the highest unmet medical need, pointed out lead investigator Dr Max Lataillade of Yale University School of Medicine in New Haven, Connecticut, US.
As they have exhausted most, if not all, classes of antiretroviral therapies, the treatment options left to design effective treatment regimens are limited for these patients, explained Lataillade. Therefore, developing new agents with a novel mechanism of action and no cross-resistance to other antiretroviral classes represents an important step forward for this population.
“FTR is a prodrug metabolized to temsavir (TMR) … which binds directly to HIV-1 gp120, [thus] preventing initial attachment to CD4 receptors on T-cells, and other host immune cells, thereby blocking infection,” said Lataillade.
A BRIGHT hope
The ongoing phase III BRIGHTE study involved 371 HTE patients with multidrug-resistant HIV-1 with contraindication to all antiretroviral drugs in ≥4 of the six existing antiretroviral classes who were separated into two cohorts: randomized and nonrandomized.
The randomized cohort comprised patients with 1–2 antiretroviral classes remaining and were randomized 3:1 to receive either FTR or placebo in addition to their current failing regimen for 8 days, followed by open-label FTR 600 mg BID plus optimized background therapy (OBT). Those without any antiretroviral options left were assigned to the nonrandomized group and received FTR + OBT starting day 1.
Results at week 48 have been reported previously, and the current findings presented at IAS 2019 were outcomes at week 96, with efficacy data mainly from the randomized cohort. [IAS 2019, abstracts MOPEB 234 and MOAB0102]
At 96 weeks, virologic response was seen in 60 percent of the patients in the randomized cohort — a 6 percent increase from 54 percent at week 48 despite continued attrition.
Furthermore, the rates of virologic response was comparable across most subgroups, regardless of whether the patients were stratified by age, sex, race or geographic region. The exceptions were the subgroups with known predictors of reduced response such as those with high baseline viral loads (≥100,000 copies/mL HIV-1 RNA; 49 percent) or low baseline CD4+ counts (<20 cells/µL; 46 percent).
In terms of immunologic response, CD4+ cell count increased by an average of 205 cells/µL at week 96 from week 48. Similarly, improvements were comparable across subgroups, including those with most immune suppressed at baseline (CD4+ counts <20 cells/μL) who had a mean increase of 240 cells/μL from week 48 to week 96.
When patients were stratified by baseline CD4+ count, 56 percent of the patients saw their CD4+ counts increased from <50 to ≥200 cells/μL while 6 percent had increase of CD4+ of ≥200 cells/μL.
“Subgroup analysis of the week 96 BRIGHTE data for the randomized cohort show remarkable efficacy with FTR across a wide spectrum of HTE patients,” said Lataillade and colleagues. “Virologic and immunologic response continued to improve in this difficult-to-treat population [at week 96].”
“Serious adverse events were predominantly in participants with very low starting CD4 counts,” they reported, noting that more patients with baseline CD4+ counts <20 cells/μL experienced serious adverse events (46 percent vs 27 percent) and deaths (8 percent vs 3 percent) compared with those with baseline CD4+ count of ≥200 cells/μL.
“BRIGHTE results support continued development of FTR as a potentially important treatment option for HTE patients with multi-drug resistant HIV,” said Lataillade.