A single high-dose infusion of GSK's N6LS led to a virologic response in all eight treatment-naïve HIV patients, according to phase 2a data presented at the 30th HIV Glasgow Conference.
Existing HIV antiretroviral therapies are mostly small-molecule drugs that require daily medication. Broadly neutralizing antibodies (bNAbs) hold promise as potential longer-term options, and GSK’s ViiV Healthcare has provided encouraging early proof-of-concept data for such a candidate.
The drug, called N6LS, came to GSK through a licensing deal with the National Institutes of Health in 2019. It targets the gp120 protein on the HIV envelope, blocking the virus from binding to CD4 on T cells and therefore preventing viral entry.
In the phase 2a BANNER study, a single dose of 40 mg/kg infusion of N6LS led to a virologic response in all eight treatment-naïve HIV patients. That means the patients had at least a 0.5 log10 copies/mL fall in viral load. The median viral count reduction was 1.72 log10 copies/mL, according to data presented at the 30th HIV Glasgow conference.
The drug’s performance represents a “nice drop” in viral load, ViiV’s head of R&D, Kimberly Smith, M.D., said in an interview with Fierce Biotech. To put the number in context, GSK’s integrase inhibitor Tivicay (dolutegravir), which Smith said is so far the most potent FDA-approved antiretroviral therapy based on its viral reduction data, showed a median 2.5 log10 copies/mL reduction in a similar proof-of-concept study. The number is also comparable to or higher than some other antiretrovirals, she said.
But the data weren’t all sunshine and roses. At a low, 4-mg/kg dose, N6LS failed to trigger a response in one of the six participants. That patient only saw a 0.3 log10 copies/mL reduction, while the median decrease in the low-dose cohort was 1.18 log10 copies/mL, according to GSK.
Across the two cohorts, side effects were reported in nine (56%) patients, including six that were considered drug-related. All of these effects were mild or moderate in nature.
Still, GSK noted that the low dose exceeded efficacy reported by other bNAbs at similarly low doses. It at least shows that “we may be able to use smaller amounts of N6LS and have efficacy,” Smith said.
“We’re going to do a whole lot of research on that individual to understand why he didn’t respond,” the ViiV exec added.
BNAbs are typically found in some people who have been dealing with HIV infection for a long time. Although called “broadly neutralizing,” bNAbs can’t neutralize all HIV strains. For N6LS, early lab tests suggest that it could tackle 96% to 97% of HIV viruses, Smith noted.
This nonresponder looks to fall in the 3% that are not covered by N6LS. GSK will study the kind of mutations the individual’s virus has in the CD4 binding site that makes N6LS ineffective, Smith said. The learning could guide future clinical development in larger populations.
Before moving to large studies, GSK wants to first identify the proper dose that is both efficacious and long-lasting for at least three months and potentially six months, Smith said.
GSK’s Cabenuva (cabotegravir and rilpivirine) represents the world’s first full long-acting HIV regimen. But, so far, Cabenuva can be administered by a healthcare professional once every two months at the longest, and industry watchers have questioned whether that dosing schedule can really shake up existing practice that’s dominated by daily orals. Various patient surveys and doctors’ feedback have suggested that a self-administered, ultralong-acting therapy could attract more interest.
GSK is moving in that direction with help from Halozyme’s Enhanze drug delivery technology, which has turned several marketed infused antibody therapies into under-the-skin injections.
Armed with Enhanze, GSK is already studying cabotegravir as a longer-acting injection and hopes N6LS could be one, too, as a potential combination partner for cabotegravir, Smith said. The company now plans to start a phase 2b study of N6LS in combination with other antiretrovirals in the second half of 2023, although Smith said a trial design hasn’t been decided.
GSK isn’t the only company working on bNAbs or long-acting HIV treatments. Gilead Sciences has won European approval for lenacapavir, or Sunlenca, a capsid inhibitor that can be given every six months. But Gilead is still searching for a long-acting combo partner for that drug.
Potential candidates Gilead is looking at include a long-acting version of bictegravir, an integrase strand transfer inhibitor that serves as the cornerstone of the company’s top-selling Biktarvy. It’s also studying a combination of two bNAbs, which it hopes could match up to lenacapavir’s six-month dosing interval.
