inhibitor S/GSK1265744 exhibited
potent and prolonged activity against a broad range of HIV subtypes, was active
against clones with resistance to raltegravir (Isentress) and elvitegravir, and appears to have a high barrier to
resistance, according to a presentation at the 52nd
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in
Integrase inhibitors work by preventing HIV from
inserting its genetic material into a host cell's chromosomes, a necessary step
in viral replication. Researchers at Shionogi and ViiV Healthcare set out to
discover integrase inhibitors that had a better resistance profile than earlier
drugs in the class, could be administered once daily and were suitable for
inclusion in a single-tablet regimen.
Their lead compound, dolutegravir (formerly
S/GSK1349572), is now in phase III development and has demonstrated good
efficacy and tolerability in both treatment-naive and treatment-experienced
people with HIV.
They also found a promising
'back-up' compound, S/GSK1265744 (or S/GSK744 for short). In a previous phase I
study, orally administered S/GSK744 exhibited robust antiviral activity, with a
30mg once-daily monotherapy dose suppressing HIV RNA by about 2.5 log10
copies/mL after eleven days.
also determined that an injectable formulation of the drug binds strongly to
human proteins, enabling it to remain active in the body much longer than
the 19th International AIDS Conference (AIDS 2012) this July, investigators reported
that a nano-suspension of S/GSK744 was generally safe and well tolerated in
healthy HIV-negative volunteers and had a half-life of 21 to 50 days after a
single injection, suggesting once-monthly dosing might be possible.
ICAAC, Tomokazu Yoshinaga
from Shionogi presented data on S/GSK744's in vitro
anti-HIV activity and resistance profile.
laboratory study, researchers looked at how well S/GSK744 works against HIV-1
and HIV-2 in cell cultures, as well as the effect of human serum proteins. To
assess cross-resistance, they tested S/GSK744 against clones containing
mutations confer resistance to other integrase inhibitors.
S/GSK744 showed antiviral activity
against a range of HIV clinical isolates from patients including HIV-1 subtypes
A to G and from Group M, HIV-1 Group O and HIV-2.
When tested in human peripheral blood
mononuclear cells, S/GSK744 had a 50% inhibitory
concentration (IC50) – the amount needed to inhibit HIV replication by
half – of 0.22 nanomolar (nM).
When exposed to human serum, the estimated
protein-adjusted IC50 was 102 nM, compared to 38 nM for
dolutegravir, 20 for the experimental integrase inhibitor elvitegravir, and 5.6
for the sole approved integrase inhibitor raltegravir.
Exposing MT-2 cells (a laboratory cell
line commonly used in retrovirus research) infected with HIV-1 IIIB to S/GSK744
for up to 112 days did not produce any highly resistant mutations.
Bioengineered site-directed mutant clones
containing single signature mutations that confer resistance to raltegravir or
elvitegravir generally showed less than a two-fold change in susceptibility to S/GSK744.
The notable exceptions were the Q148K and
Q148R mutations, with about a five-fold change. Susceptibility to S/GSK744 was
further reduced in clones containing double mutations, but even these showed
less than a twelve-fold change.
researchers concluded that
S/GSK744 demonstrated "low nM activity against a broad range of HIV-1
subtypes and HIV-2", shows "limited cross-resistance to both raltegravir
and elvitegravir", and has "a high barrier to resistance in vitro".
"These encouraging antiviral data
and demonstrated human pharmacokinetics, suggest S/GSK744 may have a favourable
profile for both HIV treatment and PrEP [pre-exposure prophylaxis]," they added.
A phase IIb trial of the S/GSK744 nano-suspension
in combination with a long-acting
injectable formulation of the NRTI rilpivirine (Edurant)
is currently underway.