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New integrase inhibitor bictegravir looks promising in early studies
Liz Highleyman, 2016-07-06 06:40:00
Gilead Sciences' novel integrase inhibitor bictegravir
(formerly GS-9883) demonstrated favourable pharmacokinetics, good tolerability,
an improved resistance profile compared to older drugs in its class, and potent
antiviral activity in laboratory and human studies, according to a set of
posters presented at the ASM Microbe conference last month in Boston.
Integrase strand transfer inhibitors (INSTIs) are an
effective and well-tolerated class of antiretroviral drugs that currently are
included in most recommended regimens in European and US HIV treatment
However, the first drug in this class, Merck's
raltegravir (Isentress), is taken
twice-daily, as is ViiV's newer dolutegravir (Tivicay, also in the Triumeq
coformulation) if a patient has pre-existing integrase resistance or is taking
potentially interacting drugs. Gilead's earlier elvitegravir (Vitekta, also in the Stribild and Genvoya coformulations) must be boosted with cobicistat or
Scott Lazerwith and colleagues at Gilead synthesised
and tested several new integrase inhibitor candidates to look for agents with higher
potency. They identified bictegravir, a compound with a larger molecular
structure known as the 'A-ring' and a novel configuration of the 'D-ring',
providing better binding to the HIV integrase enzyme and good metabolic
Bictegravir was found to have potent activity against
wild-type (non-mutated) HIV in laboratory studies and improved potency against
virus resistant to older integrase inhibitors. It showed improved
pharmacokinetics in rats and dogs, and had a half-life of about 19 hours in
humans, allowing for once-daily dosing.
Gregg Jones and colleagues further examined the in vitro resistance profile of
bictegravir, again showing potent activity against wild-type virus and mutants
resistant to nucleoside/nucleotide reverse transcriptase inhibitors, NNRTIs and
Bictegravir had a "markedly improved"
resistance profile compared to raltegravir and elvitegravir, and was more
potent than dolutegravir against HIV isolates from patients with high-level
INSTI resistance. Both bictegravir and dolutegravir had a higher barrier to
emergence of resistance than elvitegravir. Mutations selected by bictegravir
showed low-level cross-resistance to raltegravir or dolutegravir, and intermediate
cross-resistance to elvitegravir.
"Bictegravir exhibits an unsurpassed resistance
profile that supports its further clinical development for the first-line
treatment of HIV infection," the researchers concluded. "In addition,
bictegravir may be suitable for the once-daily treatment of HIV-infected
patients with pre-existing INSTI resistance."
Manuel Tsiang and colleagues, also from Gilead,
further analysed the in vitro
antiviral activity of bictegravir alone and in combination with tenofovir
alafenamide (a component of coformulations including Genvoya), emtricitabine (Emtriva),
and darunavir (Prezista).
They found that bictegravir alone was highly potent
against a diverse range of wild-type HIV-1 clinical isolates as well as HIV-2,
and it demonstrated synergistic activity when combined with the other
antiretrovirals, with minimal toxicity in human laboratory cell lines, CD4
T-cells and macrophages. Bictegravir specifically inhibited HIV, with no
measurable activity against hepatitis B or C or other viruses.
Finally, Joel Gallant from the Southwest Care Center in Santa Fe, New Mexico, and
colleagues conducted an early clinical trial testing bictegravir monotherapy
for 10 days in people with HIV.
This phase 1 study included 20 adults with chronic HIV
infection. Participants were either antiretroviral treatment-naive, or
treatment-experienced but had not previously used integrase inhibitors and were
off all antiretrovirals for at least 12 weeks. All but one were men, most were
white and the mean age was 35 years. At baseline they had a mean CD4 count of
approximately 440 cells/mm3 and a mean HIV RNA level of 4.4 log10
Participants were randomly assigned to receive
bictegravir at doses of 5, 25, 50 or 100mg, or placebo, once daily on an empty
stomach for 10 days. Drug resistance testing was done at baseline and the day
after the final dose.
Bictegravir led to rapid dose-dependent reductions in
viral load, ranging from -1.45 to -2.43 log10 at day 11, while there
was no change in the placebo group. Viral load declined throughout the
treatment period in all bictegravir-treated groups, and continued to fall
through day 14 in the 50mg arm and day 17 in the 100mg arm.
One patient in the 50mg arm and two in the 100mg arm
achieved viral suppression below 50 copies/ml by the end of treatment.
Bictegravir was safe and well-tolerated at all dose
levels, with no serious adverse events or drug discontinuations due to adverse
events. Three patients reported headaches and two reported diarrhoea. There
were no reports of primary resistance mutations in HIV integrase emerging
during this short study.
"Bictegravir 10 day monotherapy led to rapid
declines in HIV-1 RNA from baseline that were sustained through the treatment
period with no viral breakthrough," the investigators concluded.
Based on these findings, the 50mg dose of bictegravir
was selected for further clinical development in a coformulation with TAF and
emtricitabine as a single-tablet regimen for HIV treatment.