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 guidelines.
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 co-formulation) 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 co-formulations) must be boosted with cobicistat or ritonavir.
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 stability.
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 protease inhibitors.
Bictegravir had a "markedly improved" resistance profile compared to raltegravir and elvitegravir, and was more potent than dolutegravir against HIV isolates from people 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 co-formulations 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 copies/ml.
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 participant 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 people 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 co-formulation with tenofovir alafenamide and emtricitabine as a single-tablet regimen for HIV treatment.
Lazerwith S et al. Discovery of GS-9883, an HIV-1 integrase strand transfer inhibitor (INSTI) with improved pharmacokinetics and in vitro resistance profile. ASM Microbe, abstract 414, 2016. View abstract.
Jones G et al. GS-9883, a Novel HIV-1 integrase strand transfer inhibitor (INSTI) with optimized in vitro resistance profile. ASM Microbe, abstract 413, 2016. View abstract.
Tsiang M et al. Antiviral activity of GS-9883, a potent next generation HIV-1 integrase strand transfer inhibitor. ASM Microbe, abstract 416, 2016. View abstract.
Gallant J et al. Novel INSTI GS-9883 10 Day Monotherapy in HIV-1 Infected Subjects. ASM Microbe, abstract 415, 2016. View abstract.