Next generation NRTI, apricitabine (ATC), shows early promise

Apricitabine (ATC, formerly AVX754 and SPD754), a next generation NRTI active against HIV that is resistant to 3TC (lamivudine, Epivir) or FTC (emtricitabine, Emtriva), appears safe and potent following a three-week phase IIb dose-ranging study in 47 participants. ATC – which must be taken twice daily – is being developed by the Australian biotech company Avexa, which announced the headline results in a press release on Monday.

AVX-201 was a randomised, double-blind, dose-ranging phase IIb study of two doses of ATC (600mg or 800mg ATC twice daily) compared to 3TC (taken as 150mg twice daily) in treatment-experienced participants with evidence of the M184V mutation.

Participants were required to be currently taking 3TC and have a viral load over 2,000 copies/ml and a CD4 cell count over 50 cells mm³. Individuals who were hepatitis B surface antigen positive, hepatitis C RNA positive, pregnant or breast-feeding were excluded.

Although the study aimed to enrol 60 participants, only 47 individuals completed 21 days of dosing. Of these, 17 received 600mg ATC and 16 received 800mg ATC, with 14 participants in the control group receiving 3TC. Although the study was open for enrolment in Australia and the United States, most participants were recruited in Argentina. Approximately a third were female, and aged between 22 and 59.

The Avexa release notes that “results for patients in both ATC cohorts exceeded the Phase IIb trial primary endpoint by a substantial margin.” Mean plasma viral load reduction after 21 days was greater than 0.8 log₁₀ all both ATC-treated groups compared to a reduction of less than 0.03 log₁₀ in the control group.

Nine ATC-treated participants achieved a greater than 1.5 log₁₀ reduction in plasma viral load; three patients achieved a greater than 2.0 log₁₀ drop; and one individual experienced more than a 2.5 log₁₀ decline in viral load. However, no details were provided regarding participants' baseline viral load levels.

Although the press release says that “approximately half had the highest levels of drug resistance”, there was no explanation provided as to whether this referred to phenotypic or genotypic resistance tests, nor to which drugs participants had resistance. Nevertheless, the press release notes that participants “with the highest degree of drug resistance still achieved a significant benefit from treatment with ATC.”

No evidence of mutations resulting in ATC resistance was detected in any ATC-treated participant during the study, and the press release hinted that the drug may be less fragile than 3TC or FTC, both of which have a low genetic barrier to resistance. However no details were provided on the background regimens of the participants, and whether or not anyone was effectively on ATC monotherapy.

ATC also appears to be safe in the short-term, with no ATC-related serious adverse events observed and no significant incidence of hyperlipasaemia (which would indicate pancreatitis) or elevated liver enzymes.

After day 21, study participants have continued to receive either ATC or 3TC up to week 24, but have also been able to change their other antiretrovirals. After 24 weeks, open label ATC has so far been provided to 14 participants for another 24 weeks. A further six individuals have already entered an extension study (AVX-201E) in which they continue to receive ATC in addition to other antiretrovirals.

Avexa says that full scientific data from this study will be presented at a forthcoming international scientific conference, likely to be the 4^th IAS Conference on HIV Pathogenesis, Treatment and Prevention to be held in Sydney, Australia, in July.

Avexa's CEO, Dr Julian Chick notes that this “positive result allows us to continue to progress ATC into Phase III trials and towards commercialisation.” Other next generation NRTIs currently in development include Pharmasset's racivir and Achillion's elvucitabine.