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

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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.

Glossary

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

plasma

The fluid portion of the blood.

dose-ranging trial

A clinical trial where two or more doses of a drug are compared to see which works best and is least harmful, usually done at an early stage of drug development.

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

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 4th 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.

References

Avexa Press Release. Avexa reports positive Phase IIb result: ATC shows superior activity. March 19, 2007.