Apricitabine (AVX754, SPD754)

Apricitabine is a nucleoside reverse transcriptase inhibitor that is active against the M184V mutation and to other thymidine-associated mutations. It interferes with the process of HIV replication by imitating the nucleosides, or building blocks of DNA, used to produce new HIV genetic material. The drug is inserted into the DNA strand, thus inhibiting HIV reproduction. It is similar in structure to 3TC and to FTC (emtricitabine, Emtriva). As levels of apricitabine are reduced in the presence of either of these drugs, they are unlikely to be useful in combination.^{1 2}

Apricitabine (ATC, AVX754) was formerly known as BCH10618 when it was originally developed by BioChem Pharma, also the originator of 3TC (lamivudine, Epivir). This company was acquired by Shire Pharmaceuticals and the drug continued development as SPD-754.

The Australian biotechnology company Avexa acquired apricitabine development from Shire in 2005. However, development was halted in May 2010 because Avexa could neither afford to develop the drug alone nor find a partner for co-development and licensing. Avexa has subsequently decided to resume development of the drug subject to further financing.

Avexa released 96-week data from its ongoing phase II study. Viral load was undetectable in 85% of the 39 individuals who completed 96 weeks on therapy. No reports of serious adverse events or of resistance have been noted. Because apricitabine is a deoxycytidine analogue, it is active against the M184V mutation as well as other thymidine-associated mutations.

Apricitabine seems to avoid the mitochondrial toxicity found in first-generation NRTIs and has been safely and effectively used in treatment-naive and ART-experienced individuals. So far, no resistance to the drug has been seen. Avexa is moving ahead with phase III studies at a dose of  800mg.^{3 4 5}

In 2003, results from a dosing and efficacy monotherapy study in 63 HIV-infected individuals were presented.⁶ Participants had a baseline CD4 count below 250 cells/mm³ and a VL between 5000 and 100,000 copies/ml. Participants were randomised to 400, 800, 1200 or 1600mg daily or placebo for 10 days. Viral load responses at day 10 were -1.18, -1.40, -1.65 or -1.58 log₁₀, respectively, while those on placebo experienced no significant reduction in viral load.

Apricitabine was compared with 3TC in a phase IIb study in 52 patients who have resistance to 3TC and are failing treatment. Participants were initially randomised to continue 3TC, or to take either 600mg or 800mg of ATC twice daily for 21 days with their existing background regimen. Just under half (48%) of patients in the study had at least three thymidine analogue mutations (TAMS), a sign of substantial resistance to AZT and d4T, and potentially reduced response to abacavir, ddI, and tenofovir.

Apricitabine (ATC) treatment was associated with a 0.5 to 0.7 log reduction in viral load. After 21 days, the background regimen was changed to an 'optimised' background regimen. Twenty-one day results from the study showed no significant difference in viral load reduction between those with three or more TAMs and the average for the group as whole (approximately 0.7 log) in patients who received the higher 800mg dose of ATC. However, at the lower 600mg dose the response was markedly poorer in those with three or more TAMs.

After 24 weeks, 80% in the ATC arm had viral load below 400 copies/ml and more than 70% had viral load below 50 copies/ml. Viral load values in the 3TC arm were not stated by Avexa, but were planned for later release.

Only four patients on ATC had sufficient levels of virus for resistance testing at week 24, consistent with the high level of viral suppression achieved in the study, but none of them showed additional mutations in reverse transcriptase. Patients receiving ATC gained an average of around 150 CD4 cells by week 24, but details of the average baseline CD4 cell count have not been released yet.

A planned 48-week phase III trial commenced in January 2008, comparing two doses of ATC – 800mg or 1200mg daily – to 3TC. After 16 weeks, the 800mg dose was chosen as standard and given to all participants in the ATC arms. The trial itself was halted prematurely in October 2009, and 24-week data on the 246 patients enrolled were released. There was a trend toward better virologic response, with approximately 0.4 log further reduction in viral load with ATC versus 3TC; however, the results lacked statistical significance due to the early trial termination.⁷

Gender does not affect bodily processing of this drug, which is mainly cleared by the kidneys.⁸ There is no effect of food on the levels of the drug absorbed into the blood.⁹ According to the results of animal studies, AVX754 is able to penetrate the cerebrospinal fluid (CSF), considered an HIV sanctuary site.

A test tube study has also shown that apricitabine has a low potential to cause mitochondrial toxicity.¹⁰

Apricitabine is reported to be active against AZT (zidovudine, Retrovir) and 3TC-resistant virus in the test tube, with a twofold increase in the mean IC₅₀ reported when key mutations at M184V and codon 215 were present. The susceptibility of HIV to the drug is also reduced around twofold by the presence of up to five thymidine analogue mutations.¹¹

In the test tube, resistance to AVX754 is slow to develop in comparison with 3TC, and is associated with changes at codons K65R, V75I and M184V. This can cause cross-resistance to 3TC. Development of these mutations results in a loss of sensitivity of up to fourfold, but the loss of sensitivity required for resistance to develop has not yet been defined.

In patients given AVX754 alone for ten days, no new mutations were seen in HIV.¹² The drug also showed good activity against virus with common NRTI mutations present at baseline.¹³