AVX754 is an experimental anti-HIV drug which has shown promising activity in test tube, animal and human studies.

The drug was formerly known as BCH10618, (-)dOTC and SPD754. It was orginally developed by BioChem Pharma, the originator of 3TC (lamivudine, Epivir), before this company was acquired by Shire Pharmaceuticals. AVX754 is now being developed by Avexa, although Shire have retained the drug's rights in North America.

AVX754 belongs to the class of anti-HIV drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). Like other NRTIs, AVX754 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.

AVX754 is a cytidine analogue that is similar in structure to 3TC and to FTC (emtricitabine, Emtriva). As levels of AVX754 are reduced in the presence of either of these drugs, they are unlikely to be useful in combination (Bethell 2004a,e).

AVX754 is the successor compound to dOTC, whose development was suspended in 1999 by BioChem Pharma when toxicity was found in monkeys given the drug for over six months.

Current research

The first efficacy study of AVX754 in humans was presented in 2003. Sixty-three HIV-positive people who had not previously taken any antiretrovirals were given AVX754 or placebo for ten days. The once daily doses ranged from 400 to 1600mg. At day 10, viral load in patients who received the active drug had fallen by between 1.18 and 1.65 log₁₀. AVX754 was well tolerated and no specific side-effects were reported (Cahn 2003).

AVX754 will be dosed twice daily, although dosing and pharmacokinetic research conducted in HIV-negative subjects has suggested that it could eventually be given once a day. Gender does not affect bodily processing of this drug, which is mainly cleared by the kidneys (Francis 2003). There is no effect of food on the levels of the drug absorbed into the blood (Holdich 2003). 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 AVX754 has a low potential to cause mitochondrial toxicity (Bethell 2004b).

Avexa is currently conducting a Phase IIb trial designed to demonstrate AVX754's efficacy in HIV-infected patients who have demonstrated resistance to 3TC in first-line therapy. The trial is examining two different doses of AVX754 and comparing the drug to 3TC. Results are due in the first quarter of 2006.

Current clinical studies are also assessing the role of AVX754 as an alternative to 3TC or FTC in patients with the M184V mutation.

Resistance

AVX754 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 (TAMs; Bethell 2003).

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 (Bethell 2004c). The drug also showed good activity against virus with common NRTI mutations present at baseline (Bethell 2004d).

Research

Cahn (2003) conducted a dosing and efficacy montherapy study in 63 HIV-infected individuals. 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.

References

Bethell R et al. Antiviral activity of SPD754 against clinical isolates of HIV-1 resistant to other NRTIs. Seventeeth International HIV Drug Resistance Workshop, Cabo San Lucas, abstract 3, 2003.

Bethell R et al. An in vitro evaluation of the intracellular anabolism of SPD754 and FTC alone and in combination. Fifteenth International AIDS Conference, Bangkok, abstract 4622, 2004a.

Bethell R et al. Comparison of the in vitro mitochondrial toxicity of SPD754 in HepG2 cells with nine other nucleoside reverse transcriptase inhibitors. 44^th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract 2689, 2004b.

Bethell R et al. Genotypic and phenotypic analysis of HIV-1 isolates from patients after 10 days monotherapy with SPF 754. 44^th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract 2814, 2004c.

Bethell R et al. In vitro and in vivo activity of SPD754 against wild type and NRTI-resistant viruses. Fifteenth International AIDS Conference, Bangkok, abstract 5642, 2004d.

Bethell R et al. Pharmacological evaluation of a dual deoxycytidine analogue combination: 3TC and SPD754. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 138, 2004e.

Cahn P et al. Anti HIV-1 activity of SPD754 a new NRTI: results of a 10 day monotherapy study in treatment naive HIV patients. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract LB15, 2003.

De Muys RF et al. Anti-Human Immunodeficiency Virus type 1 activity, intracellular metabolism, and pharmacokinetic evaluation of 2'-deoxy-3'-oxa-4'-thiocytidine. Antimicrobial Agents Chemother 43: 1835-1844, 1999.

Francis RJ et al. Pharmacokinetics of SPD754, a new cytidine analogue in healthy volunteers. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 528, 2003.

Gu Z et al. BCH-10618, a new heterosubstituted nucleoside analogue against HIV-1 infection. Antivir Ther 6: 8-9, 2001.

Holdich T et al. Investigation of the influence of food upon the pharmacokinetics of SPD754. Ninth European AIDS Conference, Warsaw, abstract 119, 2003.

Richard N et al. Selection of resistance-conferring mutations in HIV-1 by the nucleoside reverse trancriptase inhibitors (+/-)dOTC and (+/-)dOTFC. Antiviral Chem Chemother 11: 359-365, 2000.

Taylor DL et al. Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC] Antiviral Chem Chemother 11: 291-301, 2000.