Background

Current antiretroviral therapy (ART) results in rapid suppression of viral load and improves the health and lifespan of the individual. However, ART does not cure HIV infection and chronic therapy requires surveillance for drug side effects and drug-resistant virus. The majority of drugs approved or in clinical development for HIV seek to improve on the potency and/or safety of these same drug classes and antiviral resistance; however, over time the emergence and dominance of drug-resistant viruses to these drug classes increases.

Biotron is developing a new class of drug that attacks virus in cellular reservoirs that are poorly penetrated by ART. This approach aims to utilise the potency of current ART regiments that inhibit viral replication primarily in T cells and combine it with a novel inhibitor that reduces viral replication in cells of the monocyte-macrophage lineage. The aim is to reduce HIV-1 replication in a cellular reservoir that can act as a factory of virus production and potentially eliminate the vault of drug-resistant virus that infects these cells over the course of the HIV-1 infection.

Vpu Inhibitor

BIT225 represents a new, first-in-class drug for treatment of HIV. It is a novel, oral small molecule inhibitor of HIV-1 Vpu and specifically targets HIV in the monocyte-macrophage reservoir, which is currently not targeted with existing therapies. Vpu is a well conserved protein that forms a virus ion channel and is involved in the assembly and release of infectious viral particles.

Preclinical data

BIT225 is a late-acting drug, interfering with production and release of productive, infectious virus, and preventing transmission of virus to uninfected CD4 T cells. It is active against multiple-drug resistant strains of HIV in vitro and synergistic or additive with current several current HIV drugs. Biotron has developed a transfer assay, which quantitates HIV transfer from the infected macrophage compartment to CD4 T cells; we have demonstrated that BIT225 can significantly reduce both the virus spread within the monocyte/macrophage compartment and the transfer of virus to CD4 T cells. Additionally, we have demonstrated that BIT225 can prevent transfer of HIV from endogenously infected monocyte cells isolated from HIV+ patients.

Clinical data

Phase 1b/2a trial (BIT225-004) is currently in progress. This trial is a placebo-controlled, randomized study of the safety, pharmacokinetics (PK) and antiviral activity of BIT225 in treatment-naive patients with high HIV viral loads. The primary objective is to assess the safety and tolerability of BIT225, given twice daily, for 10 consecutive days. The secondary objectives are to assess the PK and antiviral efficacy of BIT225 in these patients. The trial is expected to conclude early in 2012.

Advantages

BIT225 has the following advantages:

• New mode of action drug
• Novel Vpu inhibitor with the potential to eliminate one of the major reservoirs of HIV in the body
• Active against multiple-drug resistant strains of HIV
• Potential for use in HCV and HIV-1 co-infected patients