New wave of HIV drugs enter human trials

At the annual Conference on Retroviruses and Opportunistic Infections, taking place this week in San Francisco, US, GlaxoSmithKline and Schering-Plough all presented new data on so-called CCR5 inhibitors, designed to block HIV from entering host cells.

Meanwhile, Panacos Pharmaceuticals has revealed that it has started a clinical trial of the first HIV maturation inhibitor, while Bristol-Myers Squibb presented initial safety data on an HIV attachment inhibitor.

Until last year, there have been just three available classes of antiviral drug for HIV; the nucleoside reverse transcriptase inhibitors (RTIs), non-nucleoside RTIs and HIV protease inhibitors. Use of these drugs in combination has had dramatic impact on patients' survival, but the development of resistance is still a major cause of treatment failure.

Worryingly, a study presented last year showed that 10 per cent of newly infected HIV patients in Europe had contracted a strain of the virus that was already resistant to at least one antiretroviral drug, while the majority of patients who have been on therapy for a while harbour resistant strains. It is recognised that avoiding resistance - more than side effects and dosing profile - is the key to long-term success of HIV therapy.

Roche broke new ground in 2003 with the launch of Fuzeon (enfuvirtide). This drug binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes. While it adds another line of defence for HIV patients whose therapy is starting to lose its effect, this drug is extremely expensive and must be delivered by injection, limiting its use.

In contrast, the new classes all have the potential advantage of being suitable for oral administration.

The CCR5 inhibitors target a co-receptor that is used by HIV, along with another receptor called CD4, to gain entry into white blood cells. The virus first binds to CD4 and then latches onto CCR5, giving it the extra leverage needed to break into the cell. Block CCR5, and the virus cannot get in.

Pfizer is in the lead in the race to bring a CCR5 inhibitor to market, having completed Phase II trials of its UK-427,857 candidate and will shortly enter it into large-scale Phase III studies.

At the retroviruses meeting, GSK presented Phase I data on its 873140 in 40 healthy volunteers that showed that it could effectively block CCR5. It will now press ahead with a Phase II programme.

Meanwhile, Schering-Plough presented Phase I data on Monday on its CCR5 inhibitor SCH-D in patients already infected with HIV, with initial results suggesting that the drug achieved a 50-fold reduction in the amount of HIV circulating in the blood. The company is also gearing up to start Phase II trials of the compound.

Maturation and attachment inhibitors​

B-MS reported results of a Phase I study on BMS-488043 at the meeting. This drug blocks viral entry by binding to the viral envelope protein gp120 and preventing it from binding to cellular CD4 receptors.

The study provided the first proof-of-principle of this approach to HIV drug development, said B-MS. Preliminary data were also presented from an ongoing Phase IIa trial involving 30 HIV-infected patients, indicating that the drug achieved reductions in viral load of between 10 and 99 per cent.

Finally, Panacos' maturation inhibitor, called PA-457, blocks a key step in viral replication that occurs as new virus particles are released from infected cells. Following PA-457 treatment, newly formed virus particles have a defective core structure and are non-infectious, according to preclinical studies.

The company said its Phase I study will focus on PA-457's safety and pharmacokinetics in uninfected volunteers.

This crop of new products provides an encouraging affirmation of the commitment of the pharmaceutical industry to continue research into new treatments for HIV.

This follows a difficult period for the industry as it copes with pricing pressure from not only less developed countries, where companies have had to slash prices enter into enforced licensing agreements to allow local companies to supply generics, but also a knock-on effect on pricing in the established US and European markets.