Integrase inhibitors enter trials in human volunteers

Kristen Kresge, for

Researchers have been studying HIV’s shadowy third enzyme, integrase, and its role in virus replication for the past 12 years. Their goal was to understand integrase well enough to be able one day to develop a drug that will inhibit the enzyme and keep the virus in check. That day might be coming soon.

There are now 16 approved drugs that block HIV’s other two enzymes, protease and reverse transcriptase. Integrase inhibitors are especially attractive because they would block an additional crucial step in the HIV life cycle: the integration of the virus’s DNA into the cell’s chromosome. Finding a molecule that successfully prevents integration would prevent HIV from infecting a host cell.

This now appears possible, as two integrase inhibitors – one developed by Merck and one by the joint venture between Shionogi and GlaxoSmithKline (GSK) – enter trials in human volunteers. It has taken a long time to reach this point and researchers all share one sentiment: “It’s been a difficult target,” said Dr Daria Hazuda, Executive Director of Biological Chemistry at Merck and Co.

Why so difficult? “You’re starting completely from scratch” with integrase, said Dr Frederic Bushman, Associate Professor at the Salk Institute. First was the complication of developing an assay, or screening system that was able to correctly identify compounds active against the integrase enzyme. Early tests gave many false positives, and the compounds they identified were found to have no activity in human cells.

Complicating the screening further is the fact that integration of the viral DNA into the host cell is a multi-step process. To be a successful inhibitor of integrase, a molecule can interfere at any step of integration. Merck’s compounds prevent the late step known as strand transfer. Early assays were unable to detect this type of inhibitor, which required Merck to develop an entirely new detection system. Hazuda called its development “a critical step within the program.”

Merck reported at the 14th International AIDS Conference results of a study of its integrase inhibitor, L-870,812, in rhesus monkeys. A total of six monkeys received the experimental drug as monotherapy for 75 days. Four of the monkeys had undetectable viral loads at the end of treatment, representing a 10,000-fold (4 log) viral load reduction compared to untreated control monkeys. The other two monkeys in the test group did not receive a suitable dose of L-870,812, and their viral loads did not reach undetectable levels. But they still had an improved response over the untreated monkeys and did not become ill.

Merck has also shown in laboratory studies that there is a high barrier to forming resistance against integrase inhibitors. When drug resistance mutations develop in integrase, the HIV replicates at a much lower rate in lab tests. The resistant strains do not persist very long.

Merck’s integrase inhibitor has also been shown to retain antiviral activity in lab experiments against viral variants that have resistance to currently available drugs, including protease, nucleoside reverse transcriptase, and non-nucleoside reverse transcriptase inhibitors.

This is good news for people in salvage therapy, but Hazuda warns that resistance may still be a problem. It is “difficult, but not impossible to get resistance mutations,” she said.

Dr W Edward Robinson Jr, Associate Professor in the Department of Pathology at the University of California in Irvine, thinks resistance to integrase inhibitors is likely to be a problem. Two of the mutations found in cell culture already exist in humans, so some individuals’ HIV will be naturally less susceptible, according to Robinson. “Resistance is going to be a problem with all these new compounds,” he said.

Robinson also points out that the weakness of the resistant virus in cell culture is not that promising, since the same thing was observed when protease and reverse transcriptase inhibitors were studied in the lab.

Merck is testing its compound L-870,810 – a sister to 870,812 – in HIV-negative volunteers to gather preliminary data. A study in HIV-positive volunteers will begin in the third quarter of this year. “The data look very promising,” said Hazuda, speaking about the Phase I study.

The Shionogi-GSK compound, S-1360, is under study in an HIV-positive group to determine efficacy in treatment-experienced patients. It will include 36 volunteers who will receive S-1360 mono-therapy for two weeks.

Results from a Phase I study in healthy recruits were also presented at the International AIDS Conference. A total of 18 volunteers received S-1360, and six received placebo. The drug was well tolerated – no one discontinued the study – with the most common side effect being headache. The data looked acceptable, according to Michael Rogers at GSK. “We’ve treated a number of people and it appears to be quite safe,” he added.

But S-1360 does have problems because it binds extensively to human blood proteins in cell culture. Earlier compounds developed at Merck failed as potential drugs because a large amount became bound to blood proteins, preventing it from being effective. Its current candidates have overcome this problem. S-1360 requires additional drugs to effectively suppress HIV as a result of the protein binding, and this could increase toxicity. Rogers cautions that there are still “a lot of hurdles to get over.”

Shionogi-GSK did not do a monkey study, so it is difficult to compare S-1360 with Merck’s L-870,810. Even so, researchers in the field speculate that the Merck compound is more potent so far.

Robinson called the Merck compound “much superior,” in lab studies. Rogers at GSK also commented positively about the performance of Merck‚s integrase inhibitor in the test-tube: “Clearly it’s more active.”

Both Shionogi-GSK and Merck are committed to their integrase inhibitor programmes, and probably other pharmaceutical companies will follow suit now that integrase has been shown to be a feasible target. If these two lead compounds don’t make it to market, Robinson believes it could still be quite a while until we have an integrase inhibitor as a drug.

In the meantime, the debate will begin about how integrase inhibitors will fit into the treatment regimen. “Any new drugs will be absolutely critical for salvage therapy. That’s a clear role,” said Robinson.

Bushman at the Salk Institute foresees an eventual therapy that combines integrase inhibitors that target different sites on integrase’s surface, much the way non-nucleosides and nucleosides can jointly attack the reverse transcriptase enzyme.

“The key is to keep looking for new classes. In the next year or so we’ll learn a lot more,” said Bushman.


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