Attachment Inhibitor Shows Some Progress in Trials

Programs that have sought to develop anti-HIV drugs (of all classes) have sometimes produced candidate compounds that may appear potent in laboratory experiments with cells. However, when these compounds are later tested in people, they sometimes fail to make it through phase I, II or III clinical trials, often because of toxicity or insufficient effectiveness.

Leading treatment guidelines in high-income countries today generally encourage the use of drugs for the initial therapy of HIV, which, in most cases, are not the first member of their class that were developed. This is particularly the case for commonly used classes of HIV medicines -- nukes, non-nukes and protease inhibitors.

Looking at Drug Classes

Looking within the class of drugs called protease inhibitors, initial treatments included saquinavir (Invirase), high-dose ritonavir (Norvir) and indinavir (Crixivan). Today the U.S. Department of Health and Human Services (DHHS) guidelines -- the most comprehensive of HIV treatment guidelines -- largely prefer that doctors, if they chose to prescribe protease inhibitors, prescribe darunavir (Prezista) or atazanavir (Reyataz), both accompanied with a small dose of ritonavir. The purpose of the small dose of ritonavir is to raise, or boost, the concentration of the other protease inhibitor in the blood so that once-daily dosing is possible.

Within a drug development program, the candidate compound that finally enters phase III clinical trials is probably one of several that were developed, with the earlier versions discarded because of insufficient potency or other issues. This was the case with the pharmaceutical company Merck and its integrase inhibitor program. Although Merck scientists were searching for and creating integrase inhibitors in the early 1990s, it was only in 2007 that one integrase inhibitor, raltegravir (Isentress), successfully completed all three main phases of clinical trials to ensure that it was licensed by regulatory agencies.

Enter the Attachment Inhibitor

For the past decade, researchers at the Bristol-Myers Squibb Corporation (BMS) have been developing a new class of anti-HIV compounds called attachment inhibitors. These drugs work by interfering with a viral protein called gp120. By binding to this protein, attachment inhibitors prevent HIV from attaching to and entering and infecting a cell.

BMS has produced several attachment inhibitors but has encountered difficulties with early candidate compounds. One of the difficulties is that candidate compounds work well in lab experiments with cells and HIV. However, initial studies in people did not yield promising results. In particular, it seemed that early candidate attachment inhibitors were not well absorbed.

To help overcome this important barrier, scientists at BMS have developed a new formulation of their latest attachment inhibitor using a prodrug, an idea explained below.

About Prodrugs

BMS has a drug with the interim name BMS-663068. When this drug is swallowed and reaches the intestine, enzymes there convert it into another drug called BMS-626529 (which we shorten to '529). This latter drug, '529, is the one with active anti-HIV activity. Drugs that are taken in one form and then converted in the body into their active form are called prodrugs.

A short clinical trial with BMS-663068 as a single agent for at least eight days in HIV-positive volunteers has found that viral load fell between 1.2 and 1.7 logs.

Not everyone who took this drug had large decreases in viral load. BMS scientists were able to determine the reasons for this in five of six non-responders. It seems that HIV isolated from these five people was not susceptible to the attachment inhibitor. It appears that some strains of HIV have pre-existing, naturally occurring mutations to attachment inhibitors. These mutations allow these strains of HIV to resist the effects of attachment inhibitors.

Where Are the Mutations?

Studying attachment inhibitors and possible resistance mutations associated with them is an emerging field, so findings in this area are evolving. However, resistance to the BMS attachment inhibitor is not common in the strain of HIV that is widely found in North America, Western Europe, Australia and Japan -- subtype B. Rather, strains of HIV belonging to subtypes AE and Group O seem to have some naturally occurring, pre-existing resistance mutations to the BMS attachment inhibitors.

Study Details

In the latest clinical trial for which we have details, researchers working with BMS-663068 enrolled 250 participants. During the screening process for the trial, all participants underwent tests to have their HIV analysed to be sure that it would respond to the attachment inhibitor. After successful screening, all participants were assigned to receive the following drugs:

• raltegravir (Isentress) + tenofovir (Viread)

In addition, they were randomly assigned to receive one of four doses and schedules of BMS-663068, ranging from 400 mg twice daily to 1,200 mg once daily.

For purposes of comparison, one group of participants received the following regimen:

• raltegravir + tenofovir (Viread) + atazanavir + low-dose ritonavir

The average profile of participants at the start of the study was as follows:

• 60% male, 40% women

• age: 40 years

• HIV strains: most participants (67%) had subtype B, but some participants had subtype C and other strains

• HIV viral load: 63,000 copies/ml

• 45% of participants had a viral load greater than 100,000 copies/ml

• CD4+ count: 250 cells/ml

• 40% of participants had a CD4+ count less than 200 cells/ml

Many participants had experienced the failure of their first and second regimens prior to enrollment.

For the first part of the study, lasting about a week, participants underwent monotherapy with the attachment inhibitor. After this they took combination therapy as outlined earlier.

Results -- Monotherapy

Viral load fell depending on the dose of the attachment inhibitor used. For instance, among participants who took 400 mg twice daily, it fell an average of 0.69 log; among participants who took 1,200 mg once daily it fell by about 1.5 log.

Results -- After 24 Weeks of Combination Therapy

Here are the proportions of participants who had a viral load less than 50 copies/ml in each of the different combination therapies. Although all participants received combination therapy, because the drug of importance is the attachment inhibitor, we focus on the dose of that drug here:

• 400 mg twice daily: 80% had a viral load less than 50 copies/ml

• 800 mg twice daily: 69% had a viral load less than 50 copies/ml

• 600 mg once daily: 77% had a viral load less than 50 copies/ml

• 1,200 mg once daily: 72% had a viral load less than 50 copies/ml

For comparison, among participants who took a regimen of already approved drugs (raltegravir + tenofovir + atazanavir + ritonavir), 75% had a viral load below the 50-copy/ml mark at week 24.

Increases in CD4+ counts were similar among all participants -- about 120 more CD4+ cells/ml by week 24.

Based on the effectiveness of the 1,200 mg dose, particularly in monotherapy, partway through the study BMS decided to have all participants take a 1,200 mg once-daily dose of the attachment inhibitor.

Safety

Doctors involved with the study could not find any side effects caused by the attachment inhibitor. Four participants left the study prematurely, for reasons unrelated to exposure to the attachment inhibitor, as follows:

• one case of abnormal heart rhythms in a person who injected street drugs

• two cases of TB (some participants were recruited from countries where tuberculosis is relatively common)

• one case of severe kidney injury caused by exposure to tenofovir

Among people taking the regimen of already approved drugs, moderate-to-severe episodes of nausea, diarrhea and vomiting were reported.

Screening

Prior to enrollment, as part of the screening process, only 5% of volunteers were excluded from the study because their virus was not susceptible to the attachment inhibitor. Until larger studies are done, it is not clear what role pre-screening people for susceptibility to the attachment inhibitor will have. For instance, BMS '068 has been designed for treatment-experienced patients, many of whom will also likely be taking ritonavir-boosted protease inhibitors. Ritonavir can also boost levels of the attachment inhibitor. BMS researchers suggest that these increased levels of the attachment inhibitor carry the possibility, at least in theory, of overcoming any naturally occurring resistance some strains of HIV might have to the attachment inhibitor.

Looking ahead

BMS researchers plan to continue monitoring participants taking the attachment inhibitor for 48 weeks, perhaps longer. If this phase II study shows prolonged effectiveness of the attachment inhibitor and no problems emerge, then phase III trials are likely in the future.

Laboratory experiments suggest that if HIV does develop resistance to one attachment inhibitor, it likely remains susceptible to other experimental attachment inhibitors.

References

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