Attachment inhibitor BMS-663068 potent and well-tolerated in early study

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A novel type of drug that targets the first step of HIV entry into cells appeared safe and demonstrated good antiviral activity in a phase 2a study presented on Monday at the 18th Conference on Retroviruses and Opportunistic Infections (CROI), taking place this week in Boston.

Richard Nettles from Bristol-Myers Squibb presented the data on BMS-663068, an oral pro-drug or precursor of the HIV attachment inhibitor BMS-626529.

HIV entry is a three-step process. The virus must first attach to the CD4 receptor on the surface of a cell, then bind to a co-receptor (either CCR5 or CXCR4) and finally fuse with the cell membrane, releasing viral components into the cell. The CCR5 antagonist maraviroc (Celsentri) targets the second step and the fusion inhibitor enfuvirtide (Fuzeon) acts at the third step.



In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 


Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.


A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.


A drug that is broken down into another active form inside the body.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

BMS-663068 would be the first drug to target the initial step. Its active form, BMS-626529, works by binding to the HIV-1 envelope glycoprotein gp120, thereby interfering with its attachment to the CD4 receptor.

Previously, BMS-663068 was shown to be safe and had a good pharmacokinetic profile in studies of more than 200 healthy HIV-negative volunteers. The results presented on Monday were from the first study of the drug in HIV-positive individuals.

This open-label trial included 50 people with clade B HIV. All but three were men and the mean age was 42 years. They had CD4 cell counts of at least 200 cells/mm3 (median 432 cells/mm3) and viral load of 5000 copies/ml or more. About two-thirds were treatment-naive, whilst one-third had previously used antiretroviral therapy but had been off treatment for at least eight weeks.

Participants were randomly allocated into five arms, assigned to receive 600mg or 1200mg BMS-663068, administered as monotherapy either once or twice daily, with or without a ritonavir (Norvir) booster to raise drug levels in the blood. Treatment for all arms lasted eight days.

BMS-663068 produced "substantial" declines in HIV viral load over eight days, with the greatest decreases observed during the first three days, Nettles reported.

Median maximum viral load declines from baseline ranged from 1.22 to 1.78 log. After excluding 11 participants who were found to be ineligible, had missing data or had pre-treatment IC50 measurements above 0.1 mcM, the range was 1.59 to 1.77 log.

The maximum viral load decrease for most participants was seen several days after the last dose. HIV RNA declines were observed in all arms, but were not proportional to dose.

CD4 cell gains also occurred in all study arms. Median increases were highly variable, ranging from 28 to 106 cells/mm3 in the adjusted population. CD8 cells rose as well, with gains of 69 to 288 cells/mm3.

The pro-drug's pharmacokinetic profile showed that it could be taken either once or twice daily. Adding ritonavir only modestly increased drug concentrations, indicating that boosting is unnecessary. Furthermore, the researchers suggested that doses lower than those studied might be adequate.

BMS-663068 was well tolerated at all doses, with no deaths, serious adverse events or discontinuations due to adverse events. Two-thirds of participants experienced symptoms considered to be treatment-related. The most frequent adverse events were headache and skin rash (reported by 36% and 16%, respectively), which were mostly mild.

Given these promising findings, Nettles said, BMS-663068 will enter phase 2b clinical trials later this year. An extended release tablet is also being developed that could potentially allow less frequent dosing.

Abstract and webcast

You can view the abstract from this research on the official conference website:

Abstract 49:

You can also watch webcasts of presentations made at the conference.

The webcast from the conference session HIV: Innovative Therapeutic Approaches, ART, and Drug Resistance, includes the speaker Richard Nettles.

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Nettles R et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: a potentially first-in-class oral HIV attachment inhibitor. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 49, 2011.