SUMMARY: An experimental HIV attachment inhibitor that acts at the first step of viral entry into cells appeared potent and well-tolerated in a small study presented this week in Boston at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Based on the promising findings, a Phase 2b study is planned to start this year.

By Liz Highleyman

The initial phase of the HIV lifecycle -- entry into susceptible host cells -- is a 3-step process. The virus first attaches to the CD4 cell surface receptor, then binds to a co-receptor (either CCR5 or CXCR4), and finally fuses with the cell membrane and merges into the cell. The CCR5 antagonist maraviroc (Selzentry) acts at the second step and the fusion inhibitor enfuvirtide (T-20; Fuzeon) targets the third step.

Richard Nettles from Bristol-Myers Squibb and colleagues presented findings from a Phase 2a study of a novel agent that would be the first drug to target the initial step -- the HIV attachment inhibitor BMS-663068, an oral pro-drug of the active compound BMS-626529. The active form binds to the HIV-1 gp-120 envelope protein and prevents it from attachment to CD4 receptors.

This open-label study included 50 patients with clade B HIV. It was the first trial with HIV positive participants, after BMS-663068 was shown to have favorable pharmacokinetic and safety profiles in studies of animals and healthy HIV negative volunteers.

Earlier testing indicated that the drug is active against HIV-1 with a median IC50 (50% inhibitory concentration) in the nanomolar range. It was found to be additive or synergistic when combined with 19 approved antiretroviral drugs. A total of 8 prior studies looked as BMS-663068 doses ranging from 20 to 2400 mg for up to 14 days.

In the present analysis, participants were randomly assigned to 5 arms:

	Group A: 600 mg BMS-663068 twice-daily (every 12 hours) boosted with 100 mg ritonavir (Norvir) twice-daily;
	Group B: 1200 mg BMS-663068 once-daily with 100 mg ritonavir once-daily;
	Group C: 1200 mg BMS-663068 twice-daily with 100 mg ritonavir twice-daily;
	Group D: 1200 mg BMS-663068 twice-daily with 100 mg ritonavir once-daily;
	Group E: 1200 mg BMS-663068 twice-daily with no booster.

In all arms, BMS-663068 was used as monotherapy (except for the small boosting dose of ritonavir) for 8 days.

About two-thirds of participants were treatment-naive, while the remainder were treatment-experienced but off drugs for more than 8 weeks. All but 3 were men and the average age was 42 years. At baseline the median plasma viral load was 4.4 log and the median CD4 count was 432 cells/mm3.

Within this group, 11 people were either found to be ineligible, had baseline IC50 values > 0.1 mcM, or were missing baseline IC50 data, leaving 39 participants with baseline IC50 <0.1mcM to be included in a pharmacodynamics (PD) sub-population.

Results

	Over 8 days, BMS-663068 produced viral load declines of at least 1 log in all arms:
	Group A: -1.64 log; Group B: -1.59 log; Group C: -1.78 log; Group D: -1.63 log; Group E: -1.22 log; Overall: -1.64 log.
	Looking only at the PD sub-population, a similar pattern was seen:
	Group A: -1.76 log; Group B: -1.59 log; Group C: -1.77 log; Group D: -1.66 log; Group E: -1.60 log; Overall: -1.69 log.
	The largest decreases in HIV RNA were observed during the first 3 days of dosing.
	Maximum viral load declines were typically observed several days after the last dose.
	HIV RNA decrases were not proportional to dose.
	CD4 cell gains were seen in all arms in the PD sub-population, and again were not proportional to dose:
	Group A: median 53 cells/mm3; Group B: median 86 cells/mm3; Group C: median 106 cells/mm3; Group D: median 28 cells/mm3; Group E: median 33 cells/mm3.
	CD8 cell numbers also increased across the board:
	Group A: median 288 cells/mm3; Group B: median 184 cells/mm3; Group C: median 186 cells/mm3; Group D: median 164 cells/mm3; Group E: median 69 cells/mm3.
	Pharmacokinetic (PK) profiling showed that BMS-663068 could be taken either once or twice daily.
	Ritonavir only modestly increased concentrations of the active drug, indicating that boosting is not necessary.
	BMS-663068 was well tolerated at all doses.
	There were no deaths, serious adverse events (AEs), or discontinuations due to AEs.
	There were no clinically relevant effects on ECG, laboratory values, vital signs, or physical exam findings.
	66% of participants experienced AEs considered to be treatment-related, most of which were mild.
	The most common AEs were headache (36% overall), skin rash (16%), urgent need to urinate (14%), and nasopharyngitis (12%).

BMS-663068 used as short-term monotherapy "resulted in a substantial decline in plasma HIV-1 RNA with increases in CD4+ lymphocytes," the investigators concluded, adding that it was "generally safe and well-tolerated in Phase 1-2a studies."

They noted that the drug's PK/PD profile "supports assessing lower doses than currently studied, given once or twice daily, without the requirement for ritonavir co-administration."

Nettles said that a Phase 2b trial of treatment-experienced patients is planned to start later this year.

Investigator affiliations: Bristol-Myers Squibb, Hopewell, NJ; Charité-Univ Med Berlin, Germany; Bristol-Myers Squibb, Princeton, NJ; Bristol-Myers Squibb, Wallingford, CT.

3/4/11

Reference
R Nettles, D Schurmann, L Zhu, and others. Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068: A Potentially First-in-class Oral HIV Attachment Inhibitor. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 49.