By Liz Highleyman

HIV uses 1 of 2 co-receptors -- CCR5 or CXCR4 -- along with the CD4 receptor to enter host cells. CCR5 antagonist drugs such as maraviroc (Selzentry) are effective against HIV strains that exclusively use the CCR5 co-receptor. A related approach is to use antibodies that bind to CCR5 so the virus cannot use it.

Inhibition of virus entry of CCR5-utilizing (monocytotropic) and CXCR4-utilizing (T-cell tropic) HIV isolates by the natural ligands of the chemokine coreceptors CCR5 and CXCR4.

Previous research has shown that the genetically engineered humanized CCR5 monoclonal antibody PRO 140 exhibited good HIV inhibition in laboratory studies and potent and prolonged antiviral activity using both intravenous (IV) and subcutaneous formulations in early human clinical trials.

Since it works by a different mechanism (blocking the viral attachment site rather than changing the co-receptor's shape), PRO 140 has limited cross-resistance with maraviroc or vicriviroc (another experimental CCR5 antagonist), and actually had synergistic activity with these drugs in vitro. Unlike these agents, however, PRO 140 does not appear to interfere with the natural functions of CCR5.

In the first study in HIV positive patients (Study 1302), a single IV infusion of PRO 140 produced a mean maximum viral load reduction of 1.83 log10 -- which researchers characterized as the "largest single-dose decreases in viral load reported for any HIV drug -- with no dose-limiting toxicity.

In the present Phase 2a trial, investigators with the 2301 Study Team evaluated the pharmacokinetics, antiviral activity, and tolerability of PRO 140 in 31 HIV positive adults randomly assigned to receive single 5 mg/kg or 10 mg/kg IV doses or else placebo.

All but 2 participants were men, most were white, and the median age was about 43 years. Patients were off antiretroviral drugs for at least 12 weeks. They had a baseline viral load of at least 5000 copies and were determined to have exclusively CCR5-tropic virus using the first-generation Trofile assay. All had a CD4 count of at least 300 cells/mm3 (median 382 cells/mm3), none had a CD4 nadir (lowest-ever level) below 250 cells/mm3, and none had AIDS-defining illness. Follow-up continued for 58 days.

Results

	All but 1 of the participants who received either dose of PRO 140 experienced a > 1 log10 reduction in HIV RNA.
	The exception was an individual in the 10 mg/kg arm who turned out to have dual/mixed-tropic (i.e., partially CXCR4-tropic) virus when tested with the new enhanced sensitivity Trofile assay (excluded from further analysis).
	20% of participants receiving 5 mg/kg PRO 140 and about 55% receiving 10 mg/kg had a > 2 log10 reduction.
	The mean maximum viral load reduction in both PRO 140 dose groups was 1.8 log10, compared with 0.3 log10 in the placebo arm.
	At day 12 after dosing, HIV RNA was still reduced by a mean 1.7 log10 in both dose groups.
	There was a trend toward more prolonged activity in the higher dose group.
	At day 22, the mean reductions were 0.9 log10 in the 5 mg/kg group and 1.3 log10 in the 10 mg/kg arm.
	2 patients had low measured titres of antibodies against PRO 140, but this had no apparent effect on virological response.
	PRO 140 was again found to be safe and generally well tolerated.
	Adverse events were common, occurring in most patients in all 3 study arms.
	However, there were no serious adverse events judged to be drug-related, and no dose-limiting toxicities.
	In further studies, the investigators demonstrated that 10 mg/kg IV and 324 mg subcutaneous forms of PRO 140 had similar efficacy (day 12 viral load decreases of 1.7 vs 1.5 log10, respectively).

Based on these findings, the investigators concluded that PRO 140 demonstrated "potent, rapid, prolonged, dose-dependent, highly significant antiviral activity," and that a mean viral load reduction of > 1 log10 was maintained for 3 weeks after receiving the 10 mg/kg IV dose.

Given its antiviral equivalence, Progenics has chosen the subcutaneous formulation of PRO 140 for further development because it can potentially be self-administered by patients.

10/09/09

References
J Jacobson, M Thompson, M Fischl, and others. Phase 2a Study of PRO 140 in HIV-Infected Adults. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009). San Francisco. September 12-15, 2009. Abstract H-1229.