HIV Entry Inhibitor PRO 140 Demonstrates Favorable Activity in Phase 2 Trial
HIV entry inhibitor PRO 140 has demonstrated potent anti-HIV activity in a
Phase 2 clinical trial, according to a late-breaker poster presented last month
at the 48th International Conference on Antimicrobial Agents
and Chemotherapy (ICAAC 2008).
140, being developed by Progenics Pharmaceuticals, is a recombinant (genetically
engineered) monoclonal antibody that binds to the CCR5 cell surface co-receptor
and prevents CCR5-tropic strains of HIV from using the co-receptor to enter cells.
Some strains of HIV can use the CXCR4 coreceptor (CXCR4 tropism) or both CCR5
and CXCR4 (dual/mixed tropism), and CXCR4-tropic virus tends to emerge as disease
small-molecule CCR5 antagonists such as maraviroc
(Selzentry), PRO 140 inhibits HIV entry at concentrations that do not appear
to block the natural immune activity of CCR5, and it is not metabolized by the
study presented at ICAAC, researchers compared the antiviral activity and tolerability
of 5 mg/kg and 10 mg/kg intravenous (IV) doses of PRO 140. The study included
31 patients with exclusively CCR5-tropic virus, baseline HIV RNA > 5000 copies/mL,
CD4 count > 300 cells/mm3, and no antiretroviral therapy for at least 12 weeks.
Participants were randomly assigned to receive single doses of 5 mg/kg PRO 140,
10 mg/kg PRO 140, or placebo, and were followed for 58 days post-treatment.
poster described an interim analysis of data from the first 15 treated patients
(5 per arm). Among this group, the mean baseline viral load was about 35,500 copies/mL
and the mean CD4 count was about 400 cells/mm3.
Mean maximum log10 reductions in HIV RNA
were 1.90 (range 1.44-2.17) in the 5 mg/kg PRO 140 arm and 2.17 (range 2.09-2.26)
in the 10 mg/kg PRO 140 arm, compared with 0.48 (range 0.15-0.73) in the placebo
arm (both P < 0.0001).
At day 12, mean log10 changes in HIV RNA
were -1.88, -2.01, and +0.06, respectively (P < 0.0001).
All patients treated with 5 mg/kg PRO
140 experienced a greater than 1.0 log10 maximum reduction in viral load, while
those who received 10 mg/kg experienced a greater than 2.0 log10 maximum reduction
(both P = 0.0079).
Through day 22, the mean viral load reduction
was 1.55 log10 in the 10 mg/kg PRO 140 arm (P = 0.0005).
PRO 140 was generally well-tolerated,
with no drug-related serious adverse events or dose-limiting toxicities.
data confirm the antiviral activity reported previously for 5 mg/kg PRO 140,"
the investigators concluded. "A 10 mg/kg dose increased the duration of antiviral
antiviral activity in the 5 mg/kg PRO 140 arm of this study was similar to the
mean 1.83 log10 viral load reduction with the same dose observed in an earlier
Phase 1b study, which was initially presented at the
2007 International AIDS Society meeting in Sydney, Australia, and published
in more detail in the November 1, 2008 Journal of Infectious Diseases.
Doubling the dose produced more potent and long-lasting antiviral activity.
IV dosing is inconvenient for patients, and the company is also testing a subcutaneous
(SC) formulation of PRO 140 that is injected under the skin rather than into a
vein. In this trial, 44 patients were randomly assigned to receive 3 once-weekly
doses of 162 mg or 324 mg PRO 140; 2 bi-weekly doses of 324 mg PRO 140, or placebo.
Progenics recently announced interim data from the first 20 patients in
this study, showing a mean maximum viral load reduction of 1.77 log10 for patients
treated with 3 once-weekly 324 mg subcutaneous doses (P = 0.0006). 100% of patients
treated with 324 mg once-weekly PRO 140, and 67% of those treated with 324 mg
bi-weekly, experienced a greater than 1.0 log10 reduction in viral load (P = 0.0079
and 0.061, respectively). In both the 324 mg once-weekly and bi-weekly dose arms,
a greater than 1.0 log10 viral load reduction was maintained for 2 weeks after
the last dose. Here, too, PRO 140 was generally well-tolerated, with a minority
of patients reporting mild injection site reactions.
"The viral load
reductions observed for intravenous PRO 140 are similar in magnitude to those
observed for our most potent HIV drugs at this stage of development," said
lead investigator Jeffrey M. Jacobson, MD, in a press release issued by Progenics.
"The findings underscore the efficiency with which PRO 140 blocks HIV's access
to CCR5 and healthy cells in vivo. In addition, the antiviral and safety data
for subcutaneous PRO 140 are highly encouraging."
major potential benefit of PRO 140 is its long-lasting activity, which may allow
it to be administered as seldom as once monthly using the IV route or once-weekly
by subcutaneous injection. The company indicated that full data from both ongoing
Phase 2 trials are expected by early 2009 and will be used to select an optimum
dose for further clinical development.
Univ. College of Med., Philadelphia, PA; AIDS Research Consortium of Atlanta,
Atlanta, GA; Univ. Miami, Miami, FL; Univ. Alabama, Birmingham, AL; Montefiore
Med. Ctr., Bronx, NY; Jacobi Medical Center, Bronx, NY; Albany Med. Ctr., Albany,
NY; Quest Clinical Res., San Francisco, CA; Univ. Cincinnati, Cincinnati, OH;
NorthStar Med. Ctr., Chicago, IL; University of Rochester, Rochester, NY; University
of Maryland, Baltimore, MD; Progenics Pharmaceuticals, Tarrytown, NY.
Jacobson, MA Thompson, MA Fischl, and others. Antiviral Activity and Tolerability
of 5 mg/kg and 10 mg/kg Doses of PRO 140, a Humanized Monoclonal Antibody to CCR5.
48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC
2008). Washington, DC. October 25-28, 2008. Abstract H-1269a.
Jacobson, MS Saag, MA Thompson, and others. Antiviral Activity of Single-Dose
PRO 140, a CCR5 Monoclonal Antibody, in HIV-Infected Adults. Journal of Infectious
Diseases 198(9). November 1, 2008.
Pharmaceuticals. Progenics Reports Positive Interim Phase 2 Results for Two Dosage
Forms of Novel HIV Therapy PRO 140. Press release. October 26, 2008.