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PRO 140

Other Names: PRO-140

Drug Class: Entry and Fusion Inhibitors

PRO 140 is a type of medicine called an entry inhibitor. Entry inhibitors work by blocking the entry of HIV into human cells.

HIV/AIDS-Related Uses

PRO 140 is an investigational medicine that is not yet approved by the FDA for use outside of clinical trials. It is being studied for the treatment of HIV infection. This medicine does not cure or prevent HIV infection or AIDS and does not reduce the risk of passing the virus to other people.

Dosage Form/Administration

PRO 140 comes in liquid form that is given by intravenous infusion into a vein or subcutaneous injection.

Recommended Daily Dose

Several intravenous doses of PRO 140 from 0.1 to 10 mg/kg have been studied in clinical trials. A dose of 324 mg is being studied in a Phase 2 clinical trial.

Contraindications

Individuals should tell a doctor about any medical problems before taking this medicine.

Possible Side Effects

Along with its desired effects, PRO 140 may cause some unwanted effects. No major side effects have been reported in studies so far.

Drug and Food Interactions

A doctor should be notified of any other medications being taken, including prescription, nonprescription (over-the-counter), or herbal medications.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use PRO 140.

Manufacturer Information

PRO 140

Progenics Pharmaceuticals, Inc.
777 Old Saw Mill Road
Tarrytown, NY 10591

Last Updated: April 15, 2009

Drug Description

PRO 140 is a humanized monoclonal antibody against CCR5 and is designed to block the ability of HIV to enter and infect cells. [1]

References

[1] Progenics Pharmaceuticals Progenics Reports Positive Results From Phase I Clinical Trial of PRO 140, a Novel Monoclonal Antibody That Blocks HIV Entry [Press Release], September 9, 2005. Available at: http://www.progenics.com/releases.cfm. Accessed 04/15/09.

HIV/AIDS-Related Uses

PRO 140 is an investigational entry inhibitor being studied for the treatment of HIV infection. PRO 140 has potential utility in both treatment-experienced and treatment-naive HIV infected individuals. [1] To date, two Phase I studies studies of the safety and pharmacokinetics (PK) of PRO 140 given intravenously have been completed, one in HIV uninfected males and another in HIV-1 infected individuals of both sexes. Two Phase II studies of the safety and PK of PRO 140 given intravenously and subcutaneously are ongoing, in the interim yielding positive results. [2] [3] [4] PRO 140 was granted fast-track status by the FDA in February 2006. [5]

References

[1] IAS Conf on HIV Pathogenesis and Treatment 4th, 2007. Abstract WEPEA093.

[2] Progenics Pharmaceuticals Progenics Reports Positive Results From Phase I Clinical Trial of PRO 140, a Novel Monoclonal Antibody That Blocks HIV Entry [Press Release], September 9, 2005. Available at: http://www.progenics.com/releases.cfm. Accessed 10/16/07.

[3] Natap.org Progenics Reports Positive Interim Phase 2 Results for Two Dosage Forms 0f Novel HIV Therapy PRO 140 [Press Release], October 26, 2008. Available at: http://www.natap.org/2008/ICAAC/ICAAC_94.htm. Accessed 04/15/09.

[4] IAS Conf HIV Pathogen, Treat, Prevent- 4th, 2007 Abstract WESS201.

[5] Progenics Pharmaceuticals Progenics Pharmaceuticals' HIV Drug, PRO 140, Receives FDA Fast-Track Designation [Press Release], February 22, 2006. Available at: http://www.progenics.com/releases.cfm. Accessed 04/15/09.

Dosing Information

Mode of Delivery

Intravenous infusion and subcutaneous injection. [1] [2]

Dosage Form

Intravenous infusions of 0.1, 0.5, 2, 5, and 10 mg/kg doses of PRO 140 have been administered to both HIV infected and uninfected individuals in clinical trials. [3] [4] [5]

Subcutaneous injections of 324 mg of PRO 140 have been administered to HIV infected individuals in one clinical trial. [6]

References

[1] Natap.org Antiviral Effects and Tolerability of the CCR5 Monoclonal Antibody PRO 140: A Proof of Concept Study in HIV-Infected Individuals. Available at: http://www.natap.org/2007/ICAAC/ICAAC_21.htm. Accessed 10/16/07.

[2] Natap.org (2) Natap.org - Progenics Reports Positive Interim Phase 2 Results for Two Dosage Forms 0f Novel HIV Therapy PRO 140 [Press Release], October 26, 2008. Available at: http://www.natap.org/2008/ICAAC/ICAAC_94.htm. Accessed 04/15/09.

[3] IAS Conf on HIV Pathogenesis and Treatment 3rd, 2005. Abstract WePe6.2C04.

[4] Conf Retroviruses Opportunistic Infect 13th, 2006. Abstract 515.

[5] Natap.org Antiviral Effects and Tolerability of the CCR5 Monoclonal Antibody PRO 140: A Proof of Concept Study in HIV-Infected Individuals. Available at: http://www.natap.org/2007/ICAAC/ICAAC_21.htm. Accessed 04/15/09.

[6] Natap.org Progenics Reports Positive Interim Phase 2 Results for Two Dosage Forms 0f Novel HIV Therapy PRO 140 [Press Release], October 26, 2008. Available at: http://www.natap.org/2008/ICAAC/ICAAC_94.htm. Accessed 01/19/09.

Pharmacology

The CCR5 receptor is found on certain human inflammatory cells; HIV uses this receptor as a portal to enter and infect healthy cells. [1] PRO 140 inhibits entry of HIV into cells by preventing virus-cell binding at a distinct site on the CCR5 coreceptor without interfering with the natural activity of CCR5. It binds an extracellular (not a transmembrane) site, inhibiting HIV via a competitive (rather allosteric) mechanism. [2] PRO 140 exhibits dose-dependent binding to CCR5-expressing cells, significantly coating and protecting such cells for up to 60 days. [3] PRO 140 broadly and potently inhibits wild-type and drug-resistant, R5-tropic HIV in vitro. It is also synergistic with small-molecule CCR5 antagonists. [4] This synergistic effect seen when combining PRO 140 with other investigational CCR5 inhibitors suggests that PRO 140 may represent a distinct subclass of CCR5 inhibitors. [5]

A Phase I, randomized, double-blind, placebo-controlled study was conducted to examine the safety, PK, and pharmacodynamics of single-dose PRO 140 in 20 healthy males. Participants received intravenous PRO 140 doses of 0.1, 0.5, 2, and 5 mg/kg in sequential, dose-rising cohorts of 5 (4 active, 1 placebo) each and were evaluated for 60 days post-treatment. Serum concentrations of PRO 140 increased proportionally with dose; the serum half-life was approximately 2 weeks. Cellular CCR5 receptors remained coated with PRO 140 for greater than 60 days at the 5 mg/kg dose. No anti-PRO 140 antibodies were observed in preliminary bioanalytical testing. [6] [7]

In another Phase I, randomized, double-blind, placebo-controlled study, the safety, tolerability, antiviral activity, and PK of single-dose PRO 140 administered intravenously were studied in 39 HIV infected participants. Doses of PRO 140 of 0.5, 2, or 5 mg/kg were administered. A 10-fold (90%) reduction in viral load from baseline was observed as early as Day 5; the average viral load reduction by Day 10 was approximately 99%. All participants who received 5 mg/kg PRO 140 experienced at least a 10-fold reduction in viral load from baseline. The 2.0 mg/kg dose reduced viral load by an average of 90%; the 0.5 mg/kg dose reduced viral load by an average of 50%. A 29% (p=0.055) average increase in CD4 cells by Day 8 was also observed, suggesting a trend of increased CD4 count with PRO 140 use. Potent, rapid, prolonged, dose-dependent significant antiviral activity was observed across all dose groups. PK studies indicated that peak and total exposure increased proportionally or better with dose. Peak levels of PRO 140 were achieved within 3 to 60 minutes, and the terminal half-life of PRO 140 was determined to be about 4 days. Low titer anti-PRO 140 antibodies developed in one participant who received the 5.0 mg/kg dose; no obvious effect on PK or antiviral response could be discerned. Ex vivo fluorescently-labeled lymphocytes analyzed by flow cytometry indicated obvious coating of CCR5 lymphocytes by PRO 140, with a duration of coating of 1 to 2 weeks consistent with the compound's antiviral effects. [8]

In vitro antiviral activity of PR0 140 was independent of HIV-1 subtype and resistance to existing antiretroviral treatment classes. [9] PRO 140 exhibited potent, broad-spectrum activity in laboratory studies of more than 40 genetically diverse HIV strains. The strains failed to develop resistance to PRO 140, even after 40 weeks of continued exposure in vitro. [10]