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FDA-approved

Investigational

PRO-2000  Audio icon

Other Names: PRO2000, PRO 2000/5
Drug Class: Microbicides
Molecular Formula: (C10 H8 O3 S.C H2 O.Na)x-
Registry Number: 29321-75-3 (CAS)
Chemical Name: 2-Naphthalenesulfonic acid, sodium salt (1:1), polymer with formaldehyde
Chemical Class: Polymers
Company: Endo Pharmaceuticals, Inc.
Phase of Development: Phase III. PRO-2000 vaginal gel was found to be ineffective as a topical vaginal microbicide for preventing HIV infection in Phase II and III studies.
Chemical Image:
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PRO-2000
PRO-2000
Molecular Weight: 238.262
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, Journal of Acquired Immune Deficiency Syndromes article3, Endo Pharmaceuticals Inc. News Release4, and National Institute of Allergy and Infectious Diseases [NIAID] News Release5)
Patent Version Content

Pharmacology


Mechanism of Action: Microbicide; polyanion-based entry inhibitor. PRO-2000, a synthetic naphthalene sulfonate polymer, is an HIV-nonspecific (broad-spectrum) entry/fusion inhibitor.6,7,8 As a negatively charged polyanion, PRO-2000 inhibits HIV-1 attachment to and/or fusion with CD4 cells by binding directly to positively charged viral gp120 and interacting with CD4 and CXCR4 host cell surface receptors. PRO-2000 exhibits greater binding affinity to the V3 loop of CXCR4-tropic viruses than to the V3 loop of CCR5-tropic viruses.3,9 PRO-2000 formulated as a topical vaginal microbicide has been studied to prevent sexual acquisition of HIV-1 infection and other sexually transmitted infections.10


Dosing in Clinical Trials


PRO-2000 gel is applied intravaginally. 

Phase II/IIb (HIV-uninfected women)
  • HPTN 035: Safety and Effectiveness Study
    0.5% PRO-2000 gel, BufferGel, hydroxyethylcellulose (HEC) placebo gel, or no intervention (no gel); gels were applied within 1 hour before vaginal intercourse. (Mean follow-up period was 20.4 months.)11,12
Phase III (HIV-uninfected women)
  • MDP 301: Safety and Effectiveness Study
    0.5% or 2% PRO-2000 gel versus placebo, applied within 1 hour before vaginal intercourse. The study originally included the 2% PRO-2000 gel arm, but use of the 2% gel was discontinued during the study because of a low probability of benefit. (Follow-up period was 52 weeks; follow-up period was up to 104 weeks in Uganda for long-term safety data).6,13
Additional studies of PRO-2000 gel have also been completed.


Adverse Events


In the HPTN 035 study of 0.5% PRO-2000 vaginal gel and BufferGel used in a coitally dependent manner over approximately 20 months by more than 3000 women, systemic and local adverse event rates were similar across all study arms. Study results indicated that both 0.5% PRO-2000 vaginal gel and BufferGel were safe. The four study arms had similar overall incidence rates of deep epithelial disruption, infections with sexually transmitted organisms (i.e., Neisseria gonorrheae, Chlamydia trachomatis, Trichomonas vaginalis, and Treponema pallidum), and bacterial vaginosis. A higher incidence of blood in the vagina with no identified source was seen in the 0.5% PRO-2000 gel arm than in the placebo gel arm and the no gel arm; however, these differences were not statistically significant.12

In the Phase III MDP 301 study of 0.5% and 2% PRO-2000 vaginal gels used in a coitally dependent manner by more than 9000 women and with a follow-up period of 52 weeks, rates of primary safety events (defined as an adverse event of grade 3 or more) were similar across all groups. No gel-related deaths or serious adverse events occurred in the study. Genital itching was the most common local adverse event, and high concentrations of aspartate aminotransferase (AST) or bilirubin was the most common systemic adverse event. Rates of local and systemic events were similar across all groups. (PRO-2000 was not detected in plasma.)6


Drug Interactions


Drug interactions related to PRO-2000 vaginal gel use are currently unknown.


References


1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on March 20, 2014.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on March 20, 2014.

3. Sachdev DD, Zerhouni-Layachi B, Ortigoza M, et al. The Differential Binding and Activity of PRO 2000 Against Diverse HIV-1 Envelopes. J Acquir Immune Defic Syndr. 2009 Jun 1;51(2):125-9. Last accessed on March 20, 2014.

4. Endo Pharmaceuticals Inc.: News Release, dated January 5, 2009. Endo Pharmaceuticals to Acquire Indevus Pharmaceuticals. Last accessed on March 20, 2014.

5. National Institute of Allergy and Infectious Diseases (NIAID): News Releases, dated December 14, 2009. NIAID Web Bulletin: Major Study Finds Anti-HIV Gel Ineffective Among Women. Last accessed on March 20, 2014.

6. McCormack S, Ramjee G, Kamali A, et al. PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial. Lancet. 2010 Oct 16;376(9749):1329-37. Last accessed on March 20, 2014.

7. Vermund SH, Allen KL, Karim QA. HIV-prevention science at a crossroads: advances in reducing sexual risk. Curr Opin HIV AIDS. 2009 Jul;4(4):266-73. Last accessed on March 20, 2014.

8. Friend DR, Kiser PF. Assessment of topical microbicides to prevent HIV-1 transmission: concepts, testing, lessons learned. Antiviral Res. 2013 Sep;99(3):391-400. Last accessed on March 20, 2014.

9. Huskens D, Vermeire K, Profy AT, Schols D. The candidate sulfonated microbicide, PRO 2000, has potential multiple mechanisms of action against HIV-1. Antiviral Res. 2009 Oct;84(1):38-47. Last accessed on March 20, 2014.

10. Fletcher PS, Shattock RJ. PRO-2000, an antimicrobial gel for the potential prevention of HIV infection. Curr Opin Investig Drugs. 2008 Feb;9(2):189-200. Last accessed on March 20, 2014.

11. National Institute of Allergy and Infectious Diseases (NIAID). Phase II/IIb Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000/5 Gel (P) for the Prevention of HIV Infection in Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 11, 2003. NLM Identifier: NCT00074425. Last accessed on March 20, 2014.

12. Abdool Karim SS, Richardson BA, Ramjee G, et al. Safety and Effectiveness of BufferGel and 0.5% PRO2000 Gel for the Prevention of HIV Infection in Women. AIDS. 2011 Apr 24;25(7):957-66. Last accessed on March 20, 2014.

13. Endo Pharmaceuticals. An International Multi-centre, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of 0.5% and 2% PRO 2000/5 Gels for the Prevention of Vaginally Acquired HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 5, 2005. NLM Identifier: NCT00262106. Last accessed on March 20, 2014.


Last Reviewed: March 20, 2014

Last Updated: March 20, 2014


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