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Investigational

PRO-2000  Audio icon

Other Names: PRO 2000/5, PRO2000, naphthalene 2-sulfonate polymer, polynaphthalene sulphonate
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 (discontinued)
Chemical Image:
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PRO-2000
PRO-2000
Molecular Weight: 238.262
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Endo Pharmaceuticals Inc. News Release,3 and Medical Research Council press release4)
Patent Version Content

NOTE: The development of PRO-2000 for preventing sexually acquired HIV infection has been discontinued.


The study of PRO-2000 as a microbicide for preventing HIV infection was discontinued in 2009. Data from a Phase III study showed that PRO-2000 vaginal gel was ineffective in protecting women against sexually acquired HIV infection.4


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.5-7 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.8,9 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


Study Identifiers: HPTN 035; NCT0007442511
Phase: II/IIb
Study Purpose: To evaluate the safety and effectiveness of Carbopol 974P microbicide gel (BufferGel) and PRO-2000 gel for preventing HIV infection in women
Study Population: HIV-uninfected women in Malawi, South Africa, Zambia, Zimbabwe, and United States
Dosing: Women assigned to a gel group were instructed to apply one applicator of gel intravaginally within 1 hour before vaginal intercourse. (Mean follow-up period was 20.4 months.) Participants were randomized to one of the following four study groups:
  • Carbopol 974P microbicide gel (BufferGel)
  • 0.5% PRO-2000 gel
  • Hydroxyethylcellulose (HEC) placebo gel
  • No intervention (no gel).11-13

(See references cited above for information on study results.)

Study Identifiers: MDP 301; NCT0026210614
Phase: III
Study Purpose: To evaluate the safety and effectiveness of 0.5% and 2% PRO-2000 gels for preventing HIV infection in women
Study Population: HIV-uninfected women in South Africa, Tanzania, Uganda, and Zambia
Dosing: 0.5% or 2% PRO-2000 gel versus placebo gel, each applied intravaginally using a pre-filled applicator within 1 hour before vaginal intercourse. (Follow-up period was 52 weeks; follow-up period was up to 104 weeks in Uganda for long-term safety data). 4,5,14
* During this study, the 2% PRO-2000 gel group was discontinued because of a low probability of benefit.5,14
(See references cited above for information on study results.)


Adverse Events


In the HPTN 035 study of 0.5% PRO-2000 vaginal gel and BufferGel used 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 by more than 9000 women, 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. (The absence of systemic adverse effects was expected, as PRO-2000 was not detected in plasma.)5
 


Drug Interactions


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

 

 


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/29321-75-3. Last accessed on May 20, 2015.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on May 20, 2015.
  3. Endo Pharmaceuticals Inc.: News Release, dated January 5, 2009. Endo Pharmaceuticals to Acquire Indevus Pharmaceuticals. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=123046&p=irol-newsArticle_print&ID=1240465&highlight. Last accessed on May 20, 2015.
  4. Medical Research Council: Press Release, dated December 14, 2009. HIV ‘prevention’ gel PRO 2000 proven ineffective. Available at: http://www.mdp.mrc.ac.uk/downloads/MDP%20Microbicides%20release%20111209%20%20Embargoed%20until%20141209.pdf. Last accessed on May 20, 2015.
  5. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956883/. Last accessed on May 20, 2015.
  6. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995247/. Last accessed on May 20, 2015.
  7. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23845918. Last accessed on May 20, 2015.
  8. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718789/. Last accessed on May 20, 2015.
  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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19664662. Last accessed on May 20, 2015.
  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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18246522. Last accessed on May 20, 2015.
  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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00074425. Last accessed on May 20, 2015.
  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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083640/. Last accessed on May 20, 2015.
  13. Guffey MB, Richardson B, Husnik M, et al. HPTN 035 Phase II/IIb Randomized Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000 for the Prevention of Sexually Transmitted Infections in Women. Sex Transm Infect. 2014 Aug;90(5):363-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278566/. Last accessed on May 20, 2015.
  14. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00262106. Last accessed on May 20, 2015.
     


Last Reviewed: May 20, 2015

Last Updated: May 20, 2015


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