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PRO 2000
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Drug Class: Microbicides
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Drug Description |
| PRO 2000 is a synthetic, long-chain, naphthalene sulfonic acid polymer. The polymer is polyanionic and consists of alternating 2-naphthalene sulfonic acid sodium salt and methylene units.[1][2] |
HIV/AIDS-Related Uses |
| PRO 2000 is an antimicrobial intravaginal gel being investigated for the prevention of HIV and other sexually transmitted diseases.[3] It is being studied in Phase II/IIb and Phase III trials for safety and efficacy.[4] |
Non HIV/AIDS-Related Uses |
| In laboratory tests and animal studies, PRO 2000 demonstrated activity against Chlamydia trachomatis, Neisseriae gonorrheae, and herpes simplex virus.[5] |
Dosing Information |
Mode of Delivery |
| Intravaginal.[6] |
Dosage Form |
| The investigational product is a clear, aqueous gel formulation containing naphthalene 2-sulfonate polymer, a synthetic carbomer gelling agent, a pH 4.5 buffer, and a combination of preservatives.[7] In Phase II/IIb and III studies, 0.5% formulations of PRO 2000 are being investigated.[8] |
Storage |
| Store at 15 C to 35 C (59 F to 86 F) and protect from light.[9] |
Pharmacology |
Mechanistically, PRO 2000 disrupts the initial binding and membrane fusion steps of HIV-1 infection.[10] PRO 2000 binds to CD4 with nanomolar affinity and blocks CD4 binding to HIV gp120. It inhibits infection by a wide range of HIV isolates in a variety of cell types.[11]
Following topical administration of naphthalene 2-sulfonate polymer in animals and intravaginal application in humans, no systemic absorption was detected.[12] PRO 2000 was undetectable in plasma samples collected from three separate Phase I studies, suggesting that negligible systemic absorption of PRO 2000 occurs following intravaginal administration.[13][14]
PRO 2000 is completely compatible with the use of latex condoms. This may offer women an appealing alternative or complement to condoms, providing women with a means to control disease transmission. PRO 2000 has demonstrated greater safety in use than nonoxynol-9 spermicides, which have been shown to increase users' risk of contracting HIV and other sexually transmitted diseases; it is also highly stable, easy to store, and easy to apply.[15]
In a randomized trial comparing 5% PRO 2000 to inactive placebo for 14 days in 24 HIV negative women, levels of cytokines, interleukin-1 receptor antagonist, immunoglobulins, and human beta-defensin 2 secreted into the blood were lower in the PRO 2000 arm compared with the placebo group.[16] In contrast, in a study comparing PRO 2000, placebo, and nonoxynol-9, mice receiving intravaginal nonoxynol-9 experienced increased inflammatory responses, whereas mice treated with PRO 2000 experienced responses similar to placebo and responded with minimal inflammation.[17]
Cervicovaginal lavage has been performed in a randomized study to identify activity of PRO 2000 after vaginal application. This study found that 0.5% PRO 2000 retains substantial anti-HIV activity after vaginal application and remains sufficiently bioavailable.[18]
An ongoing Phase II/IIb trial is evaluating the safety and efficacy of 0.5% PRO 2000 compared with placebo, and an ongoing Phase III trial is evaluating the safety and efficacy of 0.5% PRO 2000 compared with placebo.[19][20] |
Adverse Events/Toxicity |
In Phase I clinical trials, PRO 2000 was safe and well tolerated. Side effects were generally mild and infrequent and included vulvovaginal ulceration, irritation, itching, burning, bleeding, and mild gastrointestinal effects. Pain on passing urine was also reported.[21]
In a Phase I trial of 63 sexually active HIV uninfected women and abstinent HIV infected women, no serious adverse events were reported. Seventy-three percent of participants experienced at least 1 adverse event, of which 82% were classified as mild.[22] In a second Phase I trial of 73 abstinent HIV uninfected women, three women developed cervical abrasion. In both trials, the 0.5% gel formulation was better tolerated than the 4% gel formulation.[23]
During a Phase I safety and acceptability study of penile application of PRO 2000, no serious adverse events or urethral inflammation were reported following a week of daily PRO 2000 application in 72 HIV uninfected and 25 HIV infected men. Seventeen percent of uninfected participants and 4% of infected participants reported at least 1 mild adverse event.[24]
In a Phase I safety and acceptability study of the 0.5% gel formulation in 42 HIV uninfected women in Pune, India of low and higher risk for HIV transmission, 24 (57%) of the participants experienced at least 1 adverse event judged possibly related to product use. Of these 24, 7 (17%) participants experienced a moderate adverse event and 17 (40%) experienced only mild adverse events. No serious adverse events were observed.[25] |
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Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use PRO 2000. |
Chemistry |
CAS Name |
| 2-naphthalenesulfonic acid, sodium salt, polymer with formaldehyde[26] |
CAS Number |
| 29321-75-3[27] |
Molecular Formula |
| (C10-H8-O3-S.C-H2O.Na)x-[28] |
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Molecular Weight |
| Approximately 5 kD[29] |
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Physical Description |
Light brown solid (active ingredient of PRO 2000).[30]
PRO 2000 is odorless and virtually colorless.[31] |
Stability |
| Manufacturer data indicate that PRO 2000 is stable at 40 C and 75% relative humidity for 12 months.[32] |
Solubility |
| Highly water soluble (approximately 1 g/5 ml).[33] |
Other Names |
Naphthalene 2-sulfonate polymer[34]
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Further Reading |
PMID/17397004 Galen GT, Martin AP, Hazrati I, Garin A, Guzman E, Wilson SS, Porter DD, Lira SA, Keller MJ, Herold BC. A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. Journal of Infectious Diseases 2007 May;195(9):1332-1339.
PMID/17301565 Keller MJ, Guzman E, Hazrati E, Kasowitz A, Cheshenko N, Wallenstein S, Cole AL, Cole AM, Profy AT, Wira CR, Hogarty K, Herold BC. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 2007 Feb;21(4):467-476.
PMID/16127029 Scordi-Bello IA, Mosoian A, He C, Chen Y, Cheng Y, Jarvis GA, Keller MJ, Hogarty K, Waller DP, Profy AT, Herold BC, Klotman ME. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob Agents Chemother. 2005 Sep;49(9):3607-15.
Ramjee G, Shattock R, Delany S, McGowan I, Morar N, Gottemoeller M. Short report: Microbicides 2006 Conference. AIDS Research and Therapy 2006, 3:25. Available at: http://www.aidsrestherapy.com/content/3/1/25. Accessed 10/09/07.
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. Available at: http://www.clinicaltrials.gov/ct/show/NCT00262106. Accessed 10/09/07.
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. Available at: http://www.clinicaltrials.gov/ct/show/NCT00074425. Accessed 10/09/07.
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Manufacturer Information |
PRO 2000
Indevus Pharmaceuticals, Inc.
33 Hayden Avenue, Suite 200
Lexington, MA 02421
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References |
[1] Protocol ID: HIVNET 020 - p. 11
[2] Alliance for Microbicide Development - Most Advanced: December 2008. Available at: http://global-campaign.org/most-advanced-microbicides.htm. Accessed 12/04/08.
[3] Indevus Pharmaceuticals, Inc. - Indevus Pharmaceuticals, Inc. - PRO 2000. Available at: http://www.indevus.com. Accessed 12/04/08.
[4] Alliance for Microbicide Development - Most Advanced: December 2008. Available at: http://global-campaign.org/most-advanced-microbicides.htm. Accessed 12/04/08.
[5] Indevus Pharmaceuticals, Inc. - Products: PRO 2000. Available at: http://www.indevus.com. Accessed 12/04/08.
[6] Indevus Pharmaceuticals, Inc. - Products: PRO 2000. Available at: http://www.indevus.com. Accessed 12/04/08.
[7] Protocol ID: HIVNET 020 - p. 12
[8] Alliance for Microbicide Development - Most Advanced: December 2008. Available at: http://global-campaign.org/most-advanced-microbicides.htm. Accessed 12/04/08.
[9] Protocol ID: HIVNET 020 - p. 12
[10] Protocol ID: HIVNET 020 - p. 1
[11] Antimicrob Agents Chemother - 1996 Jan;40(1):234-236
[12] Protocol ID: HIVNET 020 - p. 1
[13] Protocol ID: HIVNET 020 - pp. 3-4
[14] IAS Conf on HIV Pathogenesis and Treatment - 3rd, 2005. Abstract WePe10.8P09.
[15] Indevus Pharmaceuticals, Inc. - Products: PRO 2000. Available at: http://www.indevus.com. Accessed 12/04/08.
[16] AIDS - 2007 Feb;21(4):467-76
[17] J Infect Dis - 2007 May;195(9):1332-9
[18] J Infect Dis - 2006 Jan;193;27-35
[19] Indevus Pharmaceuticals, Inc. - Products: PRO 2000. Available at: http://www.indevus.com. Accessed 12/04/08.
[20] Alliance for Microbicide Development - Most Advanced: December 2008. Available at: http://global-campaign.org/most-advanced-microbicides.htm. Accessed 12/04/08.
[21] Protocol ID: HIVNET 020 - pp. 2,4
[22] AIDS - 2003 Feb 14;17(3):321-329
[23] Sex Transm Infect - 2000 Apr;76(2):126-130
[24] J Acquir Immune Defic Syndr - 2003 Aug;33(4):476-483
[25] IAS Conf on HIV Pathogenesis and Treatment - 2005. Abstract WePe10.8P09.
[26] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/04/08.
[27] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/04/08.
[28] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/04/08.
[29] Antimicrob Agents Chemother - 1996 Jan;40(1):234-236
[30] Protocol ID: HIVNET 020 - p. 11
[31] Protocol ID: HIVNET 020 - p. 11
[32] Protocol ID: HIVNET 020 - p. 12
[33] Protocol ID: HIVNET 020 - p. 11
[34] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/04/08.
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Updated December 4, 2008
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