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SPL7013
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Brand Name: VivaGel  Audio
Drug Class: Microbicides

Drug Description
SPL7013 is a lysine-based dendrimer with naphthalene disulfonic acid surface groups.[1] It is the active ingredient of VivaGel, a water-based vaginal microbicide gel.[2]

HIV/AIDS-Related Uses
SPL7013 is a potent inhibitor of HIV-1 in vitro and appears active against numerous strains.[3] It is being studied for use as the active ingredient in VivaGel, a vaginal microbicide, in the prevention of vaginal transmission of HIV and genital herpes.[4] VivaGel is at the expanded safety/Phase IIa stage of clinical development and was granted fast-track status by the FDA in January 2006.[5]

A study to test VivaGel's safety, acceptability, and ease of use in healthy, sexually active young women in the United States and Puerto Rico began enrollment in July 2007.[6][7]

A Phase I/II clinical trial is currently underway to investigate the timescale over which VivaGel retains activity against HIV and HSV-2, and the trial will measure the level of antiviral activity retained by VivaGel after vaginal administration.[8]

Non HIV/AIDS-Related Uses
SPL7013 has demonstrated activity against herpes simplex virus-2 (HSV-2).[9]

A Phase I study in healthy, sexually active American and Kenyan women to test VivaGel's safety and tolerability began enrollment in October 2006.[10] This trial is the first microbicide clinical development program specifically for the prevention of HSV-2 (genital herpes).[11]

In an independent study conducted at Johns Hopkins University, SPL7013 also exhibited a potent contraceptive effect when tested in animals.[12]

In mid-July 2007, Starpharma signed an agreement with a leading condom company in relation to the use of VivaGel as a condom coating.[13]

Dosing Information

Mode of Delivery
Intravaginal.[14]

Dosage Form
Phase I studies have evaluated VivaGel at concentrations of 0.5, 1, and 3% applied vaginally once daily for 7 days. In addition, a 5.0% vaginal gel has been evaluated in macaques.[15][16]

VivaGel would be used via a single-use, prefilled vaginal applicator.[17]

Pharmacology
Dendrimers such as SPL7013 are polymers that contain a central core, interior branches, and terminal surface groups adapted to specific targets. SPL7013 has a polyanionic outer surface that provides for multiple target interactions. The active surface groups bind to gp120 proteins on HIV's surface, preventing CD4 receptor binding by healthy cells and thus blocking transmission of HIV to healthy cells.[18][19]

A Phase I, double-blind, placebo-controlled trial evaluated the plasma absorption of SPL7013 in 36 healthy, sexually abstinent women. Women were assigned to 1 of 3 arms of 0.5, 1.0, and 3.0% gel, respectively, and all doses were administered once daily for 7 days. Eight women received active gel and four received placebo in each arm. Plasma samples after the first, third, fifth, and seventh doses showed no plasma SPL7013 levels, which confirmed localized activity of the drug.[20]

Adverse Events/Toxicity
A Phase I placebo-controlled trial in healthy women evaluated the safety and tolerability of VivaGel. No serious or significant adverse events occurred with the 0.5, 1.0, or 3.0% doses. Mild adverse effects attributed to SPL7013 were abdominal pain and painful urination. Vaginal flora levels decreased similarly across all treatment and placebo groups but rebounded to normal levels by 7 days post-treatment.[21]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use SPL7013.

Chemistry

CAS Name
L-Lysine, homopolymer [polylysine][22]

CAS Number
676271-69-5[23]

Molecular Weight
16,582 Da[24]

Physical Description
SPL7013: white to off-white solid.[25]

VivaGel: water-based gel.[26]

Solubility
Both SPL7013 and VivaGel are highly water soluble.[27]

Other Names
SPL 7013[28]

Further Reading
PMID/16219368 Gong E, Matthews B, McCarthy T, Chu J, Holan G, Raff J, Sacks S. Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses. Antiviral Res. 2005 Dec;68(3):139-46. Epub 2005 Sep 27.

PMID/15795526 Jiang YH, Emau P, Cairns JS, Flanary L, Morton WR, McCarthy TD, Tsai CC. SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses. 2005 Mar;21(3):207-13.

PMID/16053334 McCarthy TD, Karellas P, Henderson SA, Giannis M, O'Keefe DF, Heery G, Paull JR, Matthews BR, Holan G. Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention. Mol Pharm. 2005 Jul-Aug;2(4):312-8. Review.

PMID/16181143 Rosa Borges A, Schengrund CL. Dendrimers and antivirals: a review. Curr Drug Targets Infect Disord. 2005 Sep;5(3):247-54. Review.

PMID/18316528 Lackman-Smith C, Osterling C, Luckenbaugh K, Mankowski M, Snyder B, Lewis G, Paull J, Profy A, Ptak RG, Buckheit RW Jr, Watson KM, Cummins JE Jr, Sanders-Beer BE. Development of a comprehensive human immunodeficiency virus type 1 screening algorithm for discovery and preclinical testing of topical microbicides. Antimicrob Agents Chemother. 2008 May;52(5):1768-81. Epub 2008 Mar 3.

PMID/18203424 Rupp R, Rosenthal SL, Stanberry LR. VivaGel (SPL7013 Gel): a candidate dendrimer--microbicide for the prevention of HIV and HSV infection. Int J Nanomedicine. 2007;2(4):561-6.

Manufacturer Information
SPL7013
  Starpharma Ltd
  PO Box 6535
  St. Kilda Road Central
  Melbourne, Victoria,  Australia
  61385322736
    

References
[1] Starpharma - Overview: Dendrimers: Synthetic Macromolecular Pharmaceuticals, p. 2. Available at: http://www.starpharma.com/dendrimers.asp. Accessed 10/06/08.
[2] Starpharma - Latest News: Vivagel Receives Fast Track Status From FDA [Press Release], January 9, 2006. Available at: http://www.starpharma.com/data/060109%20-%20VivaGel%20Fast%20Track%20Status.pdf. Accessed 10/06/08.
[3] Starpharma - Latest News: Vivagel Receives Fast Track Status From FDA [Press Release], January 9, 2006. Available at: http://www.starpharma.com/data/060109%20-%20VivaGel%20Fast%20Track%20Status.pdf. Accessed 10/06/08.
[4] Starpharma - Latest News: U.S. NIH Funded Trial of VivaGel in Sexually Active Young Women Commences [Press Release], July 10, 2007. Available at: http://www.starpharma.com/data/070710%20%20VivaGel%20trial%20in%20sexually%20active%20young%20women.pdf. Accessed 10/06/08.
[5] Starpharma - Latest News: Vivagel Receives Fast Track Status From FDA [Press Release], January 9, 2006. Available at: http://www.starpharma.com/data/060109%20-%20VivaGel%20Fast%20Track%20Status.pdf. Accessed 10/06/08.
[6] Starpharma - Latest News: U.S. NIH Funded Trial of VivaGel in Sexually Active Young Women Commences [Press Release], July 10, 2007. Available at: http://www.starpharma.com/data/070710%20%20VivaGel%20trial%20in%20sexually%20active%20young%20women.pdf. Accessed 10/06/08.
[7] ClinicalTrials.gov - Safety and Acceptability of SPL7013 Gel (VivaGel) in Sexually Active Women. Available at: http://www.clinicaltrials.gov/ct/show/NCT00442910. Accessed 10/06/08.
[8] ClinicalTrials.gov - Retention and Duration of Activity of SPL7013 (VivaGel®) After Vaginal Dosing. Available at: http://clinicaltrials.gov/ct2/show/NCT00740584. Accessed 10/06/08.
[9] Aidsmap.com - Microbicides 2006: What Products Are in the Pipeline? Available at: http://www.aidsmap.com/en/news/E31C54A1-F80E-4155-A2CB-0852AF6A04B6.asp. Accessed 10/06/08.
[10] ClinicalTrials.gov - VivaGel in Healthy Young Women. Available at: http://www.clinicaltrials.gov/ct/show/NCT00331032. Accessed 10/06/08.
[11] Starpharma - Latest News: IND for Clinical Development of Vivagel for Genital Herpes Prevention Clears U.S. FDA [Press Release], July 19, 2006. Available at: http://www.starpharma.com/data/060719%20VivaGel%20IND%20for%20Genital%20Herpes%20trial%20clears%20US%20FDA.pdf. Accessed 10/06/08.
[12] Starpharma - VivaGel Information Sheet. Available at: http://www.starpharma.com/vivagel.asp. Accessed 10/06/08.
[13] Starpharma - Starpharma Signs Agreement for Condom Coating Application of VivaGel [Press Release], July 18, 2007. Available at: http://www.starpharma.com/data/070718%20Signs%20Agreement%20for%20Condom%20Coating%20Application.pdf. Accessed 10/06/08.
[14] Starpharma - Clinical Study Shows STARPHARMA's VivaGel is Safe; Appendix - SPL7013-001/CM4402 Phase 1 Clinical Trial Results [Press Release], December 16, 2004. Available at: http://www.starpharma.com/data/041216%20Clinical%20Study%20shows%20Starpharmas%20VivaGel%20is%20Safe.pdf. Accessed 10/06/08.
[15] Starpharma - Clinical Study Shows STARPHARMA's VivaGel is Safe; Appendix - SPL7013-001/CM4402 Phase 1 Clinical Trial Results [Press Release], December 16, 2004. Available at: http://www.starpharma.com/data/041216%20Clinical%20Study%20shows%20Starpharmas%20VivaGel%20is%20Safe.pdf. Accessed 10/06/08.
[16] AIDS Res Hum Retroviruses - 2005 Mar;21(3):207-13
[17] Starpharma - VivaGel Information Sheet, p. 2. Available at: http://www.starpharma.com/vivagel.asp. Accessed 10/06/08.
[18] Pharmaceutical Journal - 2004 Nov 27;273:793-4
[19] AIDS Res Hum Retroviruses - 2005 Mar;21(3):207-13
[20] Starpharma - Clinical Study Shows STARPHARMA's VivaGel is Safe: Appendix - SPL7013-001/CM4402 Phase 1 Clinical Trial Results [Press Release], December 16, 2004. Available at: http://www.starpharma.com/data/041216%20Clinical%20Study%20shows%20Starpharmas%20VivaGel%20is%20Safe.pdf. Accessed 10/06/08.
[21] Starpharma - Clinical Study Shows STARPHARMA's VivaGel is Safe: Appendix - SPL7013-001/CM4402 Phase 1 Clinical Trial Results [Press Release], December 16, 2004. Available at: http://www.starpharma.com/data/041216%20Clinical%20Study%20shows%20Starpharmas%20VivaGel%20is%20Safe.pdf. Accessed 10/06/08.
[22] MeSH - Available at: http://www.nlm.nih.gov/mesh/MBrowser.html. Accessed 10/06/08.
[23] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/06/08.
[24] Microbicide Research Portal - Candidate Products: VivaGel (SPL7013 Gel). Available at: https://secure.microbicide.org. Accessed 10/06/08.
[25] Microbicide Research Portal - Candidate Products: VivaGel (SPL7013 Gel). Available at: https://secure.microbicide.org. Accessed 10/06/08.
[26] Microbicide Research Portal - Candidate Products: VivaGel (SPL7013 Gel). Available at: https://secure.microbicide.org. Accessed 10/06/08.
[27] Microbicide Research Portal - Candidate Products: VivaGel (SPL7013 Gel). Available at: https://secure.microbicide.org. Accessed 10/06/08.
[28] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/06/08.
Updated October 6, 2008