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FDA-approved

Investigational

SPL-7013  Audio icon

Other Names: astodrimer, VivaGel
Drug Class: Microbicides
Chemical Name: L-Lysine, homopolymer
Chemical Class: Dendrimers
Company: Starpharma
Phase of Development: Phase I/II
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, Antimicrobial Agents and Chemotherapy article3, and American Medical Association website4)
Patent Version Content

Pharmacology


Mechanism of Action: Microbicide; polyanion-based entry inhibitor.3 SPL-7013 is a broad-spectrum dendrimer consisting of a divalent benzhydrylamine core and four layers of lysine branches. Naphthalene disulfonic acid groups are attached to the outermost branches, imparting hydrophobicity and a high anionic charge to the dendrimer surface. This allows for electrostatic interactions and multivalent binding to viral gp120, thus blocking HIV attachment to and entry into host CD4 cells.5,6,7 As an investigational topical vaginal microbicide to prevent sexual transmission of HIV-1 and HSV-2 infection, SPL-7013 has been formulated in a mucoadhesive Carbopol®-based aqueous gel.5

SPL-7013 has shown equal in vitro potency against CXCR4- and CCR5-tropic HIV-1 strains in terms of inhibiting viral entry.7 However, studies have demonstrated that SPL-7013 is directly virucidal via irreversible binding to HIV-1 envelope proteins against some HIV-1 strains using CXCR4 and against strains using both CXCR4 and CCR5, but not against HIV-1 strains that solely use CCR5. Inhibition of CCR5-tropic HIV-1 strains may be due to reversible binding—a weaker binding that does not lead to direct HIV-1 inactivation. Inhibition of CCR5-using strains may also be mediated via binding to host cell receptors.8

SPL-7013 gel has also been studied for the treatment of bacterial vaginosis (BV) and the prevention of recurrent BV.9,10


Dosing in Clinical Trials


3% SPL-7013 microbicide gel is applied intravaginally.

Phase I (HIV-uninfected women)

  • SPL7013-006/MTN-004: Safety and Acceptability Study
    SPL-7013 gel versus SPL-7013 placebo gel versus hydroxyethylcellulose (HEC) placebo gel applied twice daily over 14 days.11,12
  • SPL7013-004: Safety and Tolerability Study
    SPL-7013 gel versus SPL-7013 placebo gel applied twice daily over 14 days.13,14,15

Phase I/II (HIV-uninfected women)

  • SPL7013-003: Study to Assess Duration and Retention of Antiviral Activity
    Single-dose application of SPL-7013 gel administered on five separate occasions (with a minimum of 5 days between doses).5,16

Additional studies of SPL-7013 gel have also been completed.


Adverse Events


In the SPL7013-006/MTN-004 study of twice-daily SPL-7013 gel used over 14 days in 61 women, a significantly higher incidence of Grade 1/2 genital adverse events (AEs) that were related to product use occurred in the SPL-7013 gel arm than in the HEC placebo gel arm. No significant difference in the incidence of genital AEs was observed between the SPL-7013 gel and the SPL-7013 gel placebo arms or between the SPL-7013 gel placebo and the HEC placebo arms. The most common genital AEs reported in the SPL-7013 gel arm were dyspareunia, metrorrhagia, and vulvovaginal burning or pruritis. There were no serious AEs or study withdrawals due to an AE. Shifts in some vaginal microflora occurred in both the SPL-7013 gel and SPL-7013 placebo gel groups; however, there was no increase in the incidence of BV.12

A Phase I safety study (SPL7013-004) involved the use of twice daily SPL-7013 gel over 14 days in 54 women. This study found that mostly mild genitourinary (GU) AEs and colposcopic abnormalities consistent with mild genital epithelial irritation and inflammation occurred more frequently in the SPL-7013 gel arm than in the placebo gel arm. Two participants in the SPL-7013 gel group discontinued product use because of a GU AE.13 In addition, after 7 to 14 days of twice-daily gel applications, immune markers associated with epithelial damage (genital cytokines and T-cell subsets) were reversibly elevated in the SPL-7013 gel arm and were higher than in placebo arm.15

In the Phase I/II study of five single-dose applications of SPL-7013 gel in 11 women, no serious AEs occurred. Seven GU AEs were reported by four participants receiving at least one dose of SPL-7013 gel. Two of the 7 AEs, mild perineal irritation and moderately severe BV, were likely related to SPL-7013 gel. Three participants experienced symptoms of vaginal candidiasis, which were all mild in severity and possibly related to SPL-7013 gel exposure. No signs or symptoms of vaginal, vulvar, or cervical irritation were reported. There were no study withdrawals due to an AE.5


Drug Interactions


Drug interactions related to SPL-7013 vaginal gel use are currently unknown.


References


1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on February 2, 2014.

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

3. Sonza S, Johnson A, Tyssen D, et al. Enhancement of Human Immunodeficiency Virus Type 1 Replication is Not Intrinsic to All Polyanion-Based Microbicides. Antimicrob Agents Chemother. 2009 Aug;53(8):3565-8. Last accessed on February 2, 2014.

4. American Medical Association website. Statement on a Nonproprietary Name Adopted by the USAN Council: Astodrimer. Last accessed on February 2, 2014.

5. Price CF, Tyssen D, Sonza S, et al. SPL7013 Gel (VivaGel®) Retains Potent HIV-1 and HSV-2 Inhibitory Activity following Vaginal Administration in Humans. PLoS One. 2011;6(9):e24095. Last accessed on February 2, 2014.

6. 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. Last accessed on February 2, 2014.

7. Tyssen D, Henderson SA, Johnson A, et al. Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity. PLoS One. 2010 Aug 23;5(8):e12309. Last accessed on February 2, 2014.

8. Telwatte S, Moore K, Johnson A, et al. Virucidal Activity of the Dendrimer Microbicide SPL7013 Against HIV-1. Antiviral Res. 2011 Jun;90(3):195-9. Last accessed on February 2, 2014.

9. Starpharma: News, dated November 28, 2012. VivaGel phase 3 study results. Last accessed on February 2, 2014.

10. Starpharma Pty Ltd. A Double-blind, Multicenter, Randomized, Placebo-controlled, Dose-ranging Study to Determine the Efficacy and Safety of SPL7013 Gel (VivaGel®) Administered Vaginally to Prevent the Recurrence of Bacterial Vaginosis. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 20, 2011. NLM Identifier: NCT01437722. Last accessed on February 2, 2014.

11. Starpharma Pty Ltd. Phase 1 Study of the Safety and Acceptability of 3% w/w SPL7013 Gel (VivaGel™) Applied Vaginally in Sexually Active Young Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 2, 2007. NLM Identifier: NCT00442910. Last accessed on February 2, 2014.

12. McGowan I, Gomez K, Bruder K, et al. Phase 1 Randomized Trial of the Vaginal Safety and Acceptability of SPL7013 Gel (VivaGel) in Sexually Active Young Women (MTN-004). AIDS. 2011 May 15;25(8):1057-64. Last accessed on February 2, 2014.

13. National Institute of Allergy and Infectious Diseases (NIAID). An Expanded Phase I Randomized Placebo Controlled Trial of the Safety and Tolerability of 3 Percent w/w SPL7013 Gel (VivaGel™) in Healthy Young Women When Administered Twice Daily for 14 Days. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 25, 2006. NLM Identifier: NCT00331032. Last accessed on February 2, 2014.

14. Cohen CR, Brown J, Moscicki AB, et al. A Phase I Randomized Placebo Controlled Trial of the Safety of 3% SPL7013 Gel (VivaGel®) in Healthy Young Women Administered Twice Daily for 14 days. PLoS One. 2011 Jan 20;6(1):e16258. Last accessed on February 2, 2014.

15. Moscicki AB, Kaul R, Ma Y, et al. Measurement of mucosal biomarkers in a phase 1 trial of intravaginal 3% SPL 7013 gel (VivaGel®) to assess expanded safety. J Acquir Immune Defic Syndr. 2012 Feb 1;59(2):134-40. Last accessed on February 2, 2014.

16. Starpharma Pty Ltd. Assessment of Local Retention and Duration of Activity of SPL7013 Following Vaginal Application of 3% SPL7013 Gel (VivaGel) in Healthy Volunteers. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 21, 2008. NLM Identifier: NCT00740584. Last accessed on February 2, 2014.


Last Reviewed: February 2, 2014

Last Updated: April 25, 2014


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