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Investigational

Astodrimer  Audio icon

Other Names: SPL-7013, VivaGel, astodrimer sodium
Drug Class: Microbicides
Molecular Formula: C583-H641-N63-O287-S64
Registry Number: 137946-42-5 (CAS)
Chemical Name: N2,N6-bis(N2,N6-bis(N2,N6-bis(N2,N6-bis(N2,N6-bis((3,6-disulfonaphthalen-1-yloxy)acetyl)-l-lysyl)-l-lysyl)-l-lysyl)-l-lysyl)-N1-(diphenylmethyl)-l-lysinamide
Chemical Class: Dendrimers
Company: Starpharma
Phase of Development: Phase I/II
(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)
Patent Version Content

Pharmacology


Mechanism of Action: Microbicide; polyanion-based entry inhibitor.3 Astodrimer 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.4-6 As an investigational topical vaginal microbicide to prevent sexual transmission of HIV-1 and HSV-2 infection, astodrimer has been formulated in a mucoadhesive Carbopol®-based aqueous gel.4

Astodrimer 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 astodrimer 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.7

Astodrimer gel has also been studied for the treatment of bacterial vaginosis (BV) and is currently being studied for the prevention of recurrent BV.8-10

Resistance: Astodrimer-resistant HIV-1 has been generated in vitro. Propagation of HIV-1NL4.3 in MT-2 cells in the presence of increasing concentrations of astodrimer through 44 passages resulted in virus with only a 2- to 3-fold increase in the 50% inhibitory concentration (IC50) when compared to wild-type virus. Astodrimer demonstrated some in vitro cross-resistance to dextran sulphate and enfuvirtide (brand name: Fuzeon), but astodrimer was not significantly cross-resistant to AMD3100.11


Dosing in Clinical Trials


Study Identifiers: MTN-004; SPL7013-006; NCT0044291012
Phase: I
Study Purpose: Study to assess the safety and acceptability of astodrimer gel applied vaginally in women
Study Population: HIV-uninfected, STI-uninfected, sexually active women in the United States and Puerto Rico
Dosing: Each gel was applied intravaginally and twice daily for 14 days. Participants were randomized to one of the following three groups:
  • 3% astodrimer gel
  • Astodrimer placebo gel
  • Hydroxyethylcellulose (HEC) placebo gel.12,13

Note: Astodrimer gel acceptability in SPL7013-006 (MTN 004) participants was also evaluated in a separate study known as ATN 062 (“Tell Juliana”). ATN 062 was conducted simultaneously with MTN 004 and expanded the acceptability assessment through the use of questionnaires, teleconferences, and an interactive voice reporting system.14,15
(See references cited above for information on study results.)

Study Identifiers: SPL7013-004; NCT0033103216
Phase: I
Study Purpose: Study to assess the safety and tolerability of astodrimer gel applied vaginally in women
Study Population: HIV-uninfected, STI-uninfected, sexually abstinent (previously sexually active) women in the United States and Kenya
Dosing: 3% astodrimer gel versus astodrimer placebo gel, each applied intravaginally and twice daily for 14 days.16-18
(See references cited above for information on study results.)

Study Identifiers: SPL7013-003; NCT0074058419
Phase: I/II
Study Purpose: Study to assess the ex vivo antiviral activity and local retention of vaginally applied astodrimer gel in women
Study Population: HIV-uninfected, STI-uninfected women
Dosing: Participants applied a single dose of 3% astodrimer gel intravaginally on five separate occasions (with a minimum of 5 days between doses).4,19
(See references cited above for information on study results.)

Additional studies of astodrimer gel have also been completed.


Adverse Events


In the SPL7013-006 (MTN-004) study of twice-daily astodrimer 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 astodrimer gel arm than in the HEC placebo gel arm. No significant difference in the incidence of genital AEs was observed between the astodrimer gel and the astodrimer placebo gel arms or between the astodrimer placebo gel and the HEC placebo gel arms. The most common genital AEs reported in the astodrimer 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 astodrimer gel and astodrimer placebo gel groups; however, there was no increase in the incidence of BV.13

The Phase I safety study SPL7013-004 involved the use of twice daily astodriimer 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 astodrimer gel arm than in the placebo gel arm. Two participants in the astodrimer gel group discontinued product use because of a GU AE.17 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 astodrimer gel arm and were higher in the astodrimer gel arm than in placebo arm.18

In the SPL7013-003 study of five single-dose applications of astodrimer gel in 11 women, no serious AEs occurred. Seven GU AEs were reported by four participants receiving at least one dose of astodrimer gel. Two of the 7 AEs, mild perineal irritation and moderately severe BV, were likely related to astodrimer gel. Three participants experienced symptoms of vaginal candidiasis, which were all mild in severity and possibly related to astodrimer 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 astodrimer 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/1379746-42-5. Last accessed on April 8, 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 April 8, 2015.
  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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715623/. Last accessed on April 8, 2015.
  4. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174146/. Last accessed on April 8, 2015.
  5. Rupp R, Rosenthal SL, Stanberry LR. VivaGelTM (SPL7013 Gel): A candidate dendrimer--microbicide for the prevention of HIV and HSV infection. Int J Nanomedicine. 2007;2(4):561-6. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676817/. Last accessed on April 8, 2015.
  6. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925893/. Last accessed on April 8, 2015.
  7. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115201/. Last accessed on April 8, 2015.
  8. Starpharma: Press Release, dated November 28, 2012. VivaGel phase 3 study results. Available at: http://www.starpharma.com/news/139. Last accessed on April 8, 2015.
  9. Starpharma Pty Ltd. A Phase 3, Double-blind, Multicentre, Randomised, Placebo-controlled Study to Determine the Efficacy and Safety of SPL7013 Gel to Prevent the Recurrence of Bacterial Vaginosis. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 5, 2014. NLM Identifier: NCT02237950. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02237950. Last accessed on April 8, 2015.
  10. Starpharma Pty Ltd. A Phase 3, Double-blind, Multicentre, Randomised, Placebo-controlled Study to Determine the Efficacy and Safety of SPL7013 Gel to Prevent the Recurrence of Bacterial Vaginosis. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 5, 2014. NLM Identifier: NCT02236156. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02236156. Last accessed on April 8, 2015.
  11. Tachedjian G, Tyssen D, Henderson S, et al. Development of dendrimer-based microbicides. Abstract presented at: 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007); July 22-25, 2007; Sydney, Australia. Abstract MOPDA04. Available at: http://library.iasociety.org/AbstractView.aspx?confID=2007&abstractId=4104. Last accessed on April 8, 2015.
  12. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00442910. Last accessed on April 8, 2015.
  13. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103767/. Last accessed on April 8, 2015.
  14. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Microbicide-Use Adherence, Acceptability, and Attitudes Among Sexually Active Young Women Participating in a Phase I Microbicide Trial (MTN 004) "Tell Juliana". In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 21, 2007. NLM Identifier: NCT00490152. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00490152. Last accessed on April 8, 2015.
  15. Carballo-Diéguez A, Giguere R, Dolezal C, et al. "Tell Juliana": Acceptability of the Candidate Microbicide VivaGel® and Two Placebo Gels Among Ethnically Diverse, Sexually Active Young Women Participating in a Phase 1 Microbicide Study. AIDS Behav. 2012 Oct;16(7):1761-74. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272128/. Last accessed on April 8, 2015.
  16. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00331032. Last accessed on April 8, 2015.
  17. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024437/. Last accessed on April 8, 2015.
  18. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261360/. Last accessed on April 8, 2015.
  19. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00740584. Last accessed on April 8, 2015.
 


Last Reviewed: April 8, 2015

Last Updated: April 8, 2015


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