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Astodrimer

Other Names: SPL-7013, VivaGel, astodrimer sodium
Drug Class: Microbicides
Molecular Formula: C583 H641 N63 O287 S64
Registry Number: 1379746-42-5 (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: Astodrimer has been studied in Phase I/II clinical trials for the prevention of HIV infection.
Patent Version Content

Pharmacology


Mechanism of Action: Microbicide; polyanion-based entry inhibitor.4 Astodrimer is a broad-spectrum dendrimer consisting of a divalent benzhydrylamine core and 4 layers of lysine branches. Naphthalene disulfonic acid groups are attached to the outer branches, creating a hydrophobic dendrimer surface with a high anionic charge. This allows for electrostatic interactions and multivalent binding to viral gp120, thus blocking HIV attachment to and entry into host CD4 cells.3,5,6 As an investigational topical vaginal microbicide to prevent sexual transmission of HIV-1 and HSV-2 infection, astodrimer is formulated in a Carbopol®-based gel.3

Astodrimer has shown equal in vitro potency against CXCR4- and CCR5-tropic HIV-1 strains in terms of inhibiting viral entry.6,7 Against some HIV-1 strains using CXCR4 or both CXCR4 and CCR5, astodrimer irreversibly binds to viral envelope proteins and is directly virucidal. However, binding of astodrimer to HIV-1 strains using only CCR5 may be reversible, resulting in a weaker interaction that does not cause direct HIV-1 inactivation. Binding of astodrimer to host cell receptors may also facilitate inhibition of CCR5-using HIV strains.7 One study suggests that the mechanism by which astodrimer inhibits CCR5-tropic virus entry is through binding with gp120 in the gp120-CD4 complex but not to gp120 alone. By binding to the gp120-CD4 complex, astodrimer causes the complex to weaken and enables its dissociation.8

Astodrimer gel has also been studied for the treatment of bacterial vaginosis (BV) and was approved for marketing in the European Union (as VivaGel® BV) for the treatment and management of BV symptoms. The gel has also been studied in Phase III trials for the prevention of recurrent BV.9-12 In the United States, an application for marketing approval of VivaGel® BV for both treatment and prevention is being evaluated by FDA.13

Resistance: A study of HIV-1 infected cells exposed to increasing concentrations of astodrimer through 44 passages generated viruses with only a 2- to 3-fold increase in the 50% inhibitory concentration (IC50) when compared to wild-type virus. These viruses demonstrated some in vitro cross-resistance to dextran sulphate and enfuvirtide, but were not significantly cross-resistant to AMD3100.14


Select Clinical Trials


Study Identifiers: 1) MTN-004; SPL7013-006; NCT00442910, and 2) ATN 062; NCT00490152
Sponsors: MTN-004 was sponsored by Starpharma Pty Ltd, and ATN 062 was sponsored by University of North Carolina, Chapel Hill.
Phase: These studies were Phase I studies.
Status: These studies have been completed.
Study Purpose: The purpose of MTN-004 was to assess the safety and acceptability of astodrimer gel when applied intravaginally in women aged 18 to 24 years. ATN 062 was designed to expand the acceptability assessment of astodrimer gel in MTN-004 participants.
Study Populations: Participants were sexually active women who did not have HIV or any other STIs.
Dosing: During MTN-004, each gel was applied intravaginally twice daily for 14 days. Participants were randomized to 1 of the following 3 groups:
  • 3% astodrimer gel
  • Astodrimer placebo gel
  • Hydroxyethylcellulose (HEC) placebo gel
Note: ATN 062 ("Tell Juliana") was conducted simultaneously with MTN 004 and expanded the acceptability assessment through the use of questionnaires, teleconferences, and an interactive voice reporting system.15-19
Selected Study Results:


Study Identifiers: SPL7013-004; NCT00331032
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: I
Status: This study has been completed.
Study Purpose: The purpose of this study was to assess the safety and tolerability of astodrimer gel when applied intravaginally in young women aged 18 to 24 years.
Study Population: Participants were sexually abstinent (but previously sexually active) women who did not have HIV or any other STIs.
Dosing: Participants were randomized to either 3% astodrimer gel or astodrimer placebo gel, each applied intravaginally twice daily for 14 days.20-22
Selected Study Results:


Study Identifiers: SPL7013-003; NCT00740584
Sponsor: Starpharma Pty Ltd
Phase: I/II
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to assess the ex vivo antiviral activity and local retention of intravaginally applied astodrimer gel in women.
Study Population: Participants were sexually abstinent women who did not have HIV or any other STIs.
Dosing: Participants applied a single dose of 3% astodrimer gel intravaginally on 5 separate occasions (with a minimum of 5 days between doses).3,23
Selected Study Results:


Adverse Events


MTN-004; SPL7013-006; (NCT00442910):
In this Phase I study evaluating twice-daily astodrimer gel used over 14 days in 61 women, the incidence of Grade 1/2 genital adverse events (AEs) related to product use was significantly higher 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 (SAEs) 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.16

SPL7013-004 (NCT00331032):
In this Phase I safety study, 54 women applied astodrimer gel twice daily for 14 days. Genitourinary (GU) AEs related to product use, which were mostly mild, and colposcopic abnormalities suggestive of 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.21 In addition, after 7 to 14 days of twice-daily gel applications, there was greater reversible elevation of immune markers associated with epithelial damage (genital cytokines and T-cell subsets) in the astodrimer gel arm than in the placebo arm.22

SPL7013-003; (NCT00740584):
In this Phase I/II study of 5 single-dose applications of astodrimer gel in 12 enrolled women, no SAEs occurred. Among 4 participants who received at least 1 dose of astodrimer gel, 7 GU AEs were reported. 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 occurred in any participants. There were no study withdrawals due to an AE.3,23


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: https://chem.nlm.nih.gov/chemidplus/rn/1379746-42-5. Last accessed on June 15, 2018.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on June 15, 2018.
  3. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174146/. Last accessed on June 15, 2018.
  4. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715623/. Last accessed on June 15, 2018.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676817/. Last accessed on June 15, 2018.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925893/. Last accessed on June 15, 2018.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115201/. Last accessed on June 15, 2018.
  8. Nandy B, Saurabh S, Sahoo AK, Dixit NM, Maiti PK. The SPL7013 dendrimer destabilizes the HIV-1 gp120–CD4 complex. Nanoscale. 2015 Nov 28; 7(44): 18628-41. Available at: https://www.researchgate.net/profile/Prabal_Maiti/publication/282900534_The_SPL7013_dendrimer_destabilizes_the_HIV-1_gp120-CD4_complex/links/5633433408ae242468db83fe/The-SPL7013-dendrimer-destabilizes-the-HIV-1-gp120-CD4-complex.pdf?origin=publication_detail. Last accessed on June 15, 2018. [Archived at WebCite]
  9. Starpharma: News release, dated November 28, 2012. VivaGel phase 3 study results. Available at: http://www.starpharma.com/news/139. Last accessed on June 15, 2018. [Archived at WebCite]
  10. Starpharma: News release, dated September 24, 2015. EU marketing approval granted for VivaGel® BV. Available at: http://www.starpharma.com/news/253. Last accessed on June 15, 2018. [Archived at WebCite]
  11. 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 June 15, 2018.
  12. Starpharma: News release, dated March 30, 2017. VivaGel® BV Phase 3 trials for prevention of BV completed. Available at: http://www.starpharma.com/news/308. Last accessed on June 15, 2018. [Archived at WebCite]
  13. Starpharma: News release, dated April 30, 2018. Starpharma completes US new drug application for VivaGel® BV. Available at: http://www.starpharma.com/news/366#article366. Last accessed on June 15, 2018. [Archived at WebCite]
  14. Tachedjian G, Tyssen D, Henderson S, et al. Development of dendrimer-based microbicides. Abstract presented at: International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007); July 22-25, 2007; Sydney, Australia. Abstract MOPDA04. Available at: https://library.iasociety.org/AbstractView.aspx?confID=2007&abstractId=4104. Last accessed on June 15, 2018.
  15. 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 June 15, 2018.
  16. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103767/. Last accessed on June 15, 2018.
  17. Pellett Madan R, Dezzutti CS, Rabe L, et al. Soluble immune mediators and vaginal bacteria impact innate genital mucosal antimicrobial activity in young women. Am J Reprod Immunol. 2015 Oct; 74(4): 323–332. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573238/. Last accessed on June 15, 2018.
  18. University of North Carolina, Chapel Hill. 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 June 15, 2018.
  19. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272128/. Last accessed on June 15, 2018.
  20. 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 June 15, 2018.
  21. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024437/. Last accessed on June 15, 2018.
  22. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261360/. Last accessed on June 15, 2018.
  23. 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 June 15, 2018.


Last Reviewed: June 15, 2018