Drugs

GTU-MultiHIV B

Other Names: DNA-GTU vaccine, GTU MultiHIV multi-gene, GTU-MultiHIV, GTU-MultiHIV B Clade, GTU-MultiHIV B DNA, GTU-multi-HIVB, Gene Transport Unit (GTU)-MultiHIV DNA Vaccine Drug Class: Therapeutic Vaccines Organization: FIT Biotech Phase of Development: GTU-MultiHIV B is in Phase IIb development as a therapeutic HIV vaccine. (GTU-MultiHIV B is also being studied as a preventive HIV vaccine.)
 

(Compound details obtained from Treatment Action Group 2017 Pipeline Report,1 Frontiers in Immunology article,2 and ClinicalTrials.gov3)

Pharmacology


Mechanism of Action: Therapeutic vaccines. GTU-MultiHIV B is a DNA-based therapeutic HIV vaccine. Therapeutic vaccines are being investigated as an immunotherapeutic approach to correcting HIV-associated immune dysfunction, such as impaired dendritic cell (DC) responses to HIV and suboptimal adaptive immune responses (including HIV-specific T cell responses).4-7 A therapeutic vaccine may potentially increase the effectiveness of ART, simplify ART regimens, or allow for periodic structured treatment interruptions. A successful therapeutic vaccine would either completely eradicate the virus or improve an individual’s immune response sufficiently to suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.8

The GTU-MultiHIV B vaccine is designed to generate immune responses to 6 HIV proteins. The vaccine consists of a DNA plasmid encoding a synthetic fusion protein that contains complete sequences of HIV-1 Rev, Nef, Tat, and Gag (p17/p24) and a number of T cell epitopes from Pol and Env. The protein sequences are derived from an HIV-1 subtype B isolate.6,9-12

GTU-MultiHIV B is being clinically developed as both a preventive and therapeutic HIV vaccine.1 In a Phase II trial (FIT-06) that evaluated the immunogenicity and clinical effects of GTU-MultiHIV B in ART-naive participants, the vaccine was found to increase HIV-specific CD4 cells (TNF-alpha secreting) and CD8 cells (TNF-alpha and IFN-gamma secreting), decrease plasma viral load, and increase CD4 counts.6,10,11 As a therapeutic vaccine, GTU-MultiHIV B is also being evaluated in a Phase II trial (NCT01492985) in combination with the LIPO-5 vaccine in a prime-boost strategy and in a Phase IIb trial (NCT02972450) in combination with MVA HIV-B.3,13


Select Clinical Trials


GTU-MultiHIV B therapeutic vaccine

Study Identifiers: CUT*HIVTHER 001; NCT02457689
Sponsor: Imperial College London
Phase: I/II
Status: This study has been completed.
Study Purpose: The purpose of this trial was to investigate the safety and immunogenicity of the GTU-MultiHIV B vaccine administered by 2 different delivery methods.
Study Population:
  • Participants were adults with subtype B HIV who were receiving ART.
  • Participants had been on ART for at least 6 months and had HIV RNA <50 copies/mL on at least 2 occasions prior to study enrollment while on ART.
  • Participants have had nadir CD4 counts >250 cells/mm3 and, at screening, had CD4 counts >200 cells/mm3.
Dosing: Participants were randomized either to 1 of 2 active treatment groups or to a placebo group.
Active treatment:
  • Group 1 (transcutaneous): Participants received 3 doses of GTU-MultiHIV B vaccine by IM injection and by transcutaneous application over 12 weeks. Each dose consisted of 1.0 mL of GTU-MultiHIV B vaccine (2 mg/mL) administered by intramuscular (IM) injection and 0.2 mL of the vaccine (2 mg/mL) delivered transcutaneously.
  • Group 2 (electroporation): Participants received 3 doses of GTU-MultiHIV B vaccine by IM injection with electroporation over 12 weeks. Each dose consisted of 1.0 mL of GTU-MultiHIV B vaccine (2 mg/mL) administered by IM injection with electroporation.
Placebo: Participants assigned to the placebo comparator group received placebo vaccine to match the dosing/delivery administered in either the active transcutaneous group or the active electroporation group.14

Study Identifiers: VRI02/ANRS 149 LIGHT; NCT01492985
Sponsor: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Phase: II
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this proof-of-concept trial is to evaluate whether GTU-MultiHIV B (prime) combined with LIPO-5 (boost) can induce HIV-specific immune responses to control viral replication after treatment interruption.
Study Population:
  • Participants are adults with chronic HIV infection who are asymptomatic and have been on ART for at least 18 months.
  • Participants have had HIV RNA <50 copies/mL and CD4 cell counts ≥600 cells/mm3 for the 6 months previous to and at screening (Week 3 visit). Participants have had nadir CD4 counts ≥300 cells/mm3 while on ART.

Dosing: Participants will be randomized to either an active treatment group or a placebo group. The vaccine treatment will consist of GTU-MultiHIV B administered by intramuscular (IM) injection via a needle-free injection system at Weeks 0, 4, and 12 followed by LIPO-5 administered by IM injection at Weeks 20 and 24. Participants will continue on ART until a treatment interruption from Week 36 through Week 48. To measure the persistence of the immunizing responses, participants will be followed to Week 74.13,15,16

Selected Study Results:


Study Identifiers: FIT-06; EudraCT 2005-003071-20
Sponsor: FIT Biotech Oyj Plc
Phase: II
Status: This study has been completed.
Study Purpose: The FIT-06 trial evaluated the safety, immunogenicity, and clinical effect of GTU-MultiHIV B administered by either intradermal (ID) or IM injection and compared it to that of placebo.
Study Population:

  • Participants were treatment-naive adults with chronic subtype C HIV infection.
  • Participants had HIV RNA ≥50 copies/mL and CD4 counts ≥350 cells/mm3.

Dosing: Participants received either the GTU-MultiHIV B vaccine or placebo vaccine. Treatment involved either ID injections (0.5 mg/dose) or IM injections (1 mg/dose) at Weeks 0, 4 and 12, followed by 2 boosts (1 mg/dose ID; 2 mg/dose IM) at Weeks 76 and 80. Participants were followed up to Week 108.10,11,17,18

Selected Study Results:


Study Identifiers: EHVA T01/ANRS VRI05; NCT02972450
Sponsor: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Phase: IIb
Status: This study is not yet open for participant recruitment.
Study Purpose: The purpose of this trial is to evaluate the impact of GTU-MultiHIV B combined with MVA HIV-B on the duration of viral load control during a treatment interruption of ART.
Study Population:
  • Participants are adults who started ART after 2009 and who have been on ART for at least 1 year.
  • At screening, participants have HIV RNA <50 copies/mL and CD4 counts >600 cells/mm3. Participants have had nadir CD4 counts >300 cells/mm3.
Dosing: Participants will be stratified based on the stage of infection (primary or chronic) during which ART was started and will be randomized to receive either active vaccine treatment or placebo vaccine over 12 weeks.

The active vaccine treatment will consist of IM injections of GTU-MultiHIV B (2 mg/mL) at Weeks 0 and 4 and an IM injection of MVA HIV-B (0.5 mL at a concentration of 1 x 108 plaque-forming units/mL) at Week 12. Participants will continue on ART throughout the 12-week vaccination period and for 12 weeks thereafter. Then, participants will begin a 24-week long treatment interruption of ART. If a participant’s viral load rebounds to 10,000 copies/mL or more or CD4 count drops to 350 cells/mm3 or less during the treatment interruption period, ART will be reinitiated.3

A Phase I immunotherapeutic study (NCT01130376) of GTU-MultiHIV B given in combination with cytokine and hormone therapy in participants on suppressive ART has also been completed.19,20


Adverse Events


VRI02/ANRS 149 LIGHT (NCT01492985):
In this Phase II study evaluating GTU-MultiHIV B and LIPO-5 vaccines used in a prime-boost strategy, preliminary safety data reported by GTU-MultiHIV vaccine developers indicate that neither vaccine was associated with any substantial safety concerns.13,15,16

FIT-06 (EudraCT 2005-003071-20):
Results reported for this Phase II trial showed that GTU-MultiHIV B administered by either IM or ID injection to 63 participants was safe. There were no serious adverse events (SAEs) related to the vaccine. Mild to moderate local reactogenicity events occurring immediately or 30 minutes after administration (such as bleeding at the injection site, local indurations, and persistent local edema) were attributed more to ID injection than to IM injection. Other adverse events that occurred in both the active treatment and placebo groups included lymphadenopathy, upper respiratory tract infection, and increased CPK.10,11,17


Drug Interactions


GTU-MultiHIV B drug interactions are currently unknown.


References


  1. Frick M, Gaudino A, Harrington M, et al. Treatment Action Group. 2017 pipeline report. July 2017. Available at: http://www.pipelinereport.org/sites/default/files/2017%20Pipeline%20Report%20Final.pdf. Last accessed on December 6, 2017. [Archived at WebCite]
  2. Ensoli B, Cafaro A, Monini P, Marcotullio S, Ensoli F. Challenges in HIV vaccine research for treatment and prevention. Front Immunol. 2014; 5: 417. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157563/. Last accessed on December 6, 2017.
  3. French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS). A Phase IIb randomised therapeutic HIV vaccine trial in individuals who started antiretrovirals during primary or chronic infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 10, 2016. NLM Identifier: NCT02972450. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02972450. Last accessed on December 6, 2017.
  4. Lederman MM, Rodriguez B, Sieg S. Immunopathogenesis of HIV Infection. In: Coffey S and Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. Available at: http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Last accessed on December 6, 2017. [Archived at WebCite]
  5. Miller E and Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Expert Opin Biol Ther. 2014; 14(11): 1545-49. Available at: http://www.tandfonline.com/doi/full/10.1517/14712598.2014.950652. Last accessed on December 6, 2017. [Archived at WebCite]
  6. Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014; 6:43. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Last accessed on December 6, 2017.
  7. Routy J-P, Boulassel M-R, Yassine-Diab B, et al. Immunologic activity and safety of autologous HIV RNA–electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol. 2010 Feb; 134(2): 140. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818410/. Last accessed on December 6, 2017.
  8. Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015; 18(1): 20497. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641978/. Last accessed on December 6, 2017.
  9. Blazevic V, Männik A, Malm M, et al. Induction of human immunodeficiency virus type-1-specific immunity with a novel Gene Transport Unit (GTU)-MultiHIV DNA vaccine. AIDS Res Hum Retroviruses. 2006 Jul; 22(7): 667-77. Available at: https://www.researchgate.net/publication/6954668_Induction_of_Human_Immunodeficiency_Virus_Type-1-Specific_Immunity_with_a_Novel_Gene_Transport_Unit_GTU-MultiHIV_DNA_Vaccine. Last accessed on December 6, 2017.
  10. Vardas E, Stanescu I, Valtavaara M, et al. Indicators of therapeutic vaccine effect using GTU-MultiHIV B clade DNA in treatment-naive subtype C HIV-1 infected subjects. Abstract presented at: International AIDS Conference (IAC); July 18-23, 2010; Vienna, Austria. Abstract MOPDB102. Available at: http://www.abstract-archive.org/Abstract/Share/1945. Last accessed on December 6, 2017. [Archived at WebCite]
  11. Vardas E, Stanescu I, Leinonen M, et al. Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects. Vaccine. 2012 Jun 8; 30(27): 4046-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22549090. Last accessed on December 6, 2017.
  12. The Joint Research Centre of the European Commission. GMO Register: Notification Number B/FR/13/GT03. FIT Biotech GTU®-MultiHIV B – Part 1: Summary notification information format for the release of genetically modified organisms other than higher plants; Version 2.0; 10/04/2013. Available at: http://gmoinfo.jrc.ec.europa.eu/bsnifs-gmo/B-FR-13-GT03.pdf. Last accessed on December 6, 2017. [Archived at WebCite]
  13. French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS). Evaluation of a therapeutic immunization strategy associating a DNA vaccine (GTU-MultiHIV B) followed by a lipopeptide vaccine (LIPO-5) in the control of viral replication following antiretroviral treatment interruption in HIV-1 infected patients with a CD4 cell count ≥ 600/mm3. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 24, 2011. NLM Identifier: NCT01492985. Available at: https://clinicaltrials.gov/ct2/show/NCT01492985. Last accessed on December 6, 2017.
  14. Imperial College London. A randomized Phase I/II study to assess the safety and immunogenicity of the DNA-GTU vaccine administered by two novel routes compared to placebo in HIV-infected patients on antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 27, 2015. NLM Identifier: NCT02457689. Available at: https://clinicaltrials.gov/ct2/show/NCT02457689. Last accessed on December 6, 2017.
  15. FIT Biotech Oy: Press Release, dated June 9, 2016. FIT Biotech’s HIV vaccine demonstrated to be safe and well tolerated in two clinical studies. Available at: http://www.fitbiotech.com/tiedote/fit-biotech-oy-fit-biotechs-hiv-vaccine-demonstrated-to-be-safe-and-well-tolerated-in-two-clinical-studies/. Last accessed on December 6, 2017. [Archived at WebCite]
  16. Ghosn J, Palich R, Chaillon A, et al. Viral rebound in semen after treatment interruption in a HIV therapeutic vaccine double-blind trial (VRI02/ANRS149-LIGHT). Abstract presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. Abstract TUPDB0105. Available at: http://programme.ias2017.org/Abstract/Abstract/3125. Last accessed on December 6, 2017. [Archived at WebCite]
  17. Vardas E, Stanescu I, Leinonen M, et al. Indicators of therapeutic effect in FIT-06: A Phase II Trial of a DNA vaccine GTU®-MultiHIV, in untreated HIV-1 infected participants. Slides presented at: AIDS Vaccine 2010; September 28 – October 1, 2010; Atlanta, GA. Available at: http://www.vaccineenterprise.org/conference_archive/2010/pdf-presentations/Wednesday/Oral-Abstract-01/VardasE.pdf. Last accessed on December 6, 2017. [Archived at WebCite]
  18. EU Clinical Trials Register. EudraCT Number: 2005-003071-20; Immunogenicity and therapeutic effects of GTU-MultiHIV B clade DNA vaccine. A randomized, controlled, phase II clinical trial in treatment-naive HIV-positive subjects. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-003071-20/FI. Last accessed on December 6, 2017. [Archived at WebCite]
  19. Imperial College London. A randomised, open labelled, Phase I, safety, toxicity, and exploratory immunogenicity evaluation of therapeutic immunisation +/- IL-2, GM-CSF and growth hormone in HIV-1 infected subjects receiving highly active anti-retroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 25, 2010. NLM Identifier: NCT01130376. Available at: https://clinicaltrials.gov/ct2/show/NCT01130376. Last accessed on December 6, 2017.
  20. Herasimtschuk A, Downey J, Nelson M, et al. Therapeutic immunisation plus cytokine and hormone therapy improves CD4 T-cell counts, restores anti-HIV-1 responses and reduces immune activation in treated chronic HIV-1 infection. Vaccine. 2014 Dec 5; 32(51): 7005-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25454870. Last accessed on December 6, 2017.


Last Reviewed: December 6, 2017