Drug Database: SB-728-T

Pharmacology

Pharmacology

Mechanism of Action

Gene therapy product (zinc finger nuclease [ZFN]-mediated CCR5 gene modified cells). SB-728-T is a product generated by using ZFNs that are delivered via an adenovirus vector or mRNA to modify autologous CD4 cells at the CCR5 gene. Engineered ZFNs targeting CCR5 are designed to produce a double-stranded break at a specific site in the CCR5 gene coding region. The site is located upstream of the naturally occurring homozygous CCR5-delta-32 mutation, which is known to confer resistance to HIV-1 infection. Upon CCR5 DNA cleavage by ZFNs, innate error-prone DNA repair mechanisms are induced, leading to permanent disruption of CCR5 expression on CD4 cells.^4-8 SB-728-T gene therapy may provide individuals who have HIV with a reproducible pool of CD4 cells permanently resistant to HIV entry, potentially improving immune restoration and leading to functional control of HIV.^9.10

An SB-728-T cell product containing a mixture of CCR5-modified autologous CD4 cells and CD8 cells has also been studied. The mixed CD4/CD8 SB-728-T product allows for a simpler manufacturing process and potentially greater antiviral effect.^11,12

Half-life (T_½)

In a study (NCT00842634) of 12 participants with HIV who received a single dose of SB-728-T, modified CD4 cells had an estimated mean half-life of 48 weeks.¹³

Select Clinical Trials

Select Clinical Trials

SB-728-T: Autologous CCR5-Modified T Cell Product Generated via Adenoviral Delivery of ZFNs

Study Identifiers: SB-728-1002; NCT01252641

Sponsor: Sangamo Therapeutics
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to assess the safety of a single infusion of SB-728-T and its effect on viral load.
Study Population: Participants were adults with HIV who had HIV RNA >1,000 copies/mL and CD4 counts >500 cells/mm³ at study entry. Participants had nadir CD4 counts >400 cells/mm³.¹⁴

Study Identifiers: SB-728-1101; NCT01543152

Sponsor: Sangamo Therapeutics
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label dose escalation study was to evaluate the safety and efficacy of cyclophosphamide preconditioning when used to enhance SB-728-T engraftment. Investigators also assessed the effect of a single SB-728-T infusion on viral load levels following analytical treatment interruption (ATI) of ART.
Study Population: Participants were adults with HIV who had been on ART for at least 6 months and had undetectable viral load levels for 3 months prior to study entry. At study entry, participants were on a stable ART regimen, had undetectable viral load levels, and had CD4 counts ≥500 cells/mm³.¹⁵
Selected Study Results: Results published in Molecular Therapy (2015) and through bioRxiv (2021) indicated that cyclophosphamide pretreatment was generally well tolerated and at doses of up to 1 g/m² increased SB-728-T engraftment in participants. A single SB-728-T infusion resulted in partial control of viral load levels during ATI.^16,17
Additional Published Material:

• CROI, 2023: Single infusion of stem like CCR5-modified CD4 T cells provide long-term HIV control

Study Identifiers: TRAILBLAZER; NCT03666871

Sponsor: University of Cincinnati
Phase: 1/2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to compare the effect of SB-728-T versus ex vivo expanded unmodified autologous CD4 cells on the size of the latent HIV reservoir in participants with HIV.
Study Population: Participants are adults with HIV who are on a stable ART regimen. Participants have had HIV RNA <50 copies/mL for at least 48 weeks and have CD4 counts >350 cells/mm³ at screening.¹⁸

SB-728mR-T: Autologous CCR5-Modified T Cell Product Generated via mRNA Delivery of ZFNs

Study Identifiers: SB-728mR-1401; NCT02225665

Sponsor: Sangamo Therapeutics
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and effectiveness of repeat doses of SB-728mR-T following cyclophosphamide preconditioning in individuals with HIV.
Study Population: Participants were adults with HIV who were on ART and who had initiated ART ≤1 year of HIV diagnosis or suspected infection. Participants had undetectable viral loads for at least 2 months prior to and at screening and had CD4 counts ≥500 cells/mm³ at study entry.¹⁹

Other studies evaluating SB-728-T gene therapy have been completed or are ongoing. These include the following Phase 1 studies:

• NCT00842634: A completed trial that evaluated the safety and effects of a single infusion of SB-728-T in individuals with HIV.²⁰ Results are published in the N Engl J Med (2014).
• SB-728-0902 (NCT01044654): A completed study that evaluated the safety and effectiveness of SB-728-T in individuals with HIV who had suboptimal CD4 counts while on ART.⁹ Results are available from bioRxiv (2021) and CROI 2023.
• SB-728mR (NCT02388594): A completed trial that investigated a single infusion of SB-728mR, with and without cyclophosphamide preconditioning, in participants with HIV who were receiving ART.²¹ Results are available from J Clin Invest (2021).
• NCT03617198: A pilot study that is examining whether treatment with autologous T cells modified by SB-728mR and CD4 chimeric antigen receptor is safe and effective in adults with HIV. This study is ongoing, but not recruiting participants.²² A summary of findings are available from CROI 2022.
• SB-728-1003 (NCT04201782): A long-term follow-up study of participants who have received SB-728-T or SB-728mR-T in a previous trial. This study does not involve any treatment and is ongoing but not recruiting participants.²³

Adverse Events

Adverse Events

SB-728-1101 (NCT01543152)

In this Phase 1/2 study, participants were enrolled into five cohorts, with each cohort receiving a different dose of cyclophosphamide prior to SB-728-T infusion. Mild infusion reactions, including low-grade fever and chills, were associated with SB-728-T. A garlic-like odor (due to dimethyl sulfoxide) was also reported with SB-728-T infusions.^15,24

Cyclophosphamide was reported as being safe at doses up to 1 g/m². In Cohort 2 (cyclophosphamide 500 mg/m²), two out of three initial participants experienced Grade 2 nausea and vomiting. Three participants subsequently enrolled into Cohort 2 received prophylactic antiemetics. In Cohort 4 (cyclophosphamide 2 g/m²), one participant had Grade 4 neutropenia, and two participants had Grade 3 neutropenia. Two of the three participants in Cohort 5 (cyclophosphamide 1.5 g/m²) developed Grade 4 neutropenia.^24,25

Drug Interactions

Drug Interactions

Drug-drug interactions associated with SB-728-T are currently unknown.

References

References

1. National Center for Biotechnology Information. PubChem substance record for SID 381129581, SB-728-T, Source: ChemIDplus. Accessed December 12, 2023
2. Treatment Action Group website. Research toward a cure trials. Accessed December 12, 2023
3. Sangamo Therapeutics. Form 10-K (2021 annual report). Accessed December 12, 2023
4. Manjunath N, Yi G, Dang Y, Shankar P. Newer gene editing technologies toward HIV gene therapy. Viruses. 2013;5(11):2748-2766. Accessed December 12, 2023
5. Blick G, Lalezari J, Hsu R, et al. Cyclophosphamide enhances SB-728-T engraftment to levels associated with HIV-RNA control. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 141. Accessed December 12, 2023
6. Perez EE, Wang J, Miller JC, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26(7):808-816. Accessed December 12, 2023
7. Maier DA, Brennan AL, Jiang S, et al. Efficient clinical scale gene modification via zinc finger nuclease–targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther. 2013;24(3):245-258. Accessed December 12, 2023
8. Sangamo Therapeutics: Press Release, dated October 16, 2014. Sangamo BioSciences ZFP therapeutic program in HIV/AIDS featured at three major scientific conferences in October 2014. Accessed December 12, 2023
9. Sangamo Therapeutics. A Phase 1 dose escalation, single dose study of autologous T-cells genetically modified at the CCR5 gene by zinc finger nucleases SB-278 in HIV-infected patients who have exhibited suboptimal CD4+ T-cell gains during long-term antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 6, 2010. NLM Identifier: NCT01044654. Accessed December 12, 2023
10. Ando D. Functional control of viremia in CCR5-Δ32 heterozygous (Δ32HZ) HIV+ subjects following adoptive transfer of zinc finger nuclease CCR5 modified autologous CD4 T-cells (SB-728-T). Annual Meeting of the European Society of Gene and Cell Therapy (ESGCT and SETGyC Collaborative Congress); October 25-28, 2013; Madrid, Spain. National AIDS Treatment Advocacy Project (NATAP): HIV Articles. Accessed December 12, 2023
11. Sangamo Therapeutics: Press Release, dated February 26, 2015. Sangamo BioSciences presents new clinical data at CROI 2015 from trial of ZFP Therapeutic® designed to provide functional control of HIV. Accessed December 12, 2023
12. Sangamo Therapeutics: News Release, dated December 11, 2015. Sangamo BioSciences presents Phase 2 clinical data from two SB-728-T HIV studies. Accessed December 12, 2023
13. Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901-910. Accessed December 12, 2023
14. Sangamo Therapeutics. A Phase 1/2, open label, single infusion study of autologous T-cells genetically modified at the CCR5 gene by zinc finger nucleases (SB-728-T) in HIV infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 29, 2010. NLM Identifier: NCT01252641. Accessed December 12, 2023
15. Sangamo Therapeutics. A Phase I, open-label study to assess the effect of escalating doses of cyclophosphamide on the engraftment of SB-728-T in aviremic HIV-infected subjects on HAART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 1, 2012. NLM Identifier: NCT01543152. Accessed December 12, 2023
16. Ando D, Blick G, Lalezari J, et al. A dose escalation study of cyclophophamide (CTX) to enhance SB-728-T engraftment. Mol Ther. 2015;23:S11. Accessed December 12, 2023
17. Zeidan J, Sharma AA, Lee G, et al. Infusion of CCR5 gene-edited T cells allows immune reconstitution, HIV reservoir decay, and long-term virological control. bioRxiv. Published online March 1, 2021:2021.02.28.433290. doi:10.1101/2021.02.28.433290. Accessed December 12, 2023
18. University of Cincinnati. T-cell reinfusion after interfering with lymphocyte binding location of AIDS virus through zinc-finger-nuclease elimination of CCR5 receptors: The TRAILBLAZER Study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 7, 2018. NLM Identifier: NCT03666871. Accessed December 12, 2023
19. Sangamo Therapeutics. A Phase 1/2, open-label study to assess the safety and tolerability of repeat doses of autologous T-cells genetically modified at the CCR5 gene by zinc finger nucleases in HIV-infected subjects following cyclophosphamide conditioning. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 22, 2014. NLM Identifier: NCT02225665. Accessed December 12, 2023
20. University of Pennsylvania. A Phase I study of autologous T-cells genetically modified at the CCR5 gene by zinc finger nucleases SB-728 in HIV-infected patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 4, 2009. NLM Identifier: NCT00842634. Accessed December 12, 2023
21. University of Pennsylvania. A Phase I study of T-cells genetically modified at the CCR5 gene by zinc finger nucleases SB-728mR in HIV-infected patients, with or without the CCR5 delta-32 mutation, pre-treated with cyclophosphamide. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 24, 2015. NLM Identifier: NCT02388594. Accessed December 12, 2023
22. University of Pennsylvania. A pilot study of T cells genetically modified by zinc finger nucleases SB-728mR and CD4 chimeric antigen receptor in HIV-infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 9, 2018. NLM Identifier: NCT03617198. Accessed December 12, 2023
23. Sangamo Therapeutics. Long-term follow-up of HIV-infected subjects treated with autologous T-cells genetically modified at the CCR5 gene by zinc finger nucleases (SB-728-T or SB-728mR-T). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 13, 2019. NLM Identifier: NCT04201782. Accessed December 12, 2023
24. Blick G, Lalezari J, Hsu R, et al. A dose escalation study of cyclophosphamide (CTX) to enhance SB-728-T engraftment. Conference on Retroviruses and Opportunistic Infections; February 23-26, 2015; Seattle, WA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2015. Accessed December 12, 2023
25. Ando D, Lalezari J, Blick G, et al. HIV protected autologous zinc finger nuclease CCR5 modified CD4 cells (SB-728-T) reduce viral load (VL) in HIV subjects during treatment interruption (TI): correlates of effect, and effect of cytoxan conditioning. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Mascolini: Virologic Response During ART Interruption After CCR5-Cell Modification With SB-728-T (zinc fingers); Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Accessed December 12, 2023

Last Reviewed: December 12, 2023