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Investigational

SB-728-T  Audio icon

Other Names: CCR5-ZFN, CCR5-specific zinc finger protein nuclease, SB-728, SB-728mR, SB-728mR-T
Drug Class: Gene Therapy Products
Registry Number: S900006290 (ChemID)
Company: Sangamo BioSciences
Phase of Development: Phase I/II
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(Compound details obtained from ChemIDplus Advanced,1 HIV i-BASE/Treatment Action Group 2015 Pipeline Report,2 Viruses article,3 and Sangamo BioSciences website4)
Patent Version Content

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 T 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 T cells.3-8 SB-728-T gene therapy may provide HIV-infected individuals with a reproducible pool of CD4 T cells permanently resistant to HIV entry, potentially improving immune restoration and leading to functional control of HIV.10

Some SB-728-T participants in a recent study received a mixed CCR5-modified autologous CD4 T cell and CD8 T cell product. The mixed CD4/CD8 SB-728-T product reportedly allows for a simpler manufacturing process and potentially greater antiviral effect.11

Half-life (T½): In a study of 12 HIV-infected participants receiving a single dose of ZFN-modified autologous CD4 T cells (SB-728-T), modified cells had an estimated mean half-life of 48 weeks.12

Resistance: Resistance to SB-728-T in the context of HIV infection has not been described.


Clinical Trials


Study Identifier: NCT01044654; SB-728-09029
Phase: I/II
Study Purpose: Study to evaluate the safety and effect of SB-728-T in HIV-infected individuals.
Study Population: HIV-infected, treatment-experienced adults.
  • Cohorts 1-3: Participants on long-term antiretroviral therapy (ART) and who have undetectable viral load and suboptimal CD4 T-cell levels between 200 and 500 cells/mm3 (“immunologic non-responders”).
  • Cohort 5: Participants receiving ART and who have undetectable viral load and CD4 count >500 cells/mm3. All participants in cohort 5 were heterozygous for the CCR5-Δ32 mutation.
Dosing:
  • Cohorts 1-3: Escalating-dose cohorts (three participants per cohort) receiving a single intravenous (IV) infusion of SB-728-T (10, 20, and 30 billion ZFN-modified CD4 T cells for cohorts 1, 2, and 3, respectively).
  • Cohort 5: Single IV infusion of SB-728-T (5 to 30 billion ZFN-modified CD4 T cells), followed by a structured treatment interruption of ART for 16 weeks. ART will be reinstituted depending on participants’ CD4 cell counts and viral load levels during and after the structured interruption of ART.9,10,13-16
(See references cited above for information on study results.)


Study Identifier: NCT01543152; SB-728-110117
Phase: I/II
Study Purpose: Dose escalation study to evaluate the effect on viral load and safety of cyclophosphamide preconditioning when used to enhance SB-728-T engraftment in HIV-infected individuals.
Study Population: HIV-infected adults on ART ≥6 months and who have undetectable viral loads for 3 months and CD4 T cell count ≥500 cells/mm3.
Dosing: Five dose-escalating cohorts (3 to 6 participants per cohort):
  • Cohort 1: IV cyclophosphamide 100 mg/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 T cells).
  • Cohort 2: IV cyclophosphamide 500 mg/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 T cells). 
  • Cohort 3: IV cyclophosphamide 1 g/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 T cells). After study completion, three additional participants were enrolled into cohort 3 and received IV cyclophosphamide, followed by a new SB-728-T product containing both CD4 T cells and CD8 T cells.
  • Cohort 4: IV cyclophosphamide 2 g/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 T cells).
  • Cohort 5: IV cyclophosphamide 1.5 g/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 T cells).

All participants underwent a 16-week structured treatment interruption of ART 6 weeks after SB-728-T infusion.17-22
(See references cited above for information on study results.)


In addition, two studies will be examining SB-728-T generated by mRNA delivery of CCR5-specific ZFNs to a participant’s CD4 T cells. (This ZFN-modified CD4 T cell product is also known as SB-728mR-T.) NCT02388594, a Phase I study, will be investigating a single infusion of SB-728mR-T, with and without cyclophosphamide preconditioning, in HIV-infected participants on ART. NCT02225665 is a Phase I/II study investigating repeat infusions of SB-728mR-T after cyclophosphamide conditioning in HIV-infected participants on ART.2,8,23,24

Other studies investigating SB-728-T have also been completed.

 


Adverse Events


Infusion-related adverse events have been associated with SB-728-T treatment. In the SB-728-0902 study (NCT01044654), there were reports of mild, reversible, infusion-related adverse events.15 In a Phase I study of 12 participants receiving a single dose of SB-728-T, there was a report of one serious adverse event that was attributed to a transfusion reaction.12 

In SB-728-1101 (NCT01543152), two out of three initial participants in cohort 2 (cyclophosphamide 500 mg/m2) experienced Grade 2 nausea and vomiting. An additional three participants enrolled into cohort 2 were therefore prophylactically treated with anti-emetics. In cohort 4 (cyclophosphamide 2 g/m2), three participants developed neutropenia (Grade 4 in one participant; Grade 3 in two participants). Two participants in cohort 5 (cyclophosphamide 1.5 g/m2) developed Grade 4 neutropenia. Mild infusion reactions, including low grade fever and chills, were associated with SB-728-T. A garlic-like odor (due to dimethyl sulfoxide [DMSO]) was also reported with SB-728-T infusions.17,22
 


Drug Interactions


SB-728-T drug interactions have not been described.



References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/S900006290. Last accessed on September 13, 2015.
  2. Clayden P, Collins S, Frick M, et al. HIV i-BASE/Treatment Action Group. 2015 Pipeline Report. Benzacar A, ed. July 2015. Available at: http://i-base.info/htb/wp-content/uploads/2015/07/2015-pipeline-report-web.pdf. Last accessed on September 13, 2015.
  3. Manjunath N, Yi G, Dang Y, Shankar P. Newer Gene Editing Technologies toward HIV Gene Therapy. Viruses. 2013 Nov 14;5(11):2748-66. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856413/. Last accessed on September 13, 2015.
  4. Sangamo BioSciences website. HIV/AIDS (SB-728). Available at: http://www.sangamo.com/pipeline/sb-728.html. Last accessed on September 13, 2015.
  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: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 141. Available at: http://croi2014.org/sites/default/files/uploads/CROI2014_Final_Abstracts.pdf. Last accessed on September 13, 2015.
  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 Jul;26(7):808-16. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422503/. Last accessed on September 13, 2015.
  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 Mar;24(3):245-58. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609630/. Last accessed on September 133, 2015.
  8. Sangamo BioSciences: Press Release, dated October 16, 2014. Sangamo BioSciences ZFP Therapeutic Program in HIV/AIDS Featured at Three Major Scientific Conferences in October 2014. Available at: http://investor.sangamo.com/releasedetail.cfm?ReleaseID=876507. Last accessed on September 13, 2015.
  9. Sangamo Biosciences. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01044654. NLM Identifier: NCT01044654. Last accessed on September 13, 2015.
  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. Available at: http://www.natap.org/2013/HIV/103013_01.htm. Last accessed on September 13, 2015.
  11. Sangamo BioSciences: 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. Available at: http://investor.sangamo.com/releasedetail.cfm?ReleaseID=898529. Last accessed on September 13, 2015.
  12. 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 Mar 6;370(10):901-10. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084652/. Last accessed on September 13, 2015.
  13. Sangamo BioSciences website. Clinical Trials: HIV/AIDS (SB-728). Available at: http://www.sangamo.com/pipeline/clinical-trials.html. Last accessed on September 13, 2015.
  14. Zeidan J, Lee G, Lalezari J, et al. Host Immune Environment Significantly Impact the Level of CD4 Reconstitution and the Effects on Latent Reservoir in HIV Subjects Receiving ZFN CCR5 Modified CD4 T-cells (SB-728-T). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 10-13, 2013; Denver CO. Abstract H-674. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=1f74ce30-35e8-4251-b7b0-bb02b15f73df&cKey=457629d2-01e5-4baf-b4da-5544a73df974&mKey=%7b7DD36E88-52C3-4FF1-A5DF-1D00766558B8%7d. Last accessed on September 13, 2015.
  15. Mitsuyasu R, Lalezari J, Deeks S, et al. Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-Cells to Aviremic HIV-Infected Subjects with Suboptimal CD4 Counts. Abstract presented at: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2011; Chicago, IL. Abstract H1-375. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=d4df5ac5-0855-47ac-9c87-f2c16aaeb7a9&cKey=72e47ff3-2053-458c-8d9c-3d32c27184a9&mKey=%7b0C918954-D607-46A7-8073-44F4B537A439%7d. Last accessed on September 13, 2015.
  16. Zeidan J, Lee G, Fromentin R, et al. Adoptive Transfer of ZFN Mediated CCR5 Modified CD4 T-cells (SB-728-T) in HIV Subjects Leads to Long Term Engraftment of HIV Resistant T Memory Stem Cells and Decrease in Size of Latent Reservoir. Abstract presented at: American Society of Gene & Cell Therapy (ASGCT) 18th Annual Meeting; May 13-16, 2015; New Orleans, LA. Abstract C-7. Available at: http://www.abstracts2view.com/asgct/view.php?nu=ASGCT15L1_C-7. Last accessed on September 13, 2015.
  17. Sangamo Biosciences. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01543152. Last accessed on September 13, 2015.
  18. 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. 54th 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. Available at: http://www.natap.org/2014/ICAAC/ICAAC_36.htm. Last accessed on September 13, 2015.
  19. Blick G, Lalezari J, Hsu R, et al. Cytoxan Enhancement of SB-728-T Engraftment: A Strategy to Improve Anti-HIV Response. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 434. Available at: http://www.croiconference.org/sites/default/files/uploads/croi2015-program-abstracts.pdf. Last accessed on September 13, 2015.
  20. Sangamo BioSciences: 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. Available at: http://investor.sangamo.com/releasedetail.cfm?ReleaseID=898529. Last accessed on September 13, 2015.
  21. Ando D, Blick G, Lalezari J, et al. A Dose Escalation Study of Cyclophophamide (CTX) to Enhance SB-728-T Engraftment. Abstract presented at: American Society of Gene & Cell Therapy (ASGCT) 18th Annual Meeting; May 13-16, 2015; New Orleans, LA. Abstract 25. Available at: http://www.abstracts2view.com/asgct/view.php?nu=ASGCT15L1_25. Last accessed on September 13, 2015.
  22. Blick G, Lalezari J, Hsu R, et al. A Dose Escalation Study of Cyclophosphamide (CTX) to Enhance SB-728-T Engraftment. 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2015. Available at: http://www.natap.org/2015/CROI/croi_81.htm. Last accessed on September 13, 2015.
  23. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02388594. Last accessed on September 13, 2015.
  24. Sangamo BioSciences. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02225665. Last accessed on September 13, 2015.
 


Last Reviewed: September 13, 2015

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