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Investigational

SB-728-T  Audio icon

Other Names: CCR5-specific zinc finger protein nuclease
Drug Class: Gene Therapy Products
Company: Sangamo BioSciences
Phase of Development: Phase I/II
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Viruses article3)
Patent Version Content

Pharmacology


Mechanism of Action: Gene therapy (zinc finger nuclease [ZFN]-mediated CCR5 gene modified cells). SB-728-T is a product generated by using ZFNs 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.3-6 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.7,8

: 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.9

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


Dosing in Clinical Trials


Phase I/II (HIV-infected adults receiving antiretroviral therapy [ART])

SB-728-0902: Study to evaluate the safety and effect of SB-728-T in HIV-infected individuals.

  • Cohorts 1 to 3 - Participants on long-term ART and exhibiting suboptimal CD4 T-cell levels and undetectable viral loads: three 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 4 - Participants on failing ART and with CD4 T-cell count greater than 350 cells/mm3: single IV infusion of SB-728-T (5 to 30 billion ZFN-modified CD4 T cells).
  • Cohort 5 - Participants receiving ART and with CD4 T-cell count greater than 500 cells/mm3 and heterozygous for the CCR5 delta-32 mutation: 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.7,8,10-12

 

Phase I/II (HIV-infected adults receiving ART; undetectable viral loads for at least 3 months and CD4 T-cell count of at least 500 cells/mm3


SB-728-1101: Dose escalation study to evaluate the safety and effect on viral load of cyclophosphamide used to enhance SB-728-T engraftment in HIV-infected individuals on ART. 

  • Three escalating-dose cohorts (three participants per cohort) receiving IV cyclophosphamide (200 mg for cohort 1; 500 mg/m2 for cohort 2; 1 g/m2 for cohort 3) 1 to 3 days prior to SB-728-T infusion (5 to 30 billion ZFN-modified CD4 T cells). Six weeks following SB-728-T infusion, participants having a CD4 count of 500 cells/mm3 or greater underwent a structured interruption of ART.4,13,14 

 

Phase I/II (HIV-infected adults who have not received ART within the past 3 months; viral load greater than 1000 copies/mL and CD4 cell count greater than 500 cells/mm3)

SB-728-1002: Study to evaluate the safety and effect of SB-728-T in HIV-infected individuals. 

  • Single IV infusion of SB-728-T (5 to 30 billion ZFN-modified CD4 T cells).15

 

An additional Phase I study of SB-728-T has been completed.9

 


Adverse Events


Infusion-related adverse events have been associated with SB-728-T treatment. In the SB-728-0902 study, there were reports of mild, reversible, infusion-related adverse events.12 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.9


Drug Interactions


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



References


1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on May 24, 2014.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on May 24, 2014.

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. Last accessed on May 24, 2014.

4. 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. Last accessed on May 24, 2014.

5. 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. Last accessed on May 24, 2014.

6. 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. Last accessed on May 24, 2014.

7. 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. NLM Identifier: NCT01044654. Last accessed on May 24, 2014.

8. 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. Last accessed on May 24, 2014.

9. 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. Last accessed on May 24, 2014.

10. Sangamo BioSciences website. Product Pipeline: SB-728. Last accessed on May 24, 2014.

11. 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. Last accessed on May 24, 2014.

12. 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. Last accessed on May 24, 2014.

13. 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. Last accessed on May 24, 2014.

14. Sangamo BioSciences: Press Release, dated March 6, 2014. Sangamo Presents Clinical Data At CROI 2014 Demonstrating Enhancement Of SB-728-T Engraftment - Continued Control Of HIV Viral Load For 31 Weeks Without ART In SB-728-T Treated Subject. Last accessed on May 24, 2014.

15. Sangamo Biosciences. 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. Last accessed on May 24, 2014.


Last Reviewed: May 24, 2014

Last Updated: May 24, 2014


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