Drugs

SB-728-T

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) Organization: Sangamo Therapeutics Phase of Development: I/II

(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group 2017 Pipeline Report,2 Viruses article,3 and Sangamo Therapeutics website4)

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.3-8 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 is also being studied. The mixed CD4/CD8 SB-728-T product allows for a simpler manufacturing process and potentially greater antiviral effect.11

Half-life (T½): In a study (NCT00842634) of 12 participants with HIV who received a single dose of SB-728-T, modified cells had an estimated mean half-life of 48 weeks.12


Clinical Trials


SB-728-T: autologous CCR5-modified T cell product generated via adenoviral delivery of ZFNs
Study Identifiers: SB-728-0902; NCT01044654
Sponsor: Sangamo Therapeutics
Phase: I
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and effectiveness of SB-728-T in individuals with HIV.
Study Population: Participants were treatment-experienced adults with HIV.
  • Cohorts 1-3: Participants were on long-term ART and had undetectable viral load levels and suboptimal CD4 counts between 200 and 500 cells/mm3.
  • Cohort 5: Participants had undetectable viral load levels while on ART for at least 1 year. Participants were on a stable ART regimen at study entry, had HIV RNA <50 copies/mL within 60 days of study entry, and had CD4 counts >500 cells/mm3. All participants in cohort 5 were heterozygous for the CCR5-Δ32 mutation.
Dosing:
  • Cohorts 1-3: Cohorts 1-3 were escalating-dose cohorts, with 3 participants per cohort. Participants received a single intravenous (IV) infusion of SB-728-T (10, 20, and 30 billion ZFN-modified CD4 cells for cohorts 1, 2, and 3, respectively).
  • Cohort 5: Participants received a single IV infusion of SB-728-T (5 to 30 billion ZFN-modified CD4 cells), followed by a treatment interruption of ART for 16 weeks. ART was reinstituted depending on participants’ CD4 counts and viral load levels during and after the treatment interruption of ART.9,10,13-15
Selected Study Results:


Study Identifiers: SB-728-1101; NCT01543152
Sponsor: Sangamo Therapeutics
Phase: I/II
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label dose escalation study is to evaluate the effect on viral load and safety of cyclophosphamide preconditioning when used to enhance SB-728-T engraftment in individuals with HIV.
Study Population: Participants are adults with HIV who have been on ART for at least 6 months and have had undetectable viral load levels for the past 3 months. At study entry, participants must be on a stable ART regimen, have undetectable viral load levels, and have CD4 counts ≥500 cells/mm3.
Dosing:
  • Cohort 1: IV cyclophosphamide 100 mg/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 cells)
  • Cohort 2: IV cyclophosphamide 500 mg/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 cells)
  • Cohort 3: IV cyclophosphamide 1 g/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 cells)
  • Cohort 3*: IV cyclophosphamide 1 g/m2, followed by a single infusion of an SB-728-T product containing both CD4 cells and CD8 cells
  • Cohort 4: IV cyclophosphamide 2 g/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 cells)
  • Cohort 5: IV cyclophosphamide 1.5 g/m2, followed by a single SB-728-T infusion (5 to 30 billion ZFN-modified CD4 cells)
All participants will undergo a 16-week treatment interruption of ART 6 weeks after SB-728-T infusion. After Month 12 of the study, participants will continue to be followed long-term.16-23
Selected Study Results:


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: I/II
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and effectiveness of repeat doses of SB-728mR-T following cyclophosphamide preconditioning in individuals with HIV.
Study Population: Participants are adults with HIV who are on ART and who initiated ART ≤1 year of HIV diagnosis or suspected infection. Participants have had undetectable viral loads for at least the prior 2 months before screening and have CD4 counts ≥500 cells/mm3 at study entry.
Dosing:
  • Cohort 1: IV cyclophosphamide 1 g/m2, followed by SB-728mR-T infusions given as 2 equal doses 14 days apart (total of up to 40 billion ZFN-modified CD4 cells)
  • Cohort 2: IV cyclophosphamide 1 g/m2, followed by SB-728mR-T infusions given as 3 equal doses 14 days apart (total of up to 40 billion ZFN-modified CD4 cells)
Four weeks after the last SB-728mR-T infusion, all participants with CD4 counts of at least 500 cells/mm3 will undergo a 16-week treatment interruption of ART.23,24
Selected Study Results:


Other studies evaluating SB-728-T gene therapy have been completed or are currently ongoing, including an ongoing Phase I study (NCT02388594) investigating a single infusion of SB-728mR-T, with and without cyclophosphamide preconditioning, in participants with HIV who are receiving ART.25


Adverse Events


Infusion-related adverse events (AEs) have been associated with SB-728-T treatment. In the SB-728-0902 study (NCT01044654), there were reports of mild, reversible, infusion-related AEs.9,14 In a Phase I study (NCT00842634) of 12 participants receiving a single dose of SB-728-T, there was a report of 1 serious adverse event (SAE) that was attributed to a drug-related transfusion reaction.12

In the SB-728-1101 study (NCT01543152), 2 out of 3 initial participants in cohort 2 (cyclophosphamide 500 mg/m2) experienced Grade 2 nausea and vomiting. An additional 3 participants enrolled into cohort 2 were therefore prophylactically treated with antiemetics. In cohort 4 (cyclophosphamide 2 g/m2), Grade 4 neutropenia occurred in 1 participant, and Grade 3 neutropenia occurred in 2 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.16,21


Drug Interactions


SB-728-T drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/S900006290. Last accessed on September 7, 2017.
  2. 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 September 7, 2017.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856413/. Last accessed on September 7, 2017.
  4. Sangamo Therapeutics website. HIV. Available at: http://www.sangamo.com/product-pipeline/hiv. Last accessed on September 7, 2017.
  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. Available at: http://www.croiconference.org/sessions/cyclophosphamide-enhances-sb-728-t-engraftment-levels-associated-hiv-rna-control. Last accessed on September 7, 2017.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422503/. Last accessed on September 7, 2017.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609630/. Last accessed on September 7, 2017.
  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. Available at: http://investor.sangamo.com/press-releases/detail/259/sangamo-biosciences-zfp-therapeutic-program-in-hivaids. Last accessed on September 7, 2017.
  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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01044654. NLM Identifier: NCT01044654. Last accessed on September 7, 2017.
  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 7, 2017.
  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. Available at: http://investor.sangamo.com/press-releases/detail/272/sangamo-biosciences-presents-new-clinical-data-at-croi-2015. Last accessed on September 7, 2017.
  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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084652/. Last accessed on September 7, 2017.
  13. 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). 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 7, 2017.
  14. 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: 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 7, 2017.
  15. 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. Mol Ther. 2015 May; 23(Suppl 1): S102. Available at: http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)33865-5. Last accessed on September 7, 2017.
  16. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01543152. Last accessed on September 7, 2017.
  17. 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. Available at: http://www.natap.org/2014/ICAAC/ICAAC_36.htm. Last accessed on September 7, 2017.
  18. 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: Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 434. Available at: http://www.croiconference.org/sessions/cytoxan-enhancement-sb-728-t-engraftment-strategy-improve-anti-hiv-response. Last accessed on September 7, 2017.
  19. 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. Available at: http://investor.sangamo.com/press-releases/detail/272/sangamo-biosciences-presents-new-clinical-data-at-croi-2015. Last accessed on September 7, 2017.
  20. Ando D, Blick G, Lalezari J, et al. A dose escalation study of cyclophophamide (CTX) to enhance SB-728-T engraftment. Mol Ther. 2015 May; 23(Suppl 1): S11. Available at: http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)33629-2. Last accessed on September 7, 2017.
  21. Blick G, Lalezari J, Hsu R, et al. A Dose Escalation Study of Cyclophosphamide (CTX) to Enhance SB-728-T Engraftment. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 434. Available at: http://www.croiconference.org/sites/default/files/posters-2015/434.pdf. Last accessed on September 7, 2017.
  22. Zeidan J, Lee GK, Benne C, et al. T-Cell Homeostasis and CD8 Responses Predict Viral Control Post SB-728-T Treatment. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Abstract 358LB. Available at: http://www.croiconference.org/sessions/t-cell-homeostasis-and-cd8-responses-predict-viral-control-post-sb-728-t-treatment. Last accessed on September 7, 2017.
  23. Sangamo Therapeutics: News Release, dated December 11, 2015. Sangamo BioSciences Presents Phase 2 Clinical Data From Two SB-728-T HIV Studies. Available at: http://investor.sangamo.com/press-releases/detail/302/sangamo-biosciences-presents-phase-2-clinical-data-from-two. Last accessed on September 7, 2017.
  24. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02225665. Last accessed on September 7, 2017.
  25. 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 7, 2017.


Last Reviewed: September 7, 2017