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FDA-approved

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)

What is an investigational drug?

An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.

What is SB-728-T?

SB-728-T is an investigational gene therapy product. Gene therapy is an experimental technique that uses genes (short sections of genetic material) to treat or prevent disease. SB-728-T is a gene therapy product that involves changing a gene in immune cells, primarily CD4 T cells. (CD4 T cells are a type of immune cell that HIV attacks and destroys.)3,5

One way that HIV enters and infects immune cells, such as CD4 T cells, is by attaching to a specific protein—called a CCR5 receptor—on the immune cell surface. In some people, the CCR5 receptor is naturally genetically modified. People with this gene modification are more resistant to infection with the most common strain of HIV. SB-728-T treatment changes the gene responsible for the CCR5 receptor and makes the CCR5 receptor non-functional. By modifying the CCR5 gene, SB-728-T potentially eliminates one way for the most common type of HIV to attach to and infect immune cells.5,6

SB-728-T is being studied for its ability to restore immune function and as a possible strategy to cure HIV.3,5,7-10

How is SB-728-T made?

SB-728-T is made by first collecting immune cells, such as CD4 T cells, from an HIV-infected person. The cells are sent to a laboratory where they are genetically modified to make the CCR5 receptors non-functional. The cells are then stimulated to produce many more immune cells with non-functional CCR5 receptors. Finally, the immune cells are infused back into the person. This treatment may provide someone with a population of immune cells that are permanently resistant to HIV strains that use CCR5 as an entryway. The modified immune cells may also reproduce additional HIV-resistant immune cells in the body.3,5,6

How are clinical trials of investigational drugs conducted?

clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.11

  • Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
  • Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
  • Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.11

In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.11

In what phase of testing is SB-728-T?

SB-728-T is being studied in Phase I/II clinical trials.2

What are some studies on SB-728-T?

Study Name: NCT01044654; SB-728-0902
Phase: I/II
Location: United States
Participants: Several groups of HIV-infected participants on antiretroviral therapy (ART) were studied:

  • Groups 1 to 3: Participants had an undetectable viral load (the amount of HIV in the body) and CD4 counts between 200 to 500 cells/mm3. (A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function. The CD4 count of a healthy person ranges from 500 to 1,600 cells/mm3.) Because participants had CD4 counts below desirable levels despite an undetectable viral load while on ART, participants were considered “immunological non-responders.”
  • Group 4: ClinicalTrials.gov (NCT01044654) describes a fourth group of participants. However, this group is not mentioned in other sources.
  • Group 5: Participants had undetectable viral load levels and normal CD4 counts above 500 cells/mm3. All participants in Group 5 were CCR5-Δ32 heterozygous. This means that one copy of their CCR5 gene was already naturally mutated, while the other copy of their CCR5 gene was not mutated.
Purpose: The purpose of this study was to look at the safety and effects of SB-728-T treatment in HIV-infected individuals.
Study Design
  • Groups 1 to 3: All participants in Groups 1 to 3 were given a single intravenous (IV) infusion of SB-728-T to modify both CCR5 genes in their CD4 T cells. (An IV infusion is given directly into a vein, usually over a period of time.) The groups received different amounts of SB-728-T. Group 1 participants received the least amount of SB-728-T, and Group 3 participants received the greatest amount of SB-728-T. Participants continued to take ART throughout the study.
  • Group 5: Participants in Group 5 received a single IV infusion of SB-728-T to modify the second CCR5 gene in their CD4 T cells. Two months later, participants underwent a structured treatment interruption of ART. (A structured treatment interruption is a planned break from treatment. Structured interruption of ART is not recommended outside of clinical trials.) The structured interruption of ART was scheduled to last 16 weeks, but the exact length of the interruption depended on each participant’s viral load level and/or CD4 cell count.
Results:
  • Data from Groups 1 to 3 showed that SB—728-T treatment provided long-term increases in CD4 counts. The uninfected CCR5-modified immune cells multiplied in number and persisted in the body for 3 years after SB-728-T infusion.
  • Long-term improvement in CD4 counts appeared to be associated with reductions in participants’ latent HIV reservoirs. (Latent HIV reservoirs are resting CD4 cells or other cells that are infected with HIV but not actively producing HIV. Because the HIV “hidden” in the reservoirs is inactive, ART has no effect on it. Reducing and eliminating latent HIV reservoirs is a main goal in HIV cure research.)
  • Investigators also found that certain signs of immune system activation may determine how a person responds to SB-728-T. 
  • Data from Group 5 showed that with SB-728-T treatment, some CCR5-Δ32 heterozygous HIV-infected participants could reduce and control their viral load at or near undetectable levels during a structured treatment interruption of ART. Some participants, however, did not respond to SB-728-T treatment and stopped their structured treatment interruption early.
  • Investigators also reported that across all SB-728-T studies done so far, there have been three CCR5-Δ32 heterozygous participants who were able to maintain viral load control at either undetectable levels or less than 1000 copies/mL during a treatment interruption from ART. One of these three participants, who is enrolled in SB-728-0902 Cohort 5, has maintained viral load control at less than 500 copies/mL for more than 1 year without ART.5,7,12-16

Study Name: NCT01543152; SB-728-1101
Phase: I/II
Location: United States and Puerto Rico
Participants: HIV-infected adults on ART for more than 6 months. All participants had undetectable viral load levels for at least 3 months and a CD4 count of at least 500 cells/mm3.
Purpose: The purpose of this study was to look at whether giving HIV-infected participants IV cyclophosphamide (an FDA-approved drug for treating cancer) before participants received SB-728-T could help the CCR5-modified cells multiply and produce new cells in the body. Investigators also looked at how cyclophosphamide given before SB-728-T affected viral load levels during a structured treatment interruption of ART.
Study Design: Five groups of participants were studied, with each group receiving a different dose of IV cyclophosphamide before SB-728-T treatment.
  • Group 1: Participants were given100 mg/m2 of IV cyclophosphamide, followed by an infusion of SB-728-T.
  • Group 2: Participants were given 500 mg/m2 of IV cyclophosphamide, followed by an infusion of SB-728-T.
  • Group 3: Participants were given 1g/m2 of IV cyclophosphamide, followed by an infusion of SB-728-T. (At the end of the SB-728-1101 study, three participants in Group 3 received a new SB-728-T product that contained both CCR5-modified CD4 T cells and CD8 T cells.)
  • Group 4: Participants were given 2 g/m2 of IV cyclophosphamide, followed by an infusion of SB-728-T.
  • Group 5: Participants were given 1.5 g/m2 of IV cyclophosphamide, followed by an infusion of SB-728-T.
Six weeks after their SB-728-T infusion, all participants underwent a structured treatment interruption of ART that was scheduled to last 16 weeks.
Results:
  • Cyclophosphamide given at doses up to 1g/m2 helped the infused CCR5-modified CD4 T cells to start producing new cells in the body. Cyclophosphamide also appeared to help increase participants’ CD4 counts in each of the dosing groups up to the 1g/m2 group.
  • In some of the participants, viral load was reduced significantly and remained controlled at a lower level during a treatment interruption of ART. The largest reductions in viral load during the treatment interruption occurred in one participant in the cyclophosphamide 1 g/m2 dose group and in one participant in the cyclophosphamide 1.5 g/m2 dose group.
  • Data from Group 3 participants who received cyclophosphamide followed by a mixed CD4/CD8 SB-728-T cell product indicated that adding the CCR5-modified CD8 T cells can help with viral load control during treatment interruption of ART. At 7 days after the infusion, increases in participants’ CD8 counts were more substantial than the increases in their CD4 counts.
  • In terms of cyclophosphamide safety, some participants in Group 2 experienced nausea and vomiting that was moderate in severity. Because of this, other participants who were later enrolled into Group 2 were given medicines to prevent nausea and vomiting. Some participants in Groups 3 and 4 developed severe neutropenia. (Neutropenia is a lower-than-normal number of neutrophils, a type of white blood cell).8,15,17-20

Two other studies will continue looking at the safety and antiviral effects of SB-728-T in HIV-infected participants on ART. In these studies, the SB-728-T product will be made with an improved technology over what was previously used. (The CCR5-modified T cell product in these studies is also known as SB-728mR-T.) The first, a Phase I study (NCT02388594), will be looking at SB-728mR-T that is given with and without cyclophosphamide beforehand. The second, a Phase I/II study (NCT02225665), is looking at the use of cyclophosphamide followed by repeat infusions of SB-728mR-T in HIV-infected participants.2,21-23

Additional Phase I and Phase I/II studies of SB-728-T have been completed.24,25

What side effects might SB-728-T cause?

In the SB-728-0902 study (NCT01044654) discussed under the previous question, SB-728-T was associated with some mild, reversible, infusion-related side effects. Mild infusion reactions related to SB-728-T, such as low grade fever and chills, were also reported in the SB-728-1101 study (NCT01543152). In addition, a garlic-like odor has been associated with SB-728-T infusions.26,27

In a Phase I study, one serious side effect related to SB-728-T infusion was reported.24 

Because SB-728-T is still being studied, information on possible side effects of the drug is not complete. As testing of SB-728-T continues, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying SB-728-T?

More information about SB-728-T-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

I am interested in participating in a clinical trial of SB-728-T. How can I find more information about participating in a clinical trial?

Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.11

Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

 

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. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01044654. Last accessed on September 13, 2015.
  6. National Institute of Allergy and Infectious Diseases (NIAID): News Release, dated March 5, 2014. Genetic Modification of Cells Proves Generally Safe as HIV Treatment Strategy. Available at: http://www.niaid.nih.gov/news/newsreleases/2014/Pages/CCR5mutation.aspx. Last accessed on September 13, 2015.
  7. 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.
  8. 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.
  9. 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 9, 2015.
  10. 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.
  11. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on September 13, 2015.
  12. 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.
  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). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 10-13, 2013; Denver CO. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2013. Available at: http://www.natap.org/2013/ICAAC/ICAAC_57.htm. Last accessed on September 13, 2015.
  14. Sangamo BioSciences: Press Release, dated November 4, 2013. Sangamo BioSciences Presents Clinical Data From SB-728-T HIV Study Demonstrating Long-Term Immune Reconstitution and Reduction in the HIV DNA Reservoir In Subjects with Long-Term Infection. Available at: http://investor.sangamo.com/releasedetail.cfm?ReleaseID=803951. Last accessed on September 13, 2015.
  15. Ando D, Lalezari J, Blick G, et al. HIV Protected AutologousZinc 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.
  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. 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.
  18. 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.
  19. 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.
  20. Sangamo BioSciences: Press Release, dated May 14, 2015. Sangamo BioSciences Provides Clinical Update On SB-728-T Program and Developments In Other ZFP Therapeutic Programs at American Society of Gene and Cell Therapy Annual Meeting. Available at: http://investor.sangamo.com/releasedetail.cfm?releaseid=913218. Last accessed on September 13, 2015.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01252641. Last accessed on September 13, 2015.
  26. 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.
  27. 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; 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.
 


Last Reviewed: September 13, 2015

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