SB-728 is a ZFN-based approach for modification of the gene encoding CCR5, the major co-receptor used by HIV to infect cells of the immune system. Our first application is an autologous ZFN-CCR5-modified T-cell product (SB-728-T) which we are evaluating in an ongoing Phase 2 trial in Human Immunodeficiency Virus (HIV)-infected subjects. We also have a preclinical stage program to develop an SB-728 hematopoietic  stem-cell (HSC) product and a research-stage program to develop SB-728 as an in vivo product.

SB-728 for HIV/AIDS

Market Opportunity

HIV infection results in the death of immune system cells, particularly CD4+ T-cells leading to AIDS, a condition in which the body’s immune system is depleted to such a degree that the patient is unable to fight off common infections. Ultimately, these patients succumb to opportunistic infections or cancers. According to UNAIDS/WHO, over 2.5 million people were newly infected with HIV in 2011 with an estimated 1.7 million people dying of AIDS in the same year. There are now over 34 million people living with HIV and AIDS worldwide. The CDC estimates that, in the United States alone, there were 1.2 million people living with HIV/AIDS, approximately 50,000 new infections and 21,000 deaths in 2009.

Current Treatments and Unmet Medical Need

Current standard of care for HIV infection relies on a maintenance strategy of daily antiretroviral drugs designed to reduce viral replication and keep the infection in check. There are approximately 30 antiretroviral drugs approved by the FDA and almost all are designed to inhibit some stage of the pathway of viral replication. As HIV reproduces, variants of the virus emerge, including some that are resistant to antiretroviral drugs. Therefore, people infected with HIV take a combination of antiretroviral drugs known as highly active antiretroviral therapy (HAART). Currently available drugs do not cure HIV infection or AIDS. They can suppress the virus, even to undetectable levels, but they cannot eliminate HIV from the body. Hence, people with HIV need to take antiretroviral drugs on a daily basis which can have significant undesirable side effects. There is no therapeutic approach available which protects CD4+ T-cells, reduces viral load and does not require continuous daily dosing.

Sangamo’s Therapeutic Approach

Our therapeutic approach aims to use our ZFN-mediated gene editing technology to replicate a naturally occurring human mutation which renders individuals largely resistant to infection with the most common strain of HIV. CCR5 is a co-receptor for HIV entry into T-cells and, if CCR5 is not expressed on their surface, HIV infects them with lower efficiency.

A population of these individuals that is immune to HIV infection, despite multiple exposures to the virus, has been identified and studied extensively. The majority of these individuals have a natural mutation, CCR5delta32, resulting in the expression of a shortened, or truncated, and non-functional CCR5 protein. This mutation appears to have no observable deleterious effect. In addition, a study published in Blood in December 2010 reported an effective cure when an AIDS patient with leukemia received a bone marrow transplant from a “matched” donor with this delta-32 CCR5 mutation. This approach transferred the hematopoietic stem cells (HSCs) residing in the bone marrow from the delta-32 donor, and provided a self-renewable and potentially lifelong source of HIV-resistant immune cells. After transplantation, the patient was able to discontinue all anti-HIV drug treatments (ART), CD4 counts increased, and viral load dropped to an undetectable level, demonstrating effective transplantation of protection from HIV infection. The subject remains off ART and is widely sonsidered to be cured of his HIV infection.

We are using our ZFN-mediated gene disruption technology to disrupt the CCR5 gene in cells of a patient’s immune system to make these cells permanently resistant to HIV infection. The aim is to provide a population of HIV-resistant cells that can fight HIV and opportunistic infections thereby  mimicking the characteristics of individuals that carry the natural mutation.

Clinical Status

We have an ongoing Phase 2 clinical trial to evaluate safety and tolerability of our ZFN-CCR5-gene modification approach in CD4+ T-cells in subjects that are HIV-infected. Several trials have been completed, including a Phase 1 trial single-dose, investigator-sponsored trial at the University of Pennsylvania. Data from this trial were published in a report in the New England Journal of Medicine in 2014 (N.Eng. J. Med. 2014: 370:897-906 “Gene Editing of CCR5 in Autologous CD4 T-cells of Persons Infected with HIV.”) In addition, we have completed and continue to follow subjects treated with SB-728-T in a Phase 1 clinical trial (SB-728-T-902) of SB-728-T in subjects known as “immunologic non-responders".  These  individuals constitute approximately 20% of the HIV infected  population and while they have well-controlled levels of virus on ART have suboptimal CD4+ T-cell counts. Both Phase 1 studies were carried out in HIV-infected individuals  on highly active antiretroviral therapy (ART) and were designed primarily to evaluate the safety and tolerability of this ZFP Therapeutic approach, however subjects’ CD4 T-cell counts, levels of CCR5-modified T-cells, viral load and levels  of viral reservoir, as measured by viral DNA in the peripheral blood were also monitored. We have presented positive preliminary data from both trials at several scientific meetings.  These data have provided valuable information for the design of additional studies.

We added a fifth cohort to our SB-728-902 study (SB-728-902-Cohort 5 – a Phase 2 study) which enrolled HIV-infected subjects who were heterozygous for the CCR5 delta-32 mutation (i.e. with one CCR5 gene that is naturally modified) and are currently on HAART.  Subjects received a single intravenous infusion of SB-728-T (5 to 30 billion modified cells) and two months after SB-728-T treatment,   undergo a 16 week TI during which time their anti-retroviral therapy is discontinued. HAART will be reinstituted in subjects whose CD4 T-cell counts drop to <350 cells/mm3 and/or whose HIV-RNA increases to >100,000 /mL for three consecutive weekly measurements. At the end of the TI, subjects with an undetectable viral load will remain off HAART until HIV RNA levels are detectable or their CD4 T-cell count drops below 350 cell/mm3 for three consecutive weekly measurements.

SB-728-1101 is a dose escalation Phase 1/2 Study which was designed primarily to evaluate the safety and tolerability of escalating doses of cyclophosphamide (Cytoxan®) administered one day prior to SB-728-T infusion. Cytoxan is a drug that is used to transiently reduce the numbers of T-cells in the body which then rapidly repopulate once the drug is discontinued. Such lymphodepletive treatment has been used to enhance engraftment of adoptively transferred T-cells in the treatment of cancer and as therapy for numerous autoimmune diseases. The drug has been previously used in HIV-infected individuals and studies demonstrate that, while the drug was transiently lymphodepleting, it did not significantly reduce total CD4 T-cell counts over the long term and was adequately tolerated.

In addition to safety, the study was designed to evaluate the effect of escalating doses of Cytoxan on SB-728-T engraftment, the effect of SB-728-T treatment on viral load following HAART interruption, the change in CD4+ T-cell counts in peripheral blood and the long-term persistence of SB-728-T.

A total of 18  HIV-infected subjects on HAART have being  enrolled into 5 dose-escalating cohorts (3-6 subjects/cohort), and  receive intravenous Cytoxan (200 mg, 500 mg/m2, 1000 mg/m2,1500 mg/m2 or 2000 mg/m2). Within each cohort, treatment was staggered so that each subsequent subject could not be infused with Cytoxan until at least 2 weeks after the preceding subject. One day after receiving Cytoxan, subjects were infused with SB-728-T (5 to 30 billion cells). Six weeks after SB-728-T infusion, subjects with CD4 cell counts ≥500 cells/mm3  underwent a 16 week TI during which time their anti-retroviral therapy was discontinued.  At the end of the TI, subjects with an undetectable viral load are allowed to  remain off HAART until HIV RNA levels are detectable or their CD4 T-cell count drops below 500 cells/ mm3 for three consecutive weekly measurements.  

We presented preliminary data from these trials in May 2013 and the full data set from all cohorts in September 2014 at the 54th  Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).  It was determined that the optimal dose of Cytoxan was 1000 mg/m2.

The Company has an ongoing Phase 2 clinical trial, SB-728-mR-1401 (1401), designed to provide further evidence of functional control of HIV in additional subjects. The protocol incorporates a number of  methods to increase the engraftment of CD4 T-cells that have undergone biallelic CCR5 gene modification, including certain criteria for subject selection, optimal Cytoxan preconditioning and a number of process improvements such as mRNA delivery of the ZFNs, which will allow the administration of multiple doses of the modified cells.  In addition to a further three subjects treated at the optimal dose of Cytoxan using adenoviral delivery of ZFNs, the Company expects to enroll all nine subjects into the 1401 study by the end of 2014.

SB-728 Programs in Preclinical Development and Research Stage Programs

We also have a preclinical stage program to investigate this ZFN approach in hematopoietic stem cells (HSCs).  With our collaborators at City of Hope and the University of Southern California, we have been granted a $14.5 million Disease Team Research Award  by the California Institute for Regenerative Medicine (CIRM) to fund this program. In May 2014, Sangamo was also granted  a $5.6 million Strategic Partnership Award. The four-year grant provides matching funds to support a clinical  trial in HIV-infected individuals at City of Hope. We expect to file an Investigational New Drug (IND) application and to open the study in 2014.