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, two Phase 1/2 and two Phase 1 trials in subjects with Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS). 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
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 2.7 million people were newly infected with HIV in 2007 with an estimated 2.0 million people dying of AIDS in the same year. There are now over 33 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 54,000 new infections and 23,000 deaths in 2007.
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, CD4 counts increased, and viral load dropped to an undetectable level, demonstrating effective transplantation of protection from HIV infection. In addition, individuals that have only one of the two copies of their CCR5 gene mutated are known as “elite controllers" and, while they may become infected with the virus, they are able to keep their HIV infection in check without drugs.
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.
We have ongoing Phase 1/2 trials and two Phase 1 clinical trials to evaluate safety and tolerability of our ZFN-CCR5-gene modification approach in CD4+ T-cells in subjects that are HIV-infected. One Phase 1 trial is single-dose investigator-sponsored trial at the University of Pennsylvania. The second is a dose-escalation Phase 1 clinical trial (SB-728-T-902) of SB-728-T in subjects known as “immunologic non-responders”, subjects who are currently on highly active antiretroviral therapy (HAART) and therefore have undetectable levels of virus but suboptimal CD4+ T-cell counts. Both Phase 1 studies are in HIV-infected individuals who are on highly active antiretroviral therapy (HAART) and are 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 and viral load will also be monitored. We presented positive preliminary data from both trials in the first quarter of 2012 at the Conference for Retroviral and Opportunistic Infections (CROI) and at the 51st and 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), in September 2011 and 2012, respectively. These data have provided valuable information for the design of future studies.
We have added a fifth cohort to our SB-728-902 study (SB-728-902-Cohort 5 – a Phase 2 Study) which is enrolling HIV-infected subjects who are heterozygous for the CCR5 delta-32 mutation (i.e. with one CCR5 gene that is naturally modified) and are currently on HAART. Subjects receive 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 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 is evaluating 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.
At least 9 HIV-infected subjects on HAART are being enrolled into 3 dose-escalating cohorts (3 subjects/cohort), and receive intravenous Cytoxan (200 mg, 500 mg or 1000 mg). Within each cohort, treatment is staggered so that each subsequent subject cannot be infused with Cytoxan until at least 2 weeks after the preceding subject. One day after receiving Cytoxan, subjects are 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 undergo a 16 week TI during which time their anti-retroviral therapy is discontinued. At the end of the TI, subjects with an undetectable viral load can 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 expect to present preliminary data from these trials in the first half of 2013 and to have the full data set by the end of 2013.
A Phase 1/2 study (SB-728-T-1002) is also ongoing to evaluate SB-728-T in HIV-infected individuals who are treatment naive and not yet on HAART. We also expanded our SB-728-T-902 study to include an additional cohort of subjects that are failing HAART. With the expansion of this clinical program we are evaluating SB-728-T in a broad spectrum of HIV-infection from individuals who are recently infected and not on HAART to those who are failing HAART.
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 addition, we have a research stage program to develop our ZFN approach as an in-vivo application for which we have received a Grand Challenges Explorations grant of $100,000 from the Bill and Melinda Gates Foundation.