SB-728

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

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 2.7 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.

Clinical Status

We have an ongoing Phase 1/2 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 2011 at the Conference for Retroviral and Opportunistic Infections (CROI) and at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), in September 2011.  These data have provided valuable information for the design of future studies.

A Phase 1/2 study (SB-728-T-1002) is 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-901 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.