Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced that data from its programs to develop ZFN-based therapeutic approaches for the treatment of HIV/AIDS were discussed in four oral presentations at the 18th Conference on Retroviruses and Opportunistic Infections (CROI), held in Boston from February 27 to March 2, 2011.
"SB-728-T is a key addition to the toolbox of technologies required to move from the bone marrow transplant setting requiring a donor, to the use of the patient's own cells to replicate the 'functional cure' for HIV-infected patients in which one could create and maintain a reservoir of HIV-resistant immune cells," said Carl June, M.D., Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine and an invited speaker at the conference. "The combination of robust and reproducible manufacturing, engraftment, trafficking, persistence and selective expansion of ZFN-CCR5-modified cells set this product apart from all other HIV therapies tested to date, and is an important step to move from the allogeneic bone marrow transplant setting to the use of the patient's own cells. In particular, the data showing selective expansion and enrichment of SB-728-T in the gut mucosa establishes mechanistic proof of concept that ZFN-CCR5-modified T-cells can constitute a compartment of the immune system that is protected from HIV infection."
In a symposium held on March 2, 2011, Dr. June presented preliminary data from the ongoing investigator-sponsored Phase 1 trial at the University of Pennsylvania as well as data from Sangamo's Phase 1 dose-escalation trial SB-728-902. The presentation included new data from subjects on highly active antiretroviral therapy (HAART) who underwent a treatment interruption (TI) for a specified period after treatment with SB-728-T as well as subjects on HAART with undetectable virus but suboptimal CD4+ T-cell counts (200-500 cells/ mm3).
Clinical Trial Data Summary
The data demonstrate that SB-728-T is well-tolerated with only mild, reversible symptoms typical of infusion reactions. ZFN-CCR5-modified cells exhibited durable engraftment and persistence in the peripheral blood for over a year and behaved like normal, unmodified cells in their ability to traffic to the gut mucosa, an important reservoir of active HIV infection. Demonstration of up to a 45-fold selective expansion of ZFN-CCR5-modified T-cells in this tissue, which represents levels not previously observed in adoptive T-cell approaches, also suggests that the modified cells were resistant to HIV and establish the mechanistic proof of concept for this therapeutic approach. SB-728-T treatment was also demonstrated to improve the overall CD4 T-cell count in all subjects and the CD4:CD8 ratio, a measure of immunologic health, in multiple subjects. In addition, two subjects on a brief 12 week treatment interruption (TI) after SB-728-T treatment showed interesting patterns of HIV RNA appearance and decrease prior to re-institution of HAART. Finally, consistent manufacturing at clinical scale from different manufacturing centers demonstrate that the ZFN-CCR5-modified T-cell process is robust and reproducible.
"Data presented this week at CROI 2011 establish the mechanistic 'proof of concept' of our ZFN-CCR5-modification in autologous T-cells and support broad development of this gene modification approach to HIV therapy," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "Based on these very encouraging findings, we have recently extended our clinical studies to HIV-infected subjects who are not on HAART, or for whom HAART is no longer effective. This will enable us to comprehensively evaluate SB-728-T across the full spectrum of disease. We look forward to presenting data from all four patient segments later this year."
Abstract #165 Disruption of CCR5 in Zinc Finger Nuclease-treated CD4 T Cells: Phase I Trials (Presenter C. June)
Abstract #46 Successful and Persistent Engraftment of ZFN-M-R5-D Autologous CD4 T Cells (SB-728-T) in Aviremic HIV-infected Subjects on HAART (Presenter J. Lalezari)
Data Presented on Preclinical ZFN-Gene Modification Studies
A third presentation given by invited speaker, Paula Cannon, Ph.D., Associate Professor of Molecular Microbiology & Immunology at the Keck School of Medicine of the University of Southern California (USC), described data from Sangamo's preclinical program to develop CCR-specific ZFNs to modify the gene in hematopoietic stem cells (HSCs) to provide protection of the entire immune system from HIV infection. The work is part of a California Institute for Regenerative Medicine (CIRM) Disease Team Research Award which is funding IND-enabling studies of this approach. Dr. Cannon provided an update on progress in this program, demonstrating that the CCR5 gene of adult HSCs could be efficiently modified with ZFNs with high cell viability. In addition, the ZFN-CCR5-modified HSCs stably engraft in mouse models and retained the ability to develop into the multiple lineages of the immune system.
Abstract #164 CCR5 Knock-out in Hematopoietic Stem Cells (Presenter: P. Cannon)
Data were also presented from Sangamo's ZFN gene-modification program to generate CD4 T-cells that are resistant to so-called "X4-tropic" strains of HIV, strains of HIV that use the CXCR4 co-receptor to infect cells and are characteristic of late-stage HIV infections. This fourth presentation was given by Sangamo's collaborators in the laboratory of Robert Doms, M.D., Ph.D., Chair, Department of Microbiology, the University of Pennsylvania School of Medicine. Disruption of CXCR4 in CD4+ T cells avoids immune system toxicity associated with systemic disruption of the gene. The data demonstrated that ZFN modification of the CXCR4 gene in T-cells results in robust protection of CD4+ T cells from X4-tropic HIV challenge in vitro and confers protection from X4-tropic HIV in humanized mice. Future studies aim to combine CCR5- and CXCR4-ZFNs to totally eliminate HIV co-receptor expression to create completely HIV-resistant CD4+T cells.
Abstract # 47 Creating an HIV-resistant Immune System: Using CXCR4 ZFN to Edit the Human Genome (Presenter C. Wilen)
"Our highly specific gene-modification technology provides a novel platform for the development of transformational ZFP Therapeutics®," said Edward Lanphier, Sangamo's president and CEO. "As these presentations have demonstrated, Sangamo is rapidly advancing a broad pipeline of ZFN-based approaches to HIV/AIDS designed to address the spectrum of the disease. The ground-breaking clinical and preclinical data that we and our collaborators are generating validate our ZFN technology platform for development of novel therapeutic strategies for unmet medical needs, such as HIV and monogenic diseases. The processes and pathways that we have demonstrated in these programs are directly relevant to development of our future ZFP Therapeutics."
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