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Author Topic: Sangamo reveals successful ZFP results @ ICAAC 2012  (Read 3048 times)

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Online Common_ground

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Sangamo reveals successful ZFP results @ ICAAC 2012
« on: September 10, 2012, 01:56:52 PM »
September 10, 2012

Sangamo BioSciences Announces Presentation of Clinical Data from ZFP Therapeutic® for HIV/AIDS at ICAAC 2012

Findings Demonstrate Immune Reconstitution and Potential Success of "Functional Cure" in HIV-Infected Individuals

RICHMOND, Calif., Sept. 10, 2012 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced that data from its Phase 1 clinical programs to develop SB-728-T, a novel therapeutic approach designed to generate a "functional cure" for  HIV/AIDS, were presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The meeting is being held in San Francisco from September 9-12, 2012.

"The immunologic data presented at ICAAC have predictive implications for the success of this exciting new therapeutic approach to HIV and the realization of a 'functional cure' for the disease," commented Rafick-Pierre Sékaly,  Ph.D., Co-Director & Chief Scientific Officer, the Vaccine & Gene Therapy Institute of Florida (VGTI Florida), whose laboratory carried out the analysis.  "SB-728-T treatment results in an unprecedented and durable increase in CD4+ cells.  Importantly, our analysis shows that this is primarily due to the expansion of CD4+ T-cell types that are vital for the successful reconstitution of the immune system in HIV-infected individuals - the central and transitional memory cells."

"These data are very important because CD4 T-cells, especially memory T-cells, are precisely the cell type that we would want to protect and expand to enable HIV-infected individuals to control infections, and HIV, without antiretroviral drugs," added Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "Our aim is to provide a protected reservoir of immune memory cells to replenish the cells killed by HIV and to generate an effective immune response against the virus and opportunistic infections. Central and transitional memory T-cells remember previously encountered foreign invaders, such as viruses or bacteria.  These cells can survive in the body for the individual's lifetime, and when they re-encounter the same antigen they reactivate, producing a faster and stronger immune response than the previous encounter. SB-728-T seems to both expand the total memory pool, and by CCR5 modification, protect a proportion of that pool from HIV entry, suggesting that SB-728 treatment has the potential to reconstitute and protect an effective and durable immune system in HIV-infected individuals."

SB-728-T is generated by ZFN-mediated modification of the gene encoding the CCR5 receptor in a patient's own T-cells, disrupting the expression of this key co-receptor for HIV entry and rendering the modified cells resistant to HIV infection.

In an oral presentation made on Monday, September 10th, 2012 at ICAAC, data were presented from all dosing cohorts of Sangamo's Phase 1 dose-escalation study (SB-728-902) in subjects on highly active antiretroviral therapy (HAART). The data demonstrate that SB-728-T infusion in HIV-infected subjects is well-tolerated, and results in significant and sustained increases in CD4+ T-cells above baseline throughout the year-long period reported in the study. Statistically significant improvement in CD4 counts were observed even at 12 months post infusion (p < 0.038). In particular, CD4 counts improved to greater than 500 cells/mm3 in five of nine subjects in the study at one year post-treatment, which is the usual T-cell count threshold for initiation of HAART in HIV-infected subjects.

Analysis of the specific types of CD4 T-cells that comprise the initial increase in CD4+ T-cells post-infusion revealed that they were primarily transitional memory T-cells (TTM). The frequency of TTM expressing CD25 (a marker that identifies activated T-cells) within the SB-728-T product correlated with the peak CD4 count post-infusion (r=0.733, p=0.0172). This suggests that replication of activated TTM SB-728-T cells post-infusion accounts for the initial peak improvement in CD4+ T-cells. As the infused cells consist of only 1-10% of total memory cells at six months post-treatment, the prolonged increase in absolute numbers of CD4+ T-cells may be accounted for by the enhanced survival and differentiation of host central memory T-cells (TCM). Specifically, while the magnitude of the increase in  TTM positively correlated with the peak of CD4+ T-cells in the first weeks post-infusion (r= 0.9, p=0.083), the increase in TCM correlated with the maintenance of high CD4+ T cell counts at later time points (r= 0.9, p=0.083).  Proliferation of the SB-728-T product post-infusion was sustained over the year-long period reported in the study with median modified circulating cell numbers measured to be 2.04-fold relative to input at 7 days, 0.96-fold at 6 months and 1.15-fold at 1 year post-infusion.

These preliminary data confirm the prolonged engraftment of SB-728-T, and suggest that SB-728-T has the attributes to provide sustained improvement in the CD4 memory compartment and the potential to reconstitute the immune system in immune non-responders. 

"Our Phase 1 trials continue to provide valuable insight into the durability and unprecedented effects of SB-728-T treatment on immune system health in HIV-infected individuals," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development.  "In addition we are making good progress in two Phase 2 clinical trials designed to maximize the engraftment of SB-728-T.  We expect to present preliminary data in the first half of 2013 and a full data set in the second half of next year. The ground-breaking clinical data that we and our collaborators are generating continues to validate this treatment as a promising approach to provide a 'functional cure' for HIV/AIDS."

ICAAC Presentations

Abst.#H533: "Preferential expansion of transitional (TTM) and Central Memory(TCM) CD4 T-cells following adoptive transfer of ZFN CCR5 Modified Autologous CD4 T-cells."
Monday, September 10, 2012: Oral session 073 (H) New Antiretroviral Therapy: Bench to Bedside.

Abst.#H-1581: "Digital droplet PCR (DD) qPCR allows quantiation of HIV proviral DNA in aviremic HIV+ subjects on HAART treated with ZFN CCR5 modified autologous CD4 T-cells (SB-728-T)."
Tuesday, September 11, 2012, Poster Session 180 (H) HIV-I Resistance, Tropism and Novel Laboratory Methods

The presentation will describe a new highly sensitive method developed by Sangamo scientists that enables accurate quantification of very low copy numbers of HIV DNA genomes, which may be a useful tool for evaluating interventions targeting the HIV reservoir, particularly Sangamo's approach to a 'functional cure' for the disease. For a more complete description of the technique click here

About SB-728-T

Sangamo's drug, SB-728-T, is generated by ZFN-mediated modification of the gene encoding the CCR5 receptor in a patient's own T-cells.  ZFN modification disrupts the expression of this key co-receptor for HIV entry and renders cells resistant to HIV infection. The approach is based on the observation that a naturally occurring mutation in the CCR5 gene, CCR5 delta-32, provides protection from HIV infection. Individuals in whom both copies of the CCR5 gene carry the delta-32 mutation are generally not susceptible to the most common strain of HIV.

The non-employee authors of these abstracts have no financial relationship with Sangamo.

About Sangamo

Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. Sangamo's other therapeutic programs are focused on monogenic diseases, including hemophilia and hemoglobinopathies such as sickle cell anemia and beta-thalassemia, and a program in Huntington's disease. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs).  Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire AG to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases, and it has also established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company's website at www.sangamo.com.

ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.

This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform for the treatment of HIV/AIDS, including a potential functional cure for HIV/AIDS, projected timing of release of SB-728-T clinical data, the expansion of clinical studies for HIV-infected individuals and the initiation of additional preclinical studies of ZFN-gene modification. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's public filings with the Securities and Exchange Commission, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.

http://investor.sangamo.com/releasedetail.cfm?ReleaseID=705990
2011 May - Neg.
2012 June CD4:205, 16% VL:2676 Start Truvada/Stocrin
2012 July  CD4:234, 18% VL:88
2012 Sep  CD4:238, 17% VL:UD
2013 Feb  CD4:257, 24% VL:UD -viramune/truvada
2013 May CD4:276, 26% VL:UD

Offline NYCguy

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  • Posts: 180
Re: Sangamo reveals successful ZFP results @ ICAAC 2012
« Reply #1 on: October 09, 2012, 03:48:59 PM »
I've been following these guys since first being infected in 2006...  This is exciting.  However, it seems to me that a lot of data is missing.  There is no mention of viral loads and how they changed over the course of the first year.  Has anyone else been able to find this information or have they simply not reported it.
Also, I remember that there was a member of this study who had posted on some forum somewhere - does anyone remember where and/or know if he is still doing so?
11/9/06 = #$%^&!
sometime early Dec 2006:
CD4 530 20%/VL >250,000 (&*$$%!!)
started Reyataz300mg/Norvir/Truvada 12-27-06.
1/30/07 CD4 540 30%/VL <400
4/07 CD4 600+ 33%/VL <50
6/9/07 CD4 720 37%/VL <50
10/15/07 CD4 891 (!) %? VL <50
1/2010 CD4 599 (37%) VL<50 (drop due to acute HCV)
9/2010 - looks like HCV is gone for good! And I'm finally drinking again, thank GOD
2013 - considering a switch to Stribild. but I love my Kidneys (but I hate farting all the time!)...
June 2013 - switched to Stribild.  so far so good...

Offline Dr.Strangelove

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Re: Sangamo reveals successful ZFP results @ ICAAC 2012
« Reply #2 on: October 10, 2012, 03:43:36 AM »
I got the same impression. They seem not too keen to talk about viral loads.

Yes, some of their ZFN-treated cells remain in the body for a long time. But if that doesn't bring the viral load down, then this is not a path towards functional cure (still might help people for whom any other kind of treatment is failing)

I don't want to be overly critical (and the Timothy Brown case clearly showed that generally this approach can work). But they have been testing this for a while and I really find it hard to understand why, if this is really going well ahead as planned,  they would tell us that some of their immune cells survive for very long while at the same time they decide not to talk about viral loads of their test patients.

Offline buginme2

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  • Posts: 3,118
Re: Sangamo reveals successful ZFP results @ ICAAC 2012
« Reply #3 on: October 10, 2012, 10:25:19 AM »

I don't want to be overly critical... But they have been testing this for a while and I really find it hard to understand why

Your joking. They have only been studying this for a few years.  How long do you think research takes?  Especially in a new field of study, it could be a decade, or more....and then the math is against you.

Offline geobee

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  • Posts: 284
Re: Sangamo reveals successful ZFP results @ ICAAC 2012
« Reply #4 on: October 10, 2012, 11:11:37 AM »
I think Sangamo is moving forward pretty fast.  They dosed people; one went UD.  They figured out it was b/c he was a heterozygote.  As for others they realized that the more modified cells you get the more your VL comes down.  So they quickly turned around and launched to more cohorts -- the heteros and the Cytoxan/increase-the-uptake group.  We should know the results by the first half of next year.

If the results aren't good enough, I'm assuming they'll move on to stem cells.

Offline Cosmicdancer

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Re: Sangamo reveals successful ZFP results @ ICAAC 2012
« Reply #5 on: October 25, 2012, 12:28:58 AM »
Sangamo held a 3rd quarter earnings conference call on Wednesday and the link below is a transcript of the call.  They talk about the company's HIV phase 2 trials as well as their Huntington's disease research.  There's not a lot of new information here, but they say the Phase 2 trials are progressing well.

"Our lead clinical program SB-728-T, which we are developing as a potential functional cure for HIV is currently in two Phase II studies that are progressing on plan. Both trials are designed to maximize the engraftment of SB-728-T or ZFN-mediated CCR5 disrupted autologous T-cells. We anticipate having preliminary data from these trials in the first half of 2013 and final data in the second half of the year. Meanwhile, we continue to learn from our previous Phase I trials as we analyze data and conduct long-term follow-up on subjects who participated in these studies.

In September, we and our collaborators presented immunologic data from these studies at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy or ICAAC. The data suggests that SB-728-T treatment has the potential to reconstitute the immune system in HIV infected individuals and gives us further insight into the unprecedented positive effects that we have seen on the levels of CD4 T-cells in treated subjects. I’d ask Geoff to provide you with more details later in the call." 

You can read the transcript for more info.

http://www.investorvillage.com/smbd.asp?mb=1933&mn=47433&pt=msg&mid=12233234
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
June, 2008 - undetectable, 612 cd4
January, 2009 - undetectable, 670 cd4
May, 2009 - undetectable, 593 cd4
Sept, 2009 - 83 vl, 763 cd4, 34%
Dec, 2009 - undetectable, 889 cd4, 32%
April, 2010 - undetectable, 860 cd4, 31%
October, 2010 - undetectable, 800 cd4, 38%
April, 2011 - undetectable, t-cell test not done
October, 2011 - undetectable
April, 2012 - undetectable, 850 cd4, 39%
November, 2012 - undetectable, 901 cd4, 41%
April, 2013 - undetectable, 846 cd4, 36%
October, 2013 - undetectable
May, 2014 - undetectable, 784 cd4, 48%

Offline Markmt

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  • Posts: 175
Re: Sangamo reveals successful ZFP results @ ICAAC 2012
« Reply #6 on: October 26, 2012, 08:21:43 PM »
Thanks for the update Cosmicdancer. This surely sounds very promising indeed!
"Live to love and love to live."

Leo Buscaglia

 


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