Unprecedented Immune Reconstitution Drives HIV Viral Reservoir Depletion
Encouraging Preliminary Anti-Viral HIV Data during Treatment Interruption in Ongoing SB-728-T Phase 2 Trials

Richmond, California, May 15, 2013 – Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of new clinical data from its program to develop a ZFP Therapeutic® for HIV/AIDS. The data, which demonstrate that SB-728-T treatment results in a reduction in the HIV reservoir in HIV-infected subjects, are being presented at the 16th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). The meeting is being held in Salt Lake City from May 15-18, 2013.

HIV-infected subjects enrolled in Sangamo’s ongoing SB-728-902 clinical trial (Cohorts 1-3) received a single infusion of SB-728-T which resulted in a durable increase in total CD4 T-cells driven by increased ZFN-modified CD4 central memory T-cells. The extent of exposure of subjects to circulating zinc finger nuclease (ZFN) CCR5 protected CD4 T cells correlated with a long-term decrease in the peripheral blood mononuclear cell (PBMC) HIV reservoir as measured by proviral DNA. In addition, two of four evaluable subjects in Cohort 5 of this study showed a decrease of greater than one log in their viral load during a sixteen week treatment interruption (TI) with one of the subjects achieving a transiently undetectable viral load during the TI period. In subjects in which viral load decreased, a measureable anti-HIV response was observed, specifically a multi-functional response of CD8 T-cells to elements of HIV core proteins.

“These data are quite remarkable,” commented Dale Ando, M.D., Sangamo’s vice president therapeutic development and chief medical officer. “In previous clinical studies, a decline in the HIV reservoir has never been observed in subjects on long-term anti-retroviral therapy (ART) and any increase in the levels of CD4 cells in HIV-infected subjects is often associated with a concomitant increase in the size of the reservoir. In contrast, a single SB-728-T treatment of subjects on long-term ART produced a significant and durable improvement in CD4 count and, in the majority of subjects, a notable decrease in the HIV reservoir over time. An observed correlation with circulating ZFN CCR5 protected CD4 cells is extremely promising.”

Summary of Clinical Data

SB-728-0902 Cohorts 1-3 in Immunologic Non-Responders (INR)

Treatment of HIV subjects with a single infusion of SB-728-T leads to long-term increases in CD4 counts (up to 3 years in some subjects).

Long-term increases in CD4 counts correlate with increased CD4 central memory and increased

ZFN CCR5 protected central memory T-cells.

The extent of long-term exposure to circulating ZFN-CCR5 protected CD4 cells correlates with long- term decreases in the PBMC HIV reservoir.

SB-728-0902 Cohort 5 (CCR5 delta-32 Heterozygotes)

Post SB-728-T infusion, a 16-week ART TI can lead to viral load reduction from initial peak.

o Two out of four subjects showed reduction in viral load during TI

o One subject achieved transient undetectable viral load during TI

The best viral load reduction responses are seen in subjects with CD8 T-cell HIV gag immune responses that are polyfunctional (expression of multiple cytokines) and the highest levels of bi-allelic modification of the CCR5 gene.

SB-728-1101 Immunologic Responders with Cytoxan Conditioning

Accrual and treatment in progress with ten subjects infused to date.

Analysis of numbers of modified SB-728-T cells and viral load during TI is in progress.

Viral load decreases correlate with highest levels of estimated biallelic CCR5 modification

Decreases in viral load from peak to the end of TI correlated with mean circulating bi-allelic

ZFN CCR5 protected CD4 cells during the TI for all patients to date who fully completed TI per protocol in SB-728-Penn, 902 Cohort 5 (CCR5 delta-32 Heterozygotes) and 1101 studies.

“These data continue to demonstrate the important link between SB-728-T-driven immune reconstitution and HIV viral load depletion,” said Rafick-Pierre Sékaly, Ph.D., Co-Director & Chief Scientific Officer, The Vaccine & Gene Therapy Institute of Florida (VGTI Florida), whose laboratory carried out the immunologic analyses. “Specifically, SB-728-T treatment protects long-term central memory CD4 T-cells from HIV-infection which is key for the successful development of an immunologic approach to HIV. ZFN-protected central memory cells are driving positive effects on total CD4 T-cell counts in treated subjects and appear to also play a role in breaking the cycle of HIV reservoir maintenance.”

“We are very encouraged by our data to date and by our continued progress in understanding the factors required to maximize the potential of this novel immunologic approach to a functional cure for HIV,” stated Geoff Nichol, M.B., Ch.B., Sangamo’s executive vice president of research and development. “Sangamo has demonstrated that we have the necessary factors for success: SB-728-T is well-tolerated; the modified cells engraft and traffic throughout the body, appear to be immunologically active, and importantly, persist.

We observe an unprecedented increase in total CD T-cell levels which correlates with the levels of ZFN-protected CD4 central memory T-cells, and a related long-term decrease in the viral reservoir. We have also observed reduction in viral loads during TI, to undetectable levels transiently in one of four subjects, providing a second example of this observation. Viral load changes during TI continue to correlate with circulating bi-allelic ZFN CCR protected CD4 cells. In addition, we have identified key immunologic markers of inflammation that correlate with the degree of engraftment and can potentially aid in the selection of subjects for which SB-728-T may be most effective.”

Dr. Nichol continued, “In our ongoing studies, we will continue to investigate these parameters including the threshold engraftment levels of biallelically modified T-cells and the types of HIV- reactive cells necessary to mount an immune response to the virus. We look forward to presenting the results of these completed studies at the end of 2013.”

The data were presented today by Dale Ando, M.D., Sangamo’s vice president of therapeutic development and chief medical officer in a Scientific Symposium entitled “Challenges and Success of Gene Therapy Product Approval.” Dr. Ando also chaired the symposium.

Data will also be presented from Sangamo’s Phase 1 clinical trial SB-728-902 Cohorts 1-3 in a second presentation at 2:15 pm MT, on Thursday, May 16, 2013, Abst.#: 58 “Long-term CD4 Reconstitution in HIV Subjects Receiving ZFN CCR5 Modified CD4 T-Cells (SB-728-T) May Be Attributed to the Sustained Durability of the Central Memory T-Cell Subset.”

Summary of Clinical Trial Design

About SB-728-902 Cohorts 1-3

The study is an open-label Phase 1 clinical trial to evaluate the safety and tolerability of single infusions of an escalating dose of an autologous (a patient’s own) CD4+ T-cell product genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). The trial enrolled nine HIV-infected subjects (three cohorts of three subjects each) who have sub-optimal T-cell levels and no detectable viral load on long-term ART. Subjects remained on their existing antiviral therapy while receiving treatment with SB-728-T.

About SB-728-902 Cohort 5

Up to 20 HIV-infected subjects heterozygous for the CCR5 delta-32 mutation (i.e. with one CCR5 gene that is naturally modified) who are currently on ART are being enrolled and will receive a single intravenous infusion of SB-728-T (5 to 30 billion modified cells). Two months after SB-728-T treatment, subjects undergo a 16 week TI during which time their anti-retroviral therapy is discontinued. ART will be reinstituted in subjects whose CD4 T-cell counts drop to 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 a sustained detectable HIV viral load are reinstituted on ART. Subjects with an undetectable viral load can remain off ART until HIV RNA levels are detectable or their CD4 T-cell count drops below 350 cell/mm3 for three consecutive weekly measurements.

About SB-728-1101
SB-728-1101 is an open-label, dose escalation, multi-center 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 ART 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 ART are being enrolled into 3 dose-escalating cohorts (3 subjects/cohort), and will receive intravenous Cytoxan (200 mg, 500 mg/m2 or 1000 mg/m2). 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. ART will be reinstituted in subjects whose CD4 T-cell counts drop to  t500 cells/mm3and/or whose HIV-RNA increases to >100,000 copies/ mL for three consecutive weekly measurements. At the end of the TI, subjects with a sustained detectable viral load or CD4 T-cell count cells/ mm3 are reinstituted on ART. Subjects with an undetectable viral load can remain off ART until HIV RNA levels are detectable or their CD4 T-cell count drops below 500 cells/mm3 for three consecutive weekly measurements.

Additional Presentations at ASGCT

Twelve additional presentations from Sangamo and its collaborators will be featured later in the week and include data from preclinical and research-stage human therapeutic programs.  Therapeutic areas
include additional presentations
 ZFP-based approaches for monogenic diseases such
as hemophilia, including applications of Sangamo’s proprietary In Vivo Protein Replacement Platform,
hemoglobinopathies, and oncology.  Developments in gene-editing
technology applications will also be
in presentations at the
All abstracts for the meeting are
online at  2013 ASGCT Meeting Abstracts.
About Sangamo
Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for
therapeutic gene regulation and genome editing. It has ongoing Phase 2 and Phase 1/2 clinical trials to
 novel  ZFP
 Therapeutic®  for  the  treatment  of  HIV/AIDS.

Sangamo’s other therapeutic programs are focused on monogenic diseases, including hemophilia and
as  sickle cell anemia and beta-thalassemia,  and  a program in  Parkinson’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 to develop therapeutics for hemophilia,
Huntington’s disease and other monogenic diseases and has 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

Therapeutic® is a
registered trademark
Sangamo BioSciences, Inc.
This press release may contain
forward-looking statements based on Sangamo’s current expectations. These
forward-looking statements
include, without limitation, the research and development of novel ZFP
 TFs  and
 ZFNs  as 
ZFP  Therapeutics
 and  therapeutic  applications  and
 scope  of
 such applications of Sangamo’s
technology platform to specific human diseases and unmet medical
needs, including a potential functional cure of HIV/AIDS, the
expansion of clinical studies of SB-728-T in HIV-infected individuals, expected timing for the presentation of clinical trial data, the development
of ZFP Therapeutics for monogenic diseases and stem cell applications. Actual results may differ materially from
these forward-looking statements due to a number of factors, including uncertainties relating to whether clinical trials will validate and support tolerability and efficacy of ZFP Therapeutic approaches, technological challenges, Sangamo’s ability to develop commercially viable products and technological developments by our competitors. See Sangamo’s SEC filings, and in particular, the risk
factors described in the Company’s Annual Report on Form 10-K and most recent Quarterly Report on Form
10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.
Sangamo BioSciences, Inc.
Wolffe, Ph.D.

Report from CROI-2013- My Personal Picks

CROI 2013 Report
Nelson Vergel
I was happy to attend 
CROI-2013 in Atlanta on March 3-6, 2013.  These are areas of great interest to me and
in no way attempts to summarize the main findings reported at the conference.
 For abstract information, refer to
A baby girl gets cured


The most popular media story of the conference on retrovirus and
opportunistic infections that took place in Atlanta was the story of a baby
that was cured of HIV infection. The baby was born in Mississippi from a street
drugs using mother that didn’t have HIV care during pregnancy. The hospital
where she went to give birth did not have HIV medications to give her prior
to birth to prevent HIV transmission to the baby.  Immediately after birth two different viral
loads were obtained and the baby was started on triple antiretroviral therapy.
The baby had an HIV viral load in the 20,000 copies/ml range, and rapidly
became undetectable after her doctor managed to get HIV treatment for her
within 3 days. The baby continued the treatment for at least 18 months, then
her mother and baby were lost to follow up and decided to discontinue their
HIV treatment on her own. A few months later, when they were found and the
baby returned to care, the HIV viral load remained negative and there was no
evidence of ongoing replication or infection with HIV. The baby has been
followed for several months off therapy without evidence of the virus
returning. This aggressive treatment probably worked because the baby was
very recently infected, and did not have a chance to establish a significant
reservoir, and because of that the antiretroviral treatment was capable of
clearing the infection. The amount of memory T cells in a newborn is very
small, and those cells constitute the best characterized HIV reservoir. 


This case shows that if we could prevent reservoir formation by using anti-retrovirals
alone we may be able to eliminate the virus.


New studies will aggressively treat newborns within a few hours of birth with
triple antiretroviral therapy immediately after birth, and if infection is
confirmed maintain this treatment for at least a year, and then discontinue
it and see how many children can be cured with that strategy. These studies
will have to be done in Africa because in the United States there are not
enough positive infected children since most infections are prevented by
giving antiretrovirals to HIV+ pregnant women. This fortunate case may have a
dramatic impact on eliminating HIV from newborns all over the world. It will
be our first massive cure initiative!


Neurocognitive impairment


HIV+ aging patients may present mild cognitive impairment even after long
term successful HIV treatment.  There
is a lot of controversy about whether or not using HIV antiretrovirals that
penetrate the central nervous system (CNS) better may make a difference.
Dr. Letendre of San Diego created a system that scored HIV drugs
according to their penetration in the CNS. He hypothesized  that treatments with better CNS penetration scores
would be better in preventing the development of neurocognitive impairment.


Two studies were presented at CROI that looked into this hypothesis in
different ways. In the first study, presented by Ron Ellis, individuals that
were starting a new antiretroviral regimen were randomized to a regimen with
good CNS penetration and compared to patients that were randomized to a not
CNS targeted regimen. The study was a small and with slow accrual. The
selection of CNS targeted regimen did not make a difference at 16 weeks, either
in sophisticated neurocognitive testing or in biological markers in the cerebral
spinal fluid (CFS). In fact 87% of the patients randomized to a “non-CNS
targeted” regimen reached virological suppression in the CSF, versus 68% of
those receiving a CNS targeted regimen.  Since the study only lasted 16 weeks no one
knows if an effect would be seen in the longer term.
We are seeing more evidence that it is probably not a
requirement that an antiretroviral drug has to penetrate the CSF to be able
to exert a beneficial effect in brain function. Also, some of the better CNS
penetrating drugs like efavirenz may also have CNS related side effects that
may mask the potential benefit provided by its better penetration.
Another study called PICASSO  evaluated the cognitive function of patients
were on monotherapy of boosted darunavir (Prezista)  or Kaletra versus  a combination of two nucleoside analogues
with these boosted protease inhibitors. Darunavir/ritonavir and Kaletra do
not have CNS penetration, so the hypothesis was that those patients taking
those drugs as monotherapy should have some neurocognitive deterioration as a
consequence. However, this was not the case which is yet another punch to the
theory that CNS penetration can prevent or improve cognitive problems.
Another study showed that mega HAART (more than 3 HIV
medications in combination)  did not
improve the neuropsychological performance compared to stand on
antiretroviral therapy in patients recently infected with HIV infection.
I think these studies have all failed to monitor patients’
quality of life of the different regimens to see any association on sleep
quality, fatigue, gut issues, etc on cognitive function beyond the effect of
CNS penetrating antiretrovirals. 


New HIV Medications

Several studies
were presented on new HIV medications:


 This new once a day unboosted integrase
inhibitor has been proven to reduce HIV viral load rapidly and effective when
compared to current standard of care. It also seems to present the same lack of
interactions as raltegravir. The
pharmacologic properties of dolutegravir were the topic of several
presentations. Poster 178LB investigated concentrations in the CSF, and found
that CSF concentrations were the same as  blood concentrations in HIV+ naïve patients.  The dolutegravir+ abacavir+3TC achieved an
impressive -3 log CSF viral load reduction at 16 weeks similar to that in
plasma. This combination is currently being formulated as a one-pill once a day
regimen.Poster 531 assessed drug concentrations in colorectal tissue, as well
as in male and female reproductive tracts. Low drug concentrations were
observed in reproductive tract secretions of both men and women. Interestingly,
however, tissue concentrations in female reproductive tract and rectum in the
same people were adequate.  It is
important to note that integrase inhibitors as a class seem to penetrate reservoirs
a lot better than other drug classes (NNRTIs are almost as effective in doing


Merk’s new once a day non-nucleoside MK-1439.
 Poster 527 assessed the PK of this drug on HIV- people.
The PK profile of the drug is conducive to daily dosing.  A drug interaction study with midazolam showed
that MK-1439 was not an inducer or inhibitor of CYP3A. Other studies are being
performed to asses any potential drug interactions. Presentation 100 described
a monotherapy study comparing both 25mg and 200mg daily doses of MK-1439 with
placebo for 1 week in HIV-infected individuals. During these 7 days, no serious
adverse effects judged to be associated with MK-1439 were observed. Adequate
viral load reductions in the range of -1.26-1.37 logs were attained in 7 days.
We await further studies on this non-nucleoside that may present a new
resistance profile that may possibly help treat HIV with several non-nucleoside
resistance mutations. I hope it does has the same lipid profile as others
NNRTIs without the rash and CNS issues.


24 analysis of cenicriviroc (CVC) was presented in abstract 106LB. CVC is an
entry inhibitor given once daily CCR5 and CCR2 antagonist. Two different doses
of CVC (100 mg and 200 mg once daily) were compared with efavirenz, both in
combination with Truvada in treatment-naïve adults. The percentages of
individuals experiencing virologic success were similar between the CVC and EFV
groups. However, virologic non-response was higher with CVC than with EFV. It
seemed to be better tolerated than efavirenz. We will see if the inhibition of the CCR2 receptor
will translate into reduced inflammatory markers when compared to Atripla. The
best dose is yet to be selected for phase 3 studies.


Tenofovir pro-drug – tenofovir alafenamide fumarate (TAF).
Formerly known as GS-7340. This prodrug promises
similar efficacy than tenofovir but fewer kidney issues. Posters 529 and 540
examined the effects of TAF on the kidneys. Unlike tenofovir (TDF), TAF does
not concentrate in the kidneys. Patients with renal impairment receiving TAF
had less than 2-fold increases in peak blood level concentration and drug
exposure, which is not considered clinically relevant (TDF presents a problem
in these patients). These findings suggest TAF may be able to be used in
individuals with renal dysfunction without needing to reduce the dose as
currently done with TDF.


Presentation 99LB described a phase 2 trial
comparing  elvitegravir+cobicistat+
emtriva with TDF or with TAF. At week 24, the TAF-containing regimen had
similar efficacy, and an improved side effect profile than Stribld. The group
receiving TAF experienced no renal side effects, and a significantly smaller
decline in bone density. I am looking forward
to more data!

acting formulations.
Previous data
have been presented with long acting formulations of a monthly intramuscular (IM)
injection of rilpivirine  and injectable
formulations of the integrase inhibitor GSK744 (a second generation integrase inhibitor,
both IM and sub-cutaneous) where therapeutic drug levels are sustained for well
over a month. Another drug that has been studied for a few years is the
monoclonal antibody ibalizumab as a CD4 receptor entry inhibitor to overcome
drug resistant HIV is based on intravenous delivery every 2-4 weeks.

abstract 24LB presented data on a long acting nano-formulation of GSK744. The
drug was administered via a single intramuscular injection to HIV- vounteers
and found to have a half-life of 21 to 50 days, which may allow a once monthly
or even once quarterly dosing schedule. To assess the efficacy of this long
acting GSK744 formulation for PrEP, 8 macaques received intramuscular doses of
GSK744 at two time points 4 weeks apart. All eight of the control macaques
receiving placebo became infected with SHIV. None of the 8 treated macaques had
detectable virus 3 weeks after the final viral challenge.

acting regimens including one or more injections of three compounds monthly may
require  oral lead in periods to assess tolerability
and easy withdrawal in case of side effects  Also, careful guidelines for treatment
discontinuation will be important if the three compounds have different half

 Dr Puliguji from University
of Nebraska presented results on a nanoformulation of atazanavir/ritonavir that
in a mouse study which resulted in ten-fold higher concentrations in plasma and
tissue and sustained for two weeks following a single intramuscular injection.
It will be interesting to see studies on nanoformulations of darunavir and
other popular HIV antiretrovirals in the future.  

In my opinion,
this is one of the most exciting areas of HIV drug development in the present
that may change the paradigm with improved adherence, great pre exposure and
post exposure protection, and hopefully side effect profile.