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Sangamo Announces Interim Results Of Phase 1/2 CHAMPIONS Study Showing Preliminary Evidence of In Vivo Genome Editing In Patients With MPS II Treated With SB-913

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Monday, February 11, 2019

BRISBANE, CALIFORNIA -- Sangamo Therapeutics, today reported preliminary molecular and enzymatic evidence of editing of the human genome in vivo (inside the body). These findings are part of the interim results from the Phase 1/2 CHAMPIONS Study evaluating SB-913, a zinc finger nuclease (ZFN) in vivo genome editing product candidate for the treatment of patients with Mucopolysaccharidosis Type II (MPS II). These interim results were presented today at the WORLDSymposium 2019 being held in Orlando, Florida. Also reported today were interim results from the EMPOWERS Study (announced separately) evaluating SB-318 for the treatment of MPS I. Sangamo believes data from these two studies provide complementary evidence supportive of a favorable safety profile and of the activity of the ZFN in vivo genome editing technology used in both SB-913 and SB-318. The two WORLDSymposium presentations have been made available on the Sangamo website.

MPS II, also known as Hunter syndrome, is a rare genetic disorder caused by a deficiency of iduronate-2-sulfatase (IDS), a lysosomal enzyme which is required to break down or recycle the toxic buildup of glycosaminoglycans (GAGs). Without IDS enzyme activity, GAGs accumulate in cells throughout the body, leading to widespread tissue and organ damage. The current standard-of-care treatment for MPS II is enzyme replacement therapy (ERT), given weekly as intravenous infusions. SB-913 is an investigational product candidate being evaluated to treat MPS II using ZFNs, which are designed to insert a normal copy of the IDS gene into a precise location in the DNA of liver cells. The goal of SB-913 treatment is to enable a patient's liver to produce a continuous supply of functional IDS enzyme.

"The interim results from the CHAMPIONS Study provide preliminary evidence that in vivo genome editing occurred and that genome-edited liver cells are able to generate active IDS enzyme in patients with MPS II," said Dr. Joseph Muenzer, a professor of pediatrics and genetics at the University of North Carolina School of Medicine in Chapel Hill and a lead study investigator. "More data are needed to understand whether the small increases in IDS enzyme activity observed can translate into improved outcomes in MPS II patients treated with this first generation of SB-913. I look forward to reviewing additional data later this year from the five patients who have received the high-dose of SB-913." 

In the CHAMPIONS Study, liver biopsies have been analyzed for three eligible patients – one from the low-dose cohort and two from the mid-dose cohort. Sangamo scientists developed an assay using reverse transcription polymerase chain reaction (RT-qPCR), a standard laboratory method used to amplify and detect specific molecular signals. The assay was designed to detect gene integration by identifying albumin-IDS chimeric mRNA transcripts, which can only be made if the IDS gene has successfully integrated at the expected site within the endogenous albumin gene. This assay detected albumin-IDS chimeric mRNA transcript in both mid-dose cohort patients, providing preliminary evidence of ZFN-mediated targeted integration of the IDS gene. Genome editing in mid-dose cohort patients appears to be occurring at a low frequency, as a parallel liver tissue analysis for minor genome edits conducted using MiSeq DNA sequencing, which is a less sensitive assay (lower limit of quantification of 0.1%), did not detect editing in samples from the low and mid-dose cohort patients. Liver biopsies from patients who received the high dose of SB-913 will be available for analysis later this year.

"The SB-913 and SB-318 data presented today represent an encouraging first step in the translation of genome editing technology from basic research to genomic medicine. Further data will be available throughout 2019 and will help inform our understanding of these early results," said Sandy Macrae, Sangamo's Chief Executive Officer. "With our expertise in zinc finger protein design and our understanding of the factors that contribute to efficient genome editing, our scientists have been able to engineer a second-generation of ZFNs. In preclinical studies, these have demonstrated the potential for greater potency and higher enzyme expression than our first generation ZFNs. We believe these improvements have the potential to provide greater benefit for patients."

Sangamo has developed second-generation, potentially more potent ZFN constructs designed to increase editing efficiency. Preclinical data of these second-generation ZFNs were reviewed by U.S. regulators. The preclinical data showed three potential advantages for use in the clinic: (1) a 5- to 30-fold improvement in efficiency and potency due to structural changes; (2) the ability to function equally well in the patients who have a single nucleotide polymorphism (SNP) in the target locus in the albumin gene (approximately 20% of the population); (3) improved specificity. The second-generation ZFNs are already being manufactured and are expected to be ready for evaluation in the clinic later this year. Additional data from Sangamo's in vivo genome editing programs will be assessed before potential integration plans for the second-generation ZFNs are finalized.

Interim CHAMPIONS Study Results Presented at WORLDSymposium

The primary objective of the CHAMPIONS Study is the safety and tolerability of SB-913, and secondary objectives include evaluation of change from baseline in plasma IDS activity and urine GAG levels. Biochemical measurements of urinary GAGs and plasma IDS are obtained at screening and baseline visits, every two weeks for an initial phase, and then every four weeks.

Patients with attenuated (cognitively intact) MPS II receiving ERT weekly were enrolled and treated in three dose cohorts:

  • Cohort 1 (low-dose) — 5e12 vector genomes per kilogram body weight (vg/kg) of SB-913
  • Cohort 2 (mid-dose) — 1e13 vg/kg of SB-913 (2x the starting dose)
  • Cohort 3 (high-dose) — 5e13 vg/kg of SB-913 (5x the mid-dose)

Two patients are enrolled in each cohort, along with an additional three patients, all of whom have received the high dose, in an expanded cohort.  

Safety data on eight patients were collected and analyzed. Administration of SB-913 was generally well tolerated in these patients. Of the 18 total adverse events (AEs) reported as related to study drug, 16 were mild (Grade 1), two were moderate (Grade 2), and all AEs resolved. There were no treatment-related serious adverse events (SAEs) reported.

The results of biochemical measurements were available in the first six patients who had sufficient length of follow-up for interpretation.

A newly developed sensitive quantitative assay (lower limit of quantification of 0.78 nmol/hour/mL) was used to measure plasma IDS activity. Small increases in IDS enzyme activity compared to baseline were recorded in the two patients receiving the mid-dose and in one patient receiving the high-dose. At 24 weeks these measurements remained within the expected range for baseline values (less than 10 nmol/hour/mL, as compared to the normal range which is estimated at greater than 82 nmol/hour/mL).

A more substantial increase in plasma IDS activity was measured in the second patient in the high dose cohort, with levels rising to approximately 50 nmol/hour/mL by week 6 following SB-913 administration. The plasma IDS activity levels subsequently decreased in the context of development of a mild transaminitis — a known risk of AAV-based therapies — due to a suspected immune response. Grade 1 elevations in liver function tests were measured at Day 62, 111 and 128. The patient was hospitalized on Day 121 for an incarcerated umbilical hernia considered unrelated to the study drug. The most recent observation, the patient's plasma IDS activity measured  at 14 nmol/hour/mL, above the baseline value but below the normal range.

Baseline urine GAG measurements for all six patients were in a range considered at or slightly above normal, except for heparan sulfate which was elevated in all patients at baseline. At 24 weeks, urine GAG results did not show a meaningful change.

The clinical relevance of the biochemical changes observed following administration of SB-913 will be assessed as clinical data and patient outcomes are analyzed following a trial of withdrawal from ERT. To date, two mid-dose and one high-dose patients have initiated ERT withdrawal. One mid-dose patient was recommended to resume ERT approximately 3 months after initiation of ERT withdrawal due to fatigue and increasing GAGs. Analyses from these withdrawals will be available later in 2019.

About Sangamo Therapeutics 
Sangamo Therapeutics, Inc. is focused on translating ground-breaking science into genomic medicines with the potential to transform patients' lives using the Company's platform technologies in genome editing, gene therapy, gene regulation and cell therapy. For more information about Sangamo, visit

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