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Clinical Trials

Date: 2018-09-05

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the WORLD Symposium 2019

Company: Sangamo Therapeutics (USA - CA)

Product: SB-913 (adeno-associated virus serotype 2/6 (rAAV2/6) vectors encoding zinc finger nucleases (ZFNs) and the human iduronate 2-sulfatase (hIDS) gene)

Action mechanism:

  • gene therapy/genome editing product. MPS II is 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 makes use of Sangamo's zinc finger nuclease (ZFN) genome editing technology to insert a corrective gene into a precise location in the DNA of liver cells. To restrict editing to liver cells, the ZFNs and the corrective gene are delivered in a single intravenous infusion using AAV vectors that target the liver. The ZFNs enter the cells as inactive DNA instructions in a format designed only for liver cells to unlock. Once "unlocked", the ZFNs then identify, bind to and cut the DNA in a specific location within the albumin gene. Using the cells' natural DNA repair processes, liver cells can then insert the corrective gene for IDS at that precise location.

Disease: mucopolysaccharidosis type II (MPSII - Hunter's syndrome)

Therapeutic area: Rare diseases - Genetic diseases

Country: UK, USA

Trial details:

  • The CHAMPIONS Study is the first evaluation of an in vivo genome editing treatment in humans. The clinical trial is evaluating three separate doses of SB-913 over a planned 36 month study period. The presentation included early safety and efficacy results for Cohort 1 (low dose) and Cohort 2 (mid dose), with two patients enrolled in each. Enrollment and dosing of Cohort 3 (high dose, 5x the mid dose) was recently completed. In the CHAMPIONS Study, two patients are enrolled into each of three dose cohorts:
    • Cohort 1 (low dose) — 5e12 vector genomes per kilogram body weight (vg/kg) of SB-913 (a starting dose level Sangamo determined through discussions with the United States Food and Drug Administration as appropriate for the first-ever infusions of an in vivo genome editing treatment)
    • 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)
  • All subjects receive ERT weekly. Biochemical measurements of urinary GAGs and plasma IDS are obtained at screening and baseline visits and every four weeks during the initial phase of the trial.
  • The CHAMPIONS study, is also screening subjects at hospitals specializing in the care of patients with MPS II, including hospitals in Chapel Hill, Chicago, Minneapolis and Philadelphia. (NCT03041324)

Latest news:

  • • On February 7, 2019,  Sangamo Therapeutics reported preliminary molecular and enzymatic evidence of editing of the human genome in vivo. 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 at the WORLD Symposium 2019 being held in Orlando, Florida.
  • 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). 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.
  • 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. As of the most recent observation, the patient's plasma IDS activity measured 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.
  • • On September 5, 2018, Sangamo Therapeutics reported 16 week reductions in urinary glycosaminoglycans (GAGs), a key biomarker of mucopolysaccharidosis Type II (MPS II) disease pathophysiology, in Cohort 2 of the Phase 1/2 CHAMPIONS Study evaluating SB-913.  SB-913 is a zinc finger nuclease (ZFN) in vivo genome editing product candidate being evaluated for the treatment of MPS II, also known as Hunter syndrome. In Cohort 2 at 16 weeks post-dosing, mean reductions were observed in total urinary GAGs, dermatan sulfate, and heparan sulfate of 51%, 32%, and 61%, respectively. The data were presented at the 2018 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM) being held in Athens, Greece.
  • Safety
  • Safety data presented were collected and analyzed as of July 10, 2018 and included information on the first five subjects. In all subjects, administration of SB-913 was generally well-tolerated. There were no serious adverse events (SAEs) reported as related to SB-913.  The majority of adverse events (AEs) reported were mild (Grade 1) and resolved without treatment. All AEs reported as related to SB-913 were mild (Grade 1), resolved without treatment, and did not show evidence of dose dependence. Two SAEs were reported and both were determined by the site investigator to be due to primary MPS II disease and unrelated to SB-913 treatment. No persistent transaminitis was observed in any subject.
  • Efficacy
  • Glycosaminoglycans (GAGs)

Total GAG

% Change at

16 weeks

Mean (SD)

Dermatan Sulfate

% Change at

16 weeks

Mean (SD)

Heparan Sulfate

% Change at

16 weeks

Mean (SD)

Cohort 1 (Subject 1)

+13.0

-14.5

-15.6

Cohort 1 (Subject 2)

+4.8

+22.6

-31.4

Cohort 1 Mean (SD)

 +8.9 (5.8)

+ 4.1 (26.2)

 -23.5 (11.2)

Cohort 2 (Subject 3)

-62.5

-47.4

-69.9

Cohort 2 (Subject 4)

-39.1

-16.3

-53.0

Cohort 2 Mean (SD)

-50.8 (16.5)

-31.8 (22.0)

-61.5 (12.0)

  • For Cohort 2 subjects, total GAGs, dermatan sulfate and heparan sulfate observations were below baseline throughout the sixteen weeks with the exception of one excursion when a sample was obtained four days after one subject was hospitalized for an SAE of atrial fibrillation, unrelated to study drug, and was hypotensive for several hours. At the next measurement, this patient's GAGs returned to the previous low range observed since week 4.
  • Plasma IDS
  • At baseline and for the first 16 weeks post-dosing of SB-913, plasma IDS activity (measurements obtained at trough of weekly ERT dosing) was below the level of quantification of the current assay.
  • In addition to UNC, clinical sites around the United States have been actively participating in the CHAMPIONS Study including UCSF Benioff Children's Hospital Oakland, Cincinnati Children's Hospital, The Children's Hospital of Philadelphia, Lurie Children's Hospital of Chicago, University of Minnesota, and New York University.
  • Next Steps
  • Two subjects in Cohort 3 (high dose, 5x the mid dose) have recently been infused, and the study's safety monitoring committee will review cumulative data from all three dose cohorts later this year. Sangamo will work with site investigators to determine when withdrawal of ERT is appropriate for individual patients. Sangamo plans to present longer-term safety and efficacy results from the CHAMPIONS Study in February at the 2019 WORLDSymposiummeeting in Orlando, Florida.
  • • On June 4, 2018, Sangamo Therapeutics announced that the Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom has granted the Clinical Trial Authorisation (CTA) for enrollment of subjects into ongoing Phase 1/2 clinical trials evaluating SB-913, zinc finger nuclease (ZFN) in vivo genome editing treatments= for Mucopolysaccharidosis Type II. The CTA for SB-913 allows for treatment of children as young as five years of age following a review of cumulative safety data from adult and adolescent cohorts. Sangamo expects to initiate clinical trial sites in the U.K. later this year .
  • • On February 6, 2018, Sangamo Therapeutics announced the presentation of initial safety data from the CHAMPIONS Study, the Phase 1/2 clinical trial evaluating SB-913 for the treatment of MPS type II. The data are being presented at the 2018 WORLDSymposium medical congress being held in San Diego. The poster presentation titled "Update on phase 1/2 clinical trials for MPS I and MPS II using ZFN-mediated in vivo genome editing" includes safety data collected and prepared as of December 27, 2017 and describes the first six weeks of experience of the first patient in the CHAMPIONS study, who was treated November 13, 2017 with a dose of 5.00E+12 vg/kg of SB-913. The patient tolerated the infusion well. Mild (Grade 1) adverse events related to the study drug were reported on the fourth day after dosing as dizziness, weakness, and frequent urination, all of which resolved within one day without treatment. No other adverse events related to the study drug were observed. Liver function tests have remained within normal limits for the patient since the infusion.
  • One serious adverse event has been reported and is classified as unrelated to SB-913. The subject developed an upper respiratory tract infection and was hospitalized for acute bronchitis. The subject, who recovered after receiving medical treatment, has chronic pulmonary disease and has previously been hospitalized for a similar respiratory illness.
  • A second patient was treated in the study in mid-January 2018, also at a dose of 5.00E+12 vg/kg.
  • • On November 15, 2017, Sangamo Therapeutics announced treatment of the first patient in the Phase 1/2 clinical trial ("the CHAMPIONS study") evaluating SB-913, an investigational in vivo genome editing therapy for people with mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome. Sangamo aims to treat MPS II by using genome editing to insert a corrective gene into a precise location in the DNA of liver cells with the goal of enabling a patient's liver to produce a lifelong and stable supply of an enzyme he or she currently lacks. Two additional clinical trials are underway in the United States to evaluate Sangamo's in vivo genome editing therapeutics for hemophilia B and MPS I, which is also known as Hurler or Hurler-Scheie syndrome. All three trials use ZFNs designed to edit liver cells at the same location in the albumin gene, but differ in delivering the corrective gene relevant to the respective disease.
 

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