It was a mixed bag for Sangamo Therapeutics Inc. at the 2018 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM) in Athens, Greece, on Wednesday where the company presented data from its phase I/II Champions trial testing SB-913 in patients with mucopolysaccharidosis (MPS) type II.
MPS II is caused by a mutation in iduronate-2-sulfatase (IDS), which is responsible for the breakdown of glycosaminoglycans (GAGs), resulting in an increase in the large sugar molecules, which build up in lysosomes, crowd organelles and engorge the cells, which eventually damages organs.
SB-913 uses Sangamo's zinc finger nuclease (ZFN) technology to edit the genomes of liver cells in vivo, inserting the IDS gene under the control of the albumin promoter. The IDS enzyme can then be transported throughout the body and taken up by cells in a receptor-mediated manner.
The Champions study includes three dose cohorts treating patients at 5e12 vg/kg, 1e13 vg/kg or 5e13 vg/kg. Two patients have been treated at the highest dose, but only data from four patients, split between the low- and mid-dose cohorts, were available for the interim readout at SSIEM.
Unfortunately, Sangamo couldn't detect plasma IDS activity in any of the four patients over the 16 weeks following treatment with SB-913. The lower limit of detection for the fluorometric assay is 5.2 nmol/hr/mL.
"I wish we had developed an assay that could detect lower levels," Sandy Macrae, Sangamo's CEO, told investors on a conference call. The company is working on a more sensitive assay, but as Macrae noted, "assay development is not a simple thing."
While the lack of detectable expression of the enzyme wasn't what investors were hoping for, it appears there is IDS activity in the patients since the middle dose produced a 50.8 percent mean decrease in total urine GAG. Dermatan sulfate and heparin sulfate, two other MPS II markers, were also reduced by a mean of 31.8 percent and 61.5 percent, respectively.
"I'm encouraged not only by the magnitude of the declines, but also that these observed reductions persist," Ed Conner, Sangamo's chief medical officer, told investors on the call, noting that the reduction from baseline was detectible as early as the first reading at four weeks.
Interestingly, one of the patients was hospitalized for atrial fibrillation, which was determined to be due to the underlying MPS II and not the drug. The episode caused the patient to become hypotensive, which raised the patient's total GAG well above baseline, but the total GAG returned to the reduced level at the subsequent reading.
Richmond, Calif.-based Sangamo's hypothesis is that treatment with SB-913 is causing IDS expression, but that the enzyme is being taken up by the cells and therefore the plasma concentration is below the level of detection of the company's assay.
"Cells of patients with MPS II are starving for IDS, and we believe that continuous exposure of cells to low levels of circulating IDS may be sufficient to drive enzyme uptake into cells and reduce or maintain suppression of GAGs," Conner explained.
The patients in the study continued on their weekly enzyme replacement therapy (ERT), so their GAGs are already significantly reduced compared to ERT-naïve patients, although Conner noted that they are "elevated enough to still have room for measurable decline."
Patients will have the ability to make a decision, in conjunction with their doctor, to discontinue their ERT therapy, which could help confirm that the SB-913 treatment is actually the reason for the decline in GAGs.
And of course, the highest dose, which is five times the mid dose, could also produce enough IDS to get the plasma concentration above the levels of detection. Data from that cohort would likely be available at the 15th Annual Worldsymposium in February 2019 in Orlando, Fla.
SB-913 uses an AAV6 vector to deliver packaging ZFNs and a copies of the IDS gene. Given this was the first use of AAV to perform in vivo gene editing, the company decided to start at a low dose after consulting with the FDA. Sangamo has since received clearance from the EMA and FDA to enroll adolescents in the trial after safety has been established in adults.
"It was important for us to start at a dose level where we believed it was safe and to carefully escalate prudently into doses with greater therapeutic potential," Macrae said, almost apologetically, as investors would clearly like to see data from the high-dose cohort now with Sangamo (NASDAQ:SGMO) closing down $4.50, or 23.6 percent, to $14.55 on Wednesday.
Macrae seemed to get investors' frustration with the lack of detectable IDS expression, but argued that it ultimately isn't that important. "It would be lovely to be able to measure it because you'd all feel comforted by it. But it doesn't comfort the patients. What comforts the patients is the reduction of GAG in the tissues."
Part of investors' apprehension likely lies in the Sangamo's redundant use of the gene editing technique putting genes under the albumin promoter in the company's SB-FIX therapy for hemophilia B and SB-318 for MPS I. If the ZFN technique isn't able to produce high expression levels, those programs, which are both in phase I/II studies, could fail to show an effect.