Sangamo slides on first genome-editing trial results

SB-913 cuts disease biomarkers, but the trial didn't reveal an increase in the gene product (LionFive/Pixabay)

Sangamo’s big chance to show it has a safe and efficient gene-editing technique to rival CRISPR has come—and the initial response has been a little mixed.

Preliminary results of the CHAMPIONS study of Sangamo’s gene-editing candidate SB-913 for mucopolysaccharidosis (MPS) type II—presented today at the Society for the Study of Inborn Errors of Metabolism in Athens, Greece—showed that the drug was able to cut disease biomarkers with what at first glance appears to be a dose-response relationship.

On the other hand, Sangamo wasn’t able to show an increase in blood levels of the enzyme coded by SB-913, missing an opportunity to show definitively that it was working as expected. Shares in the company were down around 11% in premarket trading, ahead of a company conference call to discuss the data, but that came against a hefty rise last week on expectation of the readout. It slipped further, down to 22%, in late morning trading.

This is the first clinical test for Sangamo’s zinc-finger nuclease approach to genome editing, which predates CRISPR/Cas9 by several years, and the first the first evaluation of an in vivo genome-editing treatment in humans, according to the company.

SB-913 is designed to precisely edit the DNA of cells inside the body, inserting a genetic sequence into liver cells that codes for an enzyme, called iduronate-2-sulfatase (IDS), that is missing in MPS II patients. Without the enzyme patients suffer a debilitating buildup of toxic glycosaminoglycans (GAGs) such as dermatan sulfate and heparan sulfate, which cause a wide range of symptoms that affect multiple organ systems and shorten life expectancy.

Treatment of patients in the open-label phase 1/2 CHAMPIONS got underway last November, and results are available on 4 of 6 patients dosed to date. The latest data focused on two patients apiece treated with a low- and mid-range dose of the drug.

The key findings? With the middle dose, total urinary GAGs declined by 51%, with dermatan sulfate down 32% and heparan sulfate reduced by 61% at 16 weeks. For the low-dose group the patients saw an increase in total GAGs, with a slight rise in dermatan sulfate offset by a decline (23.5%) in heparan sulfate.

It’s important to note that all the patients remained on their current enzyme replacement therapy (ERT) for MPS II, so the reductions were taking place where GAGs are already being reduced by drug therapy, said Sangamo CEO Sandy Macrae. The investigators in the trial intend eventually to withdraw ERT therapy from the patients if possible to gauge the underlying effect of SB-913.

Ahead of the presentation, analysts at Jefferies said that any sign of successful editing would “de-risk [Sangamo’s] approach, be a major tech achievement, and provide a boost to the gene-editing space.” Notably, they weren’t expecting to see an impact on urinary GAGs at this timepoint, suggesting this would be more likely at the six-month update early next year.

Jefferies was however hoping to see clear evidence of an increase in plasma IDS to provide proof-of-concept that SB-913 was able to edit liver cells. Sangamo revealed that at baseline and after 16 weeks, levels were “below the level of quantification of the current assay.”

That’s not necessarily an issue, according to Sangamo’s Chief Medical Officer Ed Conner, M.D., who said on the conference call that it doesn’t mean IDS is not being produced. “The cells of patients with MPS II are starving for IDS,” he pointed out, and it could be that even a very small amount of the enzyme is sufficient to suppress GAG.

“If you’d offered me a choice ahead of the study, my dream would have been to show reduced levels of GAG,” said Macrae, who said that indicated that IDS is being produced and having an impact. Sangamo is working on a more sensitive assay to try to drill down to lower IDS levels, he added.

A safety update earlier this year indicated all was on track, and Sangamo has already moved ahead with another clinical trial in MPS type I, leading some analysts to speculate ahead of today’s news that the company was confident in the outcome. That trial uses a higher dosing schedule which analysts suggested means that the low-dose cohort in CHAMPIONS may struggle to show a clinically meaningful effect.

The two patients in the high-dose cohort have already been infused with SB-913 and initial data on those should be available later this year, according to the biotech.