- Sangamo Therapeutics lost nearly a quarter of its market valuation Wednesday, as investors reacted negatively to mixed clinical results from a tiny study of the biotech's rare disease gene therapy.
- In two patients with a genetic disorder known as Hunter syndrome, levels of problematic polysaccharides tied to the disease roughly halved 16 weeks after treatment — proof, Sangamo claims, its gene therapy candidate SB-913 is working. But no measurable signs of a needed enzyme were observed in the blood, raising questions about the therapy's efficacy.
- Sangamo still awaits results from two more patients given a higher dose that the company hopes will yield greater reductions in levels of the polysaccharides, called glycosaminoglycans (GAGs). But Wednesday's update doesn't appear to have inspired much market confidence in Sangamo's gene editing technology.
Sangamo's trial, while small, has drawn attention as the first study of an in vivo genome editing treatment in humans.
Rather than edit the DNA of target cells outside of the body, Sangamo's therapy does its work inside a patient. And, in contrast to CRISPR-based approaches, the biotech uses a gene editing technology called zinc finger nucleases that it's pioneered over two decades.
Sangamo started its study of patients with Hunter syndrome last year, and the results released Wednesday are the first look at the treatment's initial efficacy.
A low dose of SB-913, given to two patients, didn't clearly reduce levels of GAGs, which build up in the organs and tissues of Hunter syndrome patients. People affected by the disorder, also called mucopolysaccharidosis Type II, lack an enzyme needed to clear GAG accumulations.
Two study participants who were treated with a mid-level dose, however, experienced reductions in GAG levels of nearly 63% and 39% from baseline after 16 weeks.
That's significant, according to Sangamo. Its therapy delivers a new copy of the gene responsible for making the enzyme in question to a specific site in the DNA of a patient's liver cells. Once the zinc finger nucleases sent with the corrective gene do their work, the liver cells are then supposed to take up the new gene and produce the missing enzyme — thereby reducing the problematic GAG build-up.
Although sizable GAG reductions were observed, investors appeared to focus on another finding that potentially weakens Sangamo's case for how its gene therapy is designed to work.
At baseline and through the 16 weeks post-dosing, Sangamo could not detect any measurable activity from the desired enzyme in the blood. The question facing investors is whether that's a sign of the gene therapy failing to effectively spur liver cells to produce more of the enzyme, called IDS.
The company, however, defended its data, indicating that the reduced GAG levels reflect the effects of SB-913.
"The absence of detectable levels of IDS doesn't mean IDS isn't being produced by SB-913-edited liver cells," said Sangamo chief medical officer Edward Conner on a Sept. 5 conference call.
One analyst, at least, largely agreed.
"We believe [enzyme activity] as a result of SB-913 is a necessary component for GAG reduction — the fact we are not seeing IDS could be a result of biology unknowns ... and/or practical assay limitations," wrote Jefferies analyst Maury Raycroft in a Sept. 6 note to investors.
Patients in the study remained on weekly enzyme replacement therapy, the standard of care for Hunter syndrome, during the period covered by Wednesday's results. It's possible that some of the GAG reduction observed could come from that treatment.
"We hope to understand the clinical relevance of these changes by conducting a controlled withdrawal of enzyme replacement therapy in patients enrolled in the study soon," said Joseph Muenzer, a professor at the University of North Carolina School of Medicine and principal investigator on Sangamo's study, in a Sept. 5 statement.
Meanwhile, Sangamo has enrolled two more patients into its study who will receive a dose five times higher than those given the mid-range dose. Results from those patients will also be tracked over 16 weeks, and Sangamo expects to give an update on all 6 trial participants next February.
In addition to studying Hunter syndrome, Sangamo is also testing zinc finger gene therapies in hemophilia and mucopolysaccharidosis Type I.