The first results from a landmark study of gene editing in humans came out today, and investors panned the study’s sponsor, Sangamo Therapeutics.
The very early returns—from only four patients still in the midst of the study—are from a gene-manipulation technology called zinc finger nucleases, which is wholly owned by Richmond, CA-based Sangamo (NASDAQ: SGMO).
The patients all have Hunter syndrome, a rare genetic disease that causes bone and organ deformities and cognitive problems. Patients are mainly boys. They often don’t survive past adolescence. There’s no cure, but the disease can be managed with a weekly infusion of a key enzyme that patients lack.
Gene editing would reprogram a patient’s cells to produce the missing enzyme, iduronate-2-sulfatase (IDS). It could be a longer-term solution, although how long it would work is one of the most important questions for this, or any, therapy in the new era of genetic manipulation.
Sangamo’s zinc-finger technology has been overshadowed by CRISPR, the gene-editing system now used in labs across the world. CRISPR-based medicines are on the cusp on human trials in the west, but Sangamo has beaten them to the punch.
On a conference call this morning, Sangamo CEO Sandy Macrae was both positive and cautious about the initial data from the study, dubbed CHAMPIONS: “There is so much more information to come, and we hope to build on these early results.”
Investors were less generous. The company’s share price has dropped nearly 24 percent to $14.52 in late trading Tuesday because of mixed signals from the smidgen of data.
The results so far come from four patients, two receiving a low dose of its zinc finger treatment, SB-913, and two receiving a medium dose. They are 16 weeks into their treatment.
One measure of the study showed that SB-913 might be having a positive effect. The therapy aims to edit a gene inside liver cells and encourage IDS production, which is needed to break down carbohydrates called glycosaminoglycans (GAGs). Without the enzyme, the molecules build up and damage a Hunter patient’s organs and tissues.
The two mid-dose patients had reductions in all three GAG-related measurements 16 weeks into the study. The two low-dose patients were mixed: One showed reductions across the board, one did not. Two patients receiving a high dose will produce data later this year, according to Sangamo.
These GAG measurements, however, aren’t definitive proof the gene editing is working. A more direct measure that gene editing is taking place, a boost of the IDS enzyme in the bloodstream, showed no gains. In fact, the protein was “below the level of quantification of the current assay,” according to Sangamo—too faint to be detected.
Conner said it might be too early in the study. “The absence of detectable levels doesn’t mean it isn’t being produced by the edited cells,” he said. Sangamo is working on a test that can detect lower levels of IDS.
Two of the six patients have had serious problems during the study, but neither—bronchitis and atrial fibrillation—was considered related to the gene editing, according to Sangamo.
Safety signals are important, not only for the gene editing field—as this is the first look at results from gene editing inside humans—but also to gauge Sangamo’s specific approach. The company owns zinc fingers; unlike the much higher-profile CRISPR-Cas9, no one else can use it to make products. As with CRISPR technology, Sangamo is also using a modified virus, called a vector, to squeeze gene-editing “scissors” into cells. The vector type (AAV-6) used in SB-913 has never been inside humans before, according to Macrae, who said Sangamo has designed its study to start at low doses and “prudently” escalate into higher doses.
AAV vectors are widely used in gene therapy, another gene manipulation technology, and so far they haven’t caused dangerous unintended problems. But experts have recently raised concerns about the safety of AAV vectors when used at high doses.
There are also persistent questions about CRISPR’s potential side effects; zinc fingers have not yet raised the same level of concerns.
The CHAMPIONS study could also provide momentum for Sangamo’s experimental therapies for MPS I and hemophilia B, which aim to make changes at the same genetic location as the Hunter treatment.
All the patients in CHAMPIONS are also taking enzyme replacement drugs, the standard of care for Hunter syndrome. For a better sense of how well SB-913 works, Sangamo will need to test patients who have been weaned off their enzyme replacement. A fuller evaluation of the CHAMPIONS study will come in February.
Macrae said Sangamo expects to have clinical data from seven experimental programs by the end of 2019.