In five patients, Sangamo’s Fabry disease gene therapy appears to be working so far

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In five patients, Sangamo’s Fabry disease gene therapy appears to be working so far

While Sangamo’s sickle cell partnership with Sanofi ground to a halt earlier this year, the California biotech’s Fabry disease program, still in its early stages, has been quietly chugging along.

In Tuesday’s update on the gene therapy trial, adding two more patients from its last interim readout in November, Sangamo reported that it has begun taking patients off enzyme replacement therapy — a biweekly treatment Fabry disease patients get to replace their missing alpha-gal enzyme, which is responsible for breaking down fats and sugars and for which Fabry disease patients have a mutated gene.

According to the press release, as of a February cutoff, one patient has been off ERT for 12 weeks, and has maintained elevated levels of alpha-gal A activity. In addition, since then, the other four patients who started the Phase I/II study on ERT have been taken off the biweekly treatment, Sangamo said. “None have had to go back on,” Sangamo CEO Sandy Macrae told Endpoints News, though he noted it was still “early days” for many of them.

They all received a one-time infusion of ST-920, or isaralgagene civaparvovec, designed to deliver a healthy copy of the GLA gene.

The true trial for Sangamo’s Fabry treatment has yet to come — as the study goes on, will patients maintain alpha-gal A activity after being taken off ERT?

The last patient in the latest data release to be dosed — a 42-year old man — reached normal alpha-gal activity levels at week 2. The other five patients, who were given the therapy between 4-15 months ago, have maintained elevated alpha-gal activities above the normal range, which was determined based on healthy male individuals, though at very different levels.

Three of the patients, two of whom were on ERT at the time of the cutoff and one who had been taken off, had over 10 times the normal mean alpha-gal activity, while two patients who were ERT-pseudo-naïve, meaning they had been off ERT for at least six months prior to the study, had enzyme activity levels about two to three times the normal mean.

Macrae said it was still too early to comment on what impact the differences in elevated alpha-GAL activities could have, saying it was important to “wait and see more patients for longer.”

Fabry disease is an X-linked disease that causes a wide range of symptoms and in the long term, can lead to nerve damage, heart disease, and kidney failure. Current treatment options include Sanofi’s enzyme replacement therapy Fabrazyme, which got accelerated approval in 2003, in the form of an IV infusion every two weeks. For patients with certain mutations, there’s also Galafold, a pill developed by Amicus, which is taken every other day.

While previous studies have suggested that the development of antibodies against alpha-GAL A in men who are being treated ERT may be associated with worse outcomes, McRae noted that whether patients had or did not have antibodies didn’t seem to have a huge impact on the outcome of their gene therapy.

On the safety front, there were no serious adverse events, with an array of Grade 1 events reported in three patients. Notably, there were no elevated liver enzyme levels reported — a toxicity signal observed with other AAV therapies.

On the biomarker front, the one patient who had high lyso-Gb3 levels prior to the study saw that cut by 40% in 10 weeks, and that reduction was sustained to 48 weeks at the update cutoff date. Higher blood lyso-Gb3 levels are associated with worse outcomes in Fabry disease.

Sangamo has added five additional patients to the trial since the February cutoff. While the current patients are all men with classic Fabry disease, two patients have been enrolled in the expansion trial, which sets out to include women, and patients with heart or renal disease. And Sangamo CMO Bettina Cockroft noted one of the patients soon-to-be dosed for the expansion study is a woman. The biotech also said it is planning a Phase III study for the program.

AUTHOR
Lei Lei Wu
News Reporter

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