Two years after investor panic, Avrobio touts 100% response as they look to chart a path toward approval
Two years after Avrobio’s early data panicked investors, the gene therapy biotech thinks they have enough data to begin plotting their bid for accelerated approval — and launch a suite of programs behind the lead drug that has dominated the company to date.
Avrobio announced Monday that a year after dosing, the first patient given the commercial form of their Fabry disease gene therapy saw 100% reduction in kidney substrate, the endpoint the FDA uses for approval. The data are just from one patient but the results add, CEO Geoff MacKay said, to the growing body of evidence that their gene therapy can significantly and indefinitely curb the genetic disease.
“Across the board — every single patient, every time point, going out as far as 3.5 years — we’re seeing what we would hope to see,” MacKay told Endpoints News, adding of the most recent result: “Certainly, we couldn’t ask for more. The effect was profound.”
To be sure, Avrobio remains a ways away from filing with the agency. But they have submitted a proposal to the FDA to expand their current 8 to 12-person study and make it pivotal, pointing them down a path that few gene therapy companies have yet gone down. And because the biotech has spent years building a closed-loop manufacturing system for their therapy, they think they’ll be able to avoid the CMC pitfalls that have snared rivals like bluebird bio.
What the FDA says remains to be seen, but MacKay says they have already gotten ahead of other companies with their new platform, called Plato, with each step OK’d by the FDA.
“We’re confident,” MacKay said. “Companies have run into trouble when they haven’t done their characterization early enough, they haven’t implemented process changes early enough and they haven’t sorted out their potency assay early up.”
“And the whole raison d’être of Plato is that we wanted to get our commercial stage platform in years earlier,” he added. “And so all our process changes that are medium or large are either FDA approved and in place and part of Plato.”
Like bluebird, Avrobio uses ex-vivo gene therapy, meaning they extract cells from a patient, genetically modify them and then implant them back into the patient. While bluebird has most notably used it for fixing inherited blood disorders like sickle cell anemia, Avrobio goes after lysosomal disorders. These disorders arise when the enzymes the body uses as a waste system malfunction; Avrobio modifies the extracted cells to secrete a healthy enzyme, which is then distributed throughout the body.
Early data showed efficacy, allowing one patient to stop taking the infusions of artificial enzyme Fabry patients receive to keep their disease (mostly) under control. But the results also showed that vector copy number, a metric that tracks how much gene therapy is staying in the body, fell precipitously.
MacKay argued at the time that this was a natural consequence of ex-vivo gene therapy, as most of the cells you implant don’t stick around and you’re left with a handful of progenitor cells that for years generate enzyme-secreting daughter cells throughout the body. Investors didn’t believe him much at the time, cutting their share price in half, and they still haven’t come back: Their stock is still a third of its September 2018 peak.
Still, the company has now shown that three out of five patients from their Phase I are off enzyme replacement therapy, with the first patient now responding for 3.5 years. And the commercial Plato platform is engineered to have a higher vector copy number at the start, although MacKay is quick to insist the older form was still good.
“Why did we notch up Plato? Simply because we could,” he said. “It just gives us more confidence.”
Avrobio also announced early data from their gene therapy for Gaucher disease, another lysosomal disorder, noting the first patient saw around a 50% reduction on a key metric from where they were on enzyme replacement therapy. In three of the patients who received their therapy for cystinosis, a rare disease where crystals form that damage a patient’s cells, they said they were seeing vector copy numbers similar to the Fabry trial. One patient saw a two-grade improvement in his ability to tolerate light, one of the hallmarks of the disease.
Now, with three programs in the clinic and one — they hope — heading toward approval, McKay is setting his sights on a longer line of therapies, including for Hunter’s disease and Pompe disease.
“We’ve entered the year as a Fabry company,” McKay said. “And we’d like to end the year with certainly clarity on Fabry but also data being generated from at least 5 of our 6 lysosomal disorder disease targets.”