Avrobio posts encouraging update for Fabry gene therapy phase 1, 2 trials

Illustration of three DNA helices
AVR-RD-01 is based on CD34+ stem cells that have been modified using a lentiviral vector to carry and express the GLA gene coding for alpha-galactosidase A, the enzyme that is missing in Fabry disease. (Darwin Laganzon)

When we caught up with Avrobio at the J.P. Morgan Healthcare Conference, the company was three months out from its last Fabry disease update. Despite signs of efficacy—and one patient being weaned off enzyme replacement therapy—the company’s shares halved, thanks to a decrease in vector copy number across the three patients for whom it had data. 

“What we hope to see in the future is more of a stabilization, more of a plateauing effect,” CEO Geoff MacKay said at the time. “What investors were asking [at the data release] was we’re not seeing plateauing yet—are we going to see it?” 

The data, MacKay said, point to yes. 

The Cambridge, Massachusetts-based biotech announced updated data on Wednesday for two trials of its lentiviral-based, ex vivo gene therapy, AVR-RD-01. The phase 1 trial is testing the safety of AVR-RD-01 in up to six patients who have received enzyme replacement therapy, and the phase 2 trial is an open-label, single-arm study assessing the efficacy and safety of the treatment in eight to 12 Fabry patients who have never received ERT. So far, the studies have dosed three patients apiece. 

RELATED: Avrobio slumps on Fabry gene therapy data

AVR-RD-01 is based on CD34+ stem cells that have been modified using a lentiviral vector to carry and express the GLA gene coding for alpha-galactosidase A (AGA), the enzyme that is missing in Fabry disease.  

The updated data shows that all three patients in the phase 1 trial had AGA plasma enzyme activity (AGA) above the diagnostic range for males with classic Fabry disease, Avrobio said. Patient 1 had AGA of 1.6 nmol/hr/ml at 22 months; patient 2 had AGA of 3.4 nmol/hr/ml at 12 months; and patient 3 had AGA of 5.4 nmol/hr/ml at six months. All three patients showed a spike in AGA activity in the two to three months after dosing, followed by a drop in enzyme levels. But patient 1’s data show that the slope of the curve is decreasing, indicating the beginning of a plateau, MacKay said. And patient 2 looks to have reached plateau earlier with AGA levels stable between the 6- and 12-month marks. 

"The other half of the story is that, for the first time, we can begin to look at substrate and metabolite,” MacKay said. “The nice thing about Fabry is it’s such a well-studied disease with 40 years of research behind it due to ERT. It’s pretty clear that when the enzyme, AGA goes up, it will drive the substrate, Gb3, down.” 

Looking at levels of Gb3 and the metabolite, lyso-Gb3, allows Avrobio to compare how its gene therapy is faring compared to ERT. One patient in the phase 2 study—the one assessing ERT-naïve patients—had an 85% reduction in lyso-Gb3. As for the phase 1 study, patient one, who had chosen to discontinue ERT, had lower lyso-Gb3 levels after gene therapy alone than while receiving ERT.  

"We believe these results are significant because the data reported show sustained AGA enzyme levels with associated reductions in substrate and metabolite levels,” said Birgitte Volck, M.D., Ph.D., Avrobio’s president of research and development, in a release. "This suggests that our gene therapy exerts its effects as intended in patients previously treated with ERT, as well as in treatment-naïve patients. Taken together, these clinical data represent a growing body of evidence of the therapeutic potential of AVR-RD-01 as a gene therapy for patients with Fabry disease.” 

As for the vector copy number (VCN) that gave investors pause in the fall, it serves as a marker for integration of the gene into cells and the activity of the therapy. A decline sparked concerns that the gene therapy’s benefits may not last. In October, patient 1 started with a VCN of 0.7 that dropped to 0.1 after 17 months. But now, that patient’s VCN "has in fact reached a plateau,” MacKay said.  

“The same 0.1 at month 17 did plateau going out 22 months. It’s just another measure of what we are hoping to demonstrate over time: a consistent pattern of robust enzyme with that stabilization. We will be reviewing the VCN of all patients. Of the most interest to people is, for the patient that is furthest out, VCN is completely flat and stable,” he said.