Shares in Avrobio were halved after the company reported results from the first three patients on its Fabry disease gene therapy, even though one was able to be weaned off enzyme replacement therapy.
Although there were signs of efficacy and a tolerable safety profile with AVR-RD-01, investors were spooked by steady declines in vector copy number (VCN) in peripheral blood in the months following one-off administration of the therapy. Shares in the company closed down 52%.
AVR-RD-01 is a therapy 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. VCN serves as a marker for integration of the gene into cells and the activity of the therapy, so the declining levels sparked concerns that the gene therapy’s benefits could be short-lived.
That’s an issue that caused problems with variable responses for bluebird bio’s LentiGlobin therapy for sickle cell disease, although a change in the manufacturing process in order to boost VCN levels seems to have put the program back on track.
Digging into the data, Avrobio reveals (PDF) the first patient started with a VCN of 0.7 that dropped back to 0.1 after 18 months, although AGA activity increased from almost zero to 2.6 nmol/hr/ml. The biotech says that enzyme level is above the diagnostic range for males with classic Fabry disease.
Patient number two saw VCN levels drop from 1.4 to 0.4 over six months, again above the diagnostic range, while the third patient—who was only dosed in July—went from 0.8 to 0.2 in a single month.
Meanwhile, a patient from Avrobio’s phase 2 FAB-201 trial of AVR-RD-01 has now passed three months since dosing and has AGA activity of 2.74 nmol/hr/ml, although VCN once again fell back from 0.7 to 0.5.
Avrobio CEO Geoff MacKay said he was encouraged by the data, and particularly that patient 1 was taken off enzyme replacement therapy in mid-July and remains off. All the patients will continue to be followed for assessment of long-term durable response.
“We continue our move towards implementation of a set of process optimization initiatives, including heightened vector efficiency, our fully closed, automated manufacturing system and conditioning,” he added.
An improved vector that has already been shown to have achieve higher VCN and AGA activity has already been put through its paces and will be used in phase 2 studies, suggesting that—like bluebird bio—Avrobio may be able to put the issue in the rearview mirror.