Avrobio’s ex vivo lentiviral gene therapy platform led to durable responses measured in years, and significant reductions in disease-related biomarkers that far exceed today’s standard of care.
AVROBIO is well on the path to developing functional cures for Fabry disease, Gaucher’s disease and cystinosis, according to data presented recently at the Barclays Gene Editing & Therapy Summit 2021 and at the Stifel 2021 Virtual Healthcare Conference.
In small trials, Avrobio’s ex vivo lentiviral gene therapy platform led to durable responses measured in years, and significant reductions in disease-related biomarkers that far exceed today’s standard of care. If these results are replicated in larger studies, it seems safe to suggest they may be functional cures.
As Avrobio CEO Geoff MacKay elaborated during the Barclays presentation, “we have 19 patients, four studies and three indications, and all are showing the efficacy and durability we expect.” Specifically, “one hundred percent of patients show more than six months durability, and the longest out is 3.5 years.
“The platform uses the same cells and vectors, but switches out the disease-specific transgene,” he said. Therefore, “the strong data we are seeing in this first wave de-risks the platform and increases its probability of success.”
Standard-of-care therapies for these three rare lysosomal diseases tend to be enzyme replacement therapy (ERT). Infusions are delivered every two weeks for temporary relief as the disease progresses. “After 12 hours, the enzyme is gone,” MacKay said.
Gene therapy, in contrast, enables long-term, continuous elevation of enzyme or protein levels after a single intravenous infusion, “untethering patients from a lifetime of bi-weekly treatments and halting disease progression,” he added.
With strong clinical data, “our attention now is on continuing to improve the patient experience related to the concomitant conditioning regimen. There are two steps: identifying the correct exposure and hitting the target.”
To that end, the company pivoted toward Bu90-TCI. Busulfan (Bu) is an alkylating agent and, therefore, has great variability. To ensure it hits the target (thus minimizing off-target toxicities and improving outcomes), Avrobio monitors a set of conditional and transient adverse events that typically appear at week two when conditioning begins and departs at the end of that week, following conditioning. Those adverse events include leukopenia, neutropenia, anemia and thrombocytopenia.
In Fabry disease, all ten patients received one infusion of gene therapy at least 12 months ago. The first of those patients was treated three-and-a-half years ago.
Results of the first two kidney biopsies assessed the number of Gb3 inclusions per peritubular capillary (PTC) after one year. In one patient, there was a 100% reduction, while a biopsy of another patient showed an 87% reduction. When enzyme activity was assessed, the biomarkers – plasma and leukocyte AGA activity – stabilized and plateaued after a single infusion. “Vector copy number also stabilized,” MacKay said. “We also saw a 70% reduction in toxic metabolites – plasma levels of lyso-Gb3 – with no waning effect over time.” Those results were in ERT-naïve populations.
Patients previously treated with ERT showed an average 25% improvement in plasma levels of lyso-Gb3, with some into the mid-40 percentages. All three patients who discontinued ERT therapy still remain off it.
In trials involving a few cystinosis patients, “there is a sharp drop in the number and size of cystine crystals in skin (35%) and rectal (76%) biopsies,” MacKay pointed out. “This demonstrates the gene therapy is present and well-distributed…and that it controls crystal volume.” Crystals significantly declined in the cornea too. This means patients can leave their homes without dark glasses during the day, and check a cell phone indoors at night, he said. Additionally, because cystinosin regulates melanin synthesis, patients’ skin, eyebrows and hair color gradually darkened, gaining a more normal appearance.
Similar improvements were seen in small trials involving patients with Gaucher disease type 1. After one infusion of Avrobio’s gene therapy, levels of chitotriosidase (a marker of inappropriate activated Gaucher cells) were reduced by 49%. Lyso-Gb1, a marker for toxic metabolite accumulation, was reduced by 44%.
Fabry, cystinosis and Gaucher disease are among the larger of the rare diseases. They have a combined patient population of about 50,000 and currently generate approximately $4.8 billion annually for standard-of-care therapies. “If we hit the target profile of a safe, effective once-and-done treatment, we can save patients and the healthcare system millions of dollars,” MacKay said.
“We are the first gene therapy in Fabry, Gaucher and cystinosis to reach the clinic, and we expect a second wave of trials in 2022. We have multiple regulatory meetings in the near future,” MacKay underscored, in anticipation of registrational trials and a pivot to commercial readiness. He said he plans to have multiple clinical and regulatory updates in 2022, including data during the WORLDSymposium™ 2022, an annual research conference dedicated to lysosomal diseases.
