Gene therapy developer Avrobio was on track to begin a pivotal study this year testing its experimental treatment for a rare metabolic disorder. Instead, the company is shelving that therapeutic candidate after a look at new clinical data showed variability in recently treated patients—enough to extend the development timeline for a program that has already had to adjust to unexpected regulatory and competitive challenges in the past year.
The experimental gene therapy, AVR-RD-01, is a potential treatment for Fabry disease, a lysosomal storage disorder stemming from an inherited deficiency of a key enzyme called alpha-galactosidase A. Without it, cells are unable to break down a type of fat, which in turn builds up and leads to organ dysfunction. While enzyme replacement therapy can be used to infuse patients with synthetic versions of the enzyme Fabry patients need, Cambridge, Massachusetts-based Avrobio aimed to address the disorder by fixing the underlying genetic problem.
AVR-RD-01 is a lentiviral gene therapy produced by harvesting a patient’s stem cells, using a lentivirus to deliver a functioning copy of a gene to those cells, and then infusing the modified cells back into the patient. What follows is called engraftment: the engineered cells are taken up by the bone marrow, where they multiply and produce a sufficient number of new cells with the functional gene. An open-label Phase 2 study has enrolled nine patients so far. Avrobio said Tuesday that the five most recently dosed patients in the clinical trial had variable engraftment patterns.
Avrobio has two other clinical-stage programs. Engraftment variability has not been observed in those clinical trials, nor has it been observed in patients in the Phase 1 test for Fabry disease, according to the company. While no safety issues have been reported in any of the Fabry disease patients, Avrobio said it will stop enrollment in that study but continue monitoring the previously dosed patients for the next 15 years, as is required by regulators.
“We’re fully aware of the impact this difficult decision has on the patients and families whom we have had the privilege to get to know over the years, but we believe deprioritizing and halting enrollment in our Fabry disease program is the right step forward for Avrobio and preserves our ability to continue developing therapies with the potential to address urgent unmet needs in the lysosomal disorder community,” Avrobio CEO Geoff MacKay said in a prepared statement.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
The surprise engraftment variability is the latest setback to a program that Avrobio had hoped would get a speedy review at the FDA. Those plans changed last March, when the FDA granted full approval to Fabrazyme, an enzyme replacement therapy that has been available under accelerated approval for the past 18 years. Full approval of that Sanofi product restricted Avrobio’s ability to also use the accelerated approval pathway unless the biotech could show a clinical benefit beyond what Fabrazyme offers. Instead, Avrobio said last year that it would seek full FDA approval using the same clinical trial goal that was the basis for Fabrazyme’s full approval. The strategy shift meant that Avrobio needed to revise its clinical trial design. Until the Tuesday, the plan was for that study to begin in the middle of this year.
Going forward, Avrobio said it plans to focus on its other two clinical-stage lysosomal storage disorder programs: Gaucher disease type 1 and cystinosis. Both are in Phase 1/2 testing; the Gaucher program is expected to post an update in the first half of this year while the cystinosis program is expected to report an update at the WORLDSymposium, an annual lysosomal diseases conference that this year is scheduled for February.
In an investor presentation, Avrobio said it plans to discuss with regulators later this year plans to advance the cystinosis program to Phase 2 testing. Avrobio’s preclinical programs are for Gaucher disease type 3, Hunter syndrome, and Pompe disease.
With the pipeline reprioritization, Avrobio said it should have enough money to support the company for the next two years. As of the end of the third quarter of 2021, the biotech reported a cash position of $201 million.
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