By Cytiva
Scale-up is one of the greatest obstacles that gene therapy companies face. That challenge extends to lentiviral gene therapies, still early in their clinical journey, with those in the space racing to find the technologies and solutions necessary to achieve commercial success.
Geoff MacKay is President and CEO of AVROBIO, a clinical-stage company pursuing investigational therapies in a handful of rare lysosomal disorders. He believes we’re on the cusp of innovations that will allow companies to scale transformational early-stage science into global therapeutic solutions. “One of the elephants in the room is this: How do you take this petri dish science and mass produce pharmaceutical grade medicine?” This is the problem AVRO and others are trying to tackle, and one that MacKay says requires plenty of creativity and adaptability across every phase of development.
Applying innovation to realize transformation
AVRO's scale-up challenges center on lentiviral gene therapy, which involves transducing a patient’s own STEM cells to deliver a functioning gene via reinfusion. “Our thoughts at AVRO are ‘how do you get this type of technology anywhere in the world at a scale that’s cost effective and convenient?’” It’s a similar hurdle to ones he faced with the advent of regenerative medicine products during more than a decade at Organogenesis. “Those were non-gene modified cell therapies, but we really wanted to do the same thing with gene therapies ― take each component of the process, break it down, figure out how to optimize it, and then scale it.” MacKay says this approach often means applying innovation, particularly automation. “How do we incorporate things that used to be done manually into a roboticized process, such that we can really scale in a way that is reproducible?”
“We’ve really tried to learn from the best practices of other domains, but clearly there’s a need to customize it to the unique requirements of a modified cell-based gene therapy,” MacKay says. One of AVRO’s customized solutions is plato, a self-contained and compact manufacturing “pod” that automates lentiviral vector transduction efficiency and resulting protein activity in target cells. Coupled with a personalized conditioning regimen that includes precision dosing of busulfan, an established conditioning agent that’s key to the "head-to-toe" benefits AVRO hopes to demonstrate with its therapies, plato enables advanced cryopreservation to extend shelf life and allow flexible scheduling for patients and healthcare providers.
The technologies and processes that form plato are intended to be replicable across programs to accelerate overall pipeline development. “It's almost like each of these diseases are like a SKU of each other; it's the same cells, the same vector. We just switch out one disease-specific transgene. And we pivot from Fabry disease to Gaucher disease, for example, or Gaucher to cystinosis. So it allows for a much more cost-effective development because we're leveraging our plato platform across each of these.”
Incremental optimization for long-term success
MacKay offers this advice for companies balancing clinical progress with process automation initiatives:
- Prioritize pre-clinical optimization: According to MacKay, AVRO was faced with the same question that plagues many biopharmas trying to achieve scale up ― how much time and money are we willing to expend to reach clinical viability? “We had to ask a very critical question at the beginning, which was ‘which of these optimization steps do we absolutely need to do before we head to the clinic?’” To ensure maximum stability as its product moved through the development pipeline, AVRO chose to optimize its STEM cells and cryopreservation strategy out of the gate.
- Focus on data generation: Because AVRO started its development journey with an academic vector and room to optimize, it began discussions with regulators as early as possible. “We really wanted a state-of-the-art vector, so we began with that academic vector, entered into pre-IND discussions with the FDA, reached an agreement on what data we would need to incorporate that state-of-the-art vector, and then incorporate that mid-trial.”
- Stick with your strengths: While the gene therapy space has traditionally seen players intent on bringing every part of their process in-house, MacKay says that approach didn’t mesh with AVRO’s intended global footprint and large-scale production. Instead, the company chose its strong suits ― primarily process development ― and found outsourcing solutions for other arenas. “We have manufacturing partners in the US, Australia, Asia, and, and Europe, but even though we rely on CMOs, the critical element, which is the automated manufacturing, is still ours.”
To learn more about gene therapy scale-up and what AVRO is doing to innovate in the space, listen to The Business of Biotech.
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