When Astellas closed its $3 billion buyout of Audentes Therapeutics in January, the J.P. Morgan conference crowd was full of “backhanded congratulations.” They offered Natalie Holles, then the newly minted CEO of Audentes, their kudos along with horror stories of biotechs that had been subsumed by Big Pharma and lost their spunk.
“It was always, ‘Oh, congratulations, that’s so exciting! I went through a merger—everybody quits,’ or ‘I went through a merger—they’re going to kill your spirit,'” Holles told Fierce Biotech.
As the Astellas deal went forward, Holles, who had joined Audentes in 2015 as chief operating officer, was already working on what integrating with its new parent was going to look like and how the gene therapy biotech would hold on to its culture through the transition. Perhaps counterintuitively, the COVID-19 pandemic lent a hand.
“I think in some ways, the COVID crisis has been helpful to me because it has forced us to create a sense of community with our employees and find ways to be more connected and be more deliberate about propagating our culture in ways we wouldn’t have had we all been showing up to the labs, plants and office every day,” Holles said.
In fact, rather than extinguishing Audentes’ small-biotech spirit, Astellas became an accelerant for its work: “The global backing both in terms of resources and expertise Astellas provided us with has been like rocket fuel for all of our efforts,” she said. “Gene therapy is a very expensive sport to be in.”
Manufacturing is a major bottleneck for gene therapy companies, so much so that ElevateBio set up shop last year to provide a centralized R&D and manufacturing team for a portfolio of companies working on cell and gene therapies. Audentes invested in manufacturing in 2016, when it was still preclinical, but having Astellas’ backing is just more insurance against being held up by manufacturing and clinical trial costs.
Its lead program, a gene replacement therapy for X-linked myotubular myopathy, is in a pivotal study ahead of regulatory filings in the U.S. and Europe. Behind that, it’s working on a similar treatment for Pompe disease as well as a trio of exon-skipping treatments for Duchenne muscular dystrophy (DMD) and an earlier-stage program in myotonic dystrophy.
The company is looking to treat DMD patients whose disease is amenable to skipping Exon 2, Exon 51 or Exon 53. Sarepta markets drugs for the latter two, Exondys 51 and Vyondys 53. Both are antisense oligonucleotides, which, when delivered “naked,” in Holles’ words, can face delivery and uptake challenges.
Audentes thinks it has a solution: “Rather than trying to increase efficiency by brute force, we’re taking what evolved naturally in nature: AAVs [adeno-associated viruses],” Holles said. “We package antisense into the AAV and dramatically increase tissue uptake and biodistribution.”
The hope is the treatment will lead the body’s muscle cells to skip faulty sections of their genetic code and produce dystrophin, the protein that is missing or defective in DMD patients. With its programs combined, Audentes believes it will eventually reach 80% of patients with DMD.
Moving forward, Audentes will consolidate its work with Astellas’ suite of AAV gene therapies into a new “genetic regulation” unit. It’s also plugging away at building its GMP capacity so it can keep up with the demand for gene therapies as it starts clinical trials. Construction started this week on a second manufacturing site in North Carolina, Holles said.
As for the horror stories? They’re just that—stories.
“We’ve been hiring like crazy, something like 60 people in the last two and a half months,” Holles said. “We don’t have to fall into the pitfalls of biotech/pharma mergers and we can find a way to take the best of both organizations and create something truly remarkable.”