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Gene therapy is finally poised to revolutionize the treatment of many diseases, but the nascent field is facing challenges -- notably in manufacturing -- that could limit its early success, experts tell 乌鸦传媒.

With two chimeric antigen receptor (CAR) T-cell treatments and two more traditional gene therapies approved, plus a handful of gene therapy products in late-stage trials, excitement is high. But manufacturing bottlenecks, paired with quality control and talent pool concerns, raise questions about the pace of progress.

While there's "a lot of exciting work" in gene therapy, Kelvin Lee, PhD, director of the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), cautioned about what the field can deliver.

"I think it is fair to say that we don't have enough capability to produce gene therapies for many of the diseases that would benefit from them, in part, because of a lack of capacity to manufacture them," Lee told 乌鸦传媒.

While manufacturers are taking measures to boost yield, such as investing in facilities and developing new production techniques, it remains to be seen whether those actions will be enough.

"Gene therapy has the potential to have a dramatic impact on patients with a wide range of serious, life-threatening diseases. The field of gene therapy is certainly growing rapidly and keeping up with the pace of progress will be an ongoing challenge for both industry and the agency," an FDA spokesperson acknowledged in response to questions from 乌鸦传媒.

Industry's Growing Pains in Manufacturing

The main challenge of making gene therapy products is scaling production for commercial use, experts said.

Many gene therapies are borne out of adeno-associated virus (AAV) vectors that deliver functional copies of genes to the patient. These AAV vectors are usually expressed in HEK293 cells that have to be grown in a labor-intensive process requiring much space and equipment.

Only two AAV-based gene therapies are currently FDA-approved: Luxturna in 2017 for a rare inherited retinal dystrophy, and Zolgensma last year for spinal muscular atrophy.

Compare that to the more than 900 investigational new drug applications for ongoing clinical studies in gene therapy, according to a recent FDA estimate.

"The challenge is meeting the capacity for clinical trial material and anticipating the commercial use which the FDA imagines. There may be up to 20 such therapies in the next 5 years," said Barry Byrne, MD, PhD, director of the University of Florida's Powell Gene Therapy Center in Gainesville. "It's a classical economic issue. Insufficient supply and a lot of demand."

Hemophilia A is a notable area where several companies are racing to have their products hit the market first.

Frontrunner BioMarin has reportedly already handed in accelerated approval requests for its "valrox" (valoctocogene roxaparvovec) therapy to U.S. and European regulators. Sangamo and Pfizer are conducting a phase III trial on a product called SB-525, while the status of Spark Therapeutics' closely watched SPK-8001 is uncertain following the firm's December acquisition by Roche (whose current lists two other SPK products for hemophilia, but not that one).

To ease growing pains in late development, gene therapy makers are partnering with contract manufacturing organizations (CMOs) or buying them outright.

For example, Thermo Fisher paid $1.7 billion to buy Brammer Bio, a viral vector CMO, in 2019. That year, Catalent also bought Paragon Bioservices for $1.2 billion, and Astellas bought Audentes Therapeutics for $3 billion.

"There have been large investments in the manufacturing capacity for gene therapy in the U.S. and elsewhere, but much of this has been through the acquisition of CMOs for the internal use of large pharma. Thus the overall capacity has grown, but the availability to the independent academic investigator or small biotech has probably not changed," according to Stephen Kaminsky, PhD, who specializes in genetic medicine at Weill Cornell Medicine in New York City.

It is notable, therefore, that Harvard and MIT are leading plans to build a 30,000-square-foot by 2021. To be located in the greater Boston area (no specific site had been selected when the project was announced 3 months ago), the facility will have reserved laboratory space for promising late-stage research coming out of academic labs and start-ups.

Byrne sees the story of gene therapy development as analogous to that of the revolution in antibody production, which took 10 years to increase capacity and lower costs.

"The problem is that many of these conditions are urgent medical problems. For the patient, 10 years is too long to wait," he said.

Challenges in Quality Control

Manufacturing capacity aside, other challenges in gene therapy include quality control: the FDA has stepped in with a clinical hold when it has found things to go awry with gene therapy development, either in the production or delivery of these products.

FDA already gives gene therapy makers some leeway as it allows use of non-GMP (good manufacturing practice) guideline-adherent plasmids as the starting material when making the AAV vectors used in gene therapy delivery.

Yet Sarepta's phase I/IIa trial for a micro-dystrophin gene therapy was placed on clinical hold in 2018 because of a manufacturing snafu in which "trace amounts of DNA fragment" were found in plasmids from a certain supplier.

The clinical hold lasted a few months . "Specific actions that we took included an audit of the plasmid supplier and a commitment to use GMP-source plasmid for all future production lots," a Sarepta spokesperson told 乌鸦传媒.

"We've been adding key personnel and staff in technical operations and quality assurance to ensure we maintain the highest levels of product quality at every stage of development and commercialization," the spokesperson added.

Thermo Fisher and Catalent also now have expanded relationships with Sarepta. "We are employing a hybrid model where Sarepta's in-house expertise is enhanced by partner capabilities," according to the company representative.

Another company, Regenxbio, had a partial hold briefly placed on its phase I/IIa investigation of RGX-314 for wet age-related macular degeneration. Regenxbio sued the FDA to overturn the clinical hold -- arguing that the problem had nothing to do with the gene therapy itself -- and . The company did not respond to 乌鸦传媒's request for comment.

The FDA slapped a clinical hold on the phase III trial for Invossa-K (a retroviral vector-based gene therapy for osteoarthritis) for missing data, recommending that the Korean manufacturer Kolon Life Sciences also remanufacture part of the product as it still contained residual HEK293 cells.

"Supporting the development and approval of gene therapy products is a significant priority for FDA's Center for Biologics Evaluation and Research," the agency told 乌鸦传媒. "In addition to the regulatory programs that support product development, FDA staff present at and organize educational workshops for gene therapy stakeholders to help advance the science of high-quality manufacturing."

To support industry, FDA recently on gene therapy manufacturing and clinical development. Additionally, a new draft guidance was issued regarding "sameness" of human gene therapy products, which determines orphan-drug designation eligibility.

"We are all learning at this point in time," commented R. Jude Samulski, PhD, of the University of North Carolina School of Medicine in Chapel Hill, who co-founded the biotech company AskBio. "We don't have enough individuals trained in this space."

A Limited Talent Pool

A pioneering gene therapy and rAAV vector researcher, Samulski himself has trained many of the people in the field.

Right now, the available talent pool overseeing manufacturing operations is "definitely limiting. To some extent, skills from other fields of manufacturing will be relevant, but there is clearly a need for more training in the area of gene therapy manufacturing," said P. J. Brooks, PhD, of the NIH's National Center for Advancing Translational Sciences.

Manufacturing is therefore not just about having the physical capacity to make enough products for those who need them, but having personnel that are well-trained to work in manufacturing operations, Lee told 乌鸦传媒.

At , Lee leads a public-private partnership that is dedicated to advancing the technology and manpower in biopharmaceutical manufacturing. Members include government agencies and pharmaceutical companies large and small.

Samulski said he had one post doc take a job at the FDA, which is a NIIMBL member stakeholder.

"There is a general problem at the moment of getting sufficiently trained staff to review gene therapy applications, not only in the review of manufacturing, but all aspects of the FDA review process," according to Brooks.

So just as industry struggles to find the talent to run its manufacturing operations, the FDA too has its work cut out in regulating the field.

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