Gene Therapy CMC Experts On Late-Stage Process Changes
By Tyler Menichiello, contributing editor
At last month’s 16th annual Bioprocessing Summit in Boston, I attended two panel discussions focused on gene therapies. The first was a collection of CMC experts from sponsor companies who spoke about the challenges of commercializing gene therapies, what to expect and consider when it comes to late-stage process changes, and the role new technologies will play in reducing the cost of these therapies.
Interius BioTherapeutics’ senior director of analytical development, James Richardson, Ph.D., moderated the panel, which featured Jinpian Diao-Piezunka, Ph.D., head of technical development at Spark Therapeutics, Phillip Ramsey, SVP of technical operations at Sangamo Therapeutics, and James Warren, Ph.D., SVP of global CMC development at Ultragenyx Pharmaceutical.
Richardson began the conversation by asking the panelists to speak about the challenges of commercializing gene therapies. Reflecting on how far the industry has come, Warren commented how nice it was to be talking about case studies in commercial readiness when just 10 years ago, the conversation at the Summit was around platforms (arguing which one was the best), novel analytics, and how to best get to IND.
Making Late-Stage Process Changes: When And Why?
The key to commercial success, and a guiding principle at Ultragenyx, Warren said, is to minimize process changes along the way — especially going into Phase 3.
“We’ve done that historically, and I think that has served us really, really well over the years,” he told the audience. “The best experience we’ve had globally, from a CMC development perspective, is where we really start with a single platform that we know is ultimately scalable and fully characterized and will avoid a time-consuming comparability campaign.”
Of course, late-stage process changes happen. “Even Luxturna was commercialized with an adherent platform and then changed afterwards,” Richardson said.
One factor that may prompt late-stage or even post-commercial process changes is an increased demand for the drug (and thus, the need to improve manufacturing capacity). Diao-Piezunka pointed to Sarepta’s gene therapy for Duchenne muscular dystrophy, Elevidys, as an example. Elevidys was approved for a label expansion earlier this year, opening up a larger market opportunity for Sarepta. To meet this new demand, Sarepta is improving its manufacturing capacity and transitioning Elevidys production from an adherent process to a suspension process.
Moving therapies into new markets can also prompt late-stage process changes. This is especially true when going into less-developed markets (e.g., in Africa and Asia), where the pricing pressure is much higher than in the U.S. or Europe. “At that point, it’s not just a scale-up-the-capacity-to-meet-demand challenge,” Diao-Piezunka said — you actually need to bring the cost down to make it worthwhile. This is where new technologies or improvements to the manufacturing process can come into play.
However, unless you know for sure that your technology and manufacturing process cannot supply Phase 3 trials or support the initial commercial product launch, it’s best to avoid changes at a later stage, said Diao-Piezunka. Late-stage comparability campaigns sap resources and may disrupt product timelines, so avoid making technology and process changes unless it’s absolutely necessary.
Demonstrating Comparability To Regulators
Having a good, working relationship with regulators can help companies through late-stage process changes and the necessary comparability campaigns, the panelists said. “Like any partnership, it takes time to develop the relationship, and you’ve got to have something to really show,” Ramsey said.
In terms of building this relationship, getting an RMAT (Regenerative Medicine Advanced Therapy) designation can help.
“I think getting RMAT designation is extremely important,” Warren said. “This allows for more frequent discussions on product, including CMC.”
Conversations with regulators should be data driven, the panelists said. Changes to the process — and their impact on product quality — should be well understood and demonstrated with in-vitro and animal data. Therefore, it’s important to make sure your company’s analytical group works closely with the preclinical group, Diao-Piezunka said.
“In my experience recently taking a number of AAV products through CMC development, I have not seen any situation where FDA or other health authorities do not respond very, very favorably to good, strong science,” Warren said. “Even in the absence of perfect congruity between one version of a process and the other.”
New Technologies To Reduce Costs
Right now, manufacturing capacity for gene therapies is limited by technological constraints. While companies can generally meet the manufacturing demand for rare diseases, it will be challenging to do so as gene therapies expand into broader indications with larger patient populations, Ramsey said.
“Some of the programs we’re working on, there’s no way you can make enough with any of the technologies right now,” he said. “You’ll have to scale up. It’ll look like Vacaville for Genentech. It’s going to be 20,000 liters to get there, unless rapid changes occur in the next few years.”
While there is still hope for new producer cell lines and higher-yield clones, the panelists agree: We’re still not there yet. “Some of the major players working on really alternative cell lines kind of stumbled,” Ramsey said. “There’s a little progress, but just not as much. It’s going to be that upfront biology that’s got to happen.”
Diao-Piezunka agreed, saying that despite looking for alternative cell lines, HEK293 still offers the best productivity, “by far.”
The panelists agreed that the answer may lie not in developing new cell lines, but rather in improving what’s already available. The industry needs to apply good bioprocess engineering to gene therapy manufacturing, “just like we did for monoclonals,” Warren said. He believes the biggest opportunity lies in improving purification technology upstream for better capsid separation.
As gene therapies move into broader indications, Diao-Piezunka said, there will likely be more pressure on the industry to put effort into cell line development to reduce treatment costs. However, until that time, a lot of progress can be made to existing platforms.
“For AAV products, I don’t think there’s a best platform out there. I think if you spend enough time working on a given platform, you’re going to make improvements in productivity and product quality,” Warren said. “Good cell line development and also good plasmid engineering are going to be fruitful in improving productivity and improving percent full coming out of transfection.”
The whole field can benefit from the collective effort of companies improving their respective platform technologies. This sentiment was similarly expressed during the second gene therapy panel discussion, which featured leading experts in in CRISPR, prime editing, base editing, and epigenetics. Keep an eye out for my upcoming editorial, where I recap the second panel’s discussion about platform technologies, CMC strategy, lifecycle management, and more.