Why Cell and Gene Therapies Need a Paradigm Shift to Enable Commercial Scale-up

Cell Therapy Research

Cell and gene therapies must scale up on an industrial level if they are to deliver their full potential to patients worldwide, according to speakers at the International Society of Cell Therapy meeting, ISCT Paris 2020 Virtual, May 29.

“As the industry moves from clinical to commercial, we are reaching an inflection point and face key challenges,” Alberto Santagastino, VP, head of the cell and gene technologies business unit at Lonza, said. Chief among them are improving process development and addressing the manufacturing pressures of technology, timeline, and costs. “We need to look at the practicalities of how to make therapies available.”

Traditional therapies experience a rapid increase in demand and then plateau. Curative cell and gene therapies, however, will have a steep adoption curve and an almost equally steep decline as the prevalence peak is treated. Afterward, only new incidences remain.

During the life of the therapy, the cost will decline, if history is to be trusted. He cited monoclonal antibodies as an example. Initially, they cost $30,000 per gram. “Now they cost hundreds of dollars, or less.” Cell and gene therapy developers should assume a similar curve.

When Santagastino talks about the need to industrialize, he really means mass customization rather than the type of industrialization associated with blockbuster drugs. Using a mass customization model, the industry will produce “a single, customized product with the same efficacy as a standard, mass-produced product.”

Embracing that model means focusing early on platforms.

“A major paradigm shift must occur,” he told the ISCT audience, to move cell therapy from what can be done at a clinical center to mass customization. For example, manufacturers need to think about moving to 3D bioreactor manufacturing and away from using viral vectors.

“Process development is the foundation for successful therapy commercialization,” Santagastino continued. He advised thinking very early about how to bring the process to the clinic. This includes determining not only which materials are best for therapeutic development, but also which are readily available in large quantities. Additionally, processes should be designed to they can be completed during one work shift. Allowing a process to extend over multiple work shifts creates difficulties, he said.

Take CAR-T therapies, for example. Autologous therapies differ batch to batch, so standardization is difficult. Developers must deal with the challenges of ensuring T-cell quality, patient health (or death while waiting for the therapy to be developed), commercial viability, scale-up, harvesting and manufacturing failures as well as supply chain issues. At the end of it all, Santagastino said, “Wide batch-to-batch variability indicates you’re not in control, and that distresses regulators.” Lonza is addressing that challenge with an automatic, scalable, single-used system, dubbed Cocoon, for improved process control.

An alternative solution to autologous challenges is to develop allogeneic therapies. They have challenges, too, in the form of multiplex gene editing, scale-up and manufacturing, large-volume downstream processes, purification, quality and GMP tissue sourcing.

For allogeneic therapies, Lonza is addressing the donor variability issue with a pool of what it calls “well-characterized super donors.” It’s also developing a scalable closed bioreactor system to address many – but not all – of the remaining issues, both upstream and down.

Whichever approach is used to develop cell therapies, Santagastino recommended taking a holistic approach that includes developing an automated quality system, addresses manufacturing variability and considers the entire supply chain.

When Novartis developed Kymriah® (tisagenlecleucel), its CAR-T therapy for oncology, it took a comprehensive approach early on. With such a complex and innovative type of therapy, it understood the value of involving multiple stakeholders early on. Therefore, the company worked closely with its scientific partners, regulators, payers and the physicians in clinical trials throughout the development process, Emanuele Ostuni, Ph.D., head of cell & gene therapies Europe at Novartis Oncology, pointed out in a following presentation.

The delivery of autologous therapies is very different from traditional drug development. “It creates a host of issues and a need to do things pharma hasn’t done before, like providing full customer support,” he said at the ISCT meeting.

Dr. Ostuni, therefore, called for a seamless, integrated approach to delivering autologous therapies, similar to the white glove services available for consumer products. This means providing full-circle customer support with live customer service in multiple languages, a secure and user-friendly web portal and a trusted chain of identity as cells are drawn from patients, shipped to manufacturers, reprogrammed and expanded, shipped to caregivers and re-infused into patients.

The global access to this autologous therapy expands the demands, but also adds value to the product. “Broad global access helps ensure the value of our therapies is recognized,” Dr. Ostuni explained. In launching globally, Novartis remained flexible, working with payers who “each have slightly different needs and approaches” to ensure the therapy was reimbursed.

From a payer’s perspective, cell therapy is unlike traditional drugs. Traditionally, payers collect one-year, budgetary data on a drug, but data from cell therapies should be analyzed over multiple years. That’s why some payers balk at therapies that are initially expensive but are cost-effective in the long-term.

“That difference creates the need for a lot of innovation to ensure the value of the therapy is recognized and that a sustainable commercial arrangement is developed,” Dr. Ostuni said. “This isn’t how most diseases are managed, and payers aren’t used to it.”

“Innovation must happen on multiple fronts,” he emphasized. For CAR-T therapy at Novartis, this meant addressing immunogenicity by using humanized constructs, safety by ensuring early anticytokine activity, resistance by targeting the tumor microenvironment and relapse by combining two CAR-T products for better targeting.

Along the way, manufacturing had to be improved to ensure scalability for this allogeneic off-the-shelf product. “Scaleup is critical,” Dr. Ostuni said. “We invested the effort and capital to ensure a broad manufacturing network to supply regions of the world and thus simplify logistics. We have a multi-source environment,” so an emergency at one facility won’t negatively affect supplies. “Two European facilities are coming on line in a few months, and more will be online later.”

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