In CAR-T, manufacturing a hurdle Novartis has yet to clear
SAN DIEGO — Swiss pharma Novartis says it has made progress remedying production issues that have hampered commercial roll-out of its cancer cell therapy Kymriah in lymphoma.
Yet, about eight months on from securing a second approval for Kymriah (tisagenlecleucel), the company is still delivering the CAR-T treatment to some patients for free, unable to charge for a product that — while OK for use in patients — doesn't meet stricter specifications established for commercial use.
"We've made significant progress in understanding the root cause, the reason for these challenges in some patients," Pascal Touchon, the pharma's head of cell and gene therapy, told BioPharma Dive in an interview at the annual meeting of the American Society of Hematology.
"We are engaged with the FDA, EMA, other regulatory authorities to change the specification to be more in line with the reality of the data we have today," Touchon said, noting the pharma has also made improvements in its production process.
While technical, Novartis' issues are an example of the difficulties in transforming a complex, individualized treatment into a commercial product. Sales to date of Kymriah have been modest, falling short of expectations from some on Wall Street.
For its part, Novartis paints Kymriah as a longer-term journey, part of a broader bet on cutting-edge, complex therapies.
As a CAR-T therapy, Kymriah is made from patient immune cells, which are genetically engineered outside the body to express a receptor capable of locking onto tumor cells.
In Novartis' case, the company has been able to produce sufficient quantities of the re-engineered cells to make a dose of Kymriah for lymphoma. Along with those CAR-T cells, however, have come inactive, senescent cells that change the percentage of viable cells in a dose of Kymriah, putting the product out of specification.
"All the product we deliver to patients, be it commercial or investigational, we have the dose," Touchon said. "The challenge is more around the percentage of viable cells."
Patients eligible to receive Kymriah are very sick, relapsed from or refractory to other treatments for their aggressive diffuse large B-cell lymphoma (DLBCL). CAR-T cell therapy can be a last option.
To ensure these patients still receive their personalized treatment, Novartis has arranged for the out-of-specification Kymriah to be delivered through either an expanded access program or through compassionate use. Both the treating physician and the Food and Drug Administration have to sign off on use, explained Touchon.
The problem isn't the first manufacturing snag Novartis has hit. In studies of Kymriah in adult lymphoblastic leukemia — its first approval — and in lymphoma, between 7% and 9% of studied patients didn't receive the CAR-T product due to manufacturing failure.
By comparison, only 1% of patients in rival Gilead's study of its CAR-T therapy Yescarta (axicabtagene ciloleucel) were unable to receive a dose due to manufacturing failure.
Through the first nine months of 2018, sales of Kymriah have totaled $48 million. Part of that stems from launching first in pediatric ALL, which represents a much smaller patient population than DLBCL.
Wall Street analysts have wondered, though, if Novartis' manufacturing issues have resulted in lower sales.
"It's hard to tell where we would be if we didn't have the challenges, but I think that what we've seen is that centers have continued to order Kymriah despite this and because they really think it's important for their patients to get Kymriah," said Elizabeth Barrett, Novartis' head of oncology, on a third quarter earnings call.
What is certain is that Novartis has made a concerted effort to build out its global manufacturing network to support CAR-T production. Currently, the pharma makes Kymriah out of a site in Morris Plains, New Jersey.
Novartis has also inked deals with French CDMO Cell for Cure and Cellular BioMedicine Group in China to help bolster Kymriah supply, while announcing plans to invest about $90 million in cell and gene therapy manufacturing in Switzerland.
"We are in a learning phase in this field. Not only we at Novartis, but other companies, regulators, patients, physicians," Touchon said. "Our vision is that it's a five-year journey."
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