Landmark Approval of Kymriah Won, Novartis' Next Test Is Scaling CAR-T Manufacturing

Company faces the challenge of proving the complex treatment can be manufactured and administered at commercial scale

As the case for CAR-T's clinical efficacy grew, one of the central questions for biopharmas like Novartis and Kite Pharma, Inc., became whether the remarkable technology would be commercially reproducible, according to a recent BioPharma Dive article.

Due to the personalized nature of each dose of CAR-T treatment, manufacturing and selling CAR-T therapies presents unique logistical hurdles that will test the ability of Novartis and others following it to scale beyond clinical studies.

In marketing tisagenlecleucel (Kymriah), Novartis will need to both successfully manage a logistics network under tight time constraints and manufacture highly personalized treatments, the article said.

Given the high-profile nature of the space, any setbacks will be scrutinized heavily—especially since Novartis has priced tisagenlecleucel at $475,000 per patient. While the company plans to collaborate with the federal government on an outcomes-based approach to payment, it will be particularly challenging if Novartis runs into difficulties keeping up with demand.

Over the next month, Novartis plans to initially introduce tisagenlecleucel to 20 treatment centers, expanding that network to 32 centers by the end of the year.

For each center, Novartis will handle onboarding directly, training medical staff on how to extract and re-infuse patient white blood cells as well as manage the common side effects to CAR-T therapy.

Cells collected from patients in those sites will then be shipped to Novartis' production facility in Morris Plains, New Jersey. For this part of the process, Novartis will use cryopreservation to protect the cells during transport, the article explained.

In manufacturing tisagenlecleucel, Novartis will need to take individual patient cells—by definition heterogeneous raw material—and reliably transform those cells into a potent and consistent CAR-T therapy.

Novartis says its cell processing takes between 10 to 12 days. Add on quality assessments and transportation, and the total time from cell extraction to re-infusion should take on average about 22 days, according to the company.

Shortening turnaround times as much as possible is particularly essential given the patient population Novartis aims to treat. Tisagenlecleucel was approved for pediatric and young adult patients with refractory B-cell acute lymphoblastic leukemia (ALL) that has relapsed more than twice. These patients have largely run out of options and don't have time to spare for manufacturing or logistic delays.

In other clinical trials in lymphoma patients, Novartis was unable to manufacture tisagenlecleucel for nine out of 141 patients, although the company says that was largely due to insufficient starting material extracted from patients. Subsequently, over the last 30 patients treated in Novartis' JULIET study, the pharma notched a 97% manufacturing success rate.

These improvements have helped build confidence both at Novartis and among analysts and investors that the company will be able to meet the demands of a controlled rollout for the treatment.

Novartis has also inked partnerships with Oxford BioMedica plc and Cryport, Inc., to ensure commercial supply of lentiviral vectors used in tisagenlecleucel manufacturing and to add cryogenic logistics support, respectively.

While Novartis will be first, Kite looks set to follow soon behind. The biotech's CAR-T therapy axi-cel (axicabtagene ciloleucel) is currently under review at the FDA for approval in diffuse large B-cell lymphoma.

If approved, Kite will face similar challenges as Novartis and has extensively prepped its manufacturing and supply capabilities ahead of an FDA decision. Company executives say they will be able to support a vein-to-vein turnaround time for their CAR-T of between 16 and 18 days, according to the article.

Source: BioPharma Dive; August 31, 2017.