Novartis, still struggling with Kymriah manufacturing, is providing some out-of-spec doses to patients who ask

Novartis released some new data on CAR-T drug Kymriah this month that it hopes will improve the uptake of the drug. But Novartis also continues to wrestle with manufacturing issues that have kept some doses from meeting specifications, a problem that is also hampering Kymriah sales.

The drugmaker says it is working on a list of improvements to the process but acknowledges that some doses are still not meeting specifications, a problem that Liz Barrett, CEO of Novartis Oncology, outlined earlier this year to shareholders. She said there was an issue around cell variability when treating relapsed large B-cell lymphoma that involved the number of inactive cells which has sometimes resulted in the drug being out of spec from the commercial specs.

Barrett said most of the patients were getting the drug. But given the seriousness of patients getting Kymriah, some doctors want to use the drug on patients even when the specs are not exact. The company confirmed a report from BioPharmaDive that under its compassionate care program it has been providing the out-of-spec drug to patients when their doctors request the last-ditch treatment, but it just can’t charge them.

"Our ultimate goal is to successfully manufacture our transformative therapy Kymriah for every patient in need," spokeswoman Julie Masow said in an email to FiercePharma. "At this time, in agreement with the FDA and at the request of treating physicians, we are providing products that do not meet commercial specifications but are expected to maintain the risk/benefit profile observed in clinical trials through different channels as compassionate use."

The manufacturing process is very complex, requiring that blood be taken from a patient, cryopreserved, shipped to a manufacturing facility, reprogrammed and manufactured in the lab, and then shipped back for infusion into the patient, all in the shortest time possible to try to outrun aggressive cancers.

Masow explained that Novartis is talking with regulatory authorities about the "potential evolution of our commercial specifications in line with clinical trials experience." Meanwhile, the drugmaker is tweaking its process and making "incremental gains" toward that goal.

Those efforts include working with Intellia Therapeutics to investigate allogeneic or so-called off-the-shelf CAR-T cells using CRISR-Cas9 gene editing. It is also internally investigating switchable technologies to control activity of CAR-Ts and limit side effects.

"We continually are making improvements to our manufacturing process to increase efficiency and reduce variability," Masow continued. We are pursuing automation of the CAR-T manufacturing process in a controlled and deliberate manner, initially targeting the parts of our process that require the most manual labor and have the highest potential for variability, to increase consistency while continuing to ensure a safe and high quality final product."

Over the long term, Novartis hopes to automate much of the process, including creating a custom-built system that would consolidate a range of blood processing equipment into one automated unit.

While sales right now have been sparse, just $48 million in the first three quarters of 2018, the drugmaker is still looking toward global acceptance of the drug and is expanding its manufacturing facilities beyond the initial one in Morris Plains, New Jersey. It has plans to open a site in Stein, Switzerland, to offer additional manufacturing capacity for Kymriah in Europe. It also has agreements with a number of contract manufacturers to add capacity around the world, including with Cellular Biomedicine Group to manufacture and supply Kymriah in China.

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