Peter Maag, PhD, CEO of Kyverna Therapeutics, recalls when people said biologics such as monoclonal antibodies would never work for mass-market applications. “People said that [biologics] are too expensive, require infusion, and are cumbersome to manufacture,” Maag told GEN Edge. “Thirty years later, every other advertisement on TV is on monoclonal antibody therapy.”
Maag believes the same is happening now with cell therapies based on chimeric antigen receptor (CAR) T cells as long as the process is more cost-effective and accessible to patients. To accomplish this, Kyverna and ElevateBio have created Ingenui-T. This proprietary autologous CAR T cell therapy manufacturing process uses a blood draw rather than apheresis to collect T cells from patients.
“I don’t know if you’ve ever been in a CAR T cell lab to see how that’s manufactured, but just think about a boutique garage setting where people run around each other for eight days—that can’t be the future of CAR T cell manufacturing,” said Maag. “We are putting [CAR T manufacturing] on a conveyor belt. It’s our [Ford] Model T, and we are at the conveyor belt stage with more to come.”
Riding impressive momentum from its ongoing clinical trials, Kyverna recently declared its plan to go public behind an initial public offering (IPO) to fund its cell therapy work. (Should Kyverna complete the IPO, its shares would trade on the Nasdaq under the symbol KYTX.) Kyverna is the fifth biotech company to file for an IPO in January, suggesting companies may be more willing to test investors’ appetite for new stock offerings amid recent market optimism. Last year, only 22 drugmakers priced offerings, the lowest total in at least six years.
Karen Walker, Kyverna’s CTO, told GEN Edge that the team has been able to isolate, activate, and expand pure T cells with high functionality into a very potent product, about tenfold more potent than what is produced through the traditional process, in just 72 hours with only 300 mL of blood drawn.
“The current process based on apheresis is very labor-intensive, invasive, and time-consuming,” said Walker. “[Ingenui-T] is a blood draw of less than what you give as a donation.”
Walker said that Kyverna is entering negotiations with the FDA and hopes to use Ingenui-T for clinical trial applications beginning at the end of this year.
Kyverna’s work on Ingenui-T was posted today on bioRxiv without peer review.
Autologous cell therapy for autoimmune indications
Maag was preparing to retire after a long and successful career in biotechnology. He served as executive chairman, president, and CEO of CareDx, growing the company from a small start-up to a public company and an industry leader in transplantation. Prior to joining CareDx in 2012, Maag held several positions at Novartis, including president of Novartis Diagnostics, managing the company’s blood-screening division. He decided to forego retirement when he saw the potential of cell therapy for autoimmune disease.
The story is essentially the same for Walker, who has a successful record that includes developing KYMRIAH® to the pivotal trial stage and submitting the first CAR T Biologics License Application (BLA) in pediatric acute lymphoblastic leukemia (ALL).
Kyverna’s lead program, KYV-101, is an autologous CD19 CAR T cell product candidate made from an underlying CAR that was licensed by the National Institutes of Health (NIH). Kyverna initially focused on lupus nephritis and systemic sclerosis, with two trials underway in lupus and a Phase I/II trial set in systemic sclerosis after the FDA cleared the study plan in October 2023. The company also received approval late last year to undertake Phase II treatment testing in myasthenia gravis.
“We are going for any autoimmune disease that has a strong B cell component to the pathology of the disease because our target is on B cells,” said Walker. “By rapidly bringing down the B cells, even the tissue-resident B cells, we are able to reset the immune system, and then when the B cells come back, based on what we’ve been able to characterize, they are naive and they are not presenting autoantibodies.”
According to Walker, the short-term results of Kyverna’s CAR T therapy in autoimmune disease have been very promising. Even though it’s unclear how this will pan out over the long term, the only way that Kyverna can deliver KYV-101 for MS is with improved CAR T manufacturing.
Given the magnitude of these indications and the fact that these are autoimmune patients, things like apheresis and lymphodepletion, as well as other traditional CAR therapy procedures, create a burden for the patients that will be difficult for them to bear. That’s where Ingenui-T comes in.
“Part of the efforts for tech ops is to industrialize CAR T manufacturing, and we don’t have that yet,” said Walker, whose main project has been to get Ingenui-T across the finish line. “The oncology indications have not forced the industry to industrialize [cell therapy] like antibodies did. So, our thought process in how we designed Ingenui-T was to industrialize this so you can serve millions of patients. We are looking for ways to improve the patient experience while significantly lowering the cost of goods, and ingenuity is that process.”
On January 4, 2024, Kyverna announced the fast-track clearance of its Investigational New Drug (IND) application by the FDA for KYV-101 to treat multiple sclerosis. “This [trial] is important for two reasons,” said Maag. “One, it signals that the FDA has opened up CAR T cell therapy to a mass indication. Two, it is an amazing opportunity for Kyverna.”
The real “patient-centric” McCoy
Myasthenia gravis is a chronic autoimmune disorder in which antibodies destroy the communication between nerves and muscles, resulting in weakness of the skeletal muscles. The autoimmune disorder affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs. In essence, it paralyzes the patient.
Kyverna has a video of a patient—”patient number two”—who had serious myasthenia gravis, was wheelchair-bound, and was in and out of intensive care when she went into a full-blown myasthenia gravis crisis that required intubation. After all treatments failed, she was treated with KYV-101.
Three weeks after the CAR T therapy, she was walking with assistance. Two weeks later, she was riding a bicycle, and a fortnight after that, she was walking with a normal gait. These milestones suggest that the nerve signals to her muscles are working and that the autoantibodies are gone. “Now, she’s hiking mountains, and her husband can’t keep up!” said Walker.
Walker said they have seen a similar recovery in “patient number one,” who was treated in May last year. “She’s completely off all of her medications and is leading a very normal life,” said Walker. “We have six myasthenia gravis patients with very similar stories and outcomes, and so that data helped us file a Phase II in myasthenia gravis in the United States, which was cleared as fast track approval and is open and enrolling.”
All in all, Kyverna has treated patients with several more autoimmune indications. “Our approach is to go rapidly into the clinic with a tried-and-true production process, and once we get clinical proof of concept, then improve the production process to treat patients better,” said Walker. “All the patients I described have been treated with the standard prodigy process utilizing our contract development and manufacturing organization (CDMO), and they are having great outcomes now.”
While Kyverna continues its clinical work, Maag said that establishing relationships with CAR T centers will be a top priority.
“There’s only 220 relevant CAR T centers in the world that will provide care to patients,” said Maag. “Last year was all about safety, safety, safety—demonstrating the safety of autoimmune disease in patients. That’s why [MS] Phase II is so important. But this year, it’s all about the race to build relationships with the CAR T cell centers because they will not entertain the 15, 20, or 30 companies doing CD 19 CAR T. Being first is very important.”
Some may take Kyverna’s small size as a disadvantage for what may prove to be a huge market. But Maag doesn’t think so—he thinks it is an advantage. “At big companies, you’re paid to do nothing wrong, and in small companies, you’re paid to do something right,” he said.
