When cell therapy first reached patients as targeted treatment for the toughest cases of blood cancer, scientists thought this novel therapeutic modality might also find use in autoimmune conditions. The challenge was making these therapies safe enough for people who aren’t nearly as sick as cancer patients. Better safety is built into the design of Kyverna Therapeutics’ drug candidates, and the biotech has raised $319 million from its IPO to finance clinical testing of a pipeline currently focused on rheumatology and neurology.
Kyverna found strong investor interest as the biotech was able to price its offering of 14.5 million shares at $22 each, which was above the $20 to $21 per share price range it set earlier in the week. After starting trading on the Nasdaq Thursday under the stock symbol “KYTX,” Kyverna shares soared as high as $35.03 before giving up some of those gains and finishing the day at $30 each, up 36% from the IPO price.
Kyverna was founded in 2018, less than a year after the first FDA approved the first CAR T-cell therapies for cancer. In an interview, CEO Peter Maag said the startup’s scientists were reading through some of the early cell therapy findings and working with the National Institutes of Health on applying this type of therapy to autoimmune diseases. Improving safety is key because the adverse effects of cell therapy, including an excessive immune response called cytokine release syndrome as well as neurotoxicity, might be acceptable in cancer patients who are facing death. But autoimmune disease patients don’t have the same risk tolerance.
“These patients have been sick for five and 10 years, receiving multiple lines of therapies,” Maag said. “They will live with their disease another 10 and 20 and 30 years. It’s very different than oncology.”
Cell therapies are made by harvesting a patient’s T cells and engineering them in a lab to express a chimeric antigen receptor—the “CAR” in CAR T-therapies. For the first cancer cell therapies, the CAR’s target is CD19, a protein highly expressed on cancer cells. After those cells are multiplied in a lab, they’re infused back into the patient. Emeryville, California-based Kyverna makes its CAR T-therapies the same way, and they also target CD19. But this protein is also found on B cells, a type of immune cell that drives some immune-mediated disorders. Kyverna’s therapies are intended to deplete these B cells.
What makes Kyverna’s therapies different than the first generation of cell therapies is a CAR designed to improve safety and tolerability. This CAR was licensed from the NIH, which had tested it in a 20-patient Phase 1 clinical trial. Results showed that this therapy produced lower levels of inflammatory cytokines and neurotoxicity compared with Yescarta, the Gilead Sciences CAR T-therapy that won FDA approval in 2017. The improvement in safety and tolerability was achieved without compromising the therapy’s antitumor effects.
The first indication for Kyverna is lupus nephritis, a kidney disease that develops in lupus patients. Kyverna estimates that the U.S. has up to 40,000 lupus nephritis patients whose disease is resistant to current therapies, placing them at high risk of developing kidney failure.
Lead Kyverna program KYV-101 has begun a Phase 1 test in the U.S. and Phase 1/2 testing in Europe. Kyverna also has clearance to begin testing this therapy in systemic sclerosis. In neurology, the company plans to test KYV-101 in multiple sclerosis and myasthenia gravis, a rare neuromuscular disorder. Kyverna has the FDA’s green light to begin clinical testing in both indications.
Kyverna revealed itself to the world in 2020, announcing a $25 million Series A financing and a collaboration with Gilead Sciences initially focused on developing cell therapies for Crohn’s disease and ulcerative colitis. That research initially pursued regulatory T cells, or Tregs, but nothing advanced to human testing. Maag said Kyverna shifted its focus to CD19-targeting CAR T-therapies. More research is needed in Tregs, whereas the targeting of CD19 with cell therapies is now proven science, he explained. Maag left the door open to revisiting Tregs, but said Kyverna’s current focus is developing CAR T-therapies. The IPO filing shows Gilead terminated both of the partnered programs in 2022; the alliance formally ended late last month.
Kyverna has another alliance with Intellia, which has granted the biotech rights to use its CRISPR technology to engineer allogeneic, or off-the-shelf, CAR T-cell therapies based on cells from healthy donors. Crohn’s disease and ulcerative colitis are among the potential indications for KYV-201, the partnered program currently in preclinical development. This partnership may also extend to the development of Tregs. Maag said Kyverna aims to bring an allogeneic CAR T-therapy into the clinic in the fourth quarter of this year.
Allogeneic cell therapies would overcome some of the manufacturing hurdles facing the cell therapy field. Making a bespoke treatment from a patient’s own cells can take as long as a month. Having readily available therapies made from donor cells would reduce the manufacturing costs. They would also save on time, which is particularly important for cancer patients whose disease can worsen while they await treatment.
Autoimmune disease does not come with the same rapid progression as cancer, and therefore has less manufacturing urgency, Maag said. A potentially more important benchmark is showing improved efficacy versus current autoimmune therapies. Patients can experience poor or mixed results with antibody drugs, such as Genentech’s Rituxan. Kyverna contends those results are due to poor tissue penetration. Maag said Kyverna’s therapies can get deep into tissues that antibody drugs cannot penetrate. The goal is to clean out those B cells, allowing for the immune system to reset, like rebooting a computer, he said. But that level of efficacy will need to be proven in clinical trials.
Though Kyverna’s cell therapy is designed for better safety, the class of cell therapies does have safety risks that antibody drugs don’t. Last year, the FDA began investigating cases of secondary cancers in patients who had received a CAR T-cell therapy in clinical trials and in real world use. The agency is now requiring manufacturers of these therapies to update their labels to reflect this risk. Maag said cancer is a theoretical risk of a cell therapy for autoimmune disease, but he added that cancer patients are much different than autoimmune disease patients. For example, the immune systems of cancer patients are heavily suppressed, placing them at higher risk of developing complications. The risks in autoimmune disease still need more study, he said.
Kyverna said in the filing it had raised $170 million prior to the IPO. Its most recent financing was a Series B round that was extended by $60 million last summer, bringing the round’s total to $145 million. The company’s largest shareholders are Vida Ventures and Westlake Village BioPartners, each holding an 11.1% post-IPO stake, according to the prospectus.
As of the end of the third quarter of 2023, Kyverna reported a cash position of $22.9 million. That capital, along with the IPO proceeds, will be used to continue development of the biotech’s pipeline. According to the filing, Kyverna plans to spend about $180 million for clinical development of lead program KYV-101 in rheumatology and neurology, including the completion of Phase 1 testing and the start of enrollment of a Phase 1/2 study. No timelines were given for those studies.
Kyverna also plans to start enrolling an open-label Phase 1/2 study evaluating KYV-101 in systemic sclerosis, a Phase 2 test in myasthenia gravis, and a Phase 2 test in multiple sclerosis. About $30 million is set aside for KYV-201, the partnered Intellia program, which the company aims to bring through preclinical testing and clinical development. With the IPO proceeds, the company expects it will have enough capital to fund operations into 2026.
Photo: Kyverna Therapeutics