In the race to turn CAR-T cell therapies against autoimmune diseases, Cabaletta Bio has always been blazing its own trail.
The Philadelphia-based biotech is edging closer to its ambition of submitting its autologous CD19-directed CAR-T resecabtagene autoleucel (rese-cel) for approval in the second half of next year to treat myositis, a condition characterized by inflammation of the muscles. A registrational study in that indication is already enrolling, with Cabaletta also running a series of other autoimmune studies across its RESET program for indications like systemic sclerosis and lupus.
The company arrived at the European Alliance of Associations for Rheumatology (EULAR) conference in London on Wednesday armed with updates from across this program, including data from two patients that back up Cabaletta’s theory that rese-cel could ultimately be administered to patients without the chemotherapy preconditioning usually required to wipe out a patient's existing lymphocytes.
“Typical chemotherapeutic agents used for certain oncology indications [were] always thought to be required to do CAR-T for a variety of reasons,” Cabaletta’s Chief Medical Officer David Chang, M.D., told Fierce in an interview on the conference sidelines.
The theory that offering higher doses of a CAR-T can avoid the need for preconditioning in autoimmune patients isn’t a new one, “but we’re the ones who are actually exploring it,” Chang said.
The benefits to patients are twofold, he explained.
“Number one: you eliminate two toxic drugs, which provides for potentially safer administration of the CAR-T,” Chang said. “Number two: you eliminate the inconvenience, because there's usually three days that you need to go in—even as an outpatient—and get this preconditioning.”
Cabaletta’s Chief Business Officer Arun Das, M.D., is hopeful the biotech will have a two- or three-year head-start in exploring this potential as other autoimmune CAR-T players begin to take an interest.
“I think the biggest difference is that most of the players who came to autoimmunity were those that pivoted from oncology. In the oncology space, there are many more reasons why preconditioning may be needed in order to drive responses,” Das told Fierce in the same interview.
“When you come from that paradigm and you shift into autoimmunity, I think it can be harder to remove some of those experiences from your thought process,” he added. “For us, from the beginning, we felt like pre-conditioning … may not be necessary.”
The company has previously reported data from the first four patients with a rare autoimmune disease called pemphigus vulgaris (PV) who received rese-cel without preconditioning. Despite the patients starting at a low dose, the company’s leadership was “pleasantly surprised” by the results, according to Chang.
“Three out of four are seeing B-cell depletion, are seeing evidence of CAR-T expansion, and we're seeing evidence of clinical responses,” he explained. “And the fourth patient had a partial response and partial B-cell depletion, so not quite as good as the other three.”
Cabaletta has since begun to test the theory in lupus patients, bringing initial translational and safety data from the first two patients in this cohort to EULAR. One of these individuals experienced deep B-cell depletion, while the second patient’s data was less impressive but still showed a reduction in peripheral B cells of around 90%.
When it comes to treating autoimmune diseases, durability of the treatment is key. While it’s easier to ensure this sort of peripheral depletion of B cells, the bigger task is nailing complete depletion in the soft tissue or secondary lymphoid organs, Chang said.
“We think we’re near the right dose, but we’re not quite there yet,” he added. For this reason, Cabaletta is already exploring a higher dose in patients with PV.
These encouraging early signs in removing the burden of preconditioning won’t impact the company’s approval plans in the near-term, however. The biotech is currently enrolling patients in the registrational myositis study—which does include preconditioning—with topline data expected mid-2027.
The trial will be split between 14 patients with dermatomyositis, which affects both the muscles and the skin, as well as three patients with another rare autoimmune disorder called antisynthetase syndrome.
While the trial’s population is very small, the FDA has been understanding of the study’s design, which will see patients come off all of their immunomodulator medicines and any higher doses of steroids for 16 weeks.
“If you have to get a single dose of immunomodulators over the duration of follow-up—no matter how much you improve clinically—you don't hit the clinical endpoint,” Das said.
Cabaletta also announced this week that the approval submission will include some data from juvenile dermatomyositis patients, which should help the company secure a priority review voucher from the FDA.
But even if Cabaletta can speed along rese-cel’s journey to regulators next year, it’s unlikely to be the first CAR-T to score an approval for autoimmune disease. That prize looks set to be taken by Kyverna Therapeutics, which has already launched a rolling submission of mivocabtagene autoleucel (miv-cel) for stiff person syndrome.
Kyverna was also a presence at EULAR, unveiling updated data from a phase 1/2 study in rheumatoid arthritis that exceeded analysts’ expectations.
While Cabaletta may not be first to market with an autoimmune CAR-T, the company has already been preparing for its own launch by building out its manufacturing capacity via contracts with multiple CDMO suppliers. The biotech has also been thinking even bigger, working with Cellares to potentially use its automated platforms to manufacture rese-cel at scale further down the line.
“Cellares com[ing] on in a post-approval expansion enables us to—as our capacity and demand is expanding—have another supplier to … scale quickly to meet the demand,” Das said.
These big approval plans require significant funds, and Cabaletta recently brought in $150 million via a stock offering to the likes of Bain Capital Life Sciences and Eli Lilly. Added to the $116 million that the company had to hand at the end of March, Cabaletta expects to be able to fund its plans into mid-2027.
But with approval expected just beyond the end of that cash runway, would Cabaletta consider turning to a Big Pharma to provide the financial support and expertise to ensure rese-cel realizes its potential?
“If an opportunity comes that facilitates us developing more safely, more efficiently for patients, we will always take into consideration that opportunity—but this is not a built-to-sell or built-to-move enterprise,” Das said.
“This is a group of people who came together last decade and wanted to make a fundamental transformation in how autoimmune patients are treated,” he added. “And we’re excited that we’re doing that.”
In true CMO fashion, Chang turns to the science to explain why Cabaletta’s leadership are in it for the long haul.
“Just like CAR-T [responses], we're looking to have a long-term durability,” he told Fierce.