showed signs of inducing the patient’s own immune system to stand down instead of attacking the engrafted organ. The donor’s blood-forming cells migrate to the patient’s bone marrow, where they make cells that mix in with the patient’s own blood cells.
To design her treatment, Ildstad focused on what are known as “facilitating cells,” which help shepherd donor stem cells to the patient’s bone marrow and stay there. She found that these facilitating cells help promote immune tolerance and thus, if harnessed, might reduce the risk that the patient’s body rejects the new organ.
The procedure that her company came up with is this: Collect stem cells and facilitating cells from the blood of a living kidney donor via an outpatient procedure done a few weeks before a kidney transplant. Combine them through a manufacturing process that “strips out” potentially damaging components, then freeze the sample and ship it back to the treating physician, Ildstad says. A day after the kidney transplant, give the patient a low-dose chemotherapy step known as “nonmyeloablative conditioning” that prepares the patient’s bone marrow to get the donor cells without destroying the host’s own bone marrow cells. The new cells are then infused into the patient, where they head to the bone marrow to start making white and red blood cells containing the donor’s genes.
If all goes well, the body will view those newly made cells as its own instead of as foreign invaders, and likewise tolerate the donated organ, allowing a patient to be weaned off drugs that would otherwise be needed to keep the patient’s immune system in check. Ildstad believes this protective effect occurs because the facilitating cells don’t just chaperone donor stem cells to the host’s bone marrow, but also switch on certain biological “processes,’’ maybe that “train both immune systems” to tolerate the donated kidney. She acknowledges, though, that the mechanism behind FCR001 isn’t fully understood. “Immunology is a very complicated field,” she says.
Ildstad spent years trying to advance this work at Regenerex, raising “substantial” funding (she wouldn’t specify how much), not from venture capital firm investments, but grants from the National Institutes of Health and the US Department of Defense. That gave her enough backing to start a Phase 2 study in 2009 to test the procedure in kidney transplant patients.
In 2012, she published results in Science Translational Medicine showing that five of the first eight patients had been weaned off immunosuppressive drugs. The data intrigued Novartis, and the partnership that resulted helped Regenerex immensely, though it was short-lived. The Swiss firm, in 2016, chose to end all cell and gene therapy research not associated with oncology. But Novartis helped build up Regenerex’s manufacturing capabilities and complete the Phase 2 study. That manufacturing site is up and running in Louisville, ready for the next test, Requadt says.
By 2016, seven years after the study began, 37 patients had been treated with FCR001. Regenerex found that 26 of them—many of whom were not perfectly matched to their donors—were surviving without immunosuppressive drugs. Three years later, those numbers have stayed the same. As of today, the patients have been tracked for a median period of five years, and in some cases, as long as 10. The lengthy follow-up is key: As with any gene or cell therapy, a durable effect is critical for FCR001 to prove its worth.
There have been two cases of graft versus host disease in the FCR001 trial; one patient died as a result. Still, without divulging specifics, Requadt says the company has found common characteristics in those two cases that made them more likely to develop the disease; those types of donors and patients will be excluded from the Phase 3 study, he says.
Taken together, the data hooked Requadt, a longtime biotech investor, spurring him to bring in Blackstone and ultimately lead the company, now known as Talaris, which has opened a Boston office. He’s envisioning the technique being used not just for kidney transplants, but also for other organ transplants and even as a possible one-time, long-lasting treatment for autoimmune diseases (he wouldn’t say which ones, though Ildstad, at an investor meeting last year, mentioned scleroderma). Other Phase 2 studies could start this year. “I thought this was such a compelling story that I wanted to become a part of it,” he says.
There are several questions ahead for Talaris. Among them: Will the new cells cause unintended problems, asks Czechowicz? Will the chemotherapy step lead to too much additional risk? Can Talaris’s new clinical trial reproduce what the company has seen in the Phase 2 trial? And if so, how broadly effective will FCR001 be?
“It’s still early to know how this will pan out for many patients,” Czechowicz says. “But their data is promising and reassuring and really addresses a critical need.”
At minimum, however, Ildstad now has a chance to see her work through. She laughs when asked about waiting so long to get that shot. “Everybody is really excited,” she says. “Word is spreading among the patients. We’ve got people on a list ready to enroll.”
