When Novartis dissolved its gene and cell therapy unit a few years ago, a bunch of projects the Swiss pharma giant had incubated were tossed aside. One of them was the work of surgeon Suzanne Ildstad, who has spent decades trying to develop a new way to improve the health outcomes of patients who need organ transplants.
That work has just been salvaged. If it plays out as Ildstad hopes, her company might not only help transform treatment for kidney failure patients—but possibly, for people suffering from other illnesses, such as autoimmune disorders.
Talaris Therapeutics, a Louisville, KY, startup founded by Ildstad (pictured) in 2002 and long known as Regenerex, has secured a $100 million Series A investment led by Blackstone Life Sciences, the biopharma investing arm of private equity firm Blackstone Group. The cash breathes new life into an experimental cell therapy known as FCR001, a one-time treatment meant to make it possible for patients who need a kidney transplant to get one from any donor—without the need for a life-long regimen of immunosuppressive drugs afterwards to prevent rejection of the outsider’s organ. There may be a significant bonus effect—the treatment might also block the continuing threat from underlying autoimmune diseases that, in some patients, caused their own kidneys to fail in the first place.
Ildstad has already tested the technique in humans and seen some promising results. But the work had stalled amidst the cell therapy unit’s revamp at Novartis, which licensed the technology from Regenerex in 2013. With the new cash, Talaris can now fund a Phase 3 study that should start by the end of the year, says CEO Scott Requadt, a former Clarus Ventures managing director and, most recently, a Blackstone venture partner.
There are more than 113,000 people currently on the waiting list for organ transplants in the US alone, and 84 percent of them (94,973) need a donor kidney because one of their kidneys has failed, according to the Organ Procurement & Transplantation Network. The nonprofit group Donate Life America estimates that patients have to wait an average of three to five years for a kidney from a deceased donor.
The wait is shorter—a year or less—if a workable living donor is found, and volunteers. But securing the right organ is still very difficult. Patients have to be “matched” with a donor, a complex process that involves a variety of factors. One of them is finding compatibility between both parties’ immune systems, a test known as “HLA (human leukocytic antigen) typing.” The more mismatched patients are—and a perfect match is rare—the more likely the body will see the donated organ as a threat, and try to destroy it—a condition called graft versus host disease. This threat of rejection is why many transplant patients have to take immunosuppressive drugs for life.
Those drugs come with a cost, something Ildstad—a longtime transplant surgeon, director of the Institute of Cellular Therapeutics, and a professor of surgery at the University of Louisville—has seen first-hand. Suppressing a patient’s immune system with drugs can lead to heart problems or malignancies, and boost the risk of dangerous infections. Heart disease was the leading cause of death among US kidney transplant recipients between 1996 and 2014, according to a paper published last year in the American Journal of Nephrology. “Transplants are wonderful and life enhancing, but the immunosuppressive drugs really take their toll,” Ildstad says in an interview.
Scientists have spent decades trying to find ways to get our bodies to tolerate implanted donor organs—to accept that two kinds of genetically different tissues, from donor and recipient, are inhabiting the same body, a condition called chimerism.
Agnieszka Czechowicz, an assistant professor of pediatrics at Stanford University’s Division of Stem Cell Transplantation and Regenerative Medicine, who isn’t associated with Talaris, notes that the field has made strides. “Various [academic] groups,” she says, have shown that tolerance to transplanted solid organs is possible through cell therapy procedures and other methods. This 2017 paper in the Journal of Organ Transplantation, for instance, highlights some of those efforts at Stanford, Northwestern University, Massachusetts General Hospital, and elsewhere.
Such a therapy, if shown to be safe and effective, “would be a game changing thing for patients,” she says. But it’s been tough to scale that work up and test it in studies large enough to prove their worth.
“Now these efforts are trying to get more rigorous,” Czechowicz says.
Ildstad’s FCR001 is among those efforts, and it’s been in development since she founded her company in 2002.
In her treatment approach, patients not only receive a donor’s kidney, but they also receive an infusion of the same donor’s stem cells and other cells, which in Talaris studies have 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.”