Talaris is now moving into a final phase 3 clinical trial before applying for FDA approval. Known as Freedom-1, this trial has 17 sites open across the United States, and Talaris will enroll a total of 120 kidney transplant recipients. One day after receiving the donor’s kidney, 80 people will undergo the company’s treatment, including donor stem cells and other critical cells processed in their facility. Forty people will undergo a regular kidney transplant and will remain immunosuppressed to provide a control group.
Susan Eldstad pioneered the procedure for decades as a faculty member at the University of Pittsburgh before becoming the founding CEO and then chief scientific officer of Talaris. If the FDA approves this method, it could soon become the standard of care for patients who need a kidney transplant.
“We are working on a way to reprogram the immune system of a transplant recipient so that it sees the donated organ [belonging to one]”The self and don’t attack it,” explains Scott Ricorat, CEO of Talaris. “This obviates the need for lifelong immunosuppression.”
Each year, there are approximately 20,000 kidney transplants, making the kidney the most transplanted organ. About 6,500 of these come from living donors, while deceased donors give close to 13,000.
One challenge, Ricade notes, is that kidney transplant recipients are not always aware of all the effects of immunosuppression. Typically, they will need to take about 20 anti-rejection drugs several times a day to suppress the immune system as well as treat complications caused by the toxicities of the immunosuppressive drugs. Side effects of chronic immunosuppression include weight gain, high blood pressure, and high cholesterol. These cardiovascular comorbidities are “more often the cause of death than failure of a transplanted organ,” Ricorat says.
Patients who are chronically immunosuppressed have significantly higher rates of infections and of cancers that have an immune component, such as skin cancers.
Over the past two years, these patients have experienced heightened anxiety due to the COVID-19 pandemic. The immunosuppressive drugs used to protect their new organs also make it difficult for patients to build up immunity against foreign invaders such as COVID-19.
A study appearing in the Proceedings of the National Academy of Sciences found that the probability of a pandemic with an impact similar to COVID-19 is about 2 percent in any one year, and estimated that the probability of a new outbreak would grow threefold the next day. Few decades. All of this is all the more reason to select an FDA-approved alternative to harsh immunosuppressive drugs.
Of the 18 patients during the phase 2 research trial who received Talaris, did not take the immunosuppressive drug and were vaccinated, only two ended up with a COVID infection, according to a data review. Among patients who needed to continue taking immunosuppressants or those who did not get them but were not vaccinated, infection rates were between 40 and 60 percent.
In Talaris’ previous phase II study with 37 patients, the combined transplant approach allowed 70 percent of patients to clear all types of immunosuppression.
“We followed this entire cohort for over six and a half years, and one of them for 12 years from transplant, and every patient who came out of immunosuppression was able to stay away,” Ricade says.
That patient, Robert Waddell, 55, was especially grateful to be weaned off the immunosuppressive medication about a year after the transplant. The Louisville resident has long seen his mother, sister and other family members with Polycystic Kidney Disease, or PKD, suffer the effects of chronic immunosuppression. This became his biggest fear when he was diagnosed with end stage kidney failure.
Waddle joined Phase II research taking place in Louisville after learning about it in early 2006. He chose to stay in the study when it moved its clinical headquarters to Northwestern University Medical Center in Chicago two years later.
Before surgery, he underwent an inhibitor regimen of chemotherapy and radiation. The patient’s bone marrow cells need to be removed so that they can be replaced with donor cells. The result was worth it, Waddell says: He had a stem cell transplant for the immune system and kidney in May 2009, without any need for chronic immunosuppression.
“I call it ‘short-term pain, long-term gain,'” he says, “because it was hard to go through conditioning, but after that, it was great.” “I’ve spoken to a lot of kidney recipients who have said, ‘I wish I would,’ because most people don’t think about clinical trials, but I’ve been very lucky.”
Waddell has every reason to support the success of this research, especially given the genetic disorder, PKD, that has plagued his family. One of his four sons suffers from PKD. He is eager for the procedure to become a standard of care, should his son need it.
“The beauty of this procedure is that I don’t have to take all the anti-rejection medications for a transplanted organ,” says Waddell, a financial expert. “I forgot that I had any kidney problems. That is the extent of their impact.”
Talaris will continue to follow Waddell and the rest of his group to track the efficacy and safety of the procedure. According to Requadt, the average lifespan of a transplanted kidney is 12 to 15 years, in part because immunosuppressive drugs worsen the organ’s functioning each year.
“We were the first group to show that we can do this robustly and fairly in a clinical setting in humans,” Riccadt says. “Importantly, we were able to show that we can still get a good synthesis of stem cells from the donor, even if there is … a profound mismatch between the immune system of the donor and recipient.”
In kidney transplantation, it is important to match with human leukocyte antigen (HLA) because there is better graft survival in HLA-matched kidney transplants than in HLA-mismatched transplants.
About three months after transplant, Talaris researchers are looking for evidence that the donated immune cells and stem cells have developed, while they build a donor immune system for the patient. If more than 50 percent of the T cells contain the donor’s DNA after six months, patients can start taking fewer immunosuppressants.
“We know from the second stage that in our patients they were able to tolerate [accept the organ without rejection] To the donated organ, we saw kidney function completely preserved and in fact slightly increased. “So it makes sense that if you rule out the drugs that are associated with worsening kidney function, they will maintain kidney function, so hopefully the patient will have that one kidney for life.”
Matthew Cooper, director of kidney and pancreas transplantation at the MedStar Georgetown Transplant Institute in Washington, D.C., stated, “Currently, we have a long waiting list and a few donors are dying every day waiting to receive a kidney. Organ transplantation. Ultimately, we will eradicate the organ shortage. So that people don’t die from organ failure.”
Cooper, a nationally recognized clinical transplant surgeon for 20 years, says when he started his career, finding a way for patients to forgo immunosuppression was the “holy grail” of modern transplant medicine.
“Now that we’ve established the protocols and some personal examples of how this can happen, it’s very exciting to see it all come together,” he adds.