It’s early days for xenotransplantation, but eGenesis, Eledon, United Therapeutics and more are working to develop solutions to make this approach a viable option and help ease the organ shortage crisis.
Breakthroughs in gene editing coupled with the next generation of anti-CD40L antibodies could help enable xenotransplantation—the transplantation of animal organs or tissues into humans—and provide a gateway to solving a major global health crisis: a shortage of donor organs.
Each day, 20 people in the U.S. die waiting for an organ transplant. The country’s kidney transplant list is about 90,000 patients deep, but surgeons only perform some 25,000–30,000 transplants per year, according to Mike Curtis, CEO of eGenesis, a biotech developing genetically engineered pig organs and cells for transplantation. And this list doesn’t come close to capturing all of the patients in need, he added.
“The reality of the situation is about 450,000 patients on dialysis,” Curtis told BioSpace. “The majority of patients with end-stage renal disease never hit a transplant waitlist. So, if you can solve the organ shortage problem, not only can you eliminate the waitlist, you can actually eliminate dialysis.”
eGenesis and others are betting that gene-edited pigs can help solve this dilemma, providing a potentially endless supply of available organs—not just kidneys but hearts and livers too. With cardiovascular disease the leading cause of death globally and liver disease ranking 10th, per the CDC, Curtis said this could be “one of the largest opportunities in pharma.”
Human test cases are starting to hit the newswires. In March 2024, an eGenesis genetically edited porcine kidney was transplanted into a 62-year-old man with end-stage kidney disease, and in 2023 two patients received genetically edited pig hearts from United Therapeutics’ subsidiary Revivicor. The kidney transplant recipient died two months later, but Massachusetts General Hospital, where the operation was performed, said there was no indication the transplant was the cause.
The first patient to receive a porcine heart lived for two months after the transplant until a sudden onset of heart failure led to his death. The University of Maryland transplant team said a multitude of factors led to the functional decline, including the patient’s poor state of health leading to the limited use of an anti-rejection regimen that proved effective in preclinical studies for xenotransplantation. The second heart transplant failed due to antibody-mediated rejection, according to the university.
Clearly, there are still hurdles to scale; first and foremost, rejection. In human-to-human transplantation, even with the use of immunosuppressants, 10–20% of transplant patients will experience at least one episode of rejection after a renal transplant. For xenotransplantation, surgeons will have to up the ante to keep the immune system from forcing out the new porcine organ. While genetic modifications to the animal organs can help stave off rejection, experts say next-gen costimulatory blockade antibodies could make the difference, with a handful in early or mid-stage development.
This foundational work is driving a lot of investor enthusiasm in a transplantation space that hasn’t seen much innovation in the past 30 years, Thomas Smith, senior research analyst at Leerink Partners, told BioSpace. “It’s early, but it feels like we’re on the cusp of something that could be quite transformational in the way that we deal with organ transplant.”
100 Years in the Making
Surgeons have been exploring xenotransplantation for over a century, with the first partial organ transplant attempts, between chimpanzees and humans, coming in the 1920s. Today, advancements in gene editing could revolutionize the organ transplant field.
Revivcor’s approach includes editing 10 genes in the pig genome to limit organ growth and prevent rejection, inflammation and blood clot formation in the transplanted organ. eGenesis similarly makes three classes of gene edits to its pigs: inactivating retroviruses in the pig genome that pose a risk to human health, eliminating antigens responsible for hyper acute rejection and introducing human regulatory genes for coagulation, compatibility, complement, innate and adaptive immunity.
“It’s somewhat like the equivalent of immunosuppression,” Curtis said of the human regulatory genes the company adds. Curtis further noted that coupled with modern immunosuppression, these genes are very important for long-term graft function.
But gene edits alone aren’t enough to ensure human acceptance of the porcine organs. While every organ transplant necessitates constant immune system suppression to prevent the body from attacking the foreign organ, xenotransplants will require a higher level of care, Adam Griesemer, a senior member of the xenotransplant research team at NYU Langone, told BioSpace.
He explained that the typical human-to-human transplant commonly requires T cell depletion at the time of transplant, followed by steroids, an antirejection medicine and an immunosuppressant. Most patients taper off the steroids six months after surgery and stay on the latter two drugs long-term.
“That regimen is not strong enough to prevent rejection in xeno,” Griesemer said, citing research in primate models. But “there is a very strong advantage of xenograft survival when you use novel medications called costimulatory blockade antibodies.”
Targeting Rejection
The most significant costimulatory pathway involved in rejection appears to be the interaction between two cell-surface proteins, CD40 and CD154, Griesemer noted. The leader in this space is Eledon, which is advancing an anti-CD40L antibody called tegoprubart that prevents the interaction between these two proteins. The asset is currently in a Phase II clinical trial for traditional kidney transplantation and preclinical testing for xenotransplantation, but it has been used in multiple compassionate use studies in collaborations with both eGenesis and United Therapeutics, according to CEO David-Alexander Gros.
Smith said tegoprubart’s selection in some of the first xenotransplants is “a strongly positive thing for Eledon.”
Gros described tegoprubart’s mechanism of action as more immunomodulation than immunosuppression. Historically, immunosuppressive drugs have worked by destroying white blood cells. “The approach that we use is much more targeted, more modern and does not work by wiping out populations of white blood cells,” Gros told BioSpace. “We’re preventing the activation of the immune system and promoting the braking system of the immune system.”
Eledon is hopeful its antibody can replace calcineurin inhibitors (CNIs) that are commonly used in the transplant drug lineup. Somewhat paradoxically, CNI drugs are nephrotoxic, meaning they damage the kidneys over time. Additionally, CNIs cause hypertension and destroy the insulin-producing cells of the pancreas, triggering post-transplant diabetes, Gros explained.
Interestingly, the CD40 pathway has been targeted before for organ rejection—unsuccessfully. Novartis halted development of its antibody iscalimab after double whammy failures in kidney and liver transplantation in 2021 and 2022, respectively. Smith said the failure was a surprise to the field, and the resounding opinion was that it was due to iscalimab’s targeting of the CD40 receptor, instead of the CD40 ligand. There’s a “multi-prong benefit you get by targeting the ligand,” he explained.
Since then, multiple companies have demonstrated that targeting the CD40 ligand is effective in autoimmune disease and in neuroinflammation. Eledon is studying tegoprubart in ALS, while Novartis is testing frexalimab in multiple sclerosis and UCB and Biogen are assessing dapirolizumab pegol in systemic lupus erythematosus. Meanwhile, Tonix Pharmaceuticals’ antibody TNX-1500, which also targets the CD40 ligand, has completed a Phase I trial in prevention of organ rejection in traditional human-to-human transplants. The biotech is collaborating on a preclinical xenotransplantation study with Mass General Hospital.
Combinations may also be key. In 2023, eGenesis published a paper in Nature showing that pairing the company’s gene-edited organs with tegoprubart has allowed porcine kidneys to survive in a monkey for more than two years and counting, Curtis said. “It’s that combination that really gets to the advances in this cross-species transplantation.”
The Path to Approval
Sometimes, though, what works in a monkey does not translate to clinical development for humans, Griesemer said, referencing the University of Maryland xenotransplantation patient who developed antibody-mediated rejection after a porcine heart transplant.
“We’re still in small numbers today,” Griesemer told BioSpace. “The whole reason the field exists is because we don’t have enough organs for everyone. To fix that problem, xenotransplant would need to provide about 130,000 organs every year, and, so far, the grand total experience with human recipients is around seven.”
Griesemer said large-scale clinical trials are needed to understand the true efficacy of anti-CD40L antibodies in humans. The “best-case scenario,” he said, is that tegoprubart “is a miracle drug” that is highly effective and works as well in humans as it does in primates. “There is a possibility, though, that won’t be the case, and then we’ll have to rely on different immunosuppressants.”
For now, NYU Langone’s xenotransplantation program is using a standard, clinically approved immunosuppression regimen equal to what would typically be used when a transplant patient has a particularly challenging immune system.
Meanwhile, both eGenesis and United Therapeutics are moving to transition their programs toward the traditional clinical trial pathway rather than the current “one-off” compassionate use, Smith said. “When you start generating controlled data via company-sponsored study, you have some of those regulatory interactions, and you can start to paint the path towards approval.”
