First-In-Human Porcine Kidney Transplant Trial Builds On Expanded Access Success

A conversation between eGenesis CEO Mike Curtis, Ph.D., and Clinical Leader Executive Editor Abby Proch

Dialysis treatment for end-stage kidney disease can be brutal on patients. The ups and downs of feeling well and feeling exhausted are physically and mentally taxing on patients, as well as their caregivers. And while allogenic transplants are possible, patients must be medically eligible and donors must be secured. It’s not always possible.

But there is an emerging alternative as researchers explore xenotransplantation. Use cases continue to mount, with one of the latest being a gene-edited porcine kidney that enabled a man to survive, thrive even, for nearly nine months. The investigative treatment enabled the man to extend his life and improve his health so that, after returning briefly to dialysis, he could secure a human kidney transplant. 

In this Q&A, we talk to eGenesis CEO Mike Curtis, who’s shepherding the first-in-human trial of EGEN-2784. The trial builds directly on the success of the company’s Expanded Access program, in which they showed not only that a porcine kidney could function in humans but also restore near-normal quality of life while awaiting a human transplant.

To start, why is a porcine transplant preferable to dialysis?

When you think about someone's journey on dialysis, it's three times a week traveling to the dialysis clinic. In between each visit, their metabolites and their creatinine rise. So, they’re on this constant rollercoaster of feeling horrible because they have this buildup of toxins. Because a dialysis treatment takes about four hours, patients experience dialysis flux. They recover the next day, and then on the third day, they're back into the dialysis clinic. Patients may get one day a week where they feel reasonably well.

With a porcine or human kidney transplant, you don't have the rollercoaster. One, you don't have to go to the clinic. And two, your creatinine and electrolytes are stable. You have a functioning kidney. We've always known that patients will do better on a human transplant. The question has been whether a porcine transplant will give a similar outcome. In our first two cases, the answer is yes.

One of those two cases involved Tim Andrews, who survived about nine months with a gene-edited porcine kidney. Ultimately, his body did reject it, but there's a lot to be happy about. In what ways was his Expanded Access experience a success?

Before Mr. Andrews was Richard Slayman in April 2024, our first Expanded Access case. That was really the turning point for the whole program — where we could match the risk-benefit to the patient and we had enough non-human primate data.

Mr. Slayman was losing access to dialysis and thinking about hospice. We did a transplant for 51 days, and the kidney worked beautifully. Unfortunately, he passed away following arrhythmia.

But we are forever indebted to Mr. Slayman. He showed us that we could transplant a porcine kidney into a person, and the postoperative care for the first few days looks just like an allogenic transplant. The porcine kidney allowed him to live dialysis independent. Our goal is to keep patients independent of dialysis. We really don't think about survival because the assumption is, worst case, that you go back to dialysis (for most patients).

Once the FDA reviewed Mr. Slayman's case, we decided to go into healthier patients. That's what led to Mr. Andrews, who was on dialysis for about two years. He had about an 8% chance of getting a human graft and about a 60% chance of dying, both in the next five years.

His transplant was uneventful, and he lived a relatively normal life, all dialysis independent. It was stunning, and we believe the learnings from that case will lead us to longer outcomes in the next cases. Mr. Andrews also taught us that the way the kidney declines is manageable. We could see Mr. Andrews’ graft loss coming for probably three months after a slow, steady rise in creatinine. It allowed us to try modification of immunosuppression to avoid the rejection and plan for the eventual loss of the graft and putting Mr. Andrews back onto dialysis.

The other big win is that we were able to safely perform a nephrectomy, return Mr. Andrews to dialysis, and then 12 weeks later allow him to get a human graft. And now he's 78 days post human allotransplant and doing well.

When he returned to dialysis after nine months, his health was much improved. And this is really important because one of the major reasons people don't get a transplant is because their health has declined too much while they're on dialysis and they get de-listed.

Because of this, the FDA has agreed to a primary endpoint in our registration trial of six months of dialysis independence.

Now, the trial you’ve designed for EGEN-2784 is a Phase 1/2/3, or phaseless, trial.  What does that look like?

Usually, Phase 1 is a safety study. We typically run healthy volunteers and increase the dose until we reach either the limit from exposure or tolerability. Phase 2 is showing some efficacy. And then Phase 3 is getting the data set to get approval.

In transplant, once you put a graft in, you're doing all those things. At first, we debated: Could you put the graft in for a week and then take it out? You could, but why would you? And so, the first time you do a transplant, you're trying to go as long as you can. You're going to measure safety and efficacy — everything that you would measure in a Phase 1, 2, and 3. 

Looking back to Mr. Slayman as you determine eligibility criteria for EGEN-2784, how has that ideal patient changed over time?

We used to think we'd only have patients like Mr. Slayman, who had few treatment options, but Mr. Slayman, Mr. Andrews, and Bill Stewart, the second EGEN-2784 kidney recipient, have taught us is the transplant process is safe and the first month or two post-transplant is uneventful. This has led to eligibility criteria for a trial that includes about two-thirds of the current transplant waitlist. This is something we've discussed with the FDA and patients: The healthier you are going into transplant, the better your outcomes. We've agreed with the FDA that patients only need to be on dialysis for three months.

What lessons have you taken from the EA to help design the first-in-human trial for EGEN-2784?

One is we have a much better understanding of the immunosuppression protocol that we're going to use in the registration trial. The other is how to adjust the immunosuppression when patients do have an infection because, inevitably, someone will get a cold or flu. That's happened a couple of times during our expanded access cases, and it's allowed us to test reducing certain drugs and increasing other drugs to give us a balance.

Are there any logistical factors that you've considered going into the trial, such as frequency of visits?

Having the EA cases has given us confidence in not having to have the patient come to the clinic every other day. In the first few cases, in the first couple of weeks post-transplant, the patients were coming into the clinic three days a week. If anything changed, those patients got admitted because we just didn't know what direction it was headed in.

But now that we have several cases six months and longer, we have a much better feel for how these kidneys respond. So, if we see a rise in creatinine on Monday, we don't necessarily have to admit the patient and do a full workup. Another thing we learned is the importance of having the patients stay close to the hospital for the first couple of weeks.

Finally, when we do see changes in kidney performance, we know it will be a gradual change. The fact that the rejection events we have seen are a low, smoldering rejection that plays out over many months is helpful when managing a patient's experience. We don't have to worry that the kidney may fail overnight.

Finally, patient advocacy, specifically from the National Kidney Foundation, played a role in shaping this program. How so?

In fall 2023, the National Kidney Foundation brought together a patient advisory group of a dozen patients with end-stage kidney disease. Some patients were on dialysis, some patients had a transplant, and some patients had a failed transplant and were returning to dialysis. The NKF asked whether they would take a porcine kidney. All patients said, depending where they were on their journey and what was available to them, they would consider it. And this was before we actually had any data.

After the meeting, Mass General went through their clinical files and found six patients who were near the end of their ability to receive dialysis, and that's where Mr. Slayman came from. Without the NKF patient advocacy meeting, there's a good chance that Mr. Slayman's transplant didn't happen.

That fall, we also published our paper in Nature showing we could achieve two years of kidney function in monkeys. We had done as much as we could do in non-human primates. The next step was patients. That led us to Mr. Slayman. Mr. Slayman's case leads to Mr. Andrews’ case. Mr. Andrews leads to Stewart, plus another case, and now the registration trial. That meeting was the catalyst that led us to where we are today.

About The Expert:

Mike Curtis, Ph.D., is the president and CEO at eGenesis. He has more than 35 years of experience in scientific research and leadership in biopharmaceutical drug development across multiple therapeutic areas. Before joining eGenesis, he served as president and head of R&D at Cadent Therapeutics, where he oversaw R&D, regulatory, and intellectual property operations. Dr. Curtis played a critical role in completing the merger between Ataxion Therapeutics and Luc Therapeutics that resulted in Cadent’s founding. Prior to Cadent, he was responsible for product development and regulatory affairs at Catabasis Pharmaceuticals. His first executive role was at the oncology company, Infinity Pharmaceuticals, where he established and led a 30-scientist team that was responsible for all product development activities. Dr. Curtis holds an A.Sc. in biotechnology from Cobleskill College and a B.Sc. in biochemistry from the College of Environmental Science and Forestry. He earned a Ph.D. in Cell and molecular biology from the State University of New York Upstate Medical University.