New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
Kidney transplant patient Robert Waddell, center, with his wife and children after being off immunosuppresants; photo aken last summer in Perdido Key, FL. Left to right: Christian, Bailey, Rob, Karen (wife), Robby and Casey.
Rob Waddell dreaded getting a kidney transplant. He suffers from a genetic condition called polycystic kidney disease that causes the uncontrolled growth of cysts that gradually choke off kidney function. The inherited defect has haunted his family for generations, killing his great grandmother, grandmother, and numerous cousins, aunts and uncles.
But he saw how difficult it was for his mother and sister, who also suffer from this condition, to live with the side effects of the drugs they needed to take to prevent organ rejection, which can cause diabetes, high blood pressure and cancer, and even kidney failure because of their toxicity. Many of his relatives followed the same course, says Waddell: "They were all on dialysis, then a transplant and ended up usually dying from cancers caused by the medications."
When the Louisville native and father of four hit 40, his kidneys barely functioned and the only alternative was either a transplant or the slow death of dialysis. But in 2009, when Waddell heard about an experimental procedure that could eliminate the need for taking antirejection drugs, he jumped at the chance to be their first patient. Devised by scientists at the University of Louisville and Northwestern University, the innovative approach entails mixing stem cells from the live kidney donor with that of the recipient to create a hybrid immune system, known as a chimera, that would trick the immune system and prevent it from attacking the implanted kidney.
The procedure itself was done at Northwestern Memorial Hospital in Chicago, using a live kidney donated by a neighbor of Waddell's, who camped out in Chicago during his recovery. Prior to surgery, Waddell underwent a conditioning treatment that consisted of low dose radiation and chemotherapy to weaken his own immune system and make room for the infusion of stem cells.
"The low intensity chemo and radiation conditioning regimen create just enough space for the donor stem cells to gain a foothold in the bone marrow and the donor's immune system takes over," says Dr. Joseph Levanthal, the transplant surgeon who performed the operation and director of kidney and pancreas transplantation at Northwestern University Feinberg School of Medicine. "That way the recipient develops an immune system that doesn't see the donor organ as foreign."
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis."
A week later, Waddell had the kidney transplant. The following day, he was infused with a complex cellular cocktail that included blood-forming stem cells derived from his donor's bone marrow mixed what are called tolerance inducing facilitator cells (FCs); these cells help the foreign stem cells get established in the recipient's bone marrow.
Over the course of the following year, he was slowly weaned off of antirejection medications—a precaution in case the procedure didn't work—and remarkably, hasn't needed them since. "I felt better than I had in decades because my kidneys [had been] degrading," recalls Waddell, now 54 and a CPA for a global beverage company. And what's even better is that this new approach offers hope for one of his sons who has also inherited the disorder.
Kidney transplants are the most frequent organ transplants in the world and more than 23,000 of these procedures were done in the United States in 2019, according to the United Network for Organ Sharing. Of this, about 7,000 operations are done annually using live organ donors; the remainder use organs from people who are deceased. Right now, this revolutionary new approach—as well as a similar strategy formulated by Stanford University scientists--is in the final phase of clinical trials. Ultimately, this research may pave the way towards realizing the holy grail of organ transplantation: preventing organ rejection by creating a tolerant state in which the recipient's immune system is compatible with the donor, which would eliminate the need for a lifetime of medications.
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis," says Dr. Suzanne Ildstad, a transplant surgeon and director of the Institute for Cellular Therapeutics at the University of Louisville, whose discovery of facilitator cells were the basis for this therapeutic platform. Ildstad, who has spent more than two decades searching for a better way, says, "This is something I have worked for my entire life."
The Louisville group uses a combination of chemo and radiation to replace the recipient's immune and blood forming cells with that of the donor. In contrast, the Stanford protocol involves harvesting the donor's blood stem cells and T-cells, which are the foot soldiers of the immune system that fight off infections and would normally orchestrate the rejection of the transplanted organ. Their transplant recipients undergo a milder form of "conditioning" that only radiates discrete parts of the body and selectively targets the recipient's T-cells, creating room for both sets of T-cells, a strategy these researchers believe has a better safety profile and less of a chance of rejection.
"We try to achieve immune tolerance by a true chimerism," says Dr. Samuel Strober, a professor of medicine for immunology and rheumatology at Stanford University and a leader of this research team. "The recipients immune system cells are maintained but mixed in the blood with that of the donor."
Studies suggest both approaches work. In a 2018 clinical trial conducted by Talaris Therapeutics, a Louisville-based biotech founded by Ildstad, 26 of 37 (70%) of the live donor kidney transplant recipients no longer need immunosuppressants. Last fall, Talaris began the final phase of clinical tests that will eventually encompass more than 120 such patients.
The Stanford group's cell-based immunotherapy, which is called MDR-101 and is sponsored by the South San Francisco biotech, Medeor Therapeutics, has had similar results in patients who received organs from live donors who were either well matched, such as one from siblings, meaning they were immunologically identical, or partially matched; Talaris uses unrelated donors where there is only a partial match.
In their 2020 clinical trial of 51 patients, 29 were fully matched and 22 were a partial match; 22 of the fully matched recipients didn't need antirejection drugs and ten of the partial matches were able to stop taking some of these medications without rejection. "With our fully matched, roughly 80% have been completely off drugs up to 14 years later," says Strober, "and reducing the number of drugs from three to one [in the partial matches] means you have far fewer side effects. The goal is to get them off of all drugs."
But these protocols are limited to a small number of patients—living donor kidney recipients. As a consequence, both teams are experimenting with ways to broaden their approach so they can use cadaver organs from deceased donors, with human tests planned in the coming year. Here's how that would work: after the other organs are removed from a deceased donor, stem cells are harvested from the donor's vertebrae in the spinal column and then frozen for storage.
"We do the transplant and give the patient a chance to recover and maintain them on drugs," says Ildstad. "Then we do the tolerance conditioning at a later stage."
If this strategy is successful, it would be a genuine game changer, and open the door to using these protocols for transplanting other cadaver organs, including the heart, lungs and liver. While the overall procedure is complex and costly, in the long run it's less expensive than repeated transplant surgeries, the cost of medications and hospitalizations for complications caused by the drugs, or thrice weekly dialysis treatments, says Ildstad.
And she adds, you can't put a price tag on the vast improvement in quality of life.
Breakthrough therapies are breaking patients' banks. Key changes could improve access, experts say.
Single-treatment therapies are revolutionizing medicine. But insurers and patients wonder whether they can afford treatment and, if they can, whether the high costs are worthwhile.
CSL Behring’s new gene therapy for hemophilia, Hemgenix, costs $3.5 million for one treatment, but helps the body create substances that allow blood to clot. It appears to be a cure, eliminating the need for other treatments for many years at least.
Likewise, Novartis’s Kymriah mobilizes the body’s immune system to fight B-cell lymphoma, but at a cost $475,000. For patients who respond, it seems to offer years of life without the cancer progressing.
These single-treatment therapies are at the forefront of a new, bold era of medicine. Unfortunately, they also come with new, bold prices that leave insurers and patients wondering whether they can afford treatment and, if they can, whether the high costs are worthwhile.
“Most pharmaceutical leaders are there to improve and save people’s lives,” says Jeremy Levin, chairman and CEO of Ovid Therapeutics, and immediate past chairman of the Biotechnology Innovation Organization. If the therapeutics they develop are too expensive for payers to authorize, patients aren’t helped.
“The right to receive care and the right of pharmaceuticals developers to profit should never be at odds,” Levin stresses. And yet, sometimes they are.
Leigh Turner, executive director of the bioethics program, University of California, Irvine, notes this same tension between drug developers that are “seeking to maximize profits by charging as much as the market will bear for cell and gene therapy products and other medical interventions, and payers trying to control costs while also attempting to provide access to medical products with promising safety and efficacy profiles.”
Why Payers Balk
Health insurers can become skittish around extremely high prices, yet these therapies often accompany significant overall savings. For perspective, the estimated annual treatment cost for hemophilia exceeds $300,000. With Hemgenix, payers would break even after about 12 years.
But, in 12 years, will the patient still have that insurer? Therein lies the rub. U.S. payers, are used to a “pay-as-you-go” model, in which the lifetime costs of therapies typically are shared by multiple payers over many years, as patients change jobs. Single treatment therapeutics eliminate that cost-sharing ability.
"As long as formularies are based on profits to middlemen…Americans’ healthcare costs will continue to skyrocket,” says Patricia Goldsmith, the CEO of CancerCare.
“There is a phenomenally complex, bureaucratic reimbursement system that has grown, layer upon layer, during several decades,” Levin says. As medicine has innovated, payment systems haven’t kept up.
Therefore, biopharma companies begin working with insurance companies and their pharmacy benefit managers (PBMs), which act on an insurer’s behalf to decide which drugs to cover and by how much, early in the drug approval process. Their goal is to make sophisticated new drugs available while still earning a return on their investment.
New Payment Models
Pay-for-performance is one increasingly popular strategy, Turner says. “These models typically link payments to evidence generation and clinically significant outcomes.”
A biotech company called bluebird bio, for example, offers value-based pricing for Zynteglo, a $2.8 million possible cure for the rare blood disorder known as beta thalassaemia. It generally eliminates patients’ need for blood transfusions. The company is so sure it works that it will refund 80 percent of the cost of the therapy if patients need blood transfusions related to that condition within five years of being treated with Zynteglo.
In his February 2023 State of the Union speech, President Biden proposed three pilot programs to reduce drug costs. One of them, the Cell and Gene Therapy Access Model calls on the federal Centers for Medicare & Medicaid Services to establish outcomes-based agreements with manufacturers for certain cell and gene therapies.
A mortgage-style payment system is another, albeit rare, approach. Amortized payments spread the cost of treatments over decades, and let people change employers without losing their healthcare benefits.
Only about 14 percent of all drugs that enter clinical trials are approved by the FDA. Pharma companies, therefore, have an exigent need to earn a profit.
The new payment models that are being discussed aren’t solutions to high prices, says Bill Kramer, senior advisor for health policy at Purchaser Business Group on Health (PBGH), a nonprofit that seeks to lower health care costs. He points out that innovative pricing models, although well-intended, may distract from the real problem of high prices. They are attempts to “soften the blow. The best thing would be to charge a reasonable price to begin with,” he says.
Instead, he proposes making better use of research on cost and clinical effectiveness. The Institute for Clinical and Economic Review (ICER) conducts such research in the U.S., determining whether the benefits of specific drugs justify their proposed prices. ICER is an independent non-profit research institute. Its reports typically assess the degrees of improvement new therapies offer and suggest prices that would reflect that. “Publicizing that data is very important,” Kramer says. “Their results aren’t used to the extent they could and should be.” Pharmaceutical companies tend to price their therapies higher than ICER’s recommendations.
Drug Development Costs Soar
Drug developers have long pointed to the onerous costs of drug development as a reason for high prices.
A 2020 study found the average cost to bring a drug to market exceeded $1.1 billion, while other studies have estimated overall costs as high as $2.6 billion. The development timeframe is about 10 years. That’s because modern therapeutics target precise mechanisms to create better outcomes, but also have high failure rates. Only about 14 percent of all drugs that enter clinical trials are approved by the FDA. Pharma companies, therefore, have an exigent need to earn a profit.
Skewed Incentives Increase Costs
Pricing isn’t solely at the discretion of pharma companies, though. “What patients end up paying has much more to do with their PBMs than the actual price of the drug,” Patricia Goldsmith, CEO, CancerCare, says. Transparency is vital.
PBMs control patients’ access to therapies at three levels, through price negotiations, pricing tiers and pharmacy management.
When negotiating with drug manufacturers, Goldsmith says, “PBMs exchange a preferred spot on a formulary (the insurer’s or healthcare provider’s list of acceptable drugs) for cash-base rebates.” Unfortunately, 25 percent of the time, those rebates are not passed to insurers, according to the PBGH report.
Then, PBMs use pricing tiers to steer patients and physicians to certain drugs. For example, Kramer says, “Sometimes PBMs put a high-cost brand name drug in a preferred tier and a lower-cost competitor in a less preferred, higher-cost tier.” As the PBGH report elaborates, “(PBMs) are incentivized to include the highest-priced drugs…since both manufacturing rebates, as well as the administrative fees they charge…are calculated as a percentage of the drug’s price.
Finally, by steering patients to certain pharmacies, PBMs coordinate patients’ access to treatments, control patients’ out-of-pocket costs and receive management fees from the pharmacies.
Therefore, Goldsmith says, “As long as formularies are based on profits to middlemen…Americans’ healthcare costs will continue to skyrocket.”
Transparency into drug pricing will help curb costs, as will new payment strategies. What will make the most impact, however, may well be the development of a new reimbursement system designed to handle dramatic, breakthrough drugs. As Kramer says, “We need a better system to identify drugs that offer dramatic improvements in clinical care.”
In today's podcast episode, law professor Gaia Bernstein talks about the challenges of keeping control over our thoughts and actions, even when some powerful forces are pushing in the other direction.
Each afternoon, kids walk through my neighborhood, on their way back home from school, and almost all of them are walking alone, staring down at their phones. It's a troubling site. This daily parade of the zombie children just can’t bode well for the future.
That’s one reason I felt like Gaia Bernstein’s new book was talking directly to me. A law professor at Seton Hall, Gaia makes a strong argument that people are so addicted to tech at this point, we need some big, system level changes to social media platforms and other addictive technologies, instead of just blaming the individual and expecting them to fix these issues.
Gaia’s book is called Unwired: Gaining Control Over Addictive Technologies. It’s fascinating and I had a chance to talk with her about it for today’s podcast. At its heart, our conversation is really about how and whether we can maintain control over our thoughts and actions, even when some powerful forces are pushing in the other direction.
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We discuss the idea that, in certain situations, maybe it's not reasonable to expect that we’ll be able to enjoy personal freedom and autonomy. We also talk about how to be a good parent when it sometimes seems like our kids prefer to be raised by their iPads; so-called educational video games that actually don’t have anything to do with education; the root causes of tech addictions for people of all ages; and what kinds of changes we should be supporting.
Gaia is Seton’s Hall’s Technology, Privacy and Policy Professor of Law, as well as Co-Director of the Institute for Privacy Protection, and Co-Director of the Gibbons Institute of Law Science and Technology. She’s the founding director of the Institute for Privacy Protection. She created and spearheaded the Institute’s nationally recognized Outreach Program, which educated parents and students about technology overuse and privacy.
Professor Bernstein's scholarship has been published in leading law reviews including the law reviews of Vanderbilt, Boston College, Boston University, and U.C. Davis. Her work has been selected to the Stanford-Yale Junior Faculty Forum and received extensive media coverage. Gaia joined Seton Hall's faculty in 2004. Before that, she was a fellow at the Engelberg Center of Innovation Law & Policy and at the Information Law Institute of the New York University School of Law. She holds a J.S.D. from the New York University School of Law, an LL.M. from Harvard Law School, and a J.D. from Boston University.
Gaia’s work on this topic is groundbreaking I hope you’ll listen to the conversation and then consider pre-ordering her new book. It comes out on March 28.
