If approved by the FDA, a new procedure for kidney transplants that doesn't require anti-rejection medication could soon become the standard of care.
Talaris is now moving into the final clinical trial, phase III, before submitting for FDA approval. Known as Freedom-1, this trial has 17 sites open throughout the U.S., and Talaris will enroll a total of 120 kidney transplant recipients. One day after receiving their donor’s kidney, 80 people will undergo the company’s therapy, involving the donor’s stem cells and other critical cells that are processed at their facility. Forty will have a regular kidney transplant and remain on immunosuppression to provide a control group.
“The beauty of this procedure is that I don’t have to take all of the anti-rejection drugs,” says Robert Waddell, a finance professional. “I forget that I ever had any kidney issues. That’s how impactful it is.”
The procedure was pioneered decades ago by Suzanne Ildstad as a faculty member at the University of Pittsburgh before she became founding CEO of Talaris and then its Chief Scientific Officer. If approved by the FDA, the method could soon become the standard of care for patients in need of a kidney transplant.
“We are working to find a way to reprogram the immune system of transplant recipients so that it sees the donated organ as [belonging to one]self and doesn’t attack it,” explains Scott Requadt, CEO of Talaris. “That obviates the need for lifelong immunosuppression.”
Each year, there are roughly 20,000 kidney transplants, making kidneys the most transplanted organ. About 6,500 of those come from living donors, while deceased donors provide roughly 13,000.
One of the challenges, Requadt points out, is that kidney transplant recipients aren’t always aware of all the implications of immunosuppression. Typically, they will need to take about 20 anti-rejection drugs several times a day to provide immunosuppression as well as treat complications caused by the toxicities of immunosuppression medications. The side effects of chronic immunosuppression include weight gain, high blood pressure, and high cholesterol. These cardiovascular comorbidities, Requadt says, are “often more frequently the cause of death than failure of a transplanted organ.”
Patients who are chronically immunosuppressed generally have much higher rates of infections and cancers that have an immune component to them, such as skin cancers.
For the past couple of years, those patients have experienced heightened anxiety because of the COVID-19 pandemic. Immune-suppressing medicine used to protect their new organ also makes it hard for patients to build immunity to foreign invaders like COVID-19.
A study appearing in the Proceedings of the National Academy of Sciences found the probability of a pandemic with similar impact to COVID-19 is about 2 percent in any year, and estimated that the probability of novel disease outbreaks will grow three-fold in the next few decades. All the more reason to identify an FDA-approved alternative to harsh immunosuppressive drugs.
Of the 18 patients during the phase II research trial who received the Talaris therapy, didn’t take immunosuppression medication and were vaccinated, only two ended up with a COVID infection, according to a review of the data. Among patients who needed to continue taking immunosuppressants or those who didn’t have them but were unvaccinated, the rates of infection were between 40 and 60 percent.
In the earlier phase II study by Talaris with 37 patients, the combined transplantation approach allowed 70 percent of patients to get off all immunosuppression.
“We’ve followed that whole cohort for more than six and a half years and one of them for 12 years from transplant, and every single patient that we got off immunosuppression has been able to stay off,” Requadt says.
That one patient, Robert Waddell, 55, was especially thankful to be weaned off immunosuppressive drugs approximately one year after his transplant procedure. The Louisville resident had long watched his mother, sister and other family members with polycystic kidney disease, or PKD, suffer the effects of chronic immunosuppression. That became his greatest fear when he was diagnosed with end stage renal failure.
Waddell enrolled in the phase II research taking place in Louisville after learning about it in early 2006. He chose to remain in the study when it relocated its clinical headquarters to Northwestern University’s medical center in Chicago a couple years later.
Before surgery, he underwent an enervating regimen of chemotherapy and radiation. It’s required to clear out a patient’s bone marrow cells so that they can be replaced by the donor’s cells. Waddell says the result was worth it: he had his combined kidney and immune system stem cell transplant in May 2009, without any need for chronic immunosuppression.
“I call it ‘short-term pain, long-term gain,’ because it was difficult to go through the conditioning, but after that, it was great,” he says. “I’ve talked to so many kidney recipients who say, ‘I wish I would have done that,’ because most people don’t think about clinical trials, but I was very fortunate.”
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 children has PKD. He is anxious for the procedure to become standard of care, if and when his son needs it.
The Talaris procedure was pioneered decades ago by Suzanne Ildstad, founding CEO of Talaris and the company's Chief Scientific Officer, pictured here with the current CEO, Scott Requadt.
Talaris
“The beauty of this procedure is that I don’t have to take all of the anti-rejection drugs,” says Waddell, a finance professional. “I forget that I ever had any kidney issues. That’s how impactful it is.”
Talaris will continue to follow Waddell and the rest of his cohort to track the effectiveness and safety of the procedure. According to Requadt, the average life of a transplanted kidney is 12 to 15 years, partly because the immunosuppressive drugs worsen the functioning of the organ each year.
“We were the first group to show that we could robustly and fairly reproducibly do this in a clinical setting in humans,” Requadt says. “Most important, we’ve been able to show that we can still get a good engraftment of the stem cells from the donor, even if there is a profound…mismatch between the donor and the recipient’s immune systems.”
In kidney transplantation, it’s important to match for human leukocyte antigens (HLA) because there is a better graft survival in HLA-identical kidney transplants compared with HLA mismatched transplants.
About three months after the transplant, Talaris researchers look for evidence that the donated immune cells and stem cells have engrafted, while making 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 phase II that in our patients who were able to tolerize [accept the organ without rejection] to their donated organ, we saw completely preserved and in fact slightly increased kidney function,” Requadt says. “So, it stands to reason that if you eliminate the drugs that are associated with declining kidney function that you would preserve kidney function, so hopefully the patient will have that one kidney for life.”
Matthew Cooper, director of kidney and pancreas transplantation for MedStar Georgetown Transplant Institute in Washington, DC, states that, “Right now, the Achilles’ heel is we have such a long waiting list and few donors that people die every day waiting for a kidney transplant. Eventually, we will eliminate the organ shortage so that people won’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 considered “the Holy Grail” of modern transplant medicine.
“Now that we’ve got the protocols in place and some personal examples of how that can happen, it’s pretty exciting to see that all coming together,” he adds.
Today's podcast guest, Dr. Renee Wegrzyn, directs ARPA-H, a new agency formed last year to spearhead health innovations. Time will tell if ARPA-H will produce advances on the level of its fellow agency, DARPA.
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How will the agency figure out which projects to take on, especially with so many patient advocates for different diseases demanding moonshot funding for rapid progress?
I talked with Dr. Wegrzyn about the opportunities and challenges, what lessons ARPA-H is borrowing from Operation Warp Speed, how she decided on the first ARPA-H project that was announced recently, why a separate agency was needed instead of reforming HHS and the National Institutes of Health to be better at innovation, and how ARPA-H will make progress on disease prevention in addition to treatments for cancer, Alzheimer’s and diabetes, among many other health priorities.
Dr. Wegrzyn’s resume leaves no doubt of her suitability for this role. She was a program manager at DARPA where she focused on applying gene editing and synthetic biology to the goal of improving biosecurity. For her work there, she received the Superior Public Service Medal and, in case that wasn’t enough ARPA experience, she also worked at another ARPA that leads advanced projects in intelligence, called I-ARPA. Before that, she ran technical teams in the private sector working on gene therapies and disease diagnostics, among other areas. She has been a vice president of business development at Gingko Bioworks and headed innovation at Concentric by Gingko. Her training and education includes a PhD and undergraduate degree in applied biology from the Georgia Institute of Technology and she did her postdoc as an Alexander von Humboldt Fellow in Heidelberg, Germany.
Dr. Wegrzyn told me that she’s “in the hot seat.” The pressure is on for ARPA-H especially after the need and potential for health innovation was spot lit by the pandemic and the unprecedented speed of vaccine development. We'll soon find out if ARPA-H can produce gamechangers in health that are equivalent to DARPA’s creation of the internet.
Show links:
ARPA-H - https://arpa-h.gov/
Dr. Wegrzyn profile - https://arpa-h.gov/people/renee-wegrzyn/
Dr. Wegrzyn Twitter - https://twitter.com/rwegrzyn?lang=en
President Biden Announces Dr. Wegrzyn's appointment - https://www.whitehouse.gov/briefing-room/statement...
Leaps.org coverage of ARPA-H - https://leaps.org/arpa/
ARPA-H program for joints to heal themselves - https://arpa-h.gov/news/nitro/ -
ARPA-H virtual talent search - https://arpa-h.gov/news/aco-talent-search/
Dr. Renee Wegrzyn was appointed director of ARPA-H last October.
Tardigrades can completely dehydrate and later rehydrate themselves, a survival trick that scientists are harnessing to preserve medicines in hot temperatures.
Formulating biologics to withstand drying and hot temperatures has been the holy grail for pharmaceutical researchers for decades. It’s a hard feat to manage. “Biologic pharmaceuticals are highly efficacious, but many are inherently unstable,” says Thomas Boothby, assistant professor of molecular biology at University of Wyoming. Therefore, during storage and shipping, they must be refrigerated at 2 to 8 degrees Celsius (35 to 46 degrees Fahrenheit). Some must be frozen, typically at -20 degrees Celsius, but sometimes as low -90 degrees Celsius as was the case with the Pfizer Covid vaccine.
For Covid, fewer than 73 percent of the global population received even one dose. The need for refrigerated or frozen handling was partially to blame.
The costly cold chain
The logistics network that ensures those temperature requirements are met from production to administration is called the cold chain. This cold chain network is often unreliable or entirely lacking in remote, rural areas in developing nations that have malfunctioning electrical grids. “Almost all routine vaccines require a cold chain,” says Christopher Fox, senior vice president of formulations at the Access to Advanced Health Institute. But when the power goes out, so does refrigeration, putting refrigerated or frozen medical products at risk. Consequently, the mRNA vaccines developed for Covid-19 and other conditions, as well as more traditional vaccines for cholera, tetanus and other diseases, often can’t be delivered to the most remote parts of the world.
To understand the scope of the challenge, consider this: In the U.S., more than 984 million doses of Covid-19 vaccine have been distributed so far. Each one needed refrigeration that, even in the U.S., proved challenging. Now extrapolate to all vaccines and the entire world. For Covid, fewer than 73 percent of the global population received even one dose. The need for refrigerated or frozen handling was partially to blame.
Globally, the cold chain packaging market is valued at over $15 billion and is expected to exceed $60 billion by 2033.
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Freeze-drying, also called lyophilization, which is common for many vaccines, isn’t always an option. Many freeze-dried vaccines still need refrigeration, and even medicines approved for storage at ambient temperatures break down in the heat of sub-Saharan Africa. “Even in a freeze-dried state, biologics often will undergo partial rehydration and dehydration, which can be extremely damaging,” Boothby explains.
The cold chain is also very expensive to maintain. The global pharmaceutical cold chain packaging market is valued at more than $15 billion, and is expected to exceed $60 billion by 2033, according to a report by Future Market Insights. This cost is only expected to grow. According to the consulting company Accenture, the number of medicines that require the cold chain are expected to grow by 48 percent, compared to only 21 percent for non-cold-chain therapies.
Tardigrades to the rescue
Tardigrades are only about a millimeter long – with four legs and claws, and they lumber around like bears, thus their nickname – but could provide a big solution. “Tardigrades are unique in the animal kingdom, in that they’re able to survive a vast array of environmental insults,” says Boothby, the Wyoming professor. “They can be dried out, frozen, heated past the boiling point of water and irradiated at levels that are thousands of times more than you or I could survive.” So, his team is gradually unlocking tardigrades’ survival secrets and applying them to biologic pharmaceuticals to make them withstand both extreme heat and desiccation without losing efficacy.
Boothby’s team is focusing on blood clotting factor VIII, which, as the name implies, causes blood to clot. Currently, Boothby is concentrating on the so-called cytoplasmic abundant heat soluble (CAHS) protein family, which is found only in tardigrades, protecting them when they dry out. “We showed we can desiccate a biologic (blood clotting factor VIII, a key clotting component) in the presence of tardigrade proteins,” he says—without losing any of its effectiveness.
The researchers mixed the tardigrade protein with the blood clotting factor and then dried and rehydrated that substance six times without damaging the latter. This suggests that biologics protected with tardigrade proteins can withstand real-world fluctuations in humidity.
Furthermore, Boothby’s team found that when the blood clotting factor was dried and stabilized with tardigrade proteins, it retained its efficacy at temperatures as high as 95 degrees Celsius. That’s over 200 degrees Fahrenheit, much hotter than the 58 degrees Celsius that the World Meteorological Organization lists as the hottest recorded air temperature on earth. In contrast, without the protein, the blood clotting factor degraded significantly. The team published their findings in the journal Nature in March.
Although tardigrades rarely live more than 2.5 years, they have survived in a desiccated state for up to two decades, according to Animal Diversity Web. This suggests that tardigrades’ CAHS protein can protect biologic pharmaceuticals nearly indefinitely without refrigeration or freezing, which makes it significantly easier to deliver them in locations where refrigeration is unreliable or doesn’t exist.
The tricks of the tardigrades
Besides the CAHS proteins, tardigrades rely on a type of sugar called trehalose and some other protectants. So, rather than drying up, their cells solidify into rigid, glass-like structures. As that happens, viscosity between cells increases, thereby slowing their biological functions so much that they all but stop.
Now Boothby is combining CAHS D, one of the proteins in the CAHS family, with trehalose. He found that CAHS D and trehalose each protected proteins through repeated drying and rehydrating cycles. They also work synergistically, which means that together they might stabilize biologics under a variety of dry storage conditions.
“We’re finding the protective effect is not just additive but actually is synergistic,” he says. “We’re keen to see if something like that also holds true with different protein combinations.” If so, combinations could possibly protect against a variety of conditions.
Commercialization outlook
Before any stabilization technology for biologics can be commercialized, it first must be approved by the appropriate regulators. In the U.S., that’s the U.S. Food and Drug Administration. Developing a new formulation would require clinical testing and vast numbers of participants. So existing vaccines and biologics likely won’t be re-formulated for dry storage. “Many were developed decades ago,” says Fox. “They‘re not going to be reformulated into thermo-stable vaccines overnight,” if ever, he predicts.
Extending stability outside the cold chain, even for a few days, can have profound health, environmental and economic benefits.
Instead, this technology is most likely to be used for the new products and formulations that are just being created. New and improved vaccines will be the first to benefit. Good candidates include the plethora of mRNA vaccines, as well as biologic pharmaceuticals for neglected diseases that affect parts of the world where reliable cold chain is difficult to maintain, Boothby says. Some examples include new, more effective vaccines for malaria and for pathogenic Escherichia coli, which causes diarrhea.
Tallying up the benefits
Extending stability outside the cold chain, even for a few days, can have profound health, environmental and economic benefits. For instance, MenAfriVac, a meningitis vaccine (without tardigrade proteins) developed for sub-Saharan Africa, can be stored at up to 40 degrees Celsius for four days before administration. “If you have a few days where you don’t need to maintain the cold chain, it’s easier to transport vaccines to remote areas,” Fox says, where refrigeration does not exist or is not reliable.
Better health is an obvious benefit. MenAfriVac reduced suspected meningitis cases by 57 percent in the overall population and more than 99 percent among vaccinated individuals.
Lower healthcare costs are another benefit. One study done in Togo found that the cold chain-related costs increased the per dose vaccine price up to 11-fold. The ability to ship the vaccines using the usual cold chain, but transporting them at ambient temperatures for the final few days cut the cost in half.
There are environmental benefits, too, such as reducing fuel consumption and greenhouse gas emissions. Cold chain transports consume 20 percent more fuel than non-cold chain shipping, due to refrigeration equipment, according to the International Trade Administration.
A study by researchers at Johns Hopkins University compared the greenhouse gas emissions of the new, oral Vaxart COVID-19 vaccine (which doesn’t require refrigeration) with four intramuscular vaccines (which require refrigeration or freezing). While the Vaxart vaccine is still in clinical trials, the study found that “up to 82.25 million kilograms of CO2 could be averted by using oral vaccines in the U.S. alone.” That is akin to taking 17,700 vehicles out of service for one year.
Although tardigrades’ protective proteins won’t be a component of biologic pharmaceutics for several years, scientists are proving that this approach is viable. They are hopeful that a day will come when vaccines and biologics can be delivered anywhere in the world without needing refrigerators or freezers en route.