The Brown family at the Grand Tetons (2019). Clockwise from left, Christine, Kevin, Keagan, Connor, and Kellen.
But Christine Brown knew none of this when the hospital called saying that standard newborn screening of her son Connor had come back positive for PKU. It was urgent that they visit a special metabolic clinic the next day, which was about a three-hour drive away.
“I was told not to go on the Internet,” Christine recalls, “So when somebody tells you not to go on the Internet, what do you do? Even back in 2005, right.” What she saw were the worst examples of retardation, which was a common outcome from PKU before newborn screening became routine. “We were just in complete shell shock, our whole world just kind of shattered and went into a tail spin.”
“I remember feeding him the night before our clinic visit and almost feeling like I was feeding him poison because I knew that breast milk must have protein in it,” she says.
“Some of my first memories are of asking, ‘Mommy, can I eat this? There were yes foods and no foods.'"
Over the next few days the dedicated staff of the metabolic clinic at the Waisman Center at the University of Wisconsin Madison began to walk she and husband Kevin back from that nightmare. They learned that a simple blood test to screen newborns had been developed in the early 1960s to detect PKU and that the condition could be managed with stringent food restrictions and vigilant monitoring of Phe levels.
Everything in Your Mouth Counts
PKU can be successfully managed with a severely restricted diet. That simple statement is factually true, but practically impossible to follow, as it requires slashing protein consumption by about 90 percent. To compensate for the missing protein, several times a day PKU patients take a medical formula – commonly referred to simply as formula – containing forms of proteins that are digestible to their bodies. Several manufacturers now add vitamins and minerals and offer a variety of formats and tastes to make it more consumer friendly, but that wasn't always the case.
“When I was a kid, it tasted horrible, was the consistency of house paint. I didn't think about it, I just drank it. I didn't like it but you get used to it after a while,” recalls Jeff Wolf, the twang of Appalachia still strong in his voice. Now age 50, he grew up in Ashland, Kentucky and was part of the first wave of persons with PKU who were identified at birth as newborn screening was rolled out across the US. He says the options of taste and consistency have improved tremendously over the years.
Some people with PKU are restricted to as little as 8 grams of protein a day from food. That's a handful of almonds or a single hard-boiled egg; a skimpy 4-ounce hamburger and slice of cheese adds up to half of their weekly protein ration. Anything above that daily allowance is more than the body can handle and toxic levels of Phe begin to accumulate in the brain.
“Some of my first memories are of asking, ‘Mommy, can I eat this? There were yes foods and no foods,’” recalls Les Clark. He has never eaten a hamburger, steak, or ribs, practically a sacrilege for someone raised in Stanton, a small town in northeastern Nebraska, a state where the number of cattle and hogs are several-fold those of people.
His grandmother learned how to make low protein bread, but it looked and tasted different. His mom struggled making birthday cakes. “I learned some bad words at a very young age” as mom struggled applying icing that would pull the cake apart or a slice would collapse into a heap of crumbs, Les recalls.
Les Clark with a birthday cake.
Courtesy Clark
Controlling the diet “is not so bad when you are a baby” because that's all you know, says Jerry Vockley, Director of the Center for Rare Disease Therapy at Children's Hospital of Pittsburgh. “But after a while, as you get older and you start tasting other things and you say, Well, gee, this stuff tastes way better than what you're giving me. What's the deal? It becomes harder to maintain the diet.”
First is the lure of forbidden foods as children venture into the community away from the watchful eyes of parents. The support system weakens further when they leave home for college or work. “Pizza was mighty tasty,” Wolf' says of his first slice.
Vockley estimates that about 90 percent of adults with PKU are off of treatment. Moving might mean finding a new metabolic clinic that treats PKU. A lapse in insurance coverage can be a factor. Finally there is plain fatigue from multiple daily dosing of barely tolerable formula, monitoring protein intake, and simply being different in terms of food restrictions. Most people want to fit in and not be defined by their medical condition.
Jeff Wolf was one of those who dropped out in his twenties and thirties. He stopped going to clinic, monitoring his Phe levels, and counting protein. But the earlier experience of living with PKU never completely left the back of his mind; he listened to his body whenever eating too much protein left him with the “fuzzy brain" of a protein hangover. About a decade ago he reconnected with a metabolic clinic, began taking formula and watching his protein intake. He still may go over his allotment for a single day but he tries to compensate on subsequent days so that his Phe levels come back into balance.
Jeff Wolf on a boat.
Courtesy Wolf
One of the trickiest parts of trying to manage phenylalanine intake is the artificial sweetener aspartame. The chemical is ubiquitous in diet and lite foods and drinks. Gum too, you don't even have to swallow to receive a toxic dose of Phe. Most PKUers say it is easier to simply avoid these products entirely rather than try to count their Phe content.
Treatments
Most rare diseases have no treatment. There are two drugs for PKU that provide some benefit to some portion of patients but those drugs often have their own burdens.
KUVAN® (sapropterin dihydrochloride) is a pill or powder that helps correct a protein folding error so that food proteins can be digested. It is approved for most types of PKU in adults and children one month and older, and often is used along with a protein-restricted diet.
“The problem is that it doesn't work for every [patient's genetic] mutation, and there are hundreds of mutations that have been identified with PKU. Two to three percent of patients will have a very dramatic response and if you're one of those small number of patients, it's great,” says Vockley. “If you have one of the other mutation, chances are pretty good you still are going to end up on a restricted diet.”
PALYNZIQ® (pegvaliase-pqpz) “has the potential to lower the Phe to normal levels, it's a real breakthrough in the field,” says Vockley. “But is a very hard drug to use. Most folks have to take either one or two 2ml injections a day of something that is basically a gel, and some individuals have to take three.”
Many PKUers have reactions at the site of the injection and some develop anaphylaxis, a severe potentially life-threatening allergic reaction that can happen within seconds and can occur at any time, even after long term use. Many patients using Palynziq carry an EpiPen, a self-injection devise containing a form of adrenaline that can reverse some of the symptoms of anaphylaxis.
Then there is the cost. With the Kuvan dosing for an adult, “you're talking between $100,000 and $200,000 a year. And Palynziq is three times that,” says Vockley. Insurance coverage through a private plan or a state program is essential. Some state programs provide generous coverage while others are skimpy. Most large insurance company plans cover the drugs, sometimes with significant copays, but companies that are self-insured are under no legal obligation to provide coverage.
Les Clark found that out the hard way when the company he worked for was sold. The new owner was self-insured and declined to continue covering his drugs. Almost immediately he was out of pocket an additional $1500 a month for formula, and that was with a substantial discount through the manufacturer's patient support program. He says, “If you don't have an insurance policy that will cover the formula, it's completely unaffordable.” He quickly began to look for a new job.
Hope
It's easy to see why PKUers are eager for advances that will make managing their condition more effect, easier, and perhaps more affordable. Synlogic's efforts have drawn their attention and raised hopes.
Just before Thanksgiving Jerry Vockley presented the latest data to a metabolism conference meeting in Australia. There were only 8 patients in this group of a phase 2 trial using the original version of the company's lead E. coli product, SYNB1618, but they were intensely studied. Each was given the probiotic and then a challenge meal. Vockley saw a 40% reduction in Phe absorption and later a 20% reduction in mean fasting Phe levels in the blood. The product was easy to use and tolerate.
The company also presented early results for SYNB1934, a follow on version that further genetically tweaked the E. coli to roughly double the capacity to chop up the target proteins. Synlogic is recruiting patients for studies to determine the best dosing, which they are planning for next year.
“It's an exciting approach,” says Lex Cowsert, Director of Research Development at the National PKU Alliance, a nonprofit that supports the patient, family, and research communities involved with PKU. “Every patient is different, every patient has a different tolerance for the type of therapy that they are willing to pursue,” and if it pans out, it will be a welcome addition, either alone or in combination with other approaches, to living with PKU.
Author's Note: Reporting this story was made possible by generous support from the National Press Foundation and the Fondation Ipsen. Thanks to the people who so generously shared their time and stories in speaking with me.
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.
