Kaylee Goodwin, 29, has struggled her whole life to control her blood levels of “phe” — the amino acid known as phenylalanine. “I was told that if my levels were controlled, I would be able to think more clearly and feel better overall,” she says.
Goodwin was born with phenylketonuria (PKU), a genetic metabolic disorder affecting roughly 1 in 16,000 newborns. Her body can’t break down phe because of a genetic mutation disabling the necessary enzyme, phenylalanine hydroxylase (PAH).
If left untreated, phe accumulates in the brain, causing intellectual disability and seizures. But starting in the early 1960s, newborn screening programs have been able to test for PKU. Goodwin tested positive and was prescribed a special phe-free diet by Harvey Levy, MD, at Boston Children’s Hospital.
Through the diet, Goodwin has dodged serious brain damage and was able to attend college and start a career as a dancer and actress. But because phe is in nearly all naturally occurring proteins, she couldn’t eat meat, eggs, dairy products, legumes, most grains and many fruits and vegetables. Instead, she had to consume a foul-tasting amino acid formula.
“I spent my entire life carrying special foods and medical formula around with me, and weighing and measuring foods,” she says. “I couldn’t sleep over at a friend’s house without bringing my special foods. Everything I ate looked different from everyone else’s, so it was a little bit embarrassing.”
Despite her best efforts, Goodwin’s phe levels were never really normal. But in 2014, that started to change. She entered a clinical trial testing an enzyme called pegvaliase (Palynziq) that substitutes for the missing PAH enzyme. Over the next year, her blood phe levels began to dip significantly.
Today, she credits the drug, approved last month by the FDA, for changing the course of her career and her life. She is now a project administrator at Vanguard, a leading investment company, and is engaged to be married. And she can eat whatever she wants. “It’s to the point where I don’t even think I have PKU anymore,” she says.
The long and rocky road to controlling phe
Ever since it was invented, the PKU diet has been widely hated, a source of anxiety and, often, social isolation.
“Until age 4 or 5, the diet is not so difficult, but once a kid is in school, it’s a different story,” says Levy, a senior physician in Boston Children’s Metabolism Program.
Over the years, PKU-friendly food options have expanded, making it easier to follow the diet. Recently, researchers discovered a more palatable protein called glycomacropeptide (GMP) that contains little or no phe, made from the whey discarded in cheese-making. A small clinical trial conducted by the University of Wisconsin and Boston Children’s found that foods made with GMP curbed phe levels as well as the traditional formula.
In 2008, the FDA approved the first PKU drug, Kuvan, which boosts the action of the PAH enzyme. While it helps some people with PKU break down phe, it didn’t help Goodwin.
“Some patients have such a severe genetic defect that they destroy PAH as soon as it is made, or the enzyme is so deformed that it doesn’t function,” Levy explains.
Borrowing from plants
The enzyme gets the blood phe level down to normal – that’s something we’ve never seen in PKU.
Pegvaliase doesn’t replace PAH, but instead introduces another enzyme, phenylalanine ammonia lyase (PAL) that also breaks down phenylalanine — but in a different way. So far, it seems to completely eliminates the need for the diet in the vast majority of those with PKU.
“The enzyme gets the blood phe level down to normal – that’s something we’ve never seen in PKU,” says Levy. “It could change the treatment of PKU dramatically.”
PAL, first discovered in the 1950s in plants, is involved in producing lignin, the substance that makes plants rigid. It works by converting phe to trans-cinnamic acid, which then gets converted to lignin. In 1980, researchers gave PAL to a single patient with PKU in capsule form and saw a reduction in blood phe levels. Over the years, scientists cloned the gene for PAL and modified the enzyme to be less reactive with the immune system.
Two Phase 3 studies, PRISM-1 and PRISM-2, sponsored by BioMarin Pharmaceutical, tested pegvaliase in 261 people with PKU age 16 and older. Boston Children’s Hospital was the lead center for these studies, which involved more than a dozen institutions.
My biggest life changes happened around the same time that my levels dropped.
Patients were taught to give themselves a daily subcutaneous injection — 72 percent for at least 12 months and 33 percent for at least two years. The results, published last month, were good.
Within two years, 61 percent of patients had their blood phe levels fall to 360 μmol/L or lower, below the recommended upper limit. In 51 percent, levels dipped to 120 μmol/L or lower — below the upper limit of normal for people without PKU. Adverse events were largely minor, mainly joint aches, reactions at the injection site, hives and headache. Twelve participants had anaphylaxis-like events, leading to a package warning and the recommendation that patients have an epi-pen available when they self-inject.
The FDA limited its approval to adults unable to maintain phe levels below 600 μmol/L. However, Levy, who co-led Phase III trials, expects that pegvaliase will be used off-label in older children who are able to tolerate the frequent injections.
After some time on pegvaliase, Goodwin noticed that she was thinking and communicating more clearly. People were finding her less “cloudy” and “scatterbrained.”
“Back when my levels were high, I would find myself talking in circles because I couldn’t really formulate my thoughts,” she says. “I would come out of what I was saying and think, ‘what am I talking about?’ I would interrupt people a lot because I was afraid I’d forget what I was going to say. At first, when my levels dropped, I felt a lot of anxiety, maybe because my brain was being stimulated fully for the first time. I began to realize lot of things. It was like an awakening. My biggest life changes happened around the same time that my levels dropped.”
People with PKU, even when on the diet, tend to have lower IQ scores. Some have problems with executive functioning, school, job stability and relationships. On pegvaliase, many patients report improvement on these fronts. The Phase 3 study also showed that the lower the blood phe level, the better patients scored on measures of attention typically used to evaluate ADHD.
Pegvaliase isn’t cheap: The FDA-approved drug, Palynziq, reportedly will have a list price of $267,000 a year ($192,000 after discounts). Some companies are working to develop oral versions which might be less expensive, and Kuvan, which helps some patients but rarely replaces the diet, can cost $200,000 a year.
Goodwin has received assurances from BioMarin that, as a study participant, she will never lose access to pegvaliase. But will payers cover its cost for everyone with PKU?
“That will be a major issue,” says Levy. “I don’t think anybody knows how it’s going to play out. It looks like Palynziq, or something like it, will be the preferred treatment for PKU. But insurance companies may balk at the argument that patients have a better quality of life. The FDA wants to know: do patients really have a higher IQ, or consistently better tests over time? That’s difficult to determine in adults, because their intellectual capacity is fairly well-set. I think over time other tests will be applied.
“The big question is, suppose you start the enzyme in children, so that they have normal phenylalanine from their earliest days,” Levy adds. “Will this allow them to be absolutely, positively normal? That’s a question we can’t answer right now.”