New PKU Drug Already Benefiting Adults


The recently approved phenylketonuria (PKU) drug, pegvaliase, is helping patients experience less disease burden—and drastically in some cases.

With the May 2018 US Food and Drug Administration (FDA) approval of the phenylketonuria (PKU) drug pegvaliase for use in adults, patients with PKU are starting to find that the disease has less of a negative impact on their lives than before—sometimes drastically so.

Pegvaliase, marketed as Palynziq, metabolizes dietary phenylalanine (Phe), which is something people with PKU are unable to do because they lack a specific enzyme. Therefore, people with PKU must stick to extremely restrictive diets in order to avoid ingesting too much protein.

This severely protein-restricted diet has been the mainstay of treatment, but researchers now realize that many people with PKU are unwilling or unable to be as vigilant about their diet as is necessary to manage the disease. The hope is that pegvaliase will fill that gap.

Rare Disease Report® spoke with Stephanie Sacharow, MD, an assistant professor at Harvard Medical School, medical geneticist, medical biochemical geneticist, and director of a clinic at Boston Children’s Hospital that treats adults with metabolic disease, chiefly PKU, to learn how pegvaliase is a game changer for her adult patients.

RareDR®: The biggest problem that people with PKU face is restrictions on what they can eat, correct?

Stephanie Sacharow, MD: The diet is so very difficult that we find that the majority of adults are not adhering to it. The diet involves not just restricting protein; [patients] need to be given protein that has no phenylalanine in it. Many adults can only take 5 grams of protein [daily]. They have to order a lot of their food from a special company. Having to [break] your protein down into amino acids usually is not palatable. It really impacts people's’ lifestyle since food is such a social occasion.

That special-order formula sounds like it could be expensive, too. What about insurance?

There’s often no coverage.

Until now, diet and a medication called sapropterin have been the mainstays of treatment for PKU. How effective has sapropterin been?

It has not worked for most, or not enough. Sapropterin is a cofactor to the nonfunctioning enzyme. People with milder PKU respond better to the cofactor while people with the greatest deficiency do not seem to respond to the cofactor.

[Interviewer’s note: According to Barbara Burton, MD, a director of the PKU clinic at the Ann & Robert H. Lurie Children’s Hospital of Chicago, only 40% of people with PKU respond to sapropterin.]

How is this new drug different?

What’s unique about this drug is that this is an enzyme substitution and not the same enzyme people are missing.

Some of your patients participated in a recent clinical trial for pegvaliase and are still taking it. How is that going?

We’re starting to see the first responses to the drug. Most people that go on the drug have significant side effects, so [we have to] desensitize them. Most of the side effects that we see happen early on, and they are side effects that can be overcome if they stick with it.

[Interviewer’s note: The ongoing clinical trial has demonstrated pegvaliase’s efficacy. Participants taking pegvaliase have had significantly lower blood levels of Phe than those taking the placebo.]

How serious are the side effects?

Anaphylaxis has been seen in 5% to 9% of patients who take the drug.

All study participants must carry EpiPens. Does that mean they must stop taking the drug if they have a reaction?

No. This is a different immunoglobulin response from an allergy. With the type of antibodies involved in pegvaliase, people can be rechallenged safely.

It can take 3 to 6 months or more than a year [for it to start working]. They start to feel better before they even know [their Phe] level is lower. And, at that point, we get to start adding protein back to their diet. We would start by adding back in about 10 grams of protein, which is a lot for someone with PKU.

How much protein can they eventually ingest?

[They can take] even 100 grams a day and no formula. People are now on completely normal diets. We heard from 1 patient who was able to take her first real vacation at a luxury, all-inclusive resort. It’s so liberating to be able to eat normal food.

Are the benefits to pegvaliase only dietary? [It’s known that people with PKU who don’t religiously stick to their diet often have comprised attention spans and struggle with depression and anxiety.

What we see in people who have poor control of the disease in adulthood is something they describe as a mental fog. [We] find that adults with PKU, even if they are treated as infants, can have some differences in their psychological functioning.

[Interviewer’s note: A 2017 study examining 57 adults with PKU who had been treated early in life exhibited lower inhibitory control and poorer memory and attention than matched controls. Motor skills also are often inferior to those of people without PKU. Another study of 631 people with PKU also found neurocognitive and other health deficits.]

A lot of the deficits are more subtle—you might not know by meeting them. [Now they experience] better attention, mood, anxiety [levels] and well-being. Their ability to focus and pay attention improves. People can take exams, get promoted—it has made all the difference to many of our patients.

Will pegvaliase be offered to children eventually?

We are hoping to try pegvaliase in older children. There are no clinical trials at this point. Adolescence is a time when people lose their good control of their PKU; I think it’s likely that this is something we can extend [to younger people].

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