What is PAL? Or PEG-PAL or Pegvaliase or Palynziq...?

There has been bit of interest from the online PKU community about a possible new treatment. You might have heard one of the names above at some point and wondered ‘what exactly is that?’ The four terms refer to different aspects of a single method of treatment for PKU. This is an enzyme replacement therapy which is usually injected. Bear with me while I try untangle it all.

PAL: the enzyme

PAL stands for Phenylalanine Ammonia Lyase which is a common enzyme in many plant species. As a quick reminder, enzymes break down the amino acids in protein. People with PKU cannot produce enough of the enzyme Pheynylalanine Hydroxylase to break down all of the amino acid called Phenylalanine. Phenylalanine is common in many foods, which is why we have to eat a restricted diet.

The similarity in the enzyme names is no coincidence, both of them break down Phenylalanine. PAL does in plants what Phenylalanine Hydrozylase does in humans. But PAL breaks the amino acid down in a different way. Fortunately, the process results in two end products which are easily processed in humans. This is why it has been developed as a treatment for people who can’t produce enough Phenylalanine Hydroxylase - those of us with PKU.

PEG-PAL: the stealth enzyme

The addition of PEG in front of PAL in this term indicates that the enzyme PAL has been mixed with Polyethlyene glycol (PEG). This is a compound which is safe for humans to consume and is commonly used in medicine. In this case, the PEG is used to disguise the PAL enzyme from the immune system.

Remember that PAL is an enzyme found in plants, so it is foreign to the human body. If it were injected without PEG then the immune system would see the enzyme as a threat and destroy it. So PEG-PAL is basically the enzyme in stealth mode, able to hide from the immune system and get to work.

Pegvaliase and Palynziq: brand names

BioMarin have developed PEG-PAL into an injectable treatment for PKU. Initially this was called ‘Pegvaliase’ but it is now called ‘Palynziq’. Essentially they are brand names for the treatment PEG-PAL; in the same way that Panadol is a brand name for paracetamol.

It is worth noting that BioMarin are the same company which developed Kuvan - the pills which can improve Phenylalanine absorption in some people with PKU.

Does it work?

This is how the four terms relate to each other and to one treatment for PKU. It works in theory, but real life is always complicated.

A double blind study1 showed that PKU patients who were not maintaining the new EU blood-Phenylalanine targets were able to reach those levels using PEG-PAL. Excitingly, the treatment also allowed some patients to increase their Phenylalanine intakes to almost normal levels. So some people were able to eat a nearly normal diet.

BUT:

Problems with using PEG-PAL (Palynziq)

As noted above, PAL is a plant enzyme and is foreign to the human body. Even with the stealth coating offered by PEG it still causes problems during treatment. It has side-effects similar to those experienced when the human immune system fights a foreign chemical. BioMarin’s own website notes some of these problems for us:

  • “joint pain
  • headache
  • skin reactions that spread and last at least 14 days (such as itching, rash, or redness)
  • itching
  • nausea
  • stomach pain
  • mouth and throat pain
  • vomiting
  • cough
  • diarrhoea…” 2

The same page also warns potential patients that the allergic reaction to Palynziq may be severe enough to become life threatening.

Participants in the study mentioned above had an unusually high number of side effects. A third of the study participants had such bad reactions that they dropped out of the trial despite the increased diet freedom. That means the reactions certainly weren’t just a small irritation. It would take a lot for someone with PKU to go back to a very restricted diet.

What next? More Science!

In May 2019 the European Commission gave permission to BioMarin to market Palynziq in Europe for the limited treatment of some PKU patients who meet certain criteria. A brief summary of the criteria are:

  • patients with phenylketonuria (PKU) aged 16 and older
  • who have blood Phe levels greater than 600 micromol/L despite being on diet.

But there are no studies into the effect that this enzyme will have over a longer time. It is possible that the immune system could fight back so much that the injected enzyme becomes ineffective; All Pain for No Gain.

There are some big unknowns here and, as ever with science, more studies are needed.

Further references:

https://www.bloomberg.com/press-releases/2019-05-06/european-commission-approves-palynziq-pegvaliase-injection-for-treatment-of-phenylketonuria-pku-in-patients-aged-16-years

Explanation of PEG-PAL by the Canadian PKU and Allied Disorders Inc. http://canpku.org/wp-content/uploads/2016/03/2009-Explanation-of-PEG-PAL.pdf

Footnotes:

  1. As reported by Dr Elaine Murphy at the Nutricia Study day in London in May 2018. ↩︎
  2. PALYNZIQ® (pegvaliase-pqpz) Injection for PKU . BioMarin website. https://www.biomarin.com/products/palynziq/ Accessed October 2019. ↩︎