Rare Disease Focus: PKU

Emily BurkeDrug Approvals, Drug Development, Edited by Sarah Van Tiem, Orphan Disease, Orphan Drugs

Biopharma To The Rescue: PKU

The ubiquitous soda can. Who hasn’t seen one? Ever look on the back, at the disturbingly long paragraph of ingredients? The list of ingredients on the back of a can of diet soda are perhaps even more unsettling. Underneath it, there’s a warning in bold: “Phenylketonurics: Contains Phenylalanine.

Phenylalanine doesn’t harm most people. But what’s the story with phenylketonurics? They are born with a rare genetic disorder called phenylketonuria. That’s fen-ul-key-toe-NU-ree-uh. More widely known as PKU, this condition results in an inability to break down the amino acid phenylalanine. Untreated, PKU sufferers can face dire health problems including brain damage and seizures.

To help control the condition, phenylketonurics must eat a severely restricted diet, limiting intake of high-protein foods such as meat, dairy, fish, nuts, beans, legumes, and tofu – all of which contain high levels of phenylalanine. Getting back to the diet soda, PKU patients can’t consume sweeteners like Equal or NutraSweet, which contain aspartame—a derivative of phenylalanine.


At long last, there’s encouraging news on the subject. On May 24th, the FDA approved BioMarin’s (San Rafael, CA) latest enzyme replacement therapy, Palynziq. Developed to treat PKU, the drug promises a more normal life for people unable to savor the simple pleasure of sharing a meal with friends and loved ones. This Biotech Primer WEEKLY examines PKU more closely and how Palynziq can treat it.

PKU Up Close

Phenylketonuria occurs most often in European Caucasions and their descendants, with a prevalence of about 1:10,000 births. The condition is autosomal recessive—meaning phenylketonurics have two defective copies of the gene. Healthy parents often have no idea if they carry the gene in question; consequently, newborns are routinely tested for PKU. Starting from day one, any infant who tests positive must be fed a highly restrictive diet. That’s because high levels of phenylalanine can cause developmental delays, irregular motor functioning, and mental retardation. Infant diets may contain limited amounts of breast milk, but rely on phenylalanine-free baby formula. Pediatricians recommend pasta, fruits and vegetables, and low protein bread when affected babies start eating solid food. Lifelong nutritional supplements are key because the PKU diet lacks protein.

Scientists still don’t know the exact mechanism behind PKU. However, its manifestations are clear. Images of patients’ brains show damage to both their white (myelinated axons) and grey matter (neuronal cell bodies).
There are two different disease pathways:

  • Classical PKU is caused by any one of several possible mutations in the gene coding for phenylalanine hydroxylase (PAH). This enzyme breaks down phenylalanine. Different mutations affect people differently—some phenylketonurics can’t metabolize phenylalanine at all while others experience only diminished ability.
  • PKU can also result from a deficiency in the PAH cofactor tetrahydrobiopterin (THB). Cofactors are chemical compounds essential to an enzyme’s activity.
The New PAL For PKU Patients

Palynziq works by replacing PAH, enabling a patient to metabolize phenylalanine. The new drug, taken by injection, is a recombinant version of phenylalanine ammonia lyase (PAL). Related to PAH, this enzyme breaks down phenylalanine. In clinical trials, people treated with Palynziq showed substantially reduced levels of phenylalanine compared to those on placebo without following the unyielding PKU diet.

BioMarin already had one drug on the market to treat PKU. Kuvan, a small molecule drug, is the synthetic form of THB. It’s taken orally and reduces blood phenylalanine levels in 30% to 50% of patients. Kuvan is indicated for phenylketonurics whose disease primarily results from THB deficiency or certain PAH mutations. While they benefit from Kuvan, these patients must still adhere to a restrictive diet.

Coming Up
  • BioMarin plans to attack PKU from yet another angle: Gene therapy. Still in preclinical development, this approach would deliver a gene that codes for the PAH enzyme directly to the liver cells (where it is normally produced) of PKU patients.
  • Synlogic (Cambridge, MA) is taking a novel platform approach–synthetic biotics. Researchers plan to engineer gut microbes—healthy bacteria—to produce phenylalanine-digesting enzymes. They hope to create microorganisms that sense changes in phenylalanine concentrations and respond appropriately. Ultimately, the scientists hope to create a “living drug” that patients can take orally and integrate into their existing gut microbiome. Synologic’s PKU treatment is currently in IND-enabling studies.
  • Rubius Therapeutics (Cambridge, MA) has announced plans to use its novel red blood cell therapeutics platform to tackle PKU. Bone marrow stem cells, marked for red blood cell formation, are programmed to produce an enzyme that breaks down phenylalanine. These phenylalanine-metabolizing red blood cells are grown in the lab and transfused into the patient where they remain in circulation for several months. This platform is still in preclinical testing but is generating a lot of excitement within research and investment communities.
Cocktail Fodder: Toxic Fungus?

Why does the defective PAH gene persist in human populations, when it can be so devastating? It’s thought that heterozygotes—people with one functional copy and one dysfunctional copy of the gene—have some protection against the effects of one of the most abundant food contaminants, fungal toxin ochratoxin A. The fungus can occur in grain, pork, coffee, and grapes. It can also hang out in water damaged houses and heating ducts. Turns out, having one copy of the gene may have helped some of our ancestors survive and thrive long enough for us to enjoy this edition of Biotech Primer WEEKLY.