Kuvan (Tetrahydrobiopterin)

choi

英国版 '我不是药神'：女子细说得而复失的救命药. BBC Chinese, Apr 18, 2019
https://www.bbc.com/zhongwen/simp/uk-47974264  

is based on

Deborah Cohen, 'I Helped Test a Wonder Drug - Then I Was Denied It.' BBC, Apr 17, 2019
https://www.bbc.com/news/stories-47954400
("Louise Moorhouse is on a special diet of pills ['more than 80 pills a day'] or foul-tasting shakes. There's a drug that would allow her to eat like anyone else - she took it for three years during a clinical trial. But the NHS [National Health Service, in England] won't pay for it * * * Louise Moorhouse, a 35-year-old teacher from Birmingham, who has a rare genetic condition called phenylketonuria or PKU. * * * People with PKU can't properly digest the amino acid phenylalanine. Amino acids are the building blocks of protein and [always proteins in food] are broken down [to individual amino acids] by the body [stomach] to [re-assemble and] make our own proteins. * * * for three years, in her early 20s, Louise was able to eat like anyone else.  That's because she took part in trials for a drug now called Kuvan (sapropterin hydrochloride) that was being developed by US biotech company, BioMarin. * * * 'Kuvan allowed me to eat a completely normal diet.' * * * In 2007, it became the only licensed drug for the condition in the US; its European licence followed in 2008. * * * BioMarin put a £70,000 price tag on it, per adult per year - and the NHS thought it wasn't worth that.  'The drug was too expensive and the NHS decided that there wasn't enough evidence of efficacy of that drug at that time and so they said no to prescribing it,' says [Professor] Anita MacDonald [if Birmingham Children's Hospital] . * * * PKU is quite a rare disease. In England it is estimated that between one in 10,000 and one in 14,000 people have PKU. So there was little financial incentive for a pharmaceutical company to turn the compound into a licensed drug. * * * In 2004, BioMarin - which specialises in drugs for rare conditions - bought the data from the early development of the compound to treat PKU. This meant that while it had to fund trials it didn't have to meet the costs of searching for an entirely novel chemical compound [the last clause is pure bullshit, in that the purchase price reflected R&D] ")

Note:
(a) "People with PKU can't properly digest the amino acid phenylalanine."

This statement is simply wrong. People with PKU can not use phenylalanine, causing it to accumulate in blood, which seeps into and harm brain -- in children and adults.

choi

(b) I have no sympathy for patients in news stories that cry wolf. They lie too much, and conceal critical facts that are in favor of pharmaceutical companies. Plus journalists, such as this one, often do not do homework, taking those patients at face value.
(i) First and foremost, even taking Kuvan a PKU patient still has to limit intake of protein containing phenylalanine, which means almost all protein.
(ii) Before I introduce you to PKU, I will talk about the drug Kuvan.
(iii) No miracle drug, Kuvan is the trade name for an ordinary chemical, which our body already produces.  See tetrahydrobiopterin
https://en.wikipedia.org/wiki/Tetrahydrobiopterin
("(BH4) also known as sapropterin, is a cofactor;" section 6 Biosynthesis and recycling)
(A) At the top of this Wiki page, you see the chemical structure of tetrahydrobiopterin, whose difference with biopterin
https://en.wikipedia.org/wiki/Biopterin
is the addition of four hydrogen atoms in right aromatic ring. The fourth hydrogen atom is not shown, as is the practice in chemistry. (By definition, in chemistry addition of (at least) one hydrogen atom is reduction 还原.)
(B) pterin
https://en.wikipedia.org/wiki/Pterin
("Pterins were first discovered in the pigments of butterfly wings (hence the origin of their name, from the Greek pteron (πτερόν), wing) and perform many roles in coloration in the biological world") (citations omitted)

pterin
https://www.merriam-webster.com/dictionary/pterin
(pronunciation)

shows p is silent.
(C) cofactor (biochemistry)
https://en.wikipedia.org/wiki/Cofactor_(biochemistry)

Many vitamins belong to this category of chemicals. These chemicals are vitamins because out (human) body can not make it, such as vitamin C.
(iv)
(A) Chemically, Kuvan is simply sapropterin dihydrochloride. The "dihydrochloride" merely means the resulting salt after adding two "HCl" per sapropterin.
(B) BH4. Schircks Laboratories (based in Bauma (20-mile air distance east of Zurich), Switzerland), Jan 26, 2016
www.schircks.ch/pteridines/data/11209_11214_11215_BH4.pdf
("It [BH4] reacts with oxygen especially in neutral and alkaline solutions [this explains why 2HCl was added, to make the solution acidic (before a patient drinks the solution, but this is a chemical company whose product is not sterile]. * * * Dry powder has different stability depending on conditions, as described in the table below ['in ampoules: RT [room temperature] several months, or -20°C several years'])

choi

(c)
(i)
(A) phenylalanine hydroxylase
https://en.wikipedia.org/wiki/Phenylalanine_hydroxylase

, where a diagram shows the enzyme (with assistance of a cofactor) converts phenylalanine to tyrosine by adding a hydroxyl group (OH- ; in para position) to phenylalanine; that is what a hydroxylase does. For para, see arene substitution pattern
https://en.wikipedia.org/wiki/Arene_substitution_pattern
(B) In a nutshell, PKU patients, due to genetic defects of the gene for phenylalanine hydroxylase, can not make enough functional phenylalanine hydroxylase. Various defects in this gene bring about a range of functional enzyme, but always of lower level than that of normal persons.  See next.
(ii) How ingestion of Kuvan (sapropterin dihydrochloride) helps some but not all PLU patients.

Zurflüh MR et al, Molecular Genetics of Tetrahydrobiopterin-Responsive Phenylalanine Hydroxylase Deficiency. Human Mutation, 29: 167 (2008)
https://www.ncbi.nlm.nih.gov/pubmed/17935162
("More than 89% of patients are found to be compound heterozygotes [the one from father and the other from mother carry different mutations in the same gene]. The three most common mutations found in >5% of BH(4)-responsive patients are p.A403V, p.R261Q, and p.Y414C")

(A) Atlas of Genetics and Cytogenetics in Oncology and Haematology. undated
http://atlasgeneticsoncology.org/Educ/NomMutID30067ES.html
(B) den Dunnen JT and Antonarakis SE, Nomenclature for the Description of Sequence Variations. Human Genetics, 109: 121 (2001)
www.hgmd.cf.ac.uk/docs/mut_nom.html

both says the same thing: the p stands for protein; whose numbering starts from methionine (the same amino acid in all form of life on earth). The p.A403V means that the 403rd amino acid changes from the normal A to abnomal V, where A and V is one-letter (it can also be three-letter) representation of amino acids.

choi

(d)
(i) Paldeep S Atwal, Phenylketonuria. National Organization for for Rare Disorders, undated
https://rarediseases.org/rare-diseases/phenylketonuria/
("To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life. Most experts recommend that a phenylalanine-restricted diet should be life-long in persons with classical PKU")
(ii) How KUVAN Works. BioMarin, undated
https://www.kuvan.com/about-kuvan/how-kuvan-works/
("The active ingredient in KUVAN® (sapropterin dihydrochloride) Tablets or Powder for Oral Solution is a pharmaceutical version of BH4. It works in the same way as your body’s BH4. KUVAN adds more BH4 and stimulates the PAH enzyme to process Phe in people with PKU. * * * KUVAN has been prescribed along with a low-Phe diet")
(iii)
(A) Pearl Buck 赛珍珠 had a daughter Carol in 1920 who suffered from PKU; its cause was unknown at the time. Buck institutionalized Carol for the rest of Carol's life.
(B) Norwegian physician Ivar Asbjørn Følling in 1934 discovered cause of PKU: elevated level of phenylalanine in blood causes brain damage. In 1954, [German physician] Horst Bickel, English woman] Evelyn Hickmans and John Gerrard published a paper that described how they created a diet that was low in phenylalanine. Robert Guthrie [American; MD, PhD] introduced the newborn screening test for PKU in the early 1960s. en.wikipedia.org for phenylketonuria.