Aspartame Must Avoid People With Phenylketonuria!

Aspartame is a certain type of artificial sweetener which is often used as a sugar substitute in numerous different types of beverages and foods. It is actually a non-saccharide methyl ester of the phenylalanine dipeptide aspartic acid. It was first introduced in 1965, but its patent expired in 1992 so it is now available on the market under numerous different sorts of brand names. There are countless internet hoaxes, congressional hearings, medical controversies and political controversies associated with the safety of aspartame. Even though it was approved as safe for use by the United States Food and Drug Administration in 1974, there are still people who suffer from various sorts of genetic medical conditions who need to avoid to aspartame completely. There are two different types of approaches to the synthesis of aspartame which are in commercial use.

Aspartame must avoid people with phenylketonuria!

Aspartame Controversy

Aspartame has long been the subject of numerous controversies ever since it has been approved in 1974 by the United States Food and Drug Administration. This is mainly due to the fact that certain health risks can be associated with the consumption of aspartame. According to certain officials, aspartame has been the subject of numerous studies and tests in order approve its safety. It is a non-nutritive sweetener which is completely safe to use in moderate levels, according to the same officials. Aspartame is completely different from all other sorts of intense sweeteners, because its intake can be compared with the intake of the same substances derived from the natural types of food. Certain medicinal studies have tried to show that the consumption of aspartame may be associated with an increased risk of the development of brain tumors, but no scientific data have confirmed such claims.

Properties and Use

For those who do not know, aspartame is approximately 200 times sweeter than table sugar. When metabolized, aspartame produces four kilocalories of energy per gram. In spite of that, one needs only to ingest in very small amounts in order to feel a sweet taste. Such small amounts are simply insignificant to be even considered when the intake of calories is in question. Aspartame has a different taste than the regular, table sugar and there are also differences in terms of how long the provided sweetness lasts. Out of all different artificial sweeteners, aspartame is the closest to table sugar when it comes to the aforementioned properties. Its sweetness lasts longer than the sweetness of table sugar so it is often successfully mixed in with other sorts of artificial sweeteners such as acesulfame potassium. It is commonly produced from synthesized L-aspartate and L-phenylalanine. If exposed to high pH or elevated temperatures, aspartame is known for breaking down its constituent amino acids. This is why it cannot be used as a baking sweetener and it does not have a particularly long shelf life. If encased in fats or maltodextrin, its stability under high temperatures may be improved to a certain extent. Aspartame is commonly used as a sweetener in soft drinks, because they have a certain well balanced pH which makes it stable. When intended for use with a longer shelf life, aspartame needs to be mixed in with some other sorts of artificial sweeteners such as saccharin. When used in powdered beverages, the aldehyde of the aspartame needs to be protected as an acetal so that the loss of flavor and sweetness does not occur. Aspartame usually leaves a sweet aftertaste, but in some products it may also be associated with bitter and off flavor aftertastes as well.

Discovery and Approval

Aspartame was first discovered by a chemist called James M. Schlatter, back in 1965. It was synthesized accidentally during the production of a drug intended for use against ulcers. It was approved by the United States Food and Drug Association for use as an artificial sweetener, nine years after its discovery. The United States Food and Drug Association also approved it for use in carbonated beverages in 1983. !993 saw the approval from the United States Food and Drug Association which claimed it was safe for use in confections, baked goods and all sorts of beverages. In 1996, all restrictions were removed, so aspartame now can be used in all different sorts of food and beverage items.

 Metabolism and Phenylketonuria

After it gets ingested, aspartame breaks down into certain residual components which include methanol, phenylalanine and aspartic acid. These components are then broken down even further, so the products of those processes include formic acid and formaldehyde. Phenylketonuria is a rather rare type of medical condition. It can only be inherited and it can only be characterized as an inability to metabolize phenylalanine in a proper manner. People who suffer from this medical condition need to avoid aspartame because it is actually an additional source of phenylalanine, which may be a big problem for them



My Diet Isn’t About Weight, It’s About Not Getting Schizophrenia: Living With PKU

How About We Popcicle

When I was born, my mother thought I was an angel. Her angel became modified with “perfect” the first two weeks home from the hospital, when I was so quiet and peaceful, you would have hardly known there was a new baby in the house.

Then Mom got the phone call that would forever change both of our lives. The doctors told her I had Phenylketonuria (PKU), and I had to come back immediately for a second blood test. My mother first assured them that they had the wrong baby, then she took me back to the hospital.

The second blood test confirmed I had PKU, a rare genetically inherited metabolic disorder. The doctors and dietitians put me on the PKU diet and sure enough I began to scream and cry like a normal baby.

Having PKU means my body can’t break down the amino acid phenylalanine, found in foods that have protein. Since I can’t break down phenylalanine, it builds up as a poison to my body, eating away at the protective covering around my nerves. If it goes untreated between the ages of 1-3, PKU causes mental retardation. If I went off diet now, as an adult, I would have nerve damage leading to schizophrenia among other things. You can imagine why my mother, a geneticist by training who already knew the ramifications of a diagnosis of PKU, would initially refuse to believe I had it.

PKU was only discovered as a disorder in 1960, so when I was born, the oldest living person who had been diagnosed with it was only 30. There were literally no examples of successful, powerful people in their 30s, 40s, 50s, who had PKU, because they were all mentally retarded. In fact, even early on in the 1960s, 70s, and 80s, after PKU was discovered, it was widely believed relaxing or going off the PKU diet after the age of 6 was acceptable.

Later they realized going off the PKU diet–at any point–caused mental illness, violent mood swings, a lower IQ, declining academic performance, and an all around inability to reach one’s full potential.

The PKU Diet

Phenylalanine is found in foods high in protein, so I have an extremely low protein diet. I cannot eat meat, cheese, yogurt, eggs, milk, nuts, or beans. It’s possible I was such a quiet baby before my diagnosis because I was being poisoned by my mother’s high protein breast milk.

Each person with PKU has a slightly different diet based on what their phenylalanine (phe) tolerance is. I have a slightly higher tolerance (atypical PKU), which means some small part of my enzyme that breaks down phe works, so I can eat limited amounts of bread, pasta, and rice. Those who have Classical PKU have a lower phe tolerance and can’t eat bread and pasta, instead they eat substitutes made from starch. Fruits and vegetables are basically unlimited foods for all people with PKU.

Then there’s (what I like to call) our shake. Everyone with PKU has a prescribed amount of daily shake intake. I need to have 18 scoops of Phenyl Free 2 mixed with water each day, and luckily I love it. This shake (or formula) completes my diet and provides me with a lot of important vitamins and minerals, as well as the basic vital components phenylalanine breaks down into such as the amino acid tyrosine. This shake allows me to be a fully functioning human being, no exaggeration.

WIM Publicity

I have never gone off diet. I graduated from New York University, Tisch with honors three years ago, and I’ve been freelancing as a dues-paying actor, writer, and model in New York ever since.

Living with a Rare Disorder

Though I love my diet and my shake, having to explain my disorder to others sometimes makes me defensive. Every time I sit down to eat, the person across from me will inevitably take one look at my plate and tensely or curiously asks “Are you a vegetarian? Vegan?” Often I want to simply say yes to avoid going through my whole spiel, especially when I’m hungry and want to dig into my meal.

Nowadays being considered vegan or vegetarian is cool, but it wasn’t easy being singled out like that when I was growing up and attending school. For all of us with PKU, it takes guts to explain how different we are to our peers. It takes stamina to repeat the same story to new acquaintances for decades. It takes patience to put up with things like people asking, “Why don’t you try going off the diet to see what schizophrenia is like?” Yes. This is actually a question I’ve been asked. Many times.

When someone’s reaction to my PKU is to pat me on the head or hand and say, “Oh you poor thing, you can’t eat anything”, I want to say, “Actually I can eat plenty! The PKU diet is remarkably close to the healthy Mediterranean diet, and happily my veins aren’t clogged with pig fat.” Instead I simply–and cheerfully–say, “Well I don’t know what any of it tastes like anyway, so I don’t miss it,” which is also true.

Besides, there are plenty of reasons to pat someone with PKU on the hand and empathize, none of them related to diet. Rather, it has to do with how difficult it can be to get the appropriate care for the disorder. In the United States, insurance coverage is different on a state by state basis, which makes it really hard and expensive for those who live in a state without PKU coverage. Each time I get new insurance, it’s a hassle to get them to recognize the medical necessity of my shake. Having this rare disorder can be a huge administrative headache.

Sure, I feel defensive and frustrated sometimes, but I’m grateful for my experience as a person with a treatable disorder. I know I’m one of the lucky ones. Oftentimes doctors will refer to PKU as a disease, but I beg to differ. PKU is a disorder, something I live with but control: a part of my body doesn’t work quite the way it should, that’s all. Moreover, thanks to Dr. Ivar Asbjorn Folling and Robert Guthrie, these days we know how to fix it.  Thanks to my doctor and nutritionists at Mount Sinai Metabolic Clinic, I get my blood tested for my phenylalanine level every couple of months and stay on track. Thanks to my Mom keeping me on diet as an infant, I’m not mentally retarded. Thanks to being born in the United States, I was screened for PKU at birth and put on diet. And thanks to my living in New York, my health insurance currently covers my expensive shake.

That’s a lot to be thankful for.

I’m not diseased. I’m healthy, happy, and grateful.



14 Amazing Phenylketonuria Statistics and facts

Phenylketonuria is caused by a mutation in the PAH gene. The mutation changes the way the instructions for a certain enzyme are made. Normally this enzyme is able to convert the amino acid phenylalanine into other compounds that the body needs. In Phenylketonuria, the process is muted so that not enough amino acids are converted. This eventually can lead up to an increase of amino acids so that they reach toxic levels and begin to cause brain damage.

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Statistics About Phenylketonuria

1. There are regional variations in the birth statistics of Phenylketonuria: on average, about 1 in 15,000 births have PKU, but it can be as high as 1 in 5,000 births in some regions.
2. Treatment guidelines recommend beginning treatment as early as possible, starting dietary treatment within the first week of life.
3. PKU was first discovered in 1934 and was known as Folling’s Disease for about 3 decades.
4. There is a 1 in 4 chance of having a PKU baby when both parents are carriers.
5. Children with PKU should not be fed more than 20 mg of phenylalanine in any given day.
6. 60-75% of normal protein must be taken from foods that are eaten and replaced with medical foods.
7. A PKU diet bans all meat, fish, chicken, eggs, nuts, beans, milk, and other dairy products.
8. Babies usually develop signs of PKU within a few months after birth without treatment.
9. 74 infants every day are diagnosed with PKU.
10. The approximate incidence rate in the United States is 0.01%.
11. the first child treated with a PKU diet was in the 1950’s.
12. Children who are tested for PKU before they reach 1 day in age may need to be tested again because the indicators for Phenylketonuria may not have followed developed.
13. The mutation occurs in a gene on Chromosome 12.
14. Because PKU must be treated early, babies in every U.S. state are routinely tested for the disease.

Common Traits and Interesting Facts

Phenylketonuria is better known as PKU. In its classic form, the production of this enzyme are virtually absent. If left untreated, the amino acids will quickly build up and cause damage. That’s why testing for this condition is critically important. If the mutation is discovered, then a treatment plan needs to be put into place as soon as possible. Testing happens almost immediately after birth. Thanks to the rapid response of medical professionals, when a PKU birth is detected, treatment begins promptly and virtually none of the signs and symptoms of Phenylketonuria are seen any more.

You can find phenylalanine in every protein that is eaten. That’s because it’s a building block of proteins. Some artificial sweeteners are also using phenylalanine today. Just consuming foods or these artificial sweeteners will not increase the chances of having a newborn diagnosed with PKU. Phenylketonuria is an inherited condition and can cause a number of physical and intellectual disabilities – even in children who first appear to be fine. The parents of a newborn each carry a copy of the mutated gene, but normally won’t show any signs and symptoms of the disorder.

Before conceiving a child, it may be a good idea for all couples to have some form of preconception genetic counseling. Doctors with a specialty in medical genetics can help parents understand what the risks of PKU happen to be and help to trace a family tree to determine if there may be a higher risk of having a child with PKU. If there are high risks, then couples can find the family planning help they may need As the statistics show, Phenylketonuria is not a common disorder, but it isn’t necessarily very rare either. That’s why having all newborns tested immediately is such a critical component of the treatment process.

Treatment and Condition

PKU can be a scary diagnosis for a parent to receive. The good news is that with a strict diet and the possibility of certain medications helping, it isn’t a death sentence. It doesn’t even have to affect the child’s intelligence. As long as the phenylalanine levels are kept down consistently, the only thing different between a child with PKU and a child without it are the foods that are eaten.

Families that have children with PKU or adults that are coping with this disease need a lot of support. There is a limited diet and the foods that can be eaten are often quite expensive. They need to have regular blood tests done, keep track of their foods eaten with detailed records, and make frequent visits to the doctor. Kids with PKU are known to battle their parents for the chance to eat snacks and “normal” food like everyone else.

This is one it is important to focus on the good things in life instead of the disorder. Children with PKU can do anything that other kids can do. Without a change in attention, kids tend to focus on the foods they want to eat that they aren’t allowed to eat and this might lead to food sneaking – which can be an unintended, but deadly choice.

The biggest adjustment is that households who are dealing with PKU need to be prepared to bring food with them at all times. The PKU diet allows people to eat at a restaurant regularly, although sometimes fries or a salad are the only options, but certain gatherings require food to be brought along. Speaking with school staff, teachers, and other people who interact with your family, along with a positive attitude, can make life a little easier.

Thanks to modern science, Phenylketonuria is not a death sentence any more. It doesn’t even cause brain damage, seizures, or a reduction in the overall quality of life. Although a strict diet must followed, it is possible to live a long and fulfilling life while having this disorder. With proper support from everyone, PKU can be something that is just adapted to instead of dreaded.



How I Living with Phenylketonuria

While Juan (Karel) is enjoying his pasta and his girlfriend Adélka is slowly chewing away one chip after another, they are making wedding arrangements. This is how looks the luckier variant of the life with phenylketonuria, a disease that does not allow you to eat anything (or just the bare minimum) of what contains proteins.

Today twelve-year-old Adélka from Česká Třebová does not know yet what direction her life will take. But she is sure that her life will be far from easy. A few days after her birth, just as all babies do by the time they are one week old, she had her phenylketonria tests done and this was how her mother learnt that Adélka’s life will be complicated by this disease which email a very poor diet.

The first five years, the strict diet was not a problem. Adélka’s mum cooked her food, sometimes her grandmothers helped as well. They all made sure that the child did not exceed the daily protein allowance and that, at the same time, she had all the important nutrients of the phenylketonuria diet: a special drink rich in amino-acids, microelements and vitamins – which the body lacks when it has to follow such a strict diet.

Even when Adélka started school, it did not seem at first, that she would be too limited by her „eating handicap“. The classes in the first and second year finished at lunchtime and just as all her classmates, Adélka brought her snack from home. And she simply did not take lunch at school. She did not have to. She could go straight home.

School, the basis of life

However, as she was getting older, afternoon classes started as well. Adélka’s journey to school takes forty minutes by public transport, so she did not have time to go home for lunch. And this is when the problems started.

Her parents asked the school, if Adélka could get phenyketonuria lunch at least twice a week, but the school refused. Therefore they announced the direction that Adélka would bring her own food into the canteen. However, the reply they received said, that on sanitary grounds, it is not possible in the canteen to heat up food brought in from the outside. What is more, it was insinuated to us that the best would be if Adélka did not bring any food at all in the canteen, her mother recalls the difficulties they had three years ago.

In the end, the school offered a seemingly illogical solution. Adélka can eat her food in the corridor. According to some regulations, a teacher is responsible for pupils only in the classroom, not in the corridor. This way, the school could easily get away with any complications that might come up in case something happened to Adélka while she eats her lunch; Adélka’s mum describes the situation. However, she did not like the idea at all, that Adélka should have her lunch in the corridor. Therefore she signed a declaration that she assumes all the responsibility for her daughter during and outside classes and the problem was sorted out.

Where is the humanity in all that?

Leaving aside the fact that Adélka’s mother has to cook a special meal every day from ingredients that are often hard to find, one question arises: Adélka now brings her own snack and lunch to school. She can calmly and with some dignity have her food at her desk. But is not there something else missing?

Try to remember, how many great friendships started around a spaghetti battle in the school canteen. And the number of unforgettable loves, which, but for the cheap black tea with lemon, would be impossible? We know that Adélka will always stand aside with her different eating needs. But to isolate a child from a natural collective of children is, to say the least, beyond all understanding. We know that there are regulations that the school does not want to and cannot break. Yet we do not understand why such regulations are made, Adélka’s mum shrugs her shoulders.

Detection and threat


Phenylketonuria is detected via screening of new born babies between the third and eighth day after the baby is born. A drop of blood is taken from the baby’s heel and placed onto a test card, which is sent to a special laboratory. In the Czech Republic all new born babies are tested this way. If the tests are positive or borderline, parents are immediately informed and an appointment is arranged with the advisory centre for metabolic disorders where the doctor together with the parents determines further procedure.

Phenylketonuria is a genetic disease, this is why, in order to diagnose it, and it is possible to make use of a so called pregnancy screening. This is used in case one of the parents or somebody in the family has or had the disease. The probability of phenylketonuria is said to be 1:10 000 according to some sources, and 1:8000 according to others. Every year, there are approximately ten cases of phenylketonuria diagnosed in our country.

Phenylketonurian and Mental Damage

Phenylalanin is an amino-acid found in all proteins. While a healthy organism processes this substance – it splits it and copes with any amount of it, a sick body cannot make use of it nor can it excrete it properly. As a result, phenylalanine accumulates in the body until its high concentration starts to damage cells.

Unless the disease is detected and treated in time, the development of the nervous system quickly becomes damaged, i.e. it leads to mental retardation (microcephalia) and slows down psychomotor development. People suffering from phenylketonuria often have blond hair and blue eyes. Their urine has a specific odour (so called mice odour). It is very important that a child follows a diet from the moment of detection of phenylketonuria until the completion of the development of brain. Even when adults, the diet does not end, mainly for women who wish to have babies. They have to be very careful about what they eat, so that the development of the baby is not endangered. If adults do not keep the diet, there is a risk of a direct link with Alzheimer disease.



Cambrooke Launches RESTORE Powder and RESTORE Lite Powder, for the dietary management of Phenylketonuria (PKU).

Cambrooke Therapeutics Inc., a leader in therapeutic nutrition for inborn errors of metabolism and ketogenic diet therapy, announces the launch of Glytactin RESTORE Powder™ and Glytactin RESTORE Lite Powder™, two medical food hydration beverages offered in convenient, portable, single-serve, stick-packs for the dietary management of Phenylketonuria (PKU).

Cambrooke's Glytactin RESTORE Lite Powder™ comes in a delicious, all-natural orange flavor. (Photo: Business Wire)

Glytactin with GMP is made from a natural whole protein derived from whey called glycomacropeptide (GMP). Published clinical evidence conducted at the University of Wisconsin, Madison, suggests that intact proteins made with GMP have important benefits for patients with PKU versus traditional synthetic amino acid based formulas. These benefits include: improved taste, increased satiety, lower dietary acid load and improved protein utilization (van Calcar, S.C., MacLeod, E.L., Gleason, S.T., Etzel, M.R., Clayton, M.K., Wolff, J.A. and Ney, D.M. “Improved Nutritional Management of Phenylketonuria by Using a Diet Containing Glycomacropeptide Compared with Amino Acids.” The American Journal of Clinical Nutrition. 89:1068-1077, 2009; MacLeod E., Clayton M., van Calcar S., Ney D. “Breakfast with Glycomacropeptide Compared with Amino Acids Suppresses Plasma Ghrelin Levels in Individuals with Phenylketonuria.” Molecular Genetics and Metabolism. 2010: Vol. 100, Issue 4: 303-308).

Patient acceptance of metabolic medical food can be a challenge. A recently published study found that the overall acceptance of medical food with glytactin products was statistically higher than traditional synthetic amino acid based formulas (Clayton M., Levy H., Murali, S., Ney D., Rice, G. Rohr F., Stroup, B., “Glycomacropeptide for Nutritional Management of Phenylketonuria: a Randomized, Controlled, Crossover Trial.” The American Journal of Clinical Nutrition, 10.3945, 116.135293, 2016).

Glytactin RESTORE Powder contains 5g protein equivalents (PE) and Glytactin RESTORE Lite Powder contains 10g PE with 55% fewer calories than Glytactin RESTORE Powder per gram of PE. The formulation contains B vitamins and electrolytes, which are important for individuals with PKU that have an active lifestyle as they help to replenish electrolytes lost during activities. Glytactin RESTORE Powder comes in two all-natural, delicious berry and orange flavors. Glytactin RESTORE Lite Powder comes in an all-natural orange flavor. The stick-pack shape of the RESTORE Powder packets makes them easy to mix into a bottle of water or an on-the-go sports bottle. Glytactin Restore Powder is an ideal addition to any PKU diet program for use at school, sports or any time on-the-go convenience is desired.

“My son stays active playing soccer but struggles to take his PKU formula before practice because he gets an upset stomach after drinking his amino acid formula. In addition, the formula is difficult to measure and mix. The RESTORE Powder is an easy, quick option for him to both take his formula and stay hydrated at the same time,” says Linda K., a mom whose son has PKU.

About Cambrooke Therapeutics – Founded in 2000, Cambrooke Therapeutics is a private equity-backed, Massachusetts-based therapeutic nutrition company and global provider of medical nutrition products for patients with serious unmet medical needs. The company works with physicians and researchers from around the world to develop, test and commercialize products that are focused on inborn errors of metabolism and intractable epilepsy. .



Driving Microbiome Science: PKU and Probiotics

Evolution of the Bacterial Trade

Although the inception of probiotics dates back to more than a century,1 it is only in recent years that scientific milestones have come to harness the potential of symbiotic relationships between microbiota and the human host.   In fact, the beneficial impact conferred on the human host set a historical antecedent for what has come to be known as modern day probiotics more than a decade before the time of Fleming’s discovery of penicillin.1  And, 2012 research endeavors championed by a consortium of members to the Human Microbiome Project finally mapped out the normal microbial make-up of the human body.2

Partners to the National Institutes of Health spanned a variety of multi-disciplinary backgrounds, including allergy and infectious disease, arthritis, musculoskeletal and skin diseases; dental and craniofacial research; cancer, diabetes, digestive and kidney diseases.2  With support from the NIH Common Fund, DNA sequencing techniques, and metagenomics, the bacterial contribution for 81-99% of genera identified and their metabolic capabilities has become much appreciated.2

Dr. James Anderson, Director of the NIH Division of Program Coordination, Planning and Strategic Initiatives announced for the first time, “We now have a very good idea of what is normal for a healthy Western population and are beginning to learn how changes in the microbiome correlate with physiology and disease.2

“We are all walking condominiums of bacteria3

The benefits of this research and understanding the role of microbiota are much geared at the development of disease-specific therapies.  This is reflected in a proliferation of the probiotics market with success contingent upon making the leap to product development and promoting consumption.1

For example, 2013 research findings from University of Maryland Baltimore (NIH-funded probiotics grant) reported the following “skyrocketing” statistics: no studies prior to 1991; 5 studies from 1995-1997; 384 from 2007-2009, and 430 from 2010-2012.4 And, according to the World Gastroenterology Organisation Global Guidelines, the strongest science behind the marketing potential involves gut health and immune function,1 with the intestine described to be “the body’s most important immune related organ” and home to approximately 60% of the body’s immune cells.1

The gut is the most heavily colonized site,5  with 100 trillion microbes that translate to virtually one to two kilograms of our weight.5  In addition, the provision of 600,000 genes to each human1 serves vital roles among energy production, barrier functions, vitamin synthesis, biotransformation of drugs and other functions for maintaining healthy equilibrium state.5

And, it makes sense for immunologic, digestive and metabolic functions5 to be of focused interest. This is much evidenced by the innovative platforms of various biotech companies in the strive to better understand what happens when there is disruption to that commensal state.  For example, Trayer Biotherapeutics, dedicated to leveraging this trailblazing research with delivery of novel therapies, is among three companies taking the lead for the rare, genetic disorder, phenylketonuria (PKU), a liver enzyme deficiency and inability to metabolize the essential amino acid, phenylalanine (phe).  PKU patients are among a finite number of inborn errors of metabolism (with incidence of 1 in 12,000 – 15,000 births).6

The disease manifestations due to the accumulation of toxic phe on neurological, psychological and mental health (that can ultimately result in mental retardation) have required early and lifelong intervention with a severely restricted therapeutic diet.  As of date, patients within the continuum of this complex disease spectrum have limited to no FDA-approved treatment options demonstrative of clinical superiority for preventing such devastating outcomes and mitigating disease other than through dietary manipulation.

At a recent July 2016 conference hosted by the National PKU Alliance, attendees learned of the pre-clinical strategies for a genetically modified probiotic to treat PKU which have now been licensed to Trayer Biotherapeutics for clinical development.  The implications for better understanding the PKU microbiome are profound on both a physiological and regulatory level.  It is hypothesized that characterization through human trials not only leads to targeted drug development, but there is potential to revolutionize existing regulatory probiotic framework with PKU as the first-ever probiotic biologic drug used in the treatment of this orphan disease.

PKU Patented Technology

The research efforts lead by Dr. Katherine Durrer-Deming and University of North Texas Health Science Center team have been described as pHENOMMenal7  in the field of genetically engineered probiotics and much facilitated by the advances of molecular technologies. The studied bacteria in typical probiotics encompass Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus and other strains8 and are commonly found in yogurt and fermented food products.

Because probiotic use is often intended for the general population, it should be noted clinical food studies have been quite limited in exploratory role of probiotics as clinical agents4  for which randomized, clinical, controlled trials have been the FDA gold standard for demonstration of efficacy.4

While the definition put forth by Joint FAO/WHO expert consultation deems probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host,4” the absence of any statutory or regulatory definition4 and shortcomings to existing regulatory framework paradoxically pose unique challenges for the commercial development of a first in its class and lend opportunity to customize the pathway for a novel, orphan therapy.

The molecular technologies used in the genetic manipulation of probiotic bacteria for PKU have become manifest in the SA-412 prototype.  The description offered by Marc Tewey of Trayer Biotherapeutics on SA-412 illustrates the qualities of a recombinant live biotherapeutic product (LBP).  SA-412 is composed of L. acidophilus that has been genetically modified by purposeful addition of a gene shown to express phenylalanine ammonia lyase (PAL), an enzyme which catabolizes phenylalaline3 and is different to the deficient enzyme in the PKU population.

On the in vitro level, functional PAL in phe metabolism has been demonstrated through trans-cinnamic acid (metabolite) production by the plasmid carried probiotic, Lactobacillus reuteri 100-23.7

On the in vivo level, studies using oral administration in the murine model have shown an average of 30-40% reduction in plasma phe depending on the length of treatment.7 SA-412 development seeks to perform Phase I/II clinical studies in hopes that a transition of the gene modification to the human specific strain will ideally lead to an alternate or even effective adjunct or combination therapy with introduction of more whole protein to the PKU diet and improved quality of life.3,7

While drawing upon atypical expertise of the Texas researchers and commercializing recombinant techniques for orphan LBP development is in of itself a potential marketing niche, the road to Phase I/II clinical trials is not without uncertainty and risk. The applicable regulations to these pioneering efforts must take into account a number of factors for SA-412 technology to be a future reality.  This includes departure from traditional probiotic use (as opposed to foods), the intended population (for patients with rare, genetic disease), and novel drug delivery systems.

Regardless of the pathway, the one constant to the equation in navigating FDA terrain is safety as an imperative. Because the PKU patient is harbor to a complex microbial environment and differs from the norm, the necessity of reliable data for safe and efficacious use really underscores the value of an investigational new drug (IND) submission.  There is the possibility that the interaction of LBPs and this environment will be a determinant factor in direction of Phase I/II studies and the implications of this on orphan drug development with low volume products are significant.

Research findings may also bring new questions and slow the progression through an already rigorous pre-market approval process on one of the highest risk categorized products ever to emerge from the FDA pipeline. Questions take money to answer; and with Phase I/II on the horizon for 2017, if the rules of the bacterial trade are not well defined from the start, it is the patients that lose out.

PKU Condominiums & Regulatory Convergence:  What Does the Future Hold?

Effective stakeholder engagement early on with the FDA would be beneficial in incentivizing and accelerating the process for filing an IND for PKU.  The opportunity for a LBP to tap into a probiotic framework that has been predominantly a “drug oriented, evidence –based medicine paradigm4 and meet FDA standards also has timely coincidence with the imminent threat of medical foods extinction.9 Dietary manipulation of phe with provision of medical foods has been the cornerstone of therapy for PKU since 1951 and is associated with an accumulation of substantial, scientific literature that more than exceeds FDA standards for a minimum of 25 years to establish history of safe use.4

However, the regulatory burden and new and emerging market entry barriers on the category of medical foods have become significantly more burdensome in recent years.  For example, July/August 2016 publication by Nutrition Insightreports there is “reduced access and increased costs to patients in addition to widespread confusion.9” Hence, there is serious unmet need when it comes to treatment options for PKU.  And, the biggest failure in current regulatory framework on medical foods ironically constitutes the biggest marketing advantage of a LBP for PKU: “addressing the role of foods in preventing disease, improving health, or possibly treating disease.4

The burden of proof for introducing novel therapies to the market largely rests with the manufacturer, and the question remains if the commercialization of the potentially first-ever PKU live biotherapeutic product can rise to the challenge of FDA standards and find balance with flexibility in Phase I/II clinical trials.

The preliminary specifications for FDA acceptability and recombinant DNA advisory permission must address many factors in addition to acceptable disease endpoints and functionality of the SA-412.  Regulatory considerations for live microorganisms on the path to retail distribution must take into account good manufacturing practices (or GMP) and various control measures.  These include quality and consistency, dosage forms, contaminants and purity, stability of the microbial components pre and post-manufacturing (like shelf life), mechanism of action (especially for protection against acidic environment, drug interactions), and others.

Although human applications of SA-412 technology “taking vacation in the mouse gut7”may have limitations, the good news reported by Dr. Durrer-Deming in combatting biopharmaceutical hurdles is that “treating PKU mice with pHENOMMenal did not result in systemic anti-AvPAL IgG7” or immune response to the recombinant L. acidophilus AvPAL gene.  Can PKU human condominiums of bacteria find regulatory convergence with trials slated to commence in 2017?

A live biotherapeutic product regulated as an orphan drug for PKU clearly exemplifies one size does not fit all within the existing probiotic framework.  The impact of a dynamic scientific, economic and social environment is going to take all stakeholders and collaboration with both the FDA Center for Biologics Evaluation and Research (CBER) and the FDA Office of Orphan Products (OOPD) for finding regulatory purview.  While there is no statutory definition affording the safe harbor for this novel orphan therapy PKU patients deserve and need, one thing is conclusive.

Trayer Biotherapeutics is a contentious force in defining its own regulatory pathway and certainly one to watch for driving the competition of microbiome science and unleashing the power of “bacteria, our friends.3