Today, we interview David Paolella, Founder of Cambrooke Therapeutics and the innovator and pioneer behind the success of Cambrooke Therapeutics. While building his career as an architect, little did he know he would dedicate the past 25 years to the PKU community . . .

Q: When did you first hear about PKU?

A: I heard briefly about PKU in high school in my biology class. Only one mention in a biochemistry module where we had to memorize the reactions in Glycolysis and the Krebs cycle. They used PKU as an example of enzyme disruption. Later on, I occasionally took note of the “NutraSweet Swirl” warning. “This diet soda contains Phenylalanine.” Otherwise, to that point in my life, I did not give the phenylalanine content in food a second thought.

Q: What was your first encounter with PKU or Phenylketonuria?           

A: On July 9, 1992, while working in Boston as an architect, Lynn and I had our second child, Cameron. Only a few days after bringing Cameron home, we learned that he had PKU. That single call forever changed the course of our lives. As I say often, the good news is that he was (and is) completely healthy; the bad news is that there was almost nothing he could safely eat. In total, I feel we are all better for it, and thankful to be part of this supportive community.

Q: What got you into the business of low-protein foods and eventually led to the discovery of GMP?

A: Fortunately, Cameron’s diagnosis came in the first week of life and he immediately began the low protein diet that many readers here know so well. Lynn, with an instinct for nurturing and feeding our children, faced most of the daily challenges. The Cambrooke Therapeutics you see today came from Lynn’s search for better PKU food and formula. During those first 6-8 years, we struggled with every emotion and diet management challenge. We were encouraged by every family and individual we met with PKU. Nothing gave us more confidence than meeting older children who were thriving with their PKU.

By 1997, we were well prepared to welcome our daughter Brooke, who also received a classical PKU (R408W/R261Q) diagnosis – thankfully sharing the same alleles as her brother. With the limited choices available in the 1990’s, food and formula was not very appealing to our son. He was constantly hungry. It became our family’s mission to learn about every option for PKU food and formula. Never satisfied, we took matters into our own hands and engaged both commercial food scientists and university researchers in the field to help our early development efforts.

Q: How did you team up with scientists and researchers?

A: While searching to produce better homemade bread, Lynn communicated regularly with Virginia Schuett MS RD (editor of the National PKU News and author of the Low Protein food List) and Sally Gleason MS, RD.  Sally, a clinical dietician, had the insight to work closely with the Center for Dairy Research in Wisconsin. One of their research scientists, Dr. Mark Etzel had patented a process for extracting a dairy whey peptide from the cheese making process — kappa casein glycomacropeptide — now often abbreviated just GMP. GMP is a unique 64 amino acid small protein (peptide) that contains not a single molecule of Phenylalanine, Tryptophan or Tyrosine – the aromatic amino acids. In 2000, the team of Lynn, Sally, and Virginia had a small supply of this product from Dr. Etzel’s lab. Each of them explored the use of GMP to improve the browning of low phenylalanine (PHE) bread. From 2000-2002 the team experimented with a variety of food applications — with mixed results. Overall, they were encouraged.

By 2002 Cambrooke Foods had been operating for 2 years and developed more than a dozen low protein food items distributed in the US and Canada. But Sally was determined to see Dr. Etzel’s GMP put to practical use and called me to lead a “task force” for industry and academia to explore its potential. Sally enlisted an expert research doctor from the nutritional science department to investigate the safety and efficacy of using GMP to treat PKU mice. Dr. Denise Ney raised several million dollars from both the NIH and FDA to answer this question. We are indebted to a global network of scientists who share their lifetime of learning to advance our knowledge. They focused on this little mouse, called the PAH enu-2, as an ideal candidate to test such a diet.  Before beginning the study, the team bred a small colony of ‘mice cousins’ in the hundreds with a nearly identical genetic background (PKU mutation). Such “models” are essential to minimize variation in the study design. After 2 years, UW Madison had their mice and the study began in 2004.

What was eye opening for Lynn and me were the physiologic improvements in both the PKU and ‘wild-type’ (normal) mice when fed GMP from birth to adulthood. To my surprise, even the healthy mice, when fed AA diet, had consistently poor health (inflammation, weaker bones, enlarged kidneys and spleen). In contrast, the PKU and wild type mice thrived on the GMP diet. While we know mice are not humans, we also know that nature is very conservative — the biochemistry of phenylalanine metabolism (PHE –> TYR) is very similar in all mammals. These results had us committed to further testing to see if it could help our children’s lifelong health.

Q: Was the next step testing the efficacy and safety of GMP in humans?

A: Yes, over the next few years, the research team at UW Madison conducted an in-hospital clinical trial of 11 PKU patients, an environment that allowed their diets to be carefully controlled. Each of the subjects served as their own “controls” in a classic “cross-over” design study. From the published data, we learned that GMP was not just a better tasting source of protein for PKU — but nearly all of the patients improved on 4 critical biomarkers in just a few days of GMP diet! A subsequent 4- year study, published in 2016 with 30 PKU patients, further confirmed these results.

Q: Once the trials showed success, how did you share this amazing innovation with the rest of the world?

A: In 2009, our little Cambrooke Foods had more than 120 low protein foods, a 65,000 square foot processing facility and a ready to drink amino acid product line for PKU and MSUD. We were determined to find a supplier to make a commercial grade GMP to include in a new PKU formula. While there is plenty of whey in America, the small market size, technical sophistication, and investment needed to purify the background whey from the GMP, made it very difficult to convince a commercial dairy to manufacture this product just for PKU. But luckily in the spring of 2008, I had the good fortune to meet with the CEO of Arla Food Ingredients in Denmark. At our first meeting, Henrick Andersen shook my hand and said, “I’ve been waiting 18 years to meet you!” Henrick knew something about PKU and knew GMP could be a source of low phe protein for us PKU families. We set to work planning our collaboration. Cambrooke would need many millions of dollars for development which we did not have at the time, and Arla would need to build a commercial plant to manufacture this special ingredient for the ~60,000 PKU people in the world who could benefit. Lynn and I would risk everything on the evidence that this intact natural protein would benefit all patients with PKU. In 2009, we began our journey to raise capital, expand our manufacturing facility, and bring GMP to the global PKU market.

Q: How did the discovery of GMP lead to the innovation of your product, Glytactin?

A: GMP alone is not an ideal protein. Protein quality is the result of a complete range of essential amino acids (those not made by the human body) in the right proportions. GMP, as mentioned earlier, does not contain Phenylalanine, Tyrosine, and Tryptophan and must be supplemented with five “limiting” amino acids. In addition, GMP contains high levels of Threonine and other large neutral amino acids (LNAAs) bound in the peptide. There is evidence that high LNAA concentration can reduce brain Phenylalanine by blocking LAT-1 transport. To determine the best proportion of supplemental amino acids to balance the GMP protein, the research and development team examined PKU patient serum amino acid levels, gut microbiota, and potential renal-acid load (PRAL) , among other factors, to determine the optimal formulation for this new protein substitute. The resulting formulation is Cambrooke’s patented Glytactin formulation. We have developed and refined this formulation for the past 8 years. As of now, we are proud to say that our little company Cambrooke Therapeutics, in addition to our range of low protein foods, has more than 18 Glytactin products for PKU and four products for Tyrosinemia (Tylactin) now available.  More than 1000 patients worldwide (including Cameron and Brooke) use our Bettermilk product, available in the US since 2009. We now learn from many what it is like to live with PKU.

Q: Not bad for an architect.

A:  Lynn & I have been attending medical conferences on PKU and reading the literature for the past 25 years – some of this was bound to stick. Equally important, we have been fortunate to work with some key scientists from both industry and academia. I owe my education in the fields of nutrition, biochemistry, and food processing technology to them. Dr. Chuck Sizer was attracted to Cambrooke’s mission in 2010 and left his laboratory in Chicago to become our full time Chief Scientist.  Chuck is one of those brilliant PhD chemists with 40 years of industry leadership that we are fortunate to know. With Chuck’s help, Cambrooke designed and built our aseptic processing facility and developed the first ever Glycomacropeptide liquid formulas for PKU. Chuck created the first PKU formula ever sold in a clear bottle – Restore®. It is a remarkable achievement. Attracting scientists, like Dr. Sizer, to work for our company has been very rewarding.

Q: What were the main challenges in commercializing GMP?

A: One major challenge for bringing GMP to the market is cost. Extracting GMP from its natural source, it is extremely expensive to purify and incorporate into foods. Secondly, when we began, there were no commercial suppliers of pure GMP available. Due to its unique physical properties, there were many challenges developing a ready to drink GMP formula for PKU. Each of us learned a great deal along the way. We are learning and improving every day.

Q: High prices are an issue for many, don’t you think?

A: When Lynn and I began Cambrooke, we sought to improve the diet in three ways: better taste, more variety, and lower cost.  By 2002 we realized that small batch production with the extensive testing requirements (costs) needed for medical foods, and the shipping cost associated with home delivery, would keep “low cost” a fantasy. We found that comparing medical food costs to your local groceries was un-realistic.

That year we began our Greenlight™ program– a first of its kind, to bill medical insurance directly for low protein food. This kept the cost low for families, and allowed us to have a reasonable margin to maintain our operations. We continue that program today for both food and formula under the Cambrooke Care™ program. Our dedicated reimbursement team helps customers get coverage for their formula with little out-of-pocket costs. Unfortunately, PKU diet coverage is not uniform in all 50 states. We work hard to make this process as easy as possible for our customers. Congress needs to make access to PKU treatment lifelong and accessible to all Americans. It is inhumane to do otherwise – and Newborn Screening and medical food treatments have delivered an important “return on investment” (ROI) to society. It’s the right thing to do.

 Q: Have you realized GMP’s full potential?

A: Having led the way, Cambrooke makes more GMP products than any company in the world. To date, GMP has still not reached its full potential as a first line of treatment for the PKU diet. As a natural product with strong clinical evidence, I expect GMP will become the first choice of dieticians, patients, and families in the next few years.

As a medical foods company, Cambrooke Therapeutics is constantly working to find better options for the PKU diet, and we continually explore new ingredients. Cambrooke’s continuous improvement programs generate many ideas that are tested, validated, and incorporated into new product releases on an annual basis. We see our role as a nutrition technology company, with deep manufacturing expertise and a passion to help rare disease.

Although the dietary options have improved greatly since Cameron was born, it is difficult at every stage of life to maintain metabolic control – especially for PKU teens and adults. Many symptoms of transient elevated ‘phe’ levels plague our children and others with PKU.

There are promising new pharmaceutical therapies being studied. Our family has direct experience with two of these – without success. In the future, we hope to see a safe and effective alternative to this highly restrictive diet. Until one or more of these alternatives are available, maintaining a low phenylalanine diet is both a safe and effective PKU management.

Q: Are there any last thoughts you want to share?

The message we all need to remember: “Eat healthy to stay healthy.” We are learning that this one simple concept probably has more impact on our lifelong health than exercise or proper sleep will ever deliver. Someone once told me, “You can’t exercise your way out of a poor diet”. Choose wisely!