1. Brief Description of Patient Group Supplying Input

Canadian PKU and Allied Disorders Inc. (CanPKU) is a non-profit organization dedicated to helping families and professionals dealing with phenylketonuria (PKU) and other inherited metabolic disorders by providing information, outreach, education, advocacy, and support. CanPKU has received unrestricted educational grants in 2015 and 2016 from BioMarin, Cambrooke Therapeutics, Innomar, Nutricia, Rx&D, and Vitaflo.

No conflicts of interest were declared with regard to this patient group submission.

2. Condition-Related Information

CanPKU conducted two separate online surveys between January 7 and 27, 2016 to gather information (the surveys contained free-form commentary, scoring options, and limited closed questions). Patients with PKU and their caregivers were contacted using membership databases, social media, and a partner patient group in the United States. A total of 297 of those contacted responded. Physicians and dieticians who treat PKU (n = 8) were also contacted and provided input regarding prescribing information, key factors for treatment choices, and obstacles to positive outcomes.

PKU is a metabolic disorder whereby the patients affected cannot break down phenylalanine (Phe). This subsequently leads to an increase in the amount of blood Phe to neurotoxic levels and can cause moderate to severe neurocognitive, neuropsychiatric, and developmental problems. Therefore, patients diagnosed as having PKU are required to follow a strict Phe-restricted diet, which involves controlling natural protein intake and drinking a synthetic Phe-free protein formula. Not only is this diet expensive with limited food choices, it is also laborious, complex, and unpalatable. Most patients surveyed have difficulties maintaining their strict diet and either they or their caregivers must spend a disproportionate amount of their time maintaining the diet. This includes undertaking things like cooking for the Phe-restricted diet, supervising protein intake, planning daily Phe intake, weighing foods, keeping records, ordering low proteins and amino acids, and preparing for social events. In addition, time is also consumed by clinic appointments and going for blood testing.

While each patient’s experience with PKU is unique, the management of this disorder places a large burden on both patients and their families. Patients with PKU can suffer from behavioural, mood, emotional, and social problems, psychiatric disorders, intellectual development delays, and neurological deficits. Manifestations from the aforementioned include difficulty focusing and concentrating, the inability to retain written or verbal communications, problems with short-term memory, hyperactivity, anxiety, panic attacks, depression, attention-deficit/hyperactivity disorder, developmental delays and learning disabilities, lower IQs, the inability to perform executive functioning, shaking, and seizures. In addition, the patient with PKU may also experience poor nutritional status, which subsequently can lead to poor bone strength or other nutritional issues (e.g., osteoporosis, thyroid issues, maintaining weight and muscle mass).

Isolation is experienced by both the patients and their caregivers. Children may become socially isolated at school due to dietary restrictions or behavioural issues arising from high Phe levels, while families may not attend social functions due to the time or inability to prepare appropriate foods. Travel is often decreased or halted altogether. If travel does occur, families have confessed to travelling with one additional suitcase full of medical food.

The caregivers are often affected as much as the patient with PKU. Parents often feel that they cannot be separated from their child for extensive periods of time due to fears that the child will not receive the proper food or will eat inappropriate foods, or others will not be able to appropriately control, log, weigh, or calculate everything. In addition, there is no “break” from the Phe-restricted diet. Many parents have quit employment to attend to their child’s needs, which can adversely affect the person staying home, along with the financial viability of the family. Isolation and lack of time for oneself can also be substantial, as the caregiver is often responsible for preparing, controlling, counting, logging, and calculating everything with regard to their child’s diet. Furthermore, the ordering of the food and amino acids and the trips to the clinic including for regular blood draws take additional time from their lives. As one person stated, “We don’t manage PKU around our lives; we manage our lives around PKU.” The true sacrifice that parents are often faced with is observed through the following statement, “I was very strict with her diet and it was all consuming. At McDonald’s birthday parties, I would cut fries into 2 inch pieces and count out 20 of them, knowing that was her lunch allotment. If she didn’t eat her school lunch, I would sit in the car with her in the parking lot until she finished it all. I had to run her formula to her if plans changed at school or activities because she could not wait till she got home to drink it or she would start shaking.” Stress also remains a constant factor, as caregivers are often consumed with the potential for brain damage to occur, dealing with behavioural issues or learning issues, and potentially not spending enough time with their other children. In addition, financial difficulties are often associated with the cost of the Phe-restricted diet. This, in turn, can lead to increased frustration and family strife.

3. Current Therapy-Related Information

The gold standard for PKU treatment (and, up until Kuvan, the only treatment) is the Phe-restricted diet for life. This diet is extremely limited in natural protein and requires supplementation with a Phe-free amino acid synthetic formula. This Phe-restricted treatment is one of the most restricted diets known and is unpalatable, complicated (requiring painstaking efforts in preparation, record-keeping, and blood testing), expensive, and is an extreme burden on both the patient and the caregiver. Problems with adherence in the child and adolescent populations are of particular importance as patients with PKU can suffer from isolation due to such a restrictive diet at this age. The aforementioned reasons are causes for discontinuation of the Phe-restricted diet: thus, noncompliance remains a serious disease management issue. The heavy burden of the diet treatment was confirmed by the treating clinicians in their separate survey.

There is a large unmet need for the introduction of any other form of treatment that will allow patients with PKU the chance at a more normal life. Patients and their caregivers seek new treatments that will allow the patient the ability to consume other more natural foods while keeping the Phe levels in a normal range. By simply having only one treatment option (which is hard to adhere to and is very restrictive and unpalatable), the patient is put into a position that leaves them vulnerable to neurologic, neuropsychiatric, behavioural, and developmental issues.

4. Expectations About the Drug Being Reviewed

Patients with PKU and their caregivers who do not have experience with Kuvan believe that it will help lower blood Phe levels and increase Phe tolerance so that patients will be able to eat a more varied diet and be less isolated from their peers. However, a lot of families worry about the cost of Kuvan as a treatment as, without coverage, it is financially unfeasible. This was observed from the following,

“We are very worried and saddened to think that in six months, we may not be able to afford Kuvan and our daughter will be taken off a drug that has potentially opened up her life to success in so many ways; mentally, physically, and emotionally. It is devastating to know that there is a drug available like this and we can’t have access to it; then to watch your child regress to the shell she was without it. There are no words.” Some families who were offered the trial were too afraid to enroll as they knew, once the trial was completed, they would not be able to afford the treatment.

In patients who have experience with Kuvan, Kuvan is seen as a positive, life-altering treatment that not only leads to a decrease and sometimes a stabilization in blood Phe levels, but also allows the patient to eat a more normal diet and avoid the adverse consequences associated with higher blood Phe levels. Patients on Kuvan have reported beneficial cognitive impacts, improved academic performance, improved executive functioning and focus, improved energy, and increased confidence in their futures. Some patients have reported it as their “cure,” indicating that their levels of Phe became so low that the specialized formula and severe dietary restrictions previously required were no longer a requirement. There was also an increase in the tolerance of Phe in a lot of patients who were taking Kuvan, which subsequently allowed them to eat more natural foods. In addition, patients were observed to show developmental and behavioural improvement, which was observed in one patient as improved “ability to focus and she is able to absorb and process new information. Drastically lowered anxiety, very little shaking, and no irritability.” In essence, some children on Kuvan began experiencing a normal life, as indicated in the following quote, “He is now on a normal diet. Yes, that means he can eat whatever he wants and doesn’t have to count Phes (he can now eat anything including meat, seafood, pizza, anything). He doesn’t have to drink his formula, either. He is now thinking better and growing better and is feeling more like everyone else. We only have to go for blood work once a month and his blood Phe numbers are always right on and not fluctuating up and down.” In many cases, the thought of returning to the strict Phe-restricted diet should Kuvan be unattainable is devastating. Finally, decreased costs associated with the Phe-restricted diet has relieved some of the financial burden associated with PKU treatment.

Adverse events noted by patients on Kuvan included heartburn, gastroesophageal reflux disease (GERD), or acid reflux or stomach discomfort, mild injection-site reactions, sleep disturbances, hyperactivity, stomach pain, headache, nausea, diarrhea, agitation, nasal congestion, cough, vomiting, joint pain, and dizziness; however, these were reported to be mild and often disappeared with use.