1. Brief Description of Patient Group Supplying Input

The Canadian Organization for Rare Disorders (CORD) is a registered charity that educates, advocates, and provides resources to patient groups of rare disorders. CORD advocates for health policy and a health care system that works for patients with rare disorders and their caregivers. CORD has received funding from Horizon in the past two years; however, CORD did not declare any conflict of interest with regard to this patient group submission.

2. Condition-Related Information

Information for the patient input submission was gathered using written individual testimonials or submissions, individual semi-structured interviews, and a survey created and administered by CORD. Individual interviews were performed to ascertain an in-depth understanding of cystinosis. The interview information was subsequently used to develop the survey. The survey was distributed through physicians, through one patient fundraising group using a snowballing technique, and through a posting on the Cystinosis Research Foundation (US) Facebook page. In addition, the survey was posted on Survey Monkey from June 30 to July 27, 2017 in English. Patients in Quebec were instructed to answer in either English or French, with responses subsequently translated. Five testimonials, six individual parent interviews (of children diagnosed with infantile cystinosis), and 71 survey responses (of which there was a mix of patients diagnosed with infantile, intermediate, or adult cystinosis, or who were parents/caregivers) were used to compose the submission. The average age of patients with cystinosis who were the patients of the interviews or survey responses was 15.1 years (range less than 1 year to 50 years of age), with all of the interview respondents living in Canada. Of the survey respondents, 62% were from Canada, 28% were from the US, and 5% where from elsewhere.

Patients with cystinosis experience a range of symptoms associated with the disease, including various gastrointestinal (GI) effects (e.g., vomiting, diarrhea, abdominal pain), muscle wasting, swallowing difficulties and gagging, halitosis, foul body odour, crystal buildup in the cornea/photosensitivity, extreme thirst and urination, reduced cognitive abilities, and rickets/softening of bones. Secondary impacts of the disease include kidney failure (which may occur in adolescence or early adulthood), multiple organ failure, and diabetes. With regard to patients with infantile cystinosis, parents often recollect that the first indications of the disease were vomiting, gagging, failure to thrive, and inability to roll over or lift the neck. Many parents were faced with multiple trips to the hospital emergency room and wrong diagnoses before finally obtaining the appropriate diagnosis, usually through a specialist.

The treatment regimen of Cystagon itself (which requires patients or caregivers to administer the medication every six hours) is very troublesome and burdensome. Patients and their caregivers continually have interrupted sleep which often negatively impacts all of the family members (not just caregivers and patients). In addition, patients and their families may experience reduced concentration and isolation (both social and emotional) due to the constant vigilance that is required for the care of cystinosis patients, in addition to regular clinic visits, trips to physiotherapists (to deal with weakened muscles and back pain), speech therapists, nutritionists, tutors, and psychotherapists. One caregiver described cystinosis as, “Devastating – it has affected each and every one of us in his immediate and extended family as well as personal friends, emotionally and financially and even socially.” Some parents have divorced due to the stress of the condition. Additionally, a number of parents discussed the tremendous financial burden of cystinosis, due to the direct cost of medications, supplements, and other supplies, non-reimbursed costs for health care visits, household expenses for modifications or other repairs, and the loss of income when parents have to provide continuous home care. As one parent stated, “Despite the financial assistance we had with our benefits there were still a few years without coverage for the Cystagon and eye drops. That alone was equal to our mortgage and bills at the time. The travel, eating out, and parking costs. Increased water and hydro for the extra laundry… Replacing furniture and carpeting because of the many vomiting incidences. All the meds that were not covered. Diapers. Orthotics etc.”

As illustrated above, caring for a child or spouse with cystinosis and the treatment regimens that accompany it can be very challenging and burdensome. Caregivers of children with cystinosis are responsible for not only administering the treatment but also for taking care of the child, which often includes cleaning up after their many GI troubles, ensuring they eat well (which can be a daunting task in a child who has trouble swallowing), taking them to their various medical appointments, and taking care of their emotional needs (including those feelings of isolation experienced by children with cystinosis at school and socially). In those caregivers that have a spouse with cystinosis, there is often an increased burden on the caregiver, who may also have to take on the bulk of financial and family responsibilities. All of this leads to increased isolation, family and financial stress, and an increased burden on caregivers who may be limited or unable to work outside the home.

3. Current Therapy-Related Information

Of the 32 patients who responded to the medication portion of the survey, about 90% had received therapy, with 50% currently (and 36% in the past) receiving Cystagon as the main therapy. Of those Canadian respondents, 69% were currently on Cystagon while 15% had used it in the past. Respondents felt that Cystagon saves patients’ lives, however it does not resolve all of the clinical problems of cystinosis (including deficits in sight, hearing, and cognition) and it is challenging to strictly adhere to the treatment regimen.

Noted side effects with Cystagon included mild to severe GI problems (nausea, vomiting, pain, and diarrhea), mild to very severe halitosis or skin odour, fever/chills, tiredness/dizziness, and decreased appetite. Many patients admitted to frequently not being able to follow the medication regimen of every six hours, although they were aware of the life-saving potential of Cystagon. Particular challenges reported with the medication included difficulty in taking the large number of capsules and in retaining the medication, the four times daily dosing, and the very bad taste and odour. Some parents would try to mask the taste in juice or food but then found it difficult to know how much medication their child was ingesting, especially with the associated gagging and vomiting that often ensued. Young children often used a gastrostomy feeding tube (G-tube) inserted into the stomach to avoid the problems of oral ingestion, which allow the caregiver to give the child the nighttime dose without having to awaken them. Older children however, often did not find the G-tube desirable and asked to have it removed.

The major consideration with regard to Cystagon is the four times daily administration. As one parent stated, “Our lives are lived in 6-hour increments and governed by the strict adherence to a cycle of medication that keeps our child alive. Every aspect of our lives is impacted: sleep patterns, eating schedules, when we can/can’t leave the house, how we plan and book holidays…” Another consideration is the foul odour that accompanies using Cystagon. As one parent stated, “My daughter has been bullied, chastised, and discriminated against her entire life for the unescapable sulphur-like skin odour caused by the drug.”

Additional medications and supplements are also part of the treatment paradigm. Many patients take nutrient replacements (sodium, potassium citrate, phosphate, and vitamin D), medications to aid with stomach aches and heartburn, and anti-emetics. Some patients have also taken growth hormone therapy and hormone supplements. In terms of other treatments, some patients reported being on dialysis, and more than half of patient respondents claimed they had, or were indicated for, a kidney transplant.

4. Expectations About the Drug Being Reviewed

While almost all of the respondents were aware of Procysbi, most respondents understood the difference between Cystagon and Procysbi, with only 11% being unaware of the drug or how it differed.

The expectations associated with Procysbi centred on the twice-daily dosing schedule and the patients’ hope for improved effectiveness and tolerability. The elimination of the nighttime administration was thought by many to mean that sleep would not be impacted. The elimination of the mid-day administration would help children to lead a more normal life. There was an expressed hope that cystine levels would remain low due to the extended-release form of Procysbi and that adverse events would be minimized. As one parent stated, “It would mean my daughter and my husband and I could all sleep through the night. It would also mean that my daughter would not have to take it while at school. My hope is that her nausea will decrease to the point that she rarely vomits which will also in turn increase her appetite.”

In spite of the above comments, some patients and caregivers were hesitant about switching from Cystagon, mainly due to the lack of long-term experience or data associated with Procysbi. In addition, many respondents identified cost as a potential barrier to access as there is a difference in price. Procysbi may not be accessible, even to those who have insurance. As a result, many patients and caregivers still expressed a desire to have access to Cystagon.

Of the total respondents, 35% had experience with Procysbi; however, only 15% of the Canadian cohort had experience. Methods of receiving Procysbi differed, with 6% receiving it through a clinical trial, 24% receiving it through an expanded trial or compassionate access, and 59% (who were mostly from the US) as a drug plan benefit. No patients in Canada received Procysbi through their private insurance plan.

Almost all of the respondent expectations for Procysbi were positive, especially in terms of the twice-daily dosing schedule, potential for positive impact on quality of life, greater tolerability with fewer side effects, and hope for better long-term effectiveness on symptoms and disease progression. Some patients experienced immediate benefits, while others did not. Most patients and parents were aware that longer-term benefits would not be evident in the short-term. Side effects appeared to be minimized with Procysbi. As one patient stated, “The side effects with Procysbi are…significantly less. The only downfall with Procysbi is the number of pills required since it only comes in 75 mg capsules.” Finally, most patients who had access to Procysbi felt that the benefits outweighed the risks and potentially unknown long-term effectiveness.