The Voice of the Patient Summary report resulting from an externally-conducted Patient-Focused Drug Development survey, a parallel effort to the U.S. Food and Drug Administration’s Patient-Focused Drug Development Initiative.

Familial Chylomicronemia Syndrome (FCS) FCS Patient-Focused Drug Development Survey April 14, 2017 – May 30, 2017

Conducted by:

Submitted as patient experience data for consideration pursuant to section 569C of the Federal Food, Drug, and Cosmetic Act to: Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)

This report represents the first summary report composed by a patient advocacy organization as a result of an externally-conducted Patient-Focused Drug Development survey, a parallel effort to the FDA’s Patient Focused Drug Development Initiative. This report reflects The FCS Foundation’s account of the perspectives of patients and caregivers that participated in the survey.

Table of Contents I.

Introduction ........................................................................................ 1 A. Overview of Familial Chylomicronemia Syndrome .............. 1 B. Survey Overview..................................................................... 2 C. Report Overview ................................................................... 10

II.

Familial Chylomicronemia Syndrome (FCS)................................... 10 A. Key Themes in FCS .............................................................. 10 B. Living with FCS .................................................................... 11 Most Significant Symptoms of FCS ................................ 11 Impact of FCS on Daily Life ........................................... 14 Change to Symptoms Over Time .................................... 16 C. Current Approaches to Living with FCS............................... 16 Current Treatments and Other Approaches for FCS ....... 17 Most Significant Downsides to Current Treatments ....... 19 D. Preferences for Future Therapies for FCS............................. 20

III.

Benefit-Risk Framework .................................................................. 22

IV.

Conclusion ........................................................................................ 24

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I.

Introduction

From April 14, 2017 to May 30, 2017, The FCS Foundation conducted the FCS PatientFocused Drug Development (PFDD) Survey. In this survey, familial chylomicronemia syndrome (FCS) patients and caregivers responded to questions about their experiences living with FCS, their current treatments and approaches to living with FCS, and their preferences for future FCS treatments. The survey was conducted in accordance with a parallel effort to FDA’s Patient-Focused Drug Development Initiative, an FDA commitment under the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA V) to more systematically gather patients’ perspectives on their condition and available therapies to their condition. Furthermore, this report is submitted to FDA to serve as patient experience data or related information for the Agency’s consideration in the review of applications for new drugs to treat or prevent FCS that are submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) or section 351(a) of the Public Health Service Act, pursuant to section 569C of the FD&C Act. A. Overview of Familial Chylomicronemia Syndrome Familial chylomicronemia syndrome (FCS) is a rare genetic disease characterized by the build up of chylomicrons (chylomicronemia), the largest lipoprotein particle, which are responsible for transporting dietary fat and cholesterol. Typically, the enzyme lipoprotein lipase (LPL) breaks down chylomicrons in the blood. However, in people living with FCS, LPL does not function properly. This inability to break down chylomicrons leads to an increase in triglyceride levels. Normal triglyceride levels are <150 mg/dL (or 1.7 mmol/L). With FCS, triglycerides can rise to 10 times this level, even with medication or a low-fat diet. Patients often present with several severe symptoms before FCS is diagnosed. Many experience pancreatitis, an acute recurrent inflammation of the pancreas, which causes debilitating pain and can be fatal. Others develop eruptive xanthomas (fatty deposits on the skin), lipemia retinalis (milky appearance of retinal veins and arteries), abdominal pain, and hepatosplenomegaly (an enlargement of the liver or spleen). Patients are also often fatigued, lack energy, have impaired cognition, and develop numbness/tingling that can affect their ability to handle many daily responsibilities. There are currently no approved therapies for the treatment of FCS. In most cases, patients are managed with efforts to strictly reduce the levels of fat in their diet, avoiding nearly all dietary fat, ideally approximately 10-20 grams or less daily, the equivalent of about one tablespoon of olive oil, and strict avoidance of alcohol.1 Even in patients with 1

Burnett JR, Hooper AJ, Hegele RA. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2017 Jun 22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University

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strict dietary adherence, triglyceride levels may remain at dangerously high levels, demonstrating that diet alone does not sufficiently mitigate the risk of pancreatitis in all patients.2 B. Survey Overview The FCS Foundation conducted the FCS PFDD Survey to understand, from the FCS patient and caregiver perspectives, their experiences living with FCS, their current treatments and approaches to living with FCS, and their preferences for future FCS treatments. The survey was developed as follow-up to a meeting with FDA officials, including from the Center for Drug Evaluation and Research’s Division of Metabolism and Endocrinology Products, on February 27, 2017 to share patient and caregiver experiences with FCS. The FCS PFDD Survey consisted of a series of open-ended questions designed to inform the therapeutic context for FDA’s decision-making – an analysis of the condition and unmet medical need – that were determined by The FCS Foundation staff. FCS patients were recruited using The FCS Foundation’s email database, social media accounts, and through further dissemination by health care providers expert in treating FCS. Individuals were eligible to participate if they had FCS or were the caregiver of a person with FCS (e.g., parent, spouse). The survey was conducted between April 14, 2017 and May 30, 2017. Forty-three (43) individuals responded to the survey, of which 29 were persons living with FCS and 14 were caregivers of someone living with FCS. Patient and caregiver demographic information is presented below.

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of Washington, Seattle; 1993-2017; Valdivielso P, Ramirez-Bueno A and Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med 2014; 25(8): 689-694. Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler Suppl 2010; 11(1): 55-60; Ceska R, Stulc T, Votavova L, et al. [Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment]. Vnitr Lek 2016; 62(11): 887-894; Stroes E, Moulin P, Parhofer KG, et al. Diagnostic algorithm for familial chylomicronemia syndrome. Atheroscler Suppl 2017; 23: 1-7.

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Patient Demographics The largest age range of patients who responded were individuals from age 46-55 years old (30.8%); followed by those aged 36-45, 26-35, and older than 55 (23.1%, 19.2%, and 15.4% respectively). All other age ranges represented a total of 12%, with no individuals representing those aged 9-17.

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Just over half of the patients who responded were from the United States, while one-third was from Europe, and one-eighth from North America outside of the United States.

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Most patients (61.54%) indicated that they were 0-3 years old when they began living with the symptoms of FCS. The next largest group of patients (23.08%) indicated that they were 18-25 years old, followed by 7.69% of patient respondents who indicated that they were 26-35 years old when they began living with FCS symptoms. Only 3.85% indicated that they were 4-8 years old or 36-45 years old when they began living with FCS symptoms. No patients indicated that they were 9-17 or over 46 years old when they began living with FCS symptoms.

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Most patients (61.54%) indicated that they were 0-3 years old when they were diagnosed with FCS. The next largest group (19.23%) indicated that they were 46-55 years old, followed by 7.69% of patients each who indicated that they were 26-35 and 36-45 years old. Only 3.85% indicated that they were older than 55 when they were diagnosed. No patients indicated that they 4-25 years old when they were diagnosed with FCS.

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Caregiver Demographics The largest group of caregivers who responded to the survey care for patients who are 4-8 years old (35.71%). The next largest age range of patients represented by the caregivers was 26-35 years old (21.43%), followed by 46-55 years old (14.29%). There were 7.14% of patients each in the age ranges of 0-3 years old, 13-17 years old, 36-45 years old, and older than 55 who were represented by caregivers in this survey.

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Over half of the caregivers who responded care for patients from the United States, while one-quarter were from Europe, and one-sixth were from North America outside of the United States.

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The largest percentage of caregivers who responded (57.14%) indicated that the person they care for was 0-3 years old when they began living with the symptoms of FCS, 14.29% indicated that the person they care for was 26-35 years old, and 7.14% of caregivers each indicated that the person they care for was 4-8 years old, 9-12 years old, 18-25 years old, and 36-45 years old. No caregivers indicated that they care for a patient who began living with FCS symptoms at ages 13-17 or older than 46.

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The largest percentage of caregivers who responded (46.15%) indicated that the person they care for was 0-3 years old when they were diagnosed with FCS, while 15.38% of caregivers each indicated that the person they care for was 9-12 years old, 26-35 years old, and 46-55 years old when they were diagnosed. The fewest caregivers who responded (7.69%) indicated that the person was 36-45 years old when they were diagnosed. No caregivers indicated that the person they care for was 4-8 years old, 13-25 years old, or older than 55.

C. Report Overview This report summarizes the input provided by patients and caregivers in response to the FCS PFDD Survey. To the extent possible, the terms used in this report to describe the specific symptoms and treatment experiences reflect the words used by Survey respondents. II.

Familial Chylomicronemia Syndrome (FCS) A. Key Themes in FCS

FCS patients and caregivers described a variety of symptoms associated with this disease, the different treatments and approaches to managing FCS, and how FCS affects patients’ quality of life. A number of key themes were present in the Survey responses:

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 FCS patients live with a constant and unpredictable risk of pancreatitis. Pancreatitis attacks are very severe, painful, debilitating, and frightening for patients and caregivers. Patients and caregivers described living with anxiety about the uncertainty of when a pancreatitis attack could occur. Patients attempt to avoid pancreatitis by adhering to a strict, low-fat diet, but this is not effective for all patients.  The day-to-day symptoms of FCS – pain, fatigue, and inability to focus/concentrate – impact almost every aspect of patients’ lives. The severity of these symptoms inhibit the ability of FCS patients to perform daily tasks, including working, which significantly diminishes patients’ quality of life.  The constant pain and uncertainty associated with FCS symptoms leads to a variety of negative psychological effects on patients, including low self esteem, depression, and anxiety.  The strictly controlled diet and avoidance of alcohol required to manage FCS symptoms leads to social isolation and exclusion. Because patients must be very careful about the amount of fat in foods they eat, they either avoid social situations which involve food, or they must plan for social occasions by packing meals or researching available food options.  The current treatments for FCS, including diet and prescription medications, do not adequately address the significant burdens of FCS for many patients. There is a dire need for effective treatments for FCS. B. Living with FCS The FCS PFDD Survey started with questions about patients’ experiences living with FCS, including their most significant symptoms and the impact of these symptoms on their lives. Patients discussed specific activities that are important to them, but that they cannot do fully because of FCS. Patients also described how their condition and its symptoms have changed over time. The most significant FCS symptoms, as described by patients and caregivers, are expanded upon here. Most Significant Symptoms of FCS Pancreatitis Attacks “Pancreatitis is the only thing that will knock me down for weeks.” In response to a survey question about pancreatitis, about 1/3 of patient respondents indicated that they have had between 1-15 episodes of pancreatitis. A few patients stated 11

that they have had 30 or more episodes of pancreatitis. About half of the caregiver respondents indicated that the person they care for has had 20-30 episodes of pancreatitis. One caregiver stated that the person they care for has had 1 episode, and one caregiver stated that the person they care for has had 50 episodes. These attacks were described by respondents as very severe, lasting up to a week or more for acute attacks, and the cause of anxiety. One patient stated: “Pancreatitis – it’s painful, scary, and my life comes to a standstill.” Another patient explained: “Pancreatitis is disabling. It is so painful that you could not even fight it. It is not just the pain of it. It has the power to take several days of your life from you, and then you need to spend time to deal with the after-effect.” Most pancreatitis attacks described resulted in hospitalization; a caregiver stated: “The minute he feels the onset of pancreatitis, there is no avoiding a hospital admission. An admission will last anywhere from 2-5 days which is a huge disruption to our lives.” Two patients noted that they feared or have experienced the dangerous effects of pancreatitis during pregnancy. One patient explained “pancreas crisis can lead to abortion during pregnancy so they are very dangerous.” She stated that, during her second trimester, she had to have plasmapheresis treatments 1-3 times a week. The other patient who discussed pregnancy and pancreatitis stated that she “lost [her] first child in pregnancy due to a severe case of pancreatitis.” While the acute impact and recovery from pancreatitis is significant, patients and caregivers explained just how debilitating the fear of the next pancreatitis attack can be. One patient stated: “Pancreatitis is very hard to live with. The unknown of everyday wondering if you are going to have an attack and when you do if you will die, life support, medical bills, family taking time off to help you, and of course your career being compromised by this illness.” Another patient shares: “I have had 30 pancreatitis attacks and worry about having another one multiple times every day. Every pain or slight discomfort causes me to worry that pancreatitis is about to come on. It impacts my life greatly.” Pancreatitis also imposes burden on the family. One caregiver stated: “Our daughters who also have the condition have some PTSD because of the numerous pancreatitis attacks, which makes it so that even more falls on me, the main caregiver for them all, to balance everything – the care of my husband when they happen as well as managing their anxieties about it, and potentially their own episodes of pancreatitis.” Another caregiver explained that when her husband is hospitalized, “it can be very exhausting and stressful trying to manage everything.” Pancreatitis, ultimately, was the most serious aspect of FCS. “My biggest fear is her biggest fear is the next time she has pancreatitis and goes to the hospital is she doesn’t leave the hospital. People die from pancreatitis.”

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Abdominal Pain “The pain can come on at any time and can range between minor to severe. It makes it difficult to complete tasks/ follow through with plans.” Of all the symptoms described by patients and caregivers, abdominal pain was most frequently cited as a significant symptom of FCS, which was often described as “less severe instances” of pancreatitis, and could be present on any given day. A few people noted that this abdominal pain can range from manageable to severe, and can affect patients’ abilities to participate in activities or social plans. A couple of patients even noted that this pain leaves them bed-ridden, “missing work, missing life.” Even on a good day, as one caregiver describes, there is “discomfort in the abdomen.” Fatigue “This causes me to cancel plans and sometimes dread plans that I have to attend because I know how tired I will be.” Many patients described constantly feeling fatigued or tired. This symptom was described as a chronic symptom by one patient. A few other patients explained that they feel tired all the time. One patient stated: “Fatigue impacts my life because even with a good night’s rest, I still feel extremely tired from the second I get out of bed.” Fatigue impacts all aspects of life; one caregiver explained, “fatigue makes every task require more energy and effort than it should.” This sentiment was shared by many patients and caregivers. Psychological Impact “[FCS symptoms] put me in a crummy mood. Even when I am having a blast doing something, if I do not feel well, I can only ignore the symptom for so long before it puts me in a bad mood.” About half of the patients who responded to this question explained the psychological impact of FCS. These symptoms include low mood, negative thinking, depression, and anxiety. One patient stated: “The negative impact of this disease has caused depression which is now worse than I ever had along with horrible anxiety and panic attacks.” Other patients described “very low self esteem” and anger. A caregiver explained that “depression is always there because [there are] so many restraints and complications on any and everything we do.” Gastrointestinal Issues Several patients and caregivers noted the symptom of gastrointestinal issues, including regular bloating, diarrhea, nausea, vomiting, and indigestion. One patient stated that he/she was “miserable” and “reluctant to go anywhere” because of these symptoms. 13

Pain (Other than Abdomen) Several patients described pain in areas other than the abdomen. One patient said that his/her abdominal pain will sometimes radiate to the back. A caregiver stated that the patient he/she cares for experiences joint pain. Another caregiver described “constant discomfort” and “sharp pain/wave in the ribs.” One caregiver noted that her husband and children, who are FCS patients, experience daily headaches. Inability to Focus/Concentrate and Memory Issues “He . . . suffers from memory loss, lack of clarity. All of this makes it very hard for him to focus on a job.” A few patients and one caregiver described an inability to focus or concentrate and memory issues. One patient explained that his/her inability to concentrate leads to doing “things such as leave doors/drawers open.” Another patient stated that it is “terrible to be at work and not be able to focus.” Damage to Veins/Scarring One caregiver noted that pancreatitis resulted in damage to a patient’s veins: “[H]er veins have severe scarring making it difficult for her to receive an IV and will continue to affect her increasingly as she will need [IVs in] future hospital visits or in case of emergency.” Another caregiver stated that it is hard for healthcare practitioners to find a vein for blood draws as a result of the condition. Eruptive Xanthoma One patient noted eruptive xanthoma as a symptom of FCS. Diabetes One patient listed diabetes as a significant symptom of FCS. Impact of FCS on Daily Life Social Isolation/Stigma “It’s awkward being the odd one out all the time because you can’t eat or drink what others do.” Most of the patients and several caregivers who responded to a question on daily impacts of FCS explained that their symptoms affect their ability to participate in social activities, which leads to isolation and exclusion. One patient explained that it is “hard to be social” with friends or family due to the restraints of FCS, such as “not being able to have a glass of wine with others.” Another patient said that he/she “used to be the life of the party,” 14

but “my body [won’t] let me anymore.” In addition to dietary restrictions, patients and caregivers cited pain, fatigue associated with the pain, and fear of a painful attack as a cause of social isolation. A caregiver noted that patients often are told, “You don’t look like you’re sick,” making social interactions even more difficult. A caregiver stated: “Socializing and family gatherings are very difficult because of the activities such as food and drink that are usually at them. Family, even though they try, do not understand what he is going through.” Impact on Work “Not being able to work and provide for our family is the main thing that bothers my husband mentally.” A few patients and caregivers described the impact of FCS symptoms on work. One patient stated: “After trying to make it through a week of work, I am exhausted.” One caregiver explained that it upsets her husband, an FCS patient, not to be able to work and financially provide for the family. Pancreatitis hospitalizations were frequently cited as a cause for missed work. Housework Two patients noted an inability to do housework or chores due to FCS. One patient explained that, because of the fatigue associated with FCS, he/she “can’t keep up with housework.” Another patient who has a skin graft due to a severe pancreatitis attack stated that “taking care of [the] house,” cleaning, mowing the lawn, and upkeep of the yard are “no longer an option.” Limits on Travel “When I leave home for a trip is when I stress most, because I would hate to get sick and not have access to the hospital and doctors that I am used to.” Several patients cited travel, especially travel outside the U.S., as an activity that they cannot do because of their condition. A few patients noted that their ability to travel is limited because of food restrictions. Hobbies “My hobbies have been put on hold . . . [I] miss my life.” A few patients and caregivers noted an inability to participate in hobbies at all or as fully as the patient would like to. One patient stated: “My hobbies have been put on hold too – gym, hiking, fly fishing, entertaining . . . [I] miss my life.” One caregiver explained that her husband used to coach baseball almost 7 days a week, but then he started missing a lot of practices and games due to pancreatitis and now he is unable to coach anymore due 15

to his FCS symptoms. Another caregiver explained that the person he/she cares for is not allowed to play soccer “as the ball could hit her in the stomach” or participate in yoga because “the stretching may cause injury.” Pursuing Education “Going back to school to pursue a Masters is something that I am not sure I can do.” A few patients and caregivers described the impact of FCS on the patients’ ability to pursue an education. One patient explained that he/she is concerned about the effect of school stress on triglyceride levels, stating: “Stress raises triglycerides and school can be extremely stressful. I am not sure I am willing to take the risk at this point.” Activities of Daily Living (Walking, Bending Down, Picking Up Objects) One patient described how his/her pancreatitis attacks have led to difficulty with activities of daily living due to a skin graft to close a stomach wound. This patient stated explained that he/she has to be “very careful” when walking or bending down, and cannot pick up more than 5 pounds. Additionally, this patient stated that he/she “could fall and not be able to get up by myself.” Change to Symptoms Over Time Many patients explained that their symptoms have gotten worse with age. One patient stated: “It seems the older I get, the less amount of days I can go without having negative symptoms.” A few patients stated that they are hospitalized for pancreatitis with increasing frequency from year-to-year. A few patients noted that their symptoms have gotten better over time due to volanesorsen or dietary restrictions. A few caregivers explained that the severity of symptoms is tied to certain triggers. One caregiver stated that “food and stress are the biggest factors in how the symptoms change.” Another caregiver explained that the person he/she cared for experienced the worst symptoms in college, mainly due to stress. Despite these trends, patients and caregivers commonly expressed frustration with the unexpected nature of symptom onset. This uncertainty is anxiety-producing and requires FCS patients to always be prepared to change or cancel plans. C. Current Approaches to Living with FCS Patients and caregivers described their current treatments and other approaches to living with FCS and the most significant downsides to these treatments and approaches.

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Current Treatments and Other Approaches for FCS Many patients and caregivers describe current treatments as unsatisfactory for managing FCS and its symptoms. A few individuals stated that no current approach to treatment has been able to help alleviate their FCS symptoms: “They do nothing to improve anything.” Low-Fat Diet “My daughter has recently broken down in tears with the fear of not knowing how and if she will understand how to manager her diet.” Most patients and caregivers explained that they adhere to a very strict low-fat diet (i.e., 10-20 grams per day or, if possible, even less) in order to maintain low triglyceride levels; for some patients this was all they were doing to manage their disease. Several patients explained that the low-fat diet was the only treatment or approach for FCS that they currently use. One patient stated that the low-fat diet “does the job” and keeps her triglyceride levels sufficiently low. Another patient said that his/her symptoms are “pretty controllable still [with] . . . diet.” A caregiver stated that the low-fat diet “doesn’t seem to prevent needing treatments or hospitalizations.” Even vigilant dieters, however, have difficulty avoiding fat intake. As one caregiver describes, “Hidden fat, or ‘adds trivial amount [of] fat’ actually make[s] a HUGE difference in our lives. We have to be so anal about food labels that most times it’s just not worth it to eat anywhere but from or at our house. . . . It’s an extremely hard task to monitor fat grams . . . and this is ten times harder [for an FCS patient] mostly because labels do not give enough [information] about the fat content. They do not get down to the absolute amount, which means one slip up on my end will send my husband to the ER.” Volanesorsen “Volanesorsen has improved all my symptoms and I feel I am living life to the full[est] now.” Several patients take volanesorsen. One patient who is taking this drug stated that he/she “feel[s] that the drug really works” and “do[es] not experience the daily pain/discomfort as [he/she] used to which is an amazing feeling.” One patient stated: “Since starting Volanesorsen, my most significant symptoms have vastly improved. I do not feel nearly as fatigued, have more energy to do things, and do not have pain everyday.” Prescription Drugs to Lower Triglyceride Levels Patients noted taking Tricor, Crestor, and Lovaza to lower triglyceride levels. One patient noted that he/she tried taking Niacin, but discontinued using it because it did not 17

help the patient’s triglyceride levels. One caregiver stated, “The medications are marginal at best in treating the elevated triglycerides.” Prescription Drugs for Upset Stomach or to Aid in Digestion One patient stated that she has taken metformin, Omacor, and Maxepa to treat upset stomach. Another patient stated that he/she takes Creon to aid in digestion. Sitagliptin One patient stated that sitagliptin is effective in lowering his/her blood sugar levels. Plasmapheresis One patient stated that he/she does plasmapheresis. One caregiver stated that the person he/she cares for does plasmapheresis treatments “to remove triglycerides,” which helps to reduce the patient’s pancreatic pain. Fibrates A few patients stated that they take Fenofibrate. Pain Medicine A few caregivers noted that the persons they care for take pain medication for pancreatic pain and headaches. Exercise Several patients and caregivers explained that exercise can be effective in helping to control FCS symptoms. One patient stated that cycling and yoga “calm my stress.” Another patient described participation in yoga and cardio training 2-3 times per week to help with stress and triglyceride levels. Another patient stated that “yoga and meditation help ease the anxiety.” A caregiver stated that he/she encourages exercise. Dietary Supplements and Homeopathic Remedies One patient stated that he/she takes iron supplements “to help with fatigue.” A caregiver stated that the person he/she cares for takes iron supplements to treat anemia from treatments. One patient stated that he/she has tried taking Chinese herbs, egg white protein powder, bile acid capsules, and digestive bitters, but these “seemed to not help.” One patient stated that he/she tried Omega 3 supplements and flaxseed, but these did not help. Another patient noted taking vitamins and antioxidants.

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Most Significant Downsides to Current Treatments Burden of Strictly Controlling Diet “Just hanging with friends and being able to eat and drink freely without thinking about everything I can or can’t eat would be a dream.” Most patients and a few caregivers described how FCS affects patients’ ability to eat out freely or “be spontaneous around food.” Several patients and caregivers explained the logistical difficulties and planning around availability of low-fat food, which essentially needs to be non-fat to accommodate a diet of 10-20 grams of fat per day or less. One patient explained that he/she must always pack a meal whenever participating in an activity that occurs during mealtime. Another patient stated that he/she is not able to “leave my house without having to carry food or make the calculation about where I will get my next meal.” One caregiver described how it is difficult to even determine the fat content in food. Frequency and Duration of Medical Appointments One patient stated that “regular doctor appointments and unsupportive work arrangements” were the most significant downsides to his/her current treatment routine for FCS. One patient stated that the “plasmapheresis is very time consuming extremely expensive and takes me away from my job.” A caregiver stated: “Downsides are having to drive an hour each way, 2-3 times per week for his treatments and paying for parking each time he goes.” Injection Site Reactions Several patients and caregivers described having pain and swelling due to a reaction at the injection site. One patient noted that this reaction is generally manageable with ice and Aleve. This patient stated: “I would much rather deal with that [than] pancreatitis.” Anemia One caregiver explained that the person he/she cares for becomes “pretty anemic due to the frequency of treatments.” Iron Supplement Side Effects One patient explained that the iron supplement he/she takes “makes me feel sick.” Damage to Veins One caregiver explained that the patient he/she cares for has damage to her veins due to frequent blood draws in the form of “severe scarring making it difficult for her to receive 19

an IV.” The caregiver explained that this damage will continue to affect the patient because she will need IVs at future hospital visits or in the case of emergencies. D. Preferences for Future Therapies for FCS Patients and caregivers provided input on what they are looking for in future therapies for FCS, short of a cure. Reduce Risk of Pancreatitis “I do not want to ever have pancreatitis again in my lifetime.” Several patients and caregivers stated that they would like a treatment that prevents or reduces the risk of pancreatitis. One patient said that they would like to avoid pancreatitis “at all costs.” Another patient said that pancreatitis is the “only thing that matters to me” and “a life without pancreatitis is far more important” than the ability to expand the diet. A caregiver stated: “Eliminate pancreatitis. We can cope with everything else just no more pancreatitis, because this causes the most damage.” Expand Diet “Adding wiggle room to the diet would be great.” Several patients and caregivers explained that they would like a treatment that allows them to eat a higher fat diet, so they have more flexibility in their food choices. One patient said that he/she would like “something to help me relax around food.” One caregiver stated that he/she would like to have a treatment which “allows her to eat a wider variety of food.” Another caregiver stated: “My ideal treatment would . . . give him some freedom in what he could eat, so that food could be a source of pleasure not fear.” Lower Triglyceride Levels Several patients and caregivers stated that they would like a treatment that helps to reduce their triglyceride levels. One patient stated that lowering his/her triglyceride levels is important because of the connection of triglyceride levels to pancreatitis. One caregiver’s preference is for “a treatment that would lower his triglycerides and the side effects that result from that elevation.” Address Pain A few patients and caregivers stated that the ideal treatment was one that would reduce pain, especially abdominal pain. One caregiver also explained that she would like to see a treatment that addresses joint pain and headaches caused by FCS.

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Address Gastrointestinal Symptoms A few patients and caregivers stated that they would like a treatment which addresses the gastrointestinal symptoms of FCS. One patient stated that he/she would like a treatment that reduces bloating. A few caregivers stated that they would like a treatment that addresses diarrhea and vomiting. Lose Fat/Weight One patient expressed a desire for a treatment that would “wash away the fat.” Safe/No Side Effects/Not Painful A few patients and caregivers noted that they would like a treatment which is safe, does not have side effects, and is not painful. One caregiver described a treatment which could be taken “very long term” and “could be used at a young age.” Meanwhile, for certain tradeoffs, patients are willing to tolerate risks. Affordable One patient stated that they hope for a “reasonable price for Volanesorsen” because it has “changed [his/her] life so much.” Another patient stated that he/she would like an affordable treatment. One caregiver requested “financial help from the government for a gym membership” because he/she could not afford one. Lower Risk Pregnancy One caregiver stated that he/she would like to see a “treatment that would allow her to have children without worry.” Ease in Use One patient stated that he/she would like a treatment which allows for “ease in use.”

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III.

Draft Structured Benefit/Risk Assessment Framework

In 2013, the FDA developed a plan for a structured approach to benefit-risk assessment in regulatory decision making. This framework calls for assessing certain factors for each potential therapeutic under consideration for approval: Therapeutic Context, consisting of Analysis of Condition and Current Treatment Options; Benefit; Risk; and Risk Management. In each specific use case, this framework summarizes each decision factor and explains how it influences the FDA’s rationale for its regulatory decision. The input from the FCS patient community in the FCS PFDD Survey, compiled in this report, can inform such a framework. Here we offer an example of the therapeutic context, which can be derived from the information gathered from this survey. This sample framework is likely to evolve over time, and should be incorporated into a benefit-risk assessment framework for a drug under review.

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Dimensions

Evidence and Uncertainties

Conclusions and Reasons

Analysis of Condition

- Familial chylomicronemia syndrome (FCS) is a rare genetic disease characterized by chylomicronemia, leading to an increase in triglyceride levels (up to times the normal level). - Most patients begin experiencing the symptoms of FCS when they were 0-3 years old (61.54% and 57.14% reported by patients and caregivers, respectively), which is also the age most patients are diagnosed. - All but a small portion of patients for which a strict low-fat diet completely manages their disease experience debilitating pancreatitis attacks, resulting in severe pain and often hospitalization. Patients can experience 30 or more episodes of pancreatitis. Patients with a history of pancreatitis live with anxiety about the uncertainty of when the next pancreatitis attack could occur and whether an attack could result in death, which can occur from pancreatitis. - Patients experience the burden of day-to-day symptoms resulting from high triglycerides, including pain, fatigue, and inability to focus/concentrate. These symptoms result in reduced quality of life, largely by limiting patients’ ability to perform daily tasks, including working. - The pain and uncertainty associated with FCS symptoms leads to a variety of negative psychological effects on patients, including low self esteem, depression, and anxiety. -No treatments are approved for treatment of familial chylomicronemia syndrome (FCS) - The most common approach to treating FCS is a strict low-fat diet (≤1020 grams daily) that is difficult to comply with both due to the difficulty with complying with it and because of “hidden fats” in commonly available foods. While adhering to this diet allows some patients to successfully manage FCS, including pancreatitis and other symptoms, many other vigilant dieters continue to experience the burdens of FCS. Almost all patients experience social isolation as a result of only being able to prepare diet-compliant meals in the home and wanting to avoid the stigma that occurs in social situations, which usually involve eating and/or drinking alcohol. - High triglycerides go untreated as cholesterol-lowering drugs (E.g., Tricor, Crestor, Lovaza) provide little to no benefit for FCS patients. - Patients use standard treatments for specific day-to-day symptoms (e.g. pain, upset stomach, high blood sugar) as required. - Exercise can be effective in helping control the stress and anxiety related to the unpredictable and draining FCS symptoms. - Patients express a desire a treatment primarily for the ability to eat a higher fat diet and to reduce/remove the threat of pancreatitis. Patients are willing to accept the most risk for a drug that impacts risk of pancreatitis. - Patients also request drugs to lower triglyceride levels, address day-today symptoms (pain, gastrointestinal symptoms), and aid in losing fat/weight. Generally, patients would like a treatment that is safe, not painful, and easy to use.

Familial chylomicronemia syndrome is a severe, painful, debilitating, and frightening disease. The most serious aspect of FCS is pancreatitis, which is associated with severe pain, hospitalization, and sometimes death. Patients also bear the burden of a variety of day-to-day symptoms as a result of high triglycerides, including chronic pain, fatigue, and inability to focus/ concentrate. The fear of pancreatitis and encumbrance of day-to-day symptoms results in a myriad of psychological effects, including depression and anxiety.

Current Treatment Options

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While some patients can manage their high triglycerides with a strict low-fat diet, many patients have trouble maintaining such a diet. Others, despite a strict diet, are unable to prevent high triglycerides, day-to-day symptoms, and pancreatitis attacks. Some patients use drugs to treat some day-to-day symptoms of FCS (e.g., GI issues, chronic pain), but there are not treatments available for the underlying disease. Patients express a great desire for treatments that eliminate or remove the risk of pancreatitis and, therefore, the constant fear of pancreatitis attacks. Value is also seen in being able to reduce the burden of strictly controlling diet, as well as lowering triglycerides in order to limit other day-to-day symptoms of the disease.

IV.

Conclusion

The responses to the FCS PFDD Survey highlighted the dire need for effective treatments for FCS. As explained by patients and caregivers, the current treatments for FCS, including diet and prescription medications, do not adequately address the significant burdens of FCS for many patients. This survey provided a unique opportunity to learn more about the experience of living with FCS and the most important features of future treatments directly from FCS patients and caregivers. We are grateful to all who took the time to respond to the survey.

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