Survey of the Huntington’s Disease Patient and Caregiver Community Reveals Most Impactful Symptoms and Treatment Needs

INTRODUCTION

In 2012, the U.S. Food and Drug Administration (FDA) launched a Patient-Focused Drug Development initiative as required under the fifth authorization of the Prescription Drug User Fee Act (PDUFA V). The goal of this program was to more systematically gather patients’ perspectives on their condition and the available therapies to treat their condition. As part of the process, the FDA committed to obtain the patient and caregiver perspective, focusing on the impact of disease on patients’ daily lives, the types of treatment benefit that matters most to patients, and patients’ perspectives on the adequacy of available therapies [1]. To fulfill their commitment to the patient community, FDA scheduled approximately 20 public meetings over the duration of PDUFA V, each focused on a specific disease area. HD was selected as one of the disease groups in 2013.

As noted by the FDA, physicians may prescribe a number medications to help control emotional and movement problems associated with HD, but while they may help keep some clinical symptoms under control, there is no current treatment to stop or reverse the course of the disease [2]. In the context of the hearings, the FDA specifically sought information from the patient community that would inform the clinical development and FDA review of potential treatments for HD.

The questions posed to the HD patient and caregiver community from the FDA focused on two topic areas. Topic one encompassed disease symptoms and daily impacts that matter most to patients. Topic two solicited patient perspectives on current approaches to treating HD.

After announcing that the meeting would be held in 2015, the FDA and the Huntington’s Disease Society of America (HDSA) discussed the format and above topic areas in order to prepare the community for this important forum. HDSA, founded in 1968 by Marjorie Guthrie, the wife of legendary folk singer Woody Guthrie, is the largest not-for-profit organization dedicated to improving the lives of everyone affected by HD. Through support of clinical Centers of Excellence, research, support groups and social workers, diverse educational programs and advocacy efforts, HDSA aims to provide HD families with “help for today and hope for tomorrow”. As part of an outreach and awareness raising campaign to alert the HD community to the FDA’s meeting on HD, HDSA distributed two surveys encompassing questions on topic one and topic two and soliciting specific comment on symptomatology, quality of life and therapeutic needs. The community responded en masse, with 2,591 people providing answers for questions in the symptoms survey, and 1,040 people providing answers to questions in the treatments survey. The approximately 600 patients that responded to the 2 surveys represent 2% of the estimated 30,000 symptomatic HD patients thought to live in the US.

Prior to these surveys, we are unaware if others had collected data from the HD community on their experiences of symptom impact on daily life or on treatment effectiveness to determine patient-reported outcomes.

Huntington’s disease has long been classified as a movement disorder, though prodromal features encompass cognitive and psychiatric symptoms of HD [3]. In response to questions asking caregivers what were the most impactful symptoms of HD, a majority of responses included the cognitive and psychiatric symptoms of the disease. For patients with HD/JHD and their caregivers, dysexecutive syndrome, depression/apathy and chorea were reported as the three most impactful symptoms, in varying order for each group. Dysexecutive syndrome, common in neurologic diseases like HD, is an impairment in cognitive, behavioral, or emotional domains that make executive functions such as planning, cognitive flexibility, initiation and sequencing difficult [4]. The importance of cognitive and behavioral symptoms was clear in the responses of both caregivers and people with HD/JHD. While the prevalence and frequency of symptoms varied between caregivers and people with HD/JHD, the impact of dysexecutive syndrome was obvious for both groups. In addition, the survey on treatment approaches to HD, provided clear evidence to support how limited the availability of efficacious treatments are for people with HD.

We believe that engaging a patient population as early as possible in the clinical development pathway is a critical step to help ensure more efficient clinical trials that will result in more meaningful, effective therapies for the intended patient population.

METHODS

HDSA used SurveyMonkey, a major provider of web-based surveys, to create two distinct surveys based on discussions with the U.S. Food and Drug Administration (FDA) pertaining to the topics to be covered in the Patient-Focused Drug Development meeting on HD that was to be held September 22, 2015. The first survey, entitled “FDA Topic 1: Disease Symptoms that Matter Most to Individuals with HD”, was distributed in August 2014 to members of the HD community and remained open through December 2014. The survey contained 38 questions, divided into two identical sections, one for individuals with HD/JHD and another for individuals who are or were caregivers for a person with HD. The second survey, entitled “FDA Topic 2: Perspectives on Current Approaches to Treatment”, was distributed at the beginning of September 2014 and remained open to collect responses until January 2015. The survey consisted of 167 questions, divided between questions to gather demographic information, and two identical sections of 58 questions to gather data sets from individuals with HD/JHD and caregivers of individuals with HD/JHD. The scope of the treatment survey was limited to medication interventions only. It did not inquire about ancillary treatments such as physical, occupational or speech therapy.

The surveys were distributed digitally through multiple HDSA communication channels including social media and HDSA web platforms, in order to reach the greatest number of individuals possible. Respondents could skip questions or choose not to provide information for certain questions on both surveys. As a result, the response rates to questions varied across both surveys. The surveys can be found in the Supplementary data.

RESULTS

DISCUSSION

The voice of the HD patient and caregiver can be an invaluable resource in helping to determine directions for drug development, clinical trials and approvals. Although it is a newer tool, the usefulness of the direct insight into the patient experience of a condition can provide a more comprehensive perspective of the benefits and risks from potential treatments [7]. Patient reported outcomes (PRO) have been utilized previously as supplementary evidence for approval of anti-cancer products, including directly measuring the benefits of a treatment on the ability to function and symptom experience [6].

What is striking in these data are the marked differences in the experience and perception of symptoms of HD and their impact between individuals with HD/JHD and their caregivers. The frequency and impact of symptoms appears to be felt more by caregivers than individuals with HD, especially when it comes to loss of abilities. There was also a large difference in the perception of symptom frequency between caregivers and individuals with HD. More than 90% of caregivers surveyed responded that their loved one experienced HD symptoms “frequently” or “constantly” while only 50% of individuals with HD responded similarly. Caregivers also perceived their loved one with HD as much more impaired than the individual themselves. This may be attributed to anosognosia (unawareness) that has previously been reported in HD and other neurological disorders [7–8]. Approximately 67% of caregivers responded that unawareness made it harder for their loved one to manage symptoms that were treatable with medication (Supplementary data 2). If the patient does not believe they exhibit depression or chorea, they may be less inclined to take medications to help with these symptoms.

With that being said, it is important to note how individuals with HD/JHD responded when asked to reflect on their symptom experiences. The most impactful symptoms of HD were related to their ability to maintain independence. Individuals with HD/JHD reported loss of ability to maintain employment, perform household chores and drive more frequently compared to abilities that did not impact independence as directly, such as the ability to concentrate or multi-task. Interestingly, sleep irregularities, which are a common early feature in HD were not regarded by patients nor caregivers as being that impactful on their lives [9].

The loss of independence can be linked back to the reported symptoms experienced by individuals with HD and caregivers, including cognitive and behavioral aspects of HD. Symptoms, such as slowed cognitive processing speed, decline in attention, dysexecutive syndrome and irritability/anger outbursts all affect an individual’s ability to work, to drive and to manage a household. These symptoms affect the individual with HD even in the pre-manifest stage, with an increasing prevalence of irritability, apathy and executive dysfunction as the disease progresses [10]. The importance of finding effective treatments is clear from both the perspective of the individual with HD and the caregiver, with both groups feeling the impact of these symptoms.

Survey respondents noted that there were few to no treatments for the cognitive symptoms of HD, like memory loss or decline in cognitive processing and thinking, even though these symptoms were the most impactful for individuals with HD.

Similarly, for behavioral symptoms like irritability and anger, apathy, obsessions and compulsions and sleep problems, there remains a lack of effective treatment options. Behavioral symptoms were frequently cited by respondents as having a negative impact on the lives of individuals with HD and their caregivers. For caregivers, there was not a single behavioral symptom, but rather a combination of symptoms associated with HD that together were more impactful than the motor symptoms. There was also no clear cut best practice treatment option for symptoms like irritability, apathy, anxiety or depression, as demonstrated by the numerous medications respondents noted using to treat these symptoms with varying rates of effectiveness. The large degree of heterogeneity in HD behavioral symptoms makes them difficult to be included as a reliable endpoint in a clinical trial. More quantitative and objective behavioral clinical readouts for HD must be developed so that novel drugs targeting the behavioral components can be properly evaluated in HD clinical trials.

Although there is an FDA approved treatment for chorea (tetrabenazine), there are no effective treatments for symptoms like gait impairment/falls, speech impairment, or swallow impairment/choking. Even with the treatments available for chorea, the majority of respondents reported that treatments were only “somewhat” effective in managing symptoms. Since symptoms like chorea and gait impairments/falls were reported as some of the most commonly experienced motor symptoms of HD, there is still a critical need for improvement and diversity in the treatment options for the motor symptoms of HD.

The efforts of the FDA in the implementation of the patient-focused drug development meetings and other forums to solicit the patient perspective are laudable and are already creating a positive impact on the lives of patients across the spectrum of diseases. Patient views from the melanoma community regarding the psychological and cosmetic benefits to seeing a melanoma lesion shrink that would not normally respond to conventional and previously approved therapies were influential in the FDA’s decision to grant approval for Imlygic (Talimogene laherparepvec). Perhaps the most high profile result of patient feedback on the drug development process came in September 2016 when Dr. Janet Woodcock, the Director of the Center for Drug Evaluation and Research (CDER) at the FDA overruled an advisory panel that voted 7-6 against approval Sarepta Therapeutic’s Exondys 51 (eteplirsen) for the treatment of Duchenne muscular dystrophy (DMD). Some believe that vocal disease advocates may have influenced this decision despite a lack of clinical efficacy data [11].

While the insight into the patient and caregiver perspective we have gained from these surveys is important, there are limitations to this methodology. First, the patients and caregivers responding are not matched dyads, meaning not all patients that responded had a caregiver who also participated. We also have no way of confirming the diagnosis of anyone responding as an “HD patient”. Given these surveys were completed online, the patient perspective is likely biased towards the earlier stage HD patients that were physically able to participate. Gaining a true understanding of late stage HD patients will require caregiver feedback.

One important aspect not covered in this FDA process and the corresponding surveys to the community was understanding the risks HD patients are willing to take for effective therapies to treat each of the different symptoms a patient experiences. Future studies should query HD patients to delineate the risks they are willing to take to gain access to an experimental therapy. While one may not hesitate to be subjected to regular intra-striatal injections for a potential disease-modifying therapy, being subjected to similar injections to ameliorate the chorea associated with HD or other less impactful symptoms, would likely be met with less enthusiasm. This could translate into a poorly recruited/delayed clinical trial.

In summary, patient and caregiver perspectives on HD symptomatology and treatment efficacy should be critical components in shaping future HD clinical development efforts. With this information we can tailor efforts to treat the symptoms that those impacted by HD state are the most disruptive more effectively and target symptoms that degrade quality of life. While there seems to be some effective treatments for symptoms like depression and anxiety, there are still cognitive, behavioral and motor symptoms which lack effective treatments and are severely impacting the lives of both individuals with HD and their caregivers. Taking this information into account, we can refocus efforts in research and development to offer more options, and hopefully more effective treatments for individuals impacted by Huntington’s disease. The Huntington’s Disease Society of America would like to thank the thousands of individuals with HD/JHD and families that took the time to provide their experiences so that HDSA could hold a meaningful conversation with the FDA and pharmaceutical and biotech partners as they continue the path of clinical development for new and effective therapies to treat HD.

CONFLICT OF INTEREST

There are no conflicts to report related to the surveys, their collection or analysis.