New symptomatic therapies for Huntington disease

Handbook of Clinical Neurology, Vol. 144 (3rd series) Huntington Disease A.S. Feigin and K.E. Anderson, Editors http://dx.doi.org/10.1016/B978-0-12-801893-4.00017-1 Copyright © 2017 Elsevier B.V. All rights reserved

Chapter 17

New symptomatic therapies for Huntington disease ANINDITA DEB1, SAMUEL FRANK2*, AND CLAUDIA M. TESTA3 Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States

1

2

Beth Israel Deaconess Medical Center/Harvard Medical School in Boston, MA, United States

3

Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States

Abstract Huntington disease (HD), an inherited neurodegenerative disease, results from a CAG repeat expansion creating mutant huntingtin protein and widespread neuronal damage. Motor symptoms such as chorea are often preceded by cognitive and behavioral changes. Tetrabenazine and deutetrabebenazine are the two drugs approved by the Federal Food and Drug Administrationfor HD symptoms, is an effective therapy for chorea. However, there is still a large need for other symptomatic therapies impacting functional issues, including impaired gait, behavioral, and cognitive symptoms. A number of pharmacologic agents are under investigation. Additionally, other mechanisms are being targeted in motor symptom drug development, including phosphodiesterase 10 enzyme inhibition, dopamine modulation, and inhibition of deacetylation. There is perhaps the greatest unmet need in treating nonmotor effects, such as cognition and change in disease course. PBT2, a metal chaperone, and latrepirdine, a mitochondrial stabilizer, are under investigation specifically for the possibility of cognitive benefit. Unfortunately, there is a lack of HD-specific evidence on effective treatments for behavioral and psychiatric symptoms. Further investigation of nonmedication interventions such as physical therapy is necessary. As our understanding of molecular and cellular mechanisms underlying HD broadens, a new set of mechanistic targets will become the focus of HD symptomatic therapies.

INTRODUCTION Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by a triad of symptoms, including progressive motor dysfunction, behavioral disturbance, and cognitive decline. A mutation on the short arm of chromosome 4 in the IT15 gene triggers abnormal expansion of the CAG coding region, resulting in the mutant huntingtin (mHTT) protein (Venuto et al., 2012). The exact role of this protein is not fully understood, but ultimately this mutation leads to selective neurodegeneration. While neuronal damage is widespread, some areas of the brain are particularly impacted in HD; the pattern of neurodegeneration accounts in part for the spectrum of symptoms. Early

degeneration of striatal GABAergic medium spiny neurons disrupts projections to the globus pallidus and substantia nigra, creating abnormal motor control circuitry (Albin et al., 1989). Neurodegeneration and atrophy in cerebral cortex, thalamus, subcortical white matter, and hypothalamus are also observed (Ross and Tabrizi, 2011). A common striking clinical manifestation of HD is chorea (Malekpour and Esfandbod, 2010), characterized by brief, irregular, involuntary movements often compared to the flowing movements of dance. As the disease progresses, chorea tends to decline while underlying dystonia and bradykinesia become more prominent. Dynamic forms of dystonia, bradykinesia, motor incoordination, dysphagia and dysarthria, gait disturbance, and oculomotor control changes are also common motor

*Correspondence to: Samuel Frank, MD, Boston University Department of Neurology, 72 E. Concord St, C-3, Boston MA 02118, United States. Tel: +1-617-638-5309, E-mail: [email protected]

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Fig. 17.1. Number of medications tested for symptomatic therapy in Huntington disease in 5-year epochs.

symptoms (Mestre and Ferreira, 2012). A minority of adult-onset patients and a larger proportion of juvenileonset patients have little or no chorea with a predominance of parkinsonian or dystonic motor manifestations (Quarrell et al., 2013). In many patients, behavioral or cognitive disturbances precede motor symptoms by years (Tabrizi et al., 2009). These symptoms can manifest as depression, anxiety, irritability, impulsivity, aggression, paranoia, or apathy. Cognitive decline occurs as the disease progresses, with slow development of a range of symptoms, many in subcortical or frontal executive categories. The level of cognitive symptoms compared to motor symptoms is highly variable across individuals (Tabrizi et al., 2009). Although there has been substantial progress in detecting early signs and diagnosing motor symptom manifest HD, there is still a paucity of well-defined, HD-specific symptomatic treatment options and no effective intervention to slow progression or prevent onset of disease. Current trials are aimed at developing both symptomatic and protective therapies (Fig. 17.1 and Table 17.1). Additionally, there is focus on the molecular and cellular aspects of HD in an effort to reduce or prevent the toxic effects of mHTT. This chapter addresses advances in symptomatic HD care.

MOTOR SYMPTOM TREATMENT Tetrabenazine In 2008, tetrabenazine (TBZ) was approved by the Food and Drug Administration (FDA) for HD-associated chorea, marking the first available symptomatic treatment of HD in the United States (Huntington Study Group, 2006). It inhibits vesicular monoamine transporter type 2 (VMAT2) and depletes mostly dopamine but also norepinephrine and serotonin. The action of TBZ is

Table 17.1 Pharmacotherapy studied for symptomatic treatment in Huntington disease from 1970 to 2014 Year registered to NIH or first published results 1973 1975 1976 1978 1983 1984 1997 1999 2000 2001 2002 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

a

Pharmacotherapy Levodopaa Haloperidol, lithium Clonazepama Apomorphine infusion Lisuride Sulpiride, tiapride Clozapine, fluoxetine, risperidonea Amantadine, riluzole Donepezil Olanzapine Pramipexole, quetiapine,a rivastigmine Citalopram, ethyl-eicosapentaenoic acid, phenylbutyrate, tetrabenazine Atomoxetine, memantine,a minocycline,b valproic acida Latrepirdine, ursodiolb Coenzyme Q10, creatine,b pridopidine AFQ056, aripiprazole, nabilone, ubiquinolb Venlafaxine Epigallocatechin-3-gallate (EGCG),b SEN0014196b GSK356278,b PBT2 Buproprion,b deutetrabenazineb BN82451,b cysteamine (RP1030), laquinimod,b OMS643762,b PBF-999,b PF-02545920b

Case reports. No published clinical results. NIH, National Institutes of Health. b

NEW SYMPTOMATIC THERAPIES FOR HUNTINGTON DISEASE predominantly in the caudate, putamen, and nucleus accumbens (Thibaut et al., 1995). It differs from older medications such as reserpine because it is a selective VMAT2 inhibitor, thus it does not have the significant side-effects associated with VMAT1 inhibition such as hypotension. The efficacy of TBZ as an antichorea agent was established in a double-blind placebo-controlled trial over 12 weeks in 84 patients (Huntington Study Group, 2006). Subsequently, the open-label extension of the study evaluated the long-term safety and efficacy of the drug in 45 patients at their optimal individual doses (maximum 200 mg/day) for up to 80 weeks. There was continued reduction in the mean Total Maximal Chorea (TMC) score by 4.6 units (Frank, 2009). TMC is a subset of the Total Motor Score (TMS) of the United Huntington Disease Rating Scale (UHDRS). TBZ has also been used outside the United States since the 1950s for treatment of schizophrenia, chorea, and other hyperkinetic movements such as tardive dyskinesia, tics, myoclonus, and dystonia (de Tommaso et al., 2011).

Deutetrabenazine Deutetrabenazine is a novel molecule that contains six deuterium atoms instead of six hydrogen atoms in specific positions in the TBZ molecule and retains the intrinsic pharmacologic activity of TBZ. The deuterium atoms at key positions in the molecule prolong plasma half-life and reduce metabolic variability relative to the nondeuterated metabolites from TBZ (Sampaio et al., 2014). This reduces the impact of CYP2D6 variants on drug metabolism, and can potentially reduce limiting peak dose side-effects while maintaining efficacy level. Deutetrabenazine was developed in an effort to create an effective, longer-acting, safer medication for reducing chorea. First-HD is a completed phase III randomized, double-blind, placebo-controlled trial of deutetrabenazine in 90 HD patients with chorea. After a 12-week treatment period at an individually optimized dose, patients were evaluated for a change in TMC. Deutetrabenazine was found to reduce TMC, and secondarily showed improvements in patient global impression of change, clinical global impression of change, and quality of life as measured by the SF-36 physical functioning component, implying that impacting the TMC provides a measurably positive benefit to patients (Huntington Study Group, 2016). Preliminary safety and tolerability profiles were favorable, and are being further evaluated in a long-term, open-label safety study (NCT01795859). In a separate study, ARC-HD, 36 HD patients switched overnight from TBZ to open-label deutetrabenazine, then were evaluated over a 8-week period to evaluate for safety and monitor for potential difficulties

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during the transition. Initial data from that study suggest benefit for chorea treatment is maintained with a lower total daily dose and fewer doses per day (Frank et al., 2017). These patients will also be studied in a long-term, open-label forum. Completion of the full open-label trial is estimated in late 2015 (NCT01897896). Based on these data, deutetrabenazine was approved by the FDA on April 3, 2017 and is now available in the US.

Pridopidine Pridopidine is a dopamine modulator that selectively inhibits active D2 dopamine receptors. In MermaiHD, a randomized, double-blind, placebo-controlled trial, the safety, tolerability, and efficacy of pridopidine were assessed in the European HD population. Although well tolerated, at 26 weeks, there was a lack of efficacy as measured by the modified Motor Score (mMS) of the UHDRS (de Yebenes et al., 2011). In a subsequent study (HART), in 227 patients in the United States and Canada, there were similar findings of no significant change in the mMS (Huntington Study Group HART Investigators, 2013). However, as part of the secondary analysis, both studies showed benefit in overall HD motor symptoms as measured by the UHDRS TMS and specifically a reduction of dystonia (Mestre and Ferreira, 2012). Further ongoing studies include a multicenter, multinational, active phase II placebo-controlled trial exploring a range of pridopidine doses using TMS as the primary endpoint (NCT02006472); and an open-label extension of the HART trial evaluating long-term safety and efficacy (NCT01306929). It is encouraging that large studies have suggested global improvement in motor symptoms and may also identify an effective dose range. Cognitive measures are being tracked for both safety and potential secondary benefit, and functional tasks are also being tracked in an effort to determine if impacting TMS provides functional benefit.

Phosphodiesterase 10 inhibitors The class of enzymes known as phosphodiesterases (PDE) plays a significant role in cell signaling by modifying the secondary messenger molecules, cAMP and cGMP (Chappie et al., 2012). PDE10A, a family of PDE, is highly expressed in the caudate nucleus and putamen of various mammals, including rats, mice, dogs, and Cynomolgus macaques (Seeger et al., 2003; Coskran et al., 2006). PDE10A mRNA has also been localized in human brain (Coskran et al., 2006; Lakics et al., 2010). Mutant huntingtin is thought to impair functioning of cAMP response element-binding protein (CREB), an important transcription factor. PDE10A inhibitors can increase CREB activation, specifically in the striatum, a primary area of HD pathology. Initial studies in the HD R6/2 transgenic mouse model demonstrated a 50%

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reduction in striatal atrophy area, reduced aggregation of pathologic peptides, and reduced cortical neuronal death. Additionally, the mice showed a significant delay in the start of neurologic decline, suggesting PDE10A inhibition is neuroprotective (Giampà et al., 2010). Subsequently, in the same model, PDE10A was found in high levels in striatal medium spiny neurons. Thus, inhibiting PDE10A may decrease breakdown of cAMP and cGMP, preventing further cell damage (Leuti et al., 2013). The recent studies of the PDE10 inhibitor PF02545920 in two clinical trials (NCT01806896 and NCT02197130) have been negative with no change detected in the primary outcome measures of motor function. Unfortunately, another recent phase II PDE10A inhibitor trial of OMS824, has been suspended in light of a rat study showing elevated free-plasma levels of the drug, raising safety concerns (NCT02074410).

Laquinimod Laquinimod, an anti-inflammatory agent, is being studied for use in various inflammatory diseases and also being explored for symptomatic relief in HD. There is an ongoing 12-month, phase II study evaluating the efficacy of laquinimod at three separate doses (0.5, 1.0, and 1.5 mg four times a day) on the motor symptoms of HD as measured by TMS. Its effects on caudate volume, cognition, total functional capacity, and clinician’s impression of change will also be assessed (NCT02215616).

Cysteamine A reduced form of cystamine, cysteamine, showed evidence of disease modification and improvement in motor symptoms in the R6/2 transgenic mouse model (Sampaio et al., 2014). It is FDA-approved for treatment of nephropathic cystinosis. Cysteamine is thought to increase availability of brain-derived neurotrophic factor (BDNF) and therefore, potentially slow HD progression (Borrell-Pagès et al., 2006). The mechanism may be related to the fact that production of BDNF is impaired by mHTT. Initially, tolerability of the drug in HD patients was confirmed in a phase I study in 2005 (Besouw et al., 2013). A subsequent phase II study of increasing doses of cysteamine (maximum dose 1800 mg/day) over a 16-week period in 16 HD patients established tolerability but failed to show any significant differences in UHDRS (motor, functional, behavioral, cognitive tests), Mini Mental State Examination (MMSE), or Stroop test scores over the 16 weeks (Prundean et al., 2015). Delayedrelease cysteamine (RP103) is under investigation in 96 HD patients in France in a phase II/III trial. This 36-month trial is an 18-month blinded, placebo-

controlled phase followed by an 18-month open-label phase where all patients are transitioned to RP103 (NCT02101957). Preliminary results of the initial 18-month phase showed slower TMS progression in patients treated with RP103; however, this was not statistically significant. Interestingly, when those not taking TBZ (66 subjects) were analyzed separately, there was a reduction in TMS progression by 58% ( p ¼ 0.03) compared to placebo. There were slightly more patients reporting gastrointestinal side-effects in the RP103 group versus the placebo group but otherwise, the number of subjects reporting adverse effects was found to be similar in the two groups (Raptor Pharmaceuticals, n.d.). Given the overall clinical trial results to date, improved TMS may be due to a positive symptomatic impact on motor symptoms by this agent rather than a neuroprotective effect, suggesting a potential for cysteamine in HD symptom management. However, despite suggestion of improvement in motor symptoms, the 18-month trial failed to reach its primary endpoint; therefore, there is no definitive evidence of effectiveness.

SURGICAL TREATMENT Deep-brain stimulation (DBS) has proven to be an effective treatment in Parkinson disease, essential tremor, and primary dystonia; however, there are limited data on its role in HD motor symptoms, mainly in chorea control. There is one case report of a patient with the Westphal variant of HD manifesting as rigidity, bradykinesia, dystonia, and myoclonus who showed temporary improvement in TMS after bilateral globus pallidus interna (GPi) DBS (Cislaghi et al., 2014). Velez-Lago et al. (2013) compared DBS for one dystonia-predominant HD case to one chorea-predominant presentation and found a better outcome for the latter. Maintaining longterm effect on chorea may be challenging given that there is fluctuation of chorea with disease progression, and relative benefit may be outweighed by potential adverse effects on cognition (Sampaio et al., 2014). Six case reports have noted an improvement of chorea from GPi DBS in HD (Moro et al., 2004; Hebb et al., 2006; Biolsi et al., 2008; Fasano et al., 2008; Kang et al., 2011; Velez-Lago et al., 2013). A prospective open-label study of GPi DBS on 7 patients over a 3-year period, the longest follow-up to date, reported a sustained reduction in chorea in all patients. Maximal reduction in chorea, specifically orolingual and in the upper limbs, was noted 1 year after surgery with a mean improvement of 58% in TMC. This transient effect was complicated by worsening of bradykinesia (improved with pulse width reduction and adjunct levodopa therapy) and dystonia which were attributed to both disease progression and DBS

NEW SYMPTOMATIC THERAPIES FOR HUNTINGTON DISEASE complications. There was an overall functional decline during the 2-year follow-up period as measured by the functional assessment, independence scale, and total functional capacity scores, potentially indicating a low net benefit from surgery as disease progresses. Although there was functional decline and health-related quality of life could not be objectively assessed, the clinical HD stage remained unchanged throughout follow-up. Also, there was improvement in swallowing, a dose reduction or discontinuation of neuroleptics, and no significant decline in cognitive function (Gonzalez et al., 2014). There is an ongoing prospective, randomized controlled, multicenter European phase II trial comparing stimulator ON and OFF groups for 12 weeks with primary endpoint of change in TMS and TMC (Vesper, 2014). As chorea can result in significant injury from falls and infection from skin breakdown, GPi DBS may provide short-term symptomatic relief in early- to moderate-stage patients with chorea-predominant HD. DBS specifically targeting nonchorea symptoms such as dystonia and bradykinesia in HD requires further investigation.

Nonpharmacotherapeutic interventions for Huntington disease (HD) from 1970 to 2014 Year

Interventions

1971

Neuromuscular facilitation in the treatment of Huntington’s chorea Physical therapy Physical therapy Hydrotherapy Late-stage HD: effect of treating specific disabilities Hypnosis Huntington’s disease at mid-stage Velocity modulation and rhythmic synchronization of gait Linguistic and cognitive supplementation strategies, altered movement trajectories and force control during object transport Bilateral globus pallidus stimulation Directed activity Exercise effectsa Video game play Home-based exercise Multidisciplinary rehabilitation Dance traininga Physical therapy Treadmill walkinga Aquatherapy Drumming and rhythm exercises

1987 1980 1990 1991 1992 1999 2001

2004 2007 2012 2013

NONPHARMACOLOGIC INTERVENTION In addition to traditional pharmacologic and surgical approaches to improve symptoms in HD, there has been increasing attention toward nonmedication interventions such as physical therapy, occupational therapy, speech therapy, dance therapy, and cognitive behavioral therapy (Table 17.2). The benefits of exercise have been demonstrated in neurodegenerative diseases such as Parkinson disease (Oguh et al., 2014). In an active study, HD patients are being recruited for a single session of 20 minutes of walking on a treadmill to evaluate the safety, feasibility, and utility of this intervention and, secondarily, if this can improve gait and balance (NCT02268617). A similar study evaluated the effect of dancing through video game play and found it to be motivating while improving balance while walking (Kloos et al., 2013). In addition to cardiovascular exercise, a concurrent study is using endurance exercise as a means to improve muscle strength and stability and will also analyze muscle tissue pathology as it relates to HD (NCT01879267). An interesting prospective study conducted in Norway on 10 early- to mid-stage HD patients involved a 2-year intensive multidisciplinary rehabilitation program. Outcome measures included evaluation of gait, balance, cognition using the MMSE, anxiety and depression, activities of daily living, and quality of life. In the 6 patients who completed the study, there was a nonsignificant decline in gait and balance, no significant improvement in quality of life or anxiety and depression, but also no significant cognitive decline (Piira et al.,

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Table 17.2

2014

a

Ongoing trials.

2014). Nonmedication interventions intended for motor symptoms may therefore positively impact nonmotor symptoms (Colcombe et al., 2006).

COGNITIVE SYMPTOM TREATMENT PBT2 PBT2, an 8-hydroxyquinoline transition metal ligand, acts as a cellular chaperone of iron, zinc, and copper. Since accumulation of iron and copper can promote mHTT aggregation, a chaperone ligand such as PBT2 may play an important role in preventing HD pathology. In early studies, PBT2 reduced aggregated huntingtin in the R6/2 mouse model (Nguyen et al., 2005), decreased toxic cellular effects in the Caenorhabditis elegans model (Cherny et al., 2012), and improved cognition in the Alzheimer disease mouse model (Adlard et al., 2008). A published phase II randomized double-blind placebo-controlled study evaluated the safety, efficacy, tolerability, and cognitive effects of PBT2 over a 26-week period. Early to mid-stage HD patients were randomized to PBT2 250 mg, PBT2 100 mg, or placebo. A composite score of five tests (Category Fluency Test,

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Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test) plus individual scores from Trail Making Test Part A, Montreal Cognitive Assessment, and Speeded Tapping Test was used to measure any change in cognitive ability. PBT2 was found to be generally well tolerated with adverse effects thought to be unrelated to the drug except for worsening of HD in 1 patient. However, neither dose showed any significant benefit on cognition; in the higher-dose group there was a trend towards improvement in executive function as measured by Trail Making Test Part B, which suggests some potential therapeutic benefit (Huntington Study Group Reach2HD Investigators, 2015).

Latrepirdine Mitochondrial membrane dysfunction is thought to be one of the pathophysiologic mechanisms in the progression of HD. Latrepirdine, a synthetic molecule, was found to have stabilizing effects on the mitochondrial membrane and function. Initially developed in Russia as an antihistamine, it was later identified as a lowaffinity NMDA receptor antagonist (Bezprozvanny, 2010). In a study of moderate Alzheimer disease patients, it showed significant global improvement in cognitive, behavioral, and functional symptoms (Doody et al., 2008). In light of these promising results, an initial open-label dose-escalating study showed tolerability of the drug in HD at up to 60 mg/day. Subsequently, safety and tolerability were established in a large multicenter trial across the United States and United Kingdom. Although there was improvement in mean MMSE scores, there were no significant effects on the cognitive measures of the UHDRS (verbal fluency test, the symbol digit modalities test, and the Stroop interference test), or the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Similarly, there were no significant effects on TMS or total functional capacity (Kieburtz et al., 2010). In 2013, the Huntington Study Group conducted a randomized double-blind placebo-controlled study in more than 400 mild to moderate HD patients to assess effects on cognition (primary outcome), as well as impact on behavior, daily function, motor function, and safety (secondary outcomes). Although latrepirdine was generally well tolerated, 10% of participants receiving latrepirdine had it temporarily suspended due to adverse effects compared to 5% of those on placebo. Additionally, there was no significant improvement in cognition as evaluated by the MMSE or in secondary outcomes measures (HORIZON Investigators of the Huntington Study Group and European Huntington’s Disease Network, 2013). Therefore, despite encouraging early results there

has not been any evidence to date of the effectiveness of latrepirdine in treating cognitive symptoms in HD.

EGCG Green tea polyphenon (2)-epigallocatechin-3-gallate (EGCG) has been shown to decrease oxidative stress and neurotoxicity in various models of Alzheimer and Parkinson disease (Mandel et al., 2005). Similarly, it was also shown to reduce aggregation of mHTT in yeast and transgenic fly models of HD (Ehrnhoefer et al., 2006). Investigators are studying the effect of a maximum dose of EGCG (1200 mg) compared to placebo over a 12-month period. The primary outcome measure is a change in cognition from baseline (NCT01357681).

Resveratrol Resveratrol, a plant-based phenol, is found in various types of berries. An ongoing study is looking at start in 2015 proposes to look at the effect of resveratrol in HD patients, specifically at whether it can slow disease progression as measured by rate of caudate atrophy. Patients will be followed over 12 months. Investigators will also evaluate the effect of resveratrol on apathy, anxiety, depression, and cognition (NCT02336633).

NEUROPSYCHIATRIC SYMPTOM TREATMENT Neuropsychiatric symptoms, particularly changes in mood ranging from apathy to irritability, are common in HD, often presenting before motor symptoms. These symptoms can cause functional decline, and impact managing activities of daily living or more complex tasks like work, more significantly than cognitive or motor symptoms (Hamilton et al., 2003; van Duijn et al., 2014). They are often difficult to manage and can cause considerable distress to families and caregivers. Despite the prevalence of neuropsychiatric symptoms in HD, and a range of potential interventions, surprisingly, there has not been much focus on HD-specific treatment. In fact, there have been no clinical trials on medical management of these symptoms, although clinical providers often use medication and nonmedication interventions that have been tested in other patient populations (Bonelli et al., 2002; Killoran and Biglan, 2012). Improved control of mood symptoms especially early in the disease course can potentially increase time spent working. There is a significant need for medication trials focusing on these overlooked but often severely debilitating symptoms of HD (Thompson et al., 2012; Read et al., 2013).

NEW SYMPTOMATIC THERAPIES FOR HUNTINGTON DISEASE

NEUROPROTECTIVE TREATMENT Although symptomatic treatments are necessary to improve quality of life, preventing or slowing disease progression remains the ultimate goal. New symptomatic therapies are often investigated for additional potential neuroprotective benefit, presenting some challenges to clinical trial designs. Currently, none of the therapies under development for HD symptoms is clearly also neuroprotective, although researchers continue to look to examples from other neurodegenerative disorders, such as the putative neuroprotective benefit of rasagaline or the measurable benefit of exercise in Parkinson disease. Specifically, neuroprotective therapies are covered in Chapter 19.

QUALITY OF LIFE Given the progressive and debilitating nature of HD, there is continued need to develop ways to assess symptomatic treatment success in the context of quality of life. Importantly, improved measures to evaluate quality of life can be applied to new treatments in clinical trials. HDQLIFE is an ongoing multicenter observational study with the goal of developing this new measure by assessing various mental and physical factors involved in well-being. For those living with HD, quality of life is also partly, if not wholly, determined by involvement of their caregivers. In hopes of providing guidelines for caregivers, a new study, HUNTEXPERT, is evaluating the effects of behavioral changes in HD patients on caregivers (NCT02218567). Quality of life may be measured as a general feeling, or by complex functional tasks. Driving ability can be impacted by oculomotor deficits, motor impersistence, bradykinesia, and cognitive changes; work and key family relationships may be sensitive to mild cognitive or neuropsychiatric symptoms. Measuring positive impact of symptomatic treatment on these types of outcomes is difficult, but maintaining or improving these functional areas is critically important to patients and families, and is therefore becoming an aspiration for treatment development (Read et al., 2013).

AREAS OF NEED While there are specific HD motor symptom treatments now available, some motor symptoms such as oculomotor control deficits do not have clear interventions. Other “motor” symptoms may have a large range of contributors, such as falls created by a combination of chorea affecting gait, loss of postural reflexes, impulsivity and cognitive impairment, necessitating a multifactorial symptomatic intervention approach. While cognitive symptom treatments are in development, none specific to HD are currently available. Cognitive and neuropsychiatric symptoms may be undertreated, or inadequately

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treated due to limited HD-specific data on best treatment choices despite a range of available interventions, particularly for mood-based symptoms. Quality-of-life assessments are in wider use, with HD-specific ones in development, but treatments are still focused on very specific symptoms. Outside of rehabilitation therapy work in gait and balance, development of interventions for complex functional issues impacted by multiple symptoms remains sparse. Symptomatic treatments currently focus on moderate disease stages, or, in the case of cognitive and neuropsychiatric symptoms, early to moderate stages. HD-specific treatment development is needed for late-stage disease symptoms of all types. Quality-of-life considerations can be extended to ensuring the best possible end-of-life care.

SUMMARY In the last decade, beginning with TBZ, there have been significant developments in symptomatic therapies for HD. Numerous medications aimed at reducing chorea are in clinical trials and there is now a second agent approved for chorea associated with HD, deutetrabenazine. Motor symptom treatments are becoming more available, and at the same time are moving from specific symptoms, such as chorea, to a broad consideration of overall motor function benefit. Studying patient-centered outcomes is becoming more common in motor symptom-based trials. In addition to motor symptoms, cognitive and neuropsychiatric symptoms are salient in HD but, unfortunately, have fewer clear potential treatments. These symptoms can present early in the disease course, making reducing their debilitating impact on the patient and family a treatment priority. As early symptoms, particularly nonmotor, are better reported and understood, targeting symptomatic treatments in earlier disease stages such as prior to motor symptoms is coming to the forefront. Multiple agents are under development for cognitive symptoms in HD; nonmedication interventions and those aimed at motor symptoms may also positively affect cognition. Many neuropsychiatric symptomatic interventions are available and used clinically, but none have been specifically studied in HD. Despite limitations, HD symptomatic treatment is currently a very active area with great promise to continue improvement in quality of life and overall daily functioning. Even targeted interventions, such as chorea control, may yield general functional improvements or quality-of-life gains. Targeting later disease stages and complex outcomes such as driving, quality-of-life perceptions, or work level are challenges for the field. As novel disease-modifying strategies continue in development, symptomatic care presents many opportunities to make an immediate impact in HD clinical care.

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