INTRODUCTION

Successful treatment of a neurodegenerative disorder depends on three interdependent factors: (1) the “right” treatment candidates; (2) the ability to detect the therapeutic effects in an appropriate clinical population; and (3) clinically meaningful treatment effects. Each contribution is necessary but insufficient by itself to realize therapeutic gains and ultimately clinical benefits.

These issues are illustrated for hepatolenticular degeneration, or Wilson’s disease, which in 1911 was first recognized by Samuel Alexander Kinnier Wilson as a disorder that was familial, progressive, fatal, and associated with softening of the lenticular nucleus (pallidum and putamen) and cirrhosis.¹ Hepatolenticular degeneration was linked in 1913 to an accumulation of hepatic copper² and hypothesized in 1921 to be inherited in an autosomal recessive fashion.³ However, chelating therapy was not developed and reasoned to be an effective experimental treatment until 1948–1958. Coincidentally, the copper-binding protein ceruloplasmin was found to be deficient in individuals who inherited two copies of the gene responsible for Wilson’s disease. Experimental decoppering treatments would eventually be found to slow and even reverse neurological and hepatic deterioration in clinically affected individuals.^4–6

In the case of Wilson’s disease, the right treatment emerged from an incremental knowledge base and the rational understanding that copper accumulated in vital organs could be removed or prevented by effective and reasonably safe treatments. The therapeutic effects of decoppering therapy (2,3-dimercaptopropanol or British anti-Lewisite and later penicillamine) were of such large magnitude and relatively small variance that benefits could be detected in just a few patients without placebo controls.4 The clinical meaningfulness of penicillamine therapy became clear by 1968 when this intervention was demonstrated to prevent the onset of clinical features in premanifest individuals who had deficient ceruloplasmin, increased hepatic copper, and were presumed to carry the homozygotic genetic defect accounting for Wilson’s disease.⁶ Again, the treatment effects were sufficiently strong and uniform as to be convincing without placebo controls. As may occur with disease-modifying therapies, treatment may result in initial clinical worsening (as can be the case with penicillamine⁷) before clinical improvement. Improvements in therapy would later ensue in the form of trientine and zinc treatments.⁸,⁹ Although success in the experimental therapeutics of Wilson’s disease seemed in retrospect to come in quantum scientific leaps, therapeutic benefits accrued slowly but steadily through incremental gains in clinical research. Interestingly, a molecular understanding of the genetic defects underlying Wilson’s disease only followed the development of successful treatment.¹⁰

The clinical and hereditary aspects of Huntington’s disease (HD) were first described by George Huntington in 1872. It took nearly a century to unravel the relatively selective pattern of neuronal loss and gliosis and the associated neurochemical abnormalities that characterized the neurodegeneration of HD. In the 1980s and 1990s, studies of large and multiple families and the development and application of molecular genetic techniques led eventually to identification of the gene responsible for HD.¹¹ In the past two decades, a remarkable and collaborative scientific inquiry has elucidated the key relationship of genetic dosage (CAG repeat length) to clinical features (age at onset), identified the mutant huntingtin protein, provided insights into the mechanisms underlying neuronal degeneration, and enabled the development of genetic animal models. The ability to detect premanifest HD in individuals who have inherited the mutant gene and its expanded CAG repeat has provided the opportunity to develop preventive therapies aimed at postponing or preventing the onset of illness.

CANDIDATES FOR EXPERIMENTAL THERAPEUTICS

Despite the major scientific advances in understanding HD and the efforts of many, the treatments available for HD are limited.¹² The development of treatments is costly, time intensive, and risky.¹³ Given the considerable resources required to evaluate experimental therapeutics, identifying and prioritizing candidates are important for strategic research and development.

Broadly speaking, experimental therapeutic agents emerge from two principal routes (see Table 12.1). The first route is treatments for which therapeutic evidence is largely derived from empirical observation. In many cases, the benefits of a treatment are discovered by empirical observation or what some have called planned serendipity. In contrast to empirical observation, rational treatment design has grown in influence during the past two decades, especially in situations where the underlying (frequently genetic) abnormality responsible for a particular disease has become elucidated. With pathogenetic knowledge in hand, targets can be identified, and “druggable” treatments can be specifically designed to interact with that target to ameliorate the resulting disease process. This approach of “rational treatment design” has largely supplanted efforts at mass screening of compounds against an array of possible targets (see Chapter 8, this volume). Treatments derived from empirical observation and rational drug design both have a role in the development of therapies for HD, just as they did for the successful treatments for Wilson’s disease.

TABLE 12.1

Sources of Experimental Therapeutics.

Systematic descriptions of empirical reasoning date back to at least Aristotle, who, in contrast to Plato, emphasized observations that could be perceived by the senses. Empiricism has evolved since Aristotle’s time, and many modern medical advances have their roots in empirical observations. For example, benzodiazepines were developed in a “purely empirical manner” as scientists, including Dr. Leo Sternbach, at Hoffmann-La Roche Inc. sought to develop a new class of tranquilizers to supplant barbiturates.¹⁴ Because knowledge of brain processes was limited, the investigators could not think of “an intelligent working hypothesis.” With expertise in chemical synthesis, the investigators sought to search for a new class of tranquilizers through molecular modification of existing compounds. Among the criteria the researchers used in identifying possible compounds were that the new class be relatively unexplored, be readily accessible, and “look” as if it could lead to biologically active products. The compounds that were first developed had their origins as dyes. The compound that led to the eventual development of chlordiazepoxide (Librium) was found during a “cleanup operation” where a precursor compound was sent for pharmacological testing with little hope of efficacy. The compound was found to cause muscle relaxation and sedation in animals. This serendipitous discovery led to refinement of the compound, the development of a whole class of compounds, and, like Wilson’s disease, the advancement of basic neuroscience by eventually leading to the identification of the benzodiazepine receptor.¹⁴

The development of lithium for bipolar disorder also relied principally on empirical observation. Lithium was initially used for the treatment of gout and uric acid disorders. A psychiatrist in Australia, John Cade,¹⁵ observed that guinea pigs given lithium carbonate became lethargic. Dr. Cade was originally working on the hypothesis that mania was related to intoxication by normal body products, such as urea, and that the lithium urate salt was very soluble. Dr. Cade subsequently injected lithium carbonate into fully conscious animals and found that they became extremely lethargic. Although the mechanism of action of lithium and its target were not known and not what Dr. Cade had suspected, he turned this discovery into an effective treatment for mania. Subsequent randomized, placebo-controlled trials performed two decades later confirmed the efficacy of lithium in mood disorders.¹⁶ Dr. Cade later commented, “It [seems] a long way from lethargy in guinea pigs to the control of manic excitement.”¹⁷ Although Dr. Cade’s initial observation was published in 1949, such serendipity continues. Sildenafil (Viagra) was being examined as an antianginal compound, and the effect on erectile dysfunction was discovered only by chance.¹⁸

In HD, tetrabenazine, a monoamine-depleting agent,¹⁹ was developed initially as an antipsychotic drug by Hoffmann-La Roche Inc. in the late 1950s. Its benefit for hyperkinetic movement disorders was only discovered a decade later, and 50 years later, in December 2007, the Peripheral and Central Nervous System Advisory Committee to the U.S. Food and Drug Administration (FDA) unanimously recommended its approval for the treatment of chorea associated with HD. Although the FDA has (as of June 2008) yet to act formally on the recommendation, tetrabenazine is poised to be the first treatment approved specifically for HD.

Empirical observation by astute clinicians will continue to play a role in the development of experimental therapeutics for HD. The limit of empirical observation is that it relies largely on chance and a prepared mind.²⁰ Designing experimental therapeutics solely on the basis of empirical observation is neither efficient nor sufficient.

In contrast to empirical observation, strategies based on rational design hold promise for developing effective, targeted treatments for HD. Levodopa treatment of Parkinson’s disease (PD) is perhaps the most notable example of a “rationally” designed therapeutic drug in neurology. Based on evidence that postmortem brain samples of individuals with PD were deficient in dopamine, Arvid Carlsson, Oleh Hornykiewicz, George Cotzias,²¹,²² and others showed that levodopa, a precursor to dopamine, was effective in relieving parkinsonian symptoms. However, this success came after several false starts and the eventual recognition of the need to achieve adequate dosage and duration of levodopa treatment.

Rational design grew with the increased understanding of genetics, especially in oncology. The discovery of the Philadelphia chromosome,²³ a translocation of chromosomes 9 and 22, as the genetic abnormality underlying chronic myelogenous leukemia set the stage for rational drug design. The translocation and the resulting overexpression of tyrosine kinase and subsequent increased cell division provided investigators a therapeutic target. Research, led by Dr. Brian Drucker, demonstrated that the compound STI-571 inhibited the proliferation of hematopoietic cells expressing the genetic abnormality found in chronic myelogenous leukemia. This compound inhibited tyrosine kinase and was subsequently marketed by Novartis Pharmaceuticals as imatinib mesylate (Gleevec), a remarkably effective treatment for chronic myelogenous leukemia.²⁴

Nascent clinical investigations of rationally designed experimental therapeutics are underway in HD. Based on evidence of bioenergetic mitochondrial defects in HD,²⁵,²⁶ coenzyme Q₁₀ at a dosage of 600 mg daily was examined in placebo-controlled clinical trials of 347 ambulatory patients with HD who were treated for up to 30 months.²⁷ This study marked the first time that a therapeutic signal was observed, consisting of about a 15% slowing in functional decline that was accompanied by a slowing in cognitive decline. A smaller, placebo-controlled trial of coenzyme Q₁₀ in PD showed a slowing of disease-related disability, but this was achieved only at a dosage of 1200 mg daily.²⁸ These observations have prompted the design of a larger placebo-controlled study of coenzyme Q₁₀, 2400 mg daily, in early HD patients who will be followed for up to 5 years.²⁹ Other rationally designed and promising therapeutics for HD, using innovative technologies such as gene therapy and RNA interference, have yet to proceed into clinical trials.³⁰,³¹

As our knowledge of HD has expanded, more promising targets for therapeutic action have been identified, as described in earlier chapters. To assess the current state of the therapeutic pipeline for HD, we identified all drugs with a primary indication for HD from a proprietary drug database (Pharmaprojects).³² The results in Figure 12.1 and Table 12.2 show a growing pipeline. However, most of the therapeutic candidates are in the nonclinical phase of development. Rationally designed therapies for HD may still be years away from clinical trials and it may be even longer until successful treatments become more widely available. Although the nonclinical and clinical components of the pipeline are expected to grow considerably in the coming years, time remains the chief limitation in the development of therapeutics for HD.

FIGURE 12.1

Number of drugs in development by phase for Huntington’s disease, 2004–2007.

TABLE 12.2

Drugs in Development for Huntington's Disease, 2007.

DETECTION OF THERAPEUTIC EFFECTS

The ability to detect the therapeutic effects in an appropriate clinical population is an essential part of development. Unlike Wilson’s disease, the magnitude of clinical effects detected to date in HD has been small in magnitude and somewhat variable. Clinical trials aimed at disease modification require years of follow-up evaluation and estimates of relatively large sample sizes in the hundreds and even thousands of research participants. With identification of better candidates, the magnitude of the treatment effects is expected to increase. With improved clinical research methodology, the variability of outcome measures is expected to narrow.

There are several approaches to narrowing variability of outcome measures. One is to lessen the variability between observers and ensure more consistency of ratings over time, which can be facilitated by ongoing training of clinical raters. The statistical power of the study can also be enhanced by blocking the randomization of experimental treatments according to the investigators, the largest source of variability. However, there are limits to reducing the variability in outcome measures, which after all reflect the clinical heterogeneity of the HD phenotype.

A major strategy to improve experimental therapeutics came about in the past decade as observational studies were undertaken to define the clinical precursors of premanifest HD. This is being accomplished by longitudinal examination of large research populations of adults, including more than 1,000 (1,021 as of June 2008) participants at 32 sites in North America and Australia who had become aware of their HD gene status through predictive DNA testing (PREDICT-HD)³³ and 1,001 participants at 40 North American sites who are at risk to develop HD but have chosen not to learn their gene status (PHAROS).³⁴ These innovative studies are expected to provide clearer definition of the clinical onset of HD and the clinical precursors that antedate onset. In turn, the profile and pace of clinical onset observed in PREDICT-HD and PHAROS can be used to design controlled trials aimed at delaying the earliest manifestations of illness.

An important way of detecting therapeutic effects is to develop and identify biological markers that parallel the pathogenesis of HD. So-called state biomarkers can be used in early-phase clinical trials to better identify promising treatment candidates and optimal dosages. Efforts are underway to identify “wet” biomarkers in body fluids and tissues of individuals with premanifest and manifest HD that could be measures of disease state.³⁵ Similarly, neuroimaging approaches with MRI technology and PET ligands will further enhance the state and pace of disease.³⁶ Such biomarker development is taking place in the context of many of the observational and clinical trials listed in Table 12.2 and through concerted approaches such as the COHORT observational study, a prospective study collecting phenotypic and genetic data from people with HD or individuals in an HD family,³⁷ and TRACK-HD, which is designed to determine the combination of outcome measures that is the most sensitive at detecting changes as HD state progresses.³⁸ To identify premanifest disease and to determine gene dosage in the form of the expanded CAG repeats that predicts age at clinical onset are key advantages in research and the development of biomarkers for HD. Promising biomarkers will require validation in the context of clinical trials, where learning39 how these biomarkers change over time and respond to interventions can take place. Through the test of successful clinical trials, validated biomarkers may eventually take on the role of surrogate endpoints that will further facilitate therapeutic development. Some authorities have even advocated that well-developed biomarkers might serve as the initial basis for approval, pending verification of safety, effectiveness, and clinically meaningful outcomes.⁴⁰

CLINICALLY MEANINGFUL OUTCOMES

This review has focused on so-called disease-modifying treatments that are aimed at slowing neurodegeneration and that will likely take years to demonstrate effectiveness in slowing progression of manifest illness or delaying onset of clinical manifestations. In any event, the clinical outcomes will need to be relevant in slowing or preventing the onset of functional decline or progressive disability. For example, despite tetrabenazine’s substantial reduction in chorea,¹⁹ the largely insensitive (at least over the short term) functional measures used in the study did not demonstrate any associated improvement, an issue that was raised by the FDA in its Advisory Committee review of the drug.

Efforts are currently underway to develop and catalogue outcome measures and rating scales that are clinically meaningful and have been validated in clinical trials. The HD Toolkit project⁴¹ is a cooperative approach focused on providing investigators with outcome measures appropriate to their clinical trial objectives. Researchers of the HD Toolkit project seek to identify tests that are sensitive to the subtle changes of prediagnostic and early HD based on validity, reliability, feasibility, and evidence of linear change with disease progression.⁴²

SPECIAL CHALLENGES AND OPPORTUNITIES IN HD CLINICAL TRIALS

HD as an inherited and fully penetrant, adult-onset neurodegenerative disorder has unique characteristics that pose special challenges and create valuable opportunities in the design and conduct of clinical trials. Because of its insidious course, demonstrating the efficacy of potentially disease-modifying therapies may take many years. For example, an earlier study of coenzyme Q₁₀ showed a modest benefit on “total functional capacity” of individuals after 30 months,²⁷ which is now being investigated in a 5-year study of coenzyme Q₁₀.²⁹ In addition to the long duration of many HD studies, the genetics of HD can influence recruitment, especially in observational studies of individuals at risk for HD. The fear of health insurance loss or other negative ramifications (e.g., job loss) of participation in studies can be very real for research participants. The recently passed Genetic Information Nondiscrimination Act protects individuals and family members participating in research that includes genetic testing and may help alleviate some of that fear.⁴³ Finally, because of the high risk of suicide and other neuropsychiatric problems that are associated with HD,^44–46 monitoring the safety and mental health of research participants during clinical trials is especially important. With the increasing promise of biologicals and their application to HD, safety issues will likely take on heightened importance.⁴⁷

In the future, trials in HD will have special opportunities. Among them will be the incorporation of promising biomarkers in early-stage trials, which has already begun.³⁵ Although these biomarkers will not substitute for clinical outcomes, they will provide additional insight into the disease and evidence of whether an experimental therapeutic is worthy of future investigation in lengthy (and expensive) clinical trials. In addition to biomarkers, the genetics of the disease will allow HD to serve as a paradigm for investigating therapies among individuals with “premanifest” (known carriers of the genetic mutation responsible for HD but do not yet have clear symptoms of the disease) HD. One upcoming study, PREQUEL, aims to investigate the safety and tolerability of coenzyme Q₁₀ in this population. Another opportunity for future HD clinical trials is the use of ongoing observational studies, such as COHORT and its European counterpart REGISTRY,⁴⁸ to identify research participants in those studies who may be eligible for participation in interventional studies. Thus, these large observational studies can serve as a valuable pool and introduction to clinical research for those affected by HD. Finally, involving individuals with and affected by HD more directly in the conduct of clinical trials (e.g., through participation on steering committees) will provide a unique perspective to clinical research and likely generate other secondary benefits. Research participants in HD trials have recently expressed satisfaction with learning the results of trials in a timely and accurate manner.⁴⁹ Continuing to meet their needs and encouraging their participation in clinical research in new ways is highly desirable for all stakeholders.

Involving research participants more directly in the conduct of research is another example of the collaborative nature of the HD community. Those affected by HD have fueled investments in research into the etiology and pathogenesis of HD. This scientific inquiry continues to advance at a rapid pace, catalyzed in large part by research efforts of the High Q Foundation (New York, NY) and its nonprofit discovery group CHDI, Inc. (Los Angeles, CA), the Hereditary Disease Foundation (Santa Monica, CA), the Huntington’s Disease Society of America’s Coalition for the Cure (New York, NY), the Huntington Society of Canada (Kitchener, ON), and governmental support through the National Institutes of Health, the FDA Orphan Products Division, and the European Union. These research undertakings are expected to provide more and better-defined targets for therapeutic intervention. The scientific developments have been attended by heightened interest and initiative among individuals and families affected by HD. In record numbers, patients with HD and individuals at risk for or with known premanifest HD are volunteering to participate in many large-scale interventional and observational studies (see Table 12.3). By and large, clinical trials in HD have enrolled research participants on schedule or in advance of projected timetables.

TABLE 12.3

Multicenter, Placebo-Controlled Clinical Trials for Huntington's Disease.

This growth of clinical research has been enabled by several novel collaborations aimed at developing effective treatments for HD. The Huntington Study Group⁵⁰ established in 1993 and the European Huntington’s Disease Network⁵¹ established in 2004 are not-for-profit consortia of academic investigators who are working cooperatively to improve methodology and trial design and to efficiently conduct controlled trials of experimental therapeutics for HD. The High Q Foundation, Inc.⁵² is a private philanthropic foundation established in 2002 aimed at bringing industry, academia, government agencies, and funding organizations together to facilitate the development of treatments for HD. CHDI, Inc. is a not-for-profit drug discovery arm of the High Q Foundation that identifies rational targets for experimental intervention and “druggable” treatments that show promise of becoming safe and effective treatments for HD.

A major advantage of HD research is the collegial approach that has been forged worldwide in recent years by scientists, clinical investigators, and, importantly, by the community of patients and families affected by HD. This cooperative effort will further enhance the prospects for ensuring that promising therapeutic candidates will be identified, their safety and efficacy will be detected in a reliable fashion, and that meaningful clinical outcomes will ensue. Someday, expectedly sooner rather than later, HD, like Wilson’s disease, will be taken off the rolls of untreatable neurodegenerative disorders. The ultimate success of these undertakings remains to be realized, but at a minimum, these efforts have added energy and support to the efforts of many in developing effective treatments for HD and other conditions.

ACKNOWLEDGMENTS

We thank Joel Thompson and Lisa Deuel for assistance in analyzing and preparing the data in the tables and figures.

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