Clinical Trial Design for Disease-Modifying Therapies for Genetic Epilepsies

Although trials with anti-seizure medications (ASMs) have not shown clear anti-epileptogenic or disease-modifying activity in humans to date, rapid advancements in genomic technology and emerging gene-mediated and gene replacement options offer hope for the successful development of disease-modifying therapies (DMTs) for genetic epilepsies. In fact, more than 26 potential DMTs are in various stages of preclinical and/or clinical development for genetic syndromes associated with epilepsy. The scope of disease-modification includes but is not limited to effects on the underlying pathophysiology, the condition’s natural history, epilepsy severity, developmental achievement, function, behavior, sleep, and quality of life. While conventional regulatory clinical trials for epilepsy therapeutics have historically focused on seizure reduction, similarly designed trials may prove ill-equipped to identify these broader disease-modifying benefits. As we look forward to this pipeline of DMTs, focused consideration should be given to the challenges they pose to conventional clinical trial designs for epilepsy therapeutics. Just as DMTs promise to fundamentally alter how we approach the care of patients with genetic epilepsy syndromes, DMTs likewise challenge how we traditionally construct and measure the success of clinical trials. In the following, we briefly review the historical and preclinical frameworks for DMT development for genetic epilepsies and explore the many novel challenges posed for such trials, including the choice of suitable outcome measures, trial structure, timing and duration of treatment, feasible follow-up period, varying safety profile, and ethical concerns.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01123-5.     

Challenges and directions in epilepsy diagnostics and therapeutics: Proceedings of the 17th Epilepsy Therapies and Diagnostics Development conference

Substantial efforts are underway toward optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trial execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, although seizures represent one critical therapeutic target, targeting nonseizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves and other nonseizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics, from drug discovery to translational application.     

Controversies in Alzheimer's disease drug development

Understanding of the pathophysiological basis of Alzheimer's disease (AD) is increasing rapidly and a variety of potential treatment modalities have emerged based on these improved mechanistic insights. The optimal way of proceeding with disease-modifying drug development remains to be clarified and controversies have emerged regarding the definition of Alzheimer's disease, the participation of mild cognitive impairment patients in clinical trials, the definition of disease modification, the potential impediments to satisfaction from patients receiving disease-modifying therapy, the importance of add-on therapy with symptomatic agents, the optimal clinical trial design to demonstrate disease modification, the best means of minimizing time spent in Phase II of drug development, the potential role of adaptive designs in clinical trials, the use of enrichment designs in clinical trials, the role of biomarkers in clinical trials, the treatment of advanced patients with disease-modifying agents, and distinctions between disease modification and disease prevention. The questions surrounding these issues must be resolved as disease-modifying therapies for AD are advanced. These controversies are framed and potential directions towards resolution described.     

Controversies in Alzheimer's disease drug development

Understanding of the pathophysiological basis of Alzheimer's disease (AD) is increasing rapidly and a variety of potential treatment modalities have emerged based on these improved mechanistic insights. The optimal way of proceeding with disease-modifying drug development remains to be clarified and controversies have emerged regarding the definition of Alzheimer's disease, the participation of mild cognitive impairment patients in clinical trials, the definition of disease modification, the potential impediments to satisfaction from patients receiving disease-modifying therapy, the importance of add-on therapy with symptomatic agents, the optimal clinical trial design to demonstrate disease modification, the best means of minimizing time spent in Phase II of drug development, the potential role of adaptive designs in clinical trials, the use of enrichment designs in clinical trials, the role of biomarkers in clinical trials, the treatment of advanced patients with disease-modifying agents, and distinctions between disease modification and disease prevention. The questions surrounding these issues must be resolved as disease-modifying therapies for AD are advanced. These controversies are framed and potential directions towards resolution described.     

Prevention of Epilepsy: Issues and Innovations

Epilepsy is a common brain disease and preventing epilepsy is a very relevant public health concern and an urgent unmet need. Although 40 % of all epilepsy cases are thought to have acquired causes, there is a roadblock for successful prevention. Efforts to protect the brain from epileptogenic insults are severely hampered by our lack of biomarkers to identify the few percent at high risk meriting treatment among those exposed. Preventing brain injury has been moderately effective from around birth to middle age; however, the strategy has failed to stop a substantial increase over the last decades in symptomatic epilepsy in those aged 65 and above. The traditional concept of repurposing anti-seizure drugs used for symptomatic seizure relief to prevent the onset of epilepsy has completely failed up to now. More recently, however, hope is on the horizon with a search for biomarkers and discovery of a new class of agents, called anti-epileptogenic drugs, which were specifically developed for prevention of epilepsy.     

Defining and labeling disease-modifying treatments for Alzheimer's disease

Alzheimer's disease (AD) might be treated with symptomatic, neuroprotective, or neurorestorative therapies. Neuroprotective and neurorestorative interventions are disease-modifying therapies. Disease modification can be defined as treatments or interventions that affect the underlying pathophysiology of the disease and have a beneficial outcome on the course of AD. In a clinical trial the criteria for affecting the underlying cause of the disease can be supported by demonstrating an effect on a biomarker such as medial temporal atrophy on magnetic resonance imaging (MRI) or diminished tau or phospho-tau levels in cerebrospinal fluid. The claim for a beneficial effect on the clinical course of AD is supported by a drug-placebo difference on the primary clinical outcomes of the clinical trial. A statistically significant correlation between the biomarker outcome and the clinical trial outcome would support the claim that these are based on the same underlying mechanism. Delayed start or staggered withdrawal designs might in themselves support a disease-modifying claim but are difficult to implement. A combination of clinical outcomes and biomarker measures is a more likely pathway to a disease-modifying claim. Labeling of disease-modifying agents might refer to slowing of disease progression, delay in reaching predefined disease milestones, or reduction in progression of a biomarker such as cerebral atrophy or ventricular enlargement on MRI. Prevention claims will depend heavily on biomarker outcomes.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Approaches to Disease Modification for Parkinson’s Disease: Clinical Trials and Lessons Learned

Despite many clinical trials over the last three decades, the goal of demonstrating that a treatment slows the progression of Parkinson’s disease (PD) remains elusive. Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. Here we review recent and ongoing clinical trials employing novel strategies toward disease modification, including those targeting alpha-synuclein and those repurposing drugs approved for other indications. Active and passive immunotherapy approaches are being studied with the goal to modify the spread of alpha-synuclein pathology in the brain. Classes of currently available drugs that have been proposed to have potential disease-modifying effects for PD include calcium channel blockers, antioxidants, anti-inflammatory agents, iron-chelating agents, glucagon-like peptide 1 agonists, and cAbl tyrosine kinase inhibitors. The mechanistic diversity of these treatments offers hope, but to date, results from these trials have been disappointing. Nevertheless, they provide useful lessons in guiding future therapeutic development.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00964-w.Key Words: Alpha-synuclein, clinical trial, immunotherapy, neuroprotection, repurposing     

Neuroprotection in Parkinson’s disease: Myth or reality?

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disorder with no cure. Therapies that delay or halt disease progression are urgently needed, but finding such therapies has been difficult. In this article, we review historical and recent clinical trial work in the field of neuroprotection. Several issues have arisen during the search for disease-modifying therapies, including challenges in selecting appropriate therapeutic targets, assessing potential therapies, and selecting the proper patient population to study. Advances in the understanding of PD pathogenesis are presented as they relate to selecting potential therapeutic targets, and issues with preclinical testing are described. We review recent innovations in clinical trial design, including futility studies and delayed-start designs that promise to make clinical testing more efficient. It is hoped that ongoing work in this field will lead to treatments that delay the progression of PD.     

Disease-modifying therapies for Alzheimer disease: challenges to early intervention

Prevention of Alzheimer disease (AD) is a national and global imperative. Therapy is optimally initiated when individuals are asymptomatic or exhibit mild cognitive impairment (MCI). Development of therapeutically beneficial compounds requires the creation of clinical trial methodologies for primary and secondary prevention. Populations in primary prevention trials selected only on the basis of age will have low rates of emergent MCI or AD. Epidemiologically based risk factors or biomarkers can be used to enrich trials and increase the likelihood of disease occurrence during the trial. Enrichment strategies for clinical trials with MCI include use of biomarkers such as amyloid imaging, MRI with demonstration of medial temporal lobe atrophy, bilateral parietal hypometabolism on PET, and reduced amyloid beta peptide and increased tau protein in CSF. Neuropsychological measures appropriate for trials of MCI may not be identical to those measures most suited for AD trials. Attention to these and other features of trial design, clinical assessment, and use of biomarkers is critical to improving the detection of disease-modifying effects of emerging therapies in presymptomatic or minimally symptomatic populations. The neurologic health of the growing aging population demands disease-modifying therapies and the development of methods to identify and test promising candidate agents.     

Amyotrophic lateral sclerosis: recent advances and future therapies

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis is a rare but fatal motoneuron disorder. Despite intensive research riluzole remains the only available therapy, with only marginal effects on survival. Here we review some of the recent advances in the search for a disease-modifying therapy for amyotrophic lateral sclerosis. RECENT FINDINGS: A number of established agents have recently been re-investigated for their potential as neuroprotective agents, including beta-lactam antibiotics and minocycline. Progress has also been made in exploiting growth factors for the treatment of amyotrophic lateral sclerosis, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, heat-shock protein co-inducers, which upregulate cell stress responses thereby mediating neuroprotection. Non-drug-based therapies are also under development, with progress in gene-silencing and stem cell therapies. SUMMARY: In the past few years, significant advances have been made in both our understanding of amyotrophic lateral sclerosis pathogenesis and the development of new therapeutic approaches. However, caution must be exercised in view of the long-standing failure to successfully transfer therapeutic compounds to the clinic. A deeper awareness in the research community of the need for clinically relevant preclinical studies, coupled with a better understanding of the issues surrounding clinical trial design for amyotrophic lateral sclerosis, offers hope that the growing list of validated preclinical therapeutics can finally yield an effective disease-modifying treatment.     

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0341-2) contains supplementary material, which is available to authorized users.Key Words: Antisense oligonucleotide, induced pluripotent stem cell, continual reassessment model, futility design, selection design, historical placebo     

Health economics and the value of therapy in Alzheimer’s disease

In increasingly aging societies throughout the developed and developing world, Alzheimer’s disease and related dementias are fast becoming a critical public health issue, exacting an enormous toll on individuals and healthcare systems. Over the past 10 years, five drugs have been developed and approved for the symptomatic treatment of Alzheimer’s dementia, and several disease-modifying drugs are in various stages of clinical development. While symptomatic medications were consistently shown to have clinical benefit in numerous efficacy studies, the cost effectiveness of antidementia therapies and their value to healthcare systems remain unclear. The pharmacoeconomics of antidementia therapies is an evolving field, with several unanswered questions. This poses many challenges for biopharmaceutical companies developing these therapies, regulatory agencies responsible for their approval, and payers responsible for ensuring their availability to patients. The challenge partly relates to the unique nature of dementia as a disease of impaired cognition, behavior, and function. Thus, the selection of appropriate outcome measures that directly relate to healthcare utilization, quality of life, caregiver burden, and pharmacoeconomic analysis has been difficult. The development of meaningful and widely acceptable outcome measures, as well as novel clinical-study designs, is needed to better evaluate cost effectiveness and to demonstrate the value of therapeutics for Alzheimer’s disease. Providing the decision-makers in healthcare systems with a body of evidence that demonstrates a positive relationship between clinical outcomes and the economic and humanistic benefits of antidementia therapeutics will improve patient access to novel drugs as they become available.     

The pipeline and future of drug development in schizophrenia

While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.     

New drugs in the future treatment of Parkinson's disease

During the last few decades, there has been a remarkable progress in our understanding of the biology of Parkinson's disease (PD), which has been translated into the development of numerous antiparkinsonian drugs. There are different therapeutic strategies for patients in an early stage versus patients in a late stage of the disease. The current therapeutic arsenal includes levodopa preparations, MAO-B inhibitors, dopamine agonists, COMT inhibitors and several other compounds that target non-dopaminergic systems. Much interest is focused on the potential neuroprotective effect of the already available drugs, as well as on new research approaches for the development of disease-modifying agents. These include mainly anti-glutamategic compounds, anti-apoptotic and antioxidative agents. Future therapy might include targeted delivery of trophic factors or genes involved in the pathogenesis of the disease. Apart from the classic levodopa-associated motor complications, such as dyskinesias and response fluctuations and psychosis, many other problems of advanced disease should be focused upon and solved including fatigue, freezing of gait, postural instability, depression, anxiety and panic attacks, sleep disturbances, autonomic dysfunction and sensory complaints.     

Outcome measures in clinical trials on medicinal products for the treatment of dementia: a European regulatory perspective

Based on efficacy and safety data, several drugs have been approved for symptomatic improvement of dementia of the Alzheimer type and one for the symptomatic improvement of dementia associated with Parkinson's disease. However, established treatment effects must be considered as modest. Randomized clinical trials in other subtypes of dementia (e.g. vascular dementia) have not been able to demonstrate clinically relevant symptomatic improvement, nor has it yet been possible to establish disease-modifying effects in any dementia syndrome or its subtypes. Recent progress in basic science and molecular biology of the dementias has now fostered new interest for more efficacious symptomatic treatments as well as for disease-modifying approaches in the degenerative dementias. For regulatory purposes this requires better standardization and refinement of diagnostic criteria, which allow the study of homogeneous disease populations in specialized academic centers as well as in the general community setting. Depending on the disease stages (early versus late, mild to moderate to severe impairment) and disease entities, distinct assessment tools for cognitive, functional and global endpoints should be used or newly developed. The typical design to show symptomatic improvement is a randomized, double-blind, placebo-controlled, parallel group study comparing change in two primary endpoints, one of them reflecting the cognitive domain and the second preferably reflecting the functional domain of impairment. The changes must be robust and clinically meaningful in favor of active treatment versus placebo. If a treatment claim for prevention of the emergence, slowing or stabilizing deterioration is strived for, it has to be shown that the treatment has an impact on the underlying neurobiology and pathophysiology of the process of dementia. Establishing such an effect in a highly variable progressing syndrome is complex and difficult; however, a variety of trial designs has been provided, including baseline designs, survival designs, randomized start or randomized withdrawal designs, with or without incorporation of biomarkers as surrogate endpoints (e.g. magnetic resonance tomography, emission tomography, cerebrospinal fluid markers). To be accepted as a surrogate endpoint such a biomarker ideally should respond to treatment, predict clinical response and be compellingly related to the pathophysiological process of the dementia. However, careful and sufficient validation of proposed biomarkers as a potential surrogate endpoint is a prerequisite for acceptance by regulatory bodies. This review outlines the regulatory requirements for approval of a new medicinal product for symptomatic improvement or disease-modifying effects in patients with dementia, with special emphasis on the importance of validation of the assessment tools and potential surrogate endpoints based on recent experience and discussion regarding anti-dementia drugs in the European framework.     

Regulatory aspects of vascular dementia in the United States

There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term "vascular dementia" may not be entirely appropriate to describe this population.     

Phase I trials: from traditional to newer approaches part II

In the first part of this series, the authors discussed strengths and weaknesses of traditional phase I drug development involving single ascending dose studies followed by multiple ascending dose studies in healthy volunteers. They then discussed how these traditional designs are being challenged by the development of truly novel molecular compounds that are not derived from earlier drugs and how the extent and design of phase I studies will need to be expanded and altered to investigate these novel compounds. In this column, the authors focus in more detail on limitations of traditional phase I studies for investigating truly novel compounds and propose solutions to address these problems. Adaptive trial designs and biomarker endpoints are discussed.     

Design of clinical trials of gene therapy in Parkinson disease

No current therapy for Parkinson disease has been shown to slow or reverse the progressive course of the disease. As a departure from traditional treatments, gene therapy approaches provide a new hope for realizing this long-sought goal; but before they can be widely employed for use in patients, they must first be submitted to the rigorous safety and efficacy standards of the clinical trial. Some of the challenges of gene therapy clinical trial design are similar to those in studies of conventional pharmacological agents and include addressing the heterogeneity of the disease, the need for clinical and surrogate endpoints, and the issue of distinguishing "symptomatic" from "neuroprotective" effects. Gene therapy trials also raise the issues of the risks of viral therapy, issues of dose-response, the need for sham surgery, and the long duration of risks and benefits. We conclude that the most feasible designs are for those treatments that are expected to produce a rapid improvement in directly observable symptoms. Trials of agents which are expected to produce only a slowing of progression and not a reversal of the disease course are likely to take much longer and will require the development of methods to assess quality of life and other non-motor aspects of the disease.     

Selecting promising ALS therapies in clinical trials

Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.