Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?

Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.     

Fire in the ashes: Can failed Alzheimer’s disease drugs succeed with second chances?

BackgroundSince Cognex, more than 200 Alzheimer’s disease (AD) drug candidates have failed. Investigations have identified vulnerabilities of these AD drug developments to methodological errors. (−)-Phenserine has been discussed as possibly failing due to flawed methods and practices in development.MethodsWe analyzed documentation of (−)-phenserine’s development for vulnerabilities to errors and designed interventions for a redevelopment that could provide fair or unbiased assessments of (−)-phenserine target engagement, target relevance for human diseases, and adequate presumptive evidence of efficacy as a therapeutic for one or more diagnoses to justify registration-required clinical trials.ResultsSimilar to studies of 40 other AD developments, with (−)-phenserine, we found little evidence of preemptive interventions against potentially invalidating errors, grounds to judge progress in development through stages as not scientifically justifiable, and variance excess and placebo group improvements as capable of accounting for outcomes from various studies in the development. We propose to compare a redevelopment resourced to counter these deficiencies with the original development as historical control to evaluate further our hypothesis that errors in development accounted for the (−)-phenserine failure, specifically, and other AD drug failures, potentially.ConclusionsWe find support for our earlier proposal that (−)-phenserine did not fail, but the methods of development did fail, to provide conditions where efficacy could be tested. We propose that redevelopment under conditions aimed to correct methodological deficiencies common in AD drug developments will successfully test efficacy for (−)-phenserine and hopefully lead to a disease-modifying addition to the AD therapeutic armamentarium.     

Barriers to Alzheimer disease drug discovery and development in the biotechnology industry

The major barrier to Alzheimer disease (AD) drug discovery and development in the biotechnology industry is scale. Most biotechnology companies do not have the personnel or expertise to carry a drug from the bench to the market. Much effort in the industry has been directed toward the elucidation of molecular mechanisms of AD and the identification of new targets. Advances in biotechnology have generated new insights into disease mechanisms, increased the number of lead compounds, and accelerated biologic screening. The majority of costs associated with drug development are in clinical testing and development activities, many of which are driven by regulatory issues. For most biotechnology companies, the costs of such trials and the infrastructure necessary to support them are prohibitive. Another significant barrier is the definition of therapeutic benefit for AD drugs; Food and Drug Administration (FDA) precedent has established that a drug must show superiority to placebo on a performance-based test of cognition and a measure of global clinical function. This restrictive definition is biased toward drugs that enhance performance on memory-based tests. Newer AD drugs are targeted toward slowing disease progression; however, there is currently no accepted definition of what constitutes efficacy in disease progression. Despite these obstacles, the biotechnology industry has much to offer AD drug discovery and development. Biotechnology firms have already developed essential technology for AD drug development and will continue to do so. Biotechnology companies can move more quickly; of course, the trick is to move quickly in the right direction. Speed may offset some of the problems associated with lack of scale. Additionally, biotechnology companies can afford to address markets that may be too restricted for larger pharmaceutical companies. This advantage will have increasing importance, as therapies are developed to address subtypes of AD.     

Lessons from Darwin: evolutionary biology's implications for Alzheimer's disease research and patient care

What are the aims appropriate for a science of clinical pharmacology and clinical trials: to test drugs for efficacy and safety in the clinic, to establish the optimal effectiveness and safety of drugs in patient care or both? Current designs of clinical trials test drugs for efficacy and safety in clinical settings-they do not address the clinician's problems adequately. Clinical trials better address the effectiveness of drugs in patient care with analyses to determine drug effects for each individual in the trial. We use current standards and designs for clinical trails supplemented to control random error effects for the individuals in the trials. Test-retest standard error of measurement can control random error effects for individuals. This allows individual clinical courses to be plotted with known precision and certainty. For individuals in a clinical trial the clinical course of surrogate outcome variables can be associated with long-term health outcomes in followup to develop clinical decision rules. Clinical courses on surrogate outcome variables during patient care can be interpreted using these clinical decision rules. In this Age of the Internet, Computers and Handhelds, electronic records and interpretations of clinical examinations and tests can be a part of decision making for every patient. We conclude that practical methods are available for making clinical trials more informative for clinical practice. This modification replaces "unsystematic clinical judgments" with statistically characterized data and interpretations for individuals available as care is delivered in the doctor's office. An AD demonstration can be viewed at www.healthpragmatics.com.     

Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease

The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale – the Clinical Dementia Rating Scale in particular – for the primary outcome for prodromal AD clinical trials.In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving.     

The canine model of human cognitive aging and dementia: pharmacological validity of the model for assessment of human cognitive-enhancing drugs

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.     

Neuroinflammation in Alzheimer's disease: are NSAIDs and selective COX-2 inhibitors the next line of therapy?

Alzheimer's disease (AD) is currently treated with cholinergic and glutamatergic therapies, which provide symptomatic benefit but do not reverse the underlying pathology or cognitive deficits. The prevalence of AD is expected to triple over the next 50 years, creating an urgency to develop effective "disease-modifying" therapies to reduce the economic burden of this devastating disorder. One of the main areas of therapeutic focus has been an antiinflammatory strategy based on an inflammatory hypothesis of AD. This hypothesis originated from epidemiological evidence that long-term exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) protected against the development of AD. However, large-scale double-blind placebo-controlled clinical trials have not supported the use of NSAIDS in treating AD. The following review outlines epidemiological, preclinical, and clinical evidence evaluating the efficacy of various NSAIDs and selective COX-2 inhibitors in AD. We also review recent anecdotal data with the TNF-α inhibitor, etanercept, and discuss possible explanations for the failure of preclinical data to translate into successful clinical trials.     

Impact of Neurodegenerative Diseases on Drug Binding to Brain Tissues: From Animal Models to Human Samples

Drug efficacy in the central nervous system (CNS) requires an additional step after crossing the blood–brain barrier. Therapeutic agents must reach their targets in the brain to modulate them; thus, the free drug concentration hypothesis is a key parameter for in vivo pharmacology. Here, we report the impact of neurodegeneration (Alzheimer’s disease (AD) and Parkinson’s disease (PD) compared with healthy controls) on the binding of 10 known drugs to postmortem brain tissues from animal models and humans. Unbound drug fractions, for some drugs, are significantly different between healthy and injured brain tissues (AD or PD). In addition, drugs binding to brain tissues from AD and PD animal models do not always recapitulate their binding to the corresponding human injured brain tissues. These results reveal potentially relevant implications for CNS drug discovery.     

Alzheimer's disease: how does it start?

Presently, non-genetic Alzheimer's disease (AD) is wrongly classified as a neurodegenerative disorder. When vascular lesions are present, AD is considered to be a vascular dementia. However, compelling evidence indicates that (AD) is a vascular disorder with neurodegenerative consequences. There is an urgent clinical need to ascertain the true cause of this dementia. In this review, evidence indicating that AD is a vascular disorder comes from a number of different disciplines including studies in epidemiology, pharmacology, neuroimaging, clinical medicine, pathology, physiology and experimental research. This collective evidence also addresses many previously puzzling questions regarding: i) past and present treatment failures in AD, ii) strange association of AD risk factors with many vascular-related disorders, iii) parallel lesions, clinical symptoms risk factors and potentially interchangeable treatments present in AD and vascular dementia, iv) historical difficulty in finding neurodegenerative markers to detect AD pre-clinically, and, v) paradoxical pathophysiologic events preceding AD neurodegenerative changes. Re-classifying AD as a vascular disorder would very likely improve the chances of finding a useful treatment for this disorder because clinical study designs could focus on more realistic and relevant pathologic targets than is presently practiced. A short summary of potential new research lines that may provide novel therapy in the treatment and management of AD is discussed.     

Bupropion for weight reduction

Bupropion is a norepinephrine and dopamine uptake inhibitor that has been available for several years for the treatment of depression and aiding smokers to quit. Although bupropion is not approved for treating obesity, three randomized clinical trials have shown some degree of efficacy for this drug in promoting weight loss in obese patients. The present drug profile provides a review of the pharmacology of bupropion, clinical evidence of efficacy with regard to weight reduction, tolerability and risks, and the current and future role of this drug in the management of obesity.     

Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?

Introduction

Neurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links.

BACE inhibitors as potential therapeutics for Alzheimer's disease

Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Abeta production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.     

Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy

Control of epilepsy has primarily focused on suppressing seizure activity by antiepileptic drugs (AEDs) after epilepsy has developed. AEDs have greatly improved the lives of people with epilepsy. However, the belief that AEDs, in addition to suppressing seizures, alter the underlying epileptogenic process and, in doing so, the course of the disease and its prognosis, is not supported by the current clinical and experimental data. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. A number of AEDs have been evaluated in clinical trials to test whether they prevent epileptogenesis in humans, but to date no drug has been shown to be effective in such trials. Thus, there is a pressing need for drugs that are truly antiepileptogenic to either prevent epilepsy or alter its natural course. For this purpose, animal models of epilepsy are an important prerequisite. There are various animal models with chronic brain dysfunctions thought to reflect the processes underlying human epilepsy. Such chronic models of epilepsy include the kindling model of temporal lobe epilepsy (TLE), post-status models of TLE in which epilepsy develops after a sustained status epilepticus, and genetic models of different types of epilepsy. Currently, the kindling model and post-status models, such as the pilocarpine or kainate models, are the most widely used models for studies on epileptogenic processes and on drug targets by which epilepsy can be prevented or modified. Furthermore, the seizures in these models can be used for testing of antiepileptic drug effects. A comparison of the pharmacology of chronic models with models of acute (reactive or provoked) seizures in previously healthy (non-epileptic) animals, such as the maximal electroshock seizure test, demonstrates that drug testing in chronic models of epilepsy yields data which are more predictive of clinical efficacy and adverse effects, so that chronic models should be used relatively early in drug development to minimize false positives. Interestingly, the pharmacology of elicited kindled seizures in fully kindled rats and spontaneous recurrent seizures in post-status models is remarkably similar. However, when these models are used for studying the antiepileptogenic effects of drugs, marked differences between models exist, indicating that the processes underlying epileptogenesis differ among models, even among different post-status models of TLE. A problem for clinical validation of TLE models is the lack of an AED, which effectively prevents epilepsy in humans. Thus, at present, it is not possible to judge which chronic model is best suited for developing new strategies in the search for antiepileptogenic and disease-modifying drugs, but rather a battery of models should be used to avoid false negative or positive predictions.     

AD and its comorbidities: An obstacle to develop a clinically efficient treatment?

Whilst the development of new drugs designed for the treatment of Alzheimer's disease (AD) has been widely publicised, we do not yet have treatments that are proven to slow the progression of AD. The decision taken by the US Food and Drug Administration (FDA) to grant a licence for the use of aducanumab, based on the premise that β-amyloid removal would result in downstream benefits rather than demonstration of cognitive efficacy per se contrasts with that made by the European Medicines Agency (EMA), who declined to grant a licence, citing lack of evidence of clinical improvement, and a failure to demonstrate that the treatment was sufficiently safe. Multiple factors have complicated the search for new and effective treatments for the management of AD. It is a complex neurodegenerative condition in which multiple comorbidities are common in the affected population. However, such conditions are commonly exclusion criteria in clinical trials for new treatments. Here we discuss how some of these comorbidities impact the development of clinically efficient treatments for AD. Firstly, we will examine what is meant by AD, and how definitions of this condition have changed and continue to evolve. Secondly, we describe some of the most important comorbid conditions accompanying and in some cases mimicking AD. Finally, we will examine how the inclusion, or exclusion, of these conditions from AD research may have had an effect on treatment trials, the implications of co-morbidities on “real-life” use of novel therapeutics especially when these have been trialled in patients with relatively pure disease, and how clinical trials may need to adapt to account for comorbidities in the future.     

Dimensional versus nosographic approach to Alzheimer's disease: therapeutic implications

Negative results in therapeutic trials in Alzheimer's disease (AD) usually account for the nonefficacy of the presently tested drugs. However, methodological flaws in the design of these studies, related to the commonly used nosographic approach, can also be implicated in the lack of demonstration of beneficial results. With regard to the heterogeneity of clinical manifestations of AD, the interest of the dimensional, transnosographic approach to cognitive deficits and behavioral disturbances in dementia is suggested for these trials. Both approaches can also be combined, according to the presumed biochemical action of the tested drug in the preclinical studies and the aim of the trial.     

Potential of Transcranial Direct Current Stimulation in Alzheimer’s Disease: Optimizing Trials Toward Clinical Use

Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive method for stimulating the brain that is rapidly developing into a treatment method for various neurological and psychiatric conditions. In particular, there is growing evidence of a therapeutic role for tDCS in ameliorating or delaying the cognitive decline in Alzheimer’s disease (AD). We provide a brief overview of the current development and application status of tDCS as a nonpharmacological therapeutic method for AD and mild cognitive impairment (MCI), summarize the levels of evidence, and identify the improvements needed for clinical applications. We also suggest future directions for large-scale controlled clinical trials of tDCS in AD and MCI, and emphasize the necessity of identifying the mechanistic targets to facilitate clinical applications.     

Molecular PET imaging in multicenter Alzheimer's therapeutic trials: current trends and implementation strategies

Current therapeutic approaches for Alzheimer's disease (AD) have evolved to target specific molecular biological, metabolic and neuropathologic hallmarks of the disease. Since these approaches are hypothesized to be most effective at the earliest stages of the degenerative process, the ability to accurately detect and monitor progression of AD pathology and metabolic changes in vivo may accelerate the discovery and development of disease-modifying drugs. The use of molecular imaging biomarkers can not only enhance diagnostic accuracy and facilitate patient selection/stratification, but can also serve as key outcomes for clinical trials. In this review, we discuss emerging trends in the use of PET in AD drug development and provide a roadmap for harnessing its promise in multicenter clinical trials.     

From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia

Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) may protect against Alzheimer's disease (AD). However, therapeutic studies with NSAIDs, including cyclooxygenase (COX) inhibitors and steroids have not supported such epidemiological evidence. The apparent inconsistency may be due to the fact that the epidemiological evidence is based on studies examining AD before clinical manifestations are apparent, while therapeutic studies have been carried out on people with illnesses severe enough to exceed the clinical detection threshold. Thus, it is conceivable that therapeutic strategies administered during early AD dementia or moderate dementia may not be optimally effective. Alternatively, the influence of inflammatory activity in the brain for cases at high risk to develop AD, e.g., mild cognitive impairment (MCI) cases, as a potential target of anti-inflammatory drugs in clinical studies maybe more suitable to be studied. The primary action of NSAIDs is inhibition of the COX enzymes. COX enzymes exist in an inducible form COX-2, that has been found to be elevated in the AD brain, and a constitutive form COX-1. Both COX-1 and COX-2 are known to be involved in numerous inflammatory activities as well as normal neuronal functions. In vitro, it has been demonstrated that non-selective inhibitors of COX can preferentially decrease the levels of the highly amyloidogenic amyloid-beta (Abeta)(1-42)peptide. Recent studies testing non-selective NSAIDs in murine models of AD neuropathology indicated that the frequency of Abeta plaque deposits in the brains of these animals can be significantly reduced by treatment with the non-selective COX inhibitor ibuprofen. These studies and epidemiological data strongly support a therapeutic potential for NSAIDs in the treatment of AD. Upon this premise, industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of AD. However, given the large number of candidate anti-inflammatory drugs and their widely divergent activities, it is essential to optimize drug selection and study design. A better understanding of the influence of inflammatory activity in AD, and identification of the specific mechanisms which play an early role in the disease's progression will greatly improve the likelihood of success in efforts to find an effective anti-inflammatory treatment strategy. We would like to discuss recent developments reinforcing anti-inflammatory drugs as therapeutic in the treatment of AD amyloidosis, and the relevance of understanding the role of COX and other inflammatory mediators in AD neuropathology and the clinical progression of AD dementia. These discussions may provide important criterion for the design of clinical trials of anti-inflammatory drugs in AD.     

Primary prevention and delay of onset of AD/dementia

Prevention in Alzheimer's disease and other dementias (AD/dementia) is defined on the basis of clinical states and their expressed symptoms. Primary prevention refers to delaying the development of the full-blown state of clinically expressed disease in normal individuals. Current primary prevention research is driven by evidence of AD/dementia protective factors that have emerged from epidemiological studies. The first randomized controlled trials (RCTs) of primary AD/dementia prevention have been designed to test the efficacy and safety of NSAIDs, hormonal therapy, antihypertensive drugs and antioxidants. The experience of these trials has indicated safety concerns as a key issue and highlighted significant design challenges in this type of research. These trials have required large sample sizes and unsustainable costs. There should be consideration given in future trials to enriching study samples with risk factors to increase progression rates to AD/dementia. Innovative strategies will also be needed to recruit and retain subjects given the long follow-up periods, modest perceived benefit and the potential for the risk-benefit ratio to change during the trial. It is foreseeable that regulatory authorities will be presented with primary prevention RCTs for approval and labelling, and that criteria to evaluate such evidence still need to be developed.     

Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials.

OBJECTIVE: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease (AD) and other dementia. Several clinical trials have not shown efficacy, and there have been concerns about adverse events. The objective of this study was to assess the evidence for efficacy and adverse events of atypicals for people with dementia. METHODS: MEDLINE, the Cochrane Register of Controlled Trials, meetings, presentations, and information obtained from sponsors were used in this study. Published and unpublished randomized, placebo-controlled, double-blind, parallel-group trials in patients with AD or dementia of atypical antipsychotics marketed in the United States were studied. Clinical and trials characteristics, outcomes, and adverse events were extracted. Data were checked by a second reviewer. Fifteen trials including 16 contrasts of atypical antipsychotics with placebo met selection criteria: aripiprazole (k = 3), olanzapine (k = 5), quetiapine (k = 3), and risperidone (k = 5). A total of 3,353 patients were randomized to drug and 1,757 to placebo. Standard meta-analysis methods were used to summarize outcomes. RESULTS: Quality of the reporting of trials varied. Efficacy on rating scales was observed by meta-analysis for aripiprazole and risperidone, but not for olanzapine. Response rates were frequently not reported. There were smaller effects for less severe dementia, outpatients, and patients selected for psychosis. Approximately one-third dropped out without overall differences between drug and placebo. Adverse events were mainly somnolence and urinary tract infection or incontinence across drugs, and extrapyramidal symptoms or abnormal gait with risperidone or olanzapine. Cognitive test scores worsened with drugs. There was no evidence for increased injury, falls, or syncope. There was a significant risk for cerebrovascular events, especially with risperidone; increased risk for death overall was reported elsewhere. CONCLUSIONS: Small statistical effect sizes on symptom rating scales support the evidence for the efficacy of aripiprazole and risperidone. Incomplete reporting restricts estimates of response rates and clinical significance. Dropouts and adverse events further limit effectiveness. Atypicals should be considered within the context of medical need and the efficacy and safety of alternatives. Individual patient meta-analyses are needed to better assess clinical significance and effectiveness.