[ad_1]
The usual subject of my lectures at medical-scientific conferences on Alzheimer's disease (AD) often includes discussions about the prospects for dementia prevention and future challenges in seeking treatments. These discussions of the current state of therapy development invariably raise the universal question: when to expect more effective treatment of dementia and AD.
The meaning of these in-depth questions goes beyond mere curiosity. They reflect growing concerns about the lack of sustainable treatments for the most disruptive symptoms of cognitive impairment of AD. The growing frustration expressed by patients, physicians and policy makers stems from the glaring absence of any breakthrough in the treatment of AD, the most common form of dementia.
Four decades of intense research and development (R & D) efforts have not led to effective interventions against neurodegenerative diseases. The lack of success in finding a drug to alleviate the devastating symptoms of these chronic brain disorders has been one of the biggest frustrations of modern medicine with a failure rate of nearly 99.6%, compared with 20% for anticancer drugs. This has already precipitated the strategic decision of some research-based pharmaceutical companies to end their R & D efforts on AD; thus, arouse the concern that others may also choose to close their therapy development operations.
Consumer discomfort with the pace of development of snail therapy is well founded. This impatience comes down to the timely question of "where is the ox"? The field of treatment R & D for AD is now facing a "situation", that is, in the words of Theodore Herzl, "critical but not serious".
This growing urgency for more effective interventions pushes me to shed light on the nature of the problem. A truly satisfactory answer will require a detailed explanation of how we arrived at the current state of affairs. I will highlight here some of the historical events critical of the evolution of the current situation, as well as the reasons for the current difficulties in this area.
The crucial dilemma of the primary care physician (PCP) in treating the patient with AD comes from the uncertainty as to how to address issues such as: What are the options for treatments now? What are the appropriate interventions, among those currently available, for dementia patients in my office today? The purpose of the story here is to describe the detailed circumstances that led to the current situation; my hope is to improve the understanding of the full extent of the dilemma. Hence the questions: how did we get here? What were the first barriers to seeking treatment for AD?
The official campaign against AD started in 1978 at the National Institute on Aging (NIA) of the National Institutes of Health (NIH). From the beginning, the launch of this project has been confronted with several major challenges. Among these, the most difficult initial test was the struggle to gain acceptance from the medical-scientific community regarding the idea that "systematic studies of AD" are a topic of discussion. legitimate research at NIH.
In the late 1970s, conventional wisdom, coupled with best medical practices, regarded Alzheimer's disease as a hopeless and incurable condition. Dominant theory considered "senility" as an ill-defined fuzzy concept as the main cause of dementia. Thus, the notion that "AD is an inevitable consequence of aging" is the firmly established doctrine, widely accepted without questioning. This omnipresent dogma was at the root of generalized pessimism about the usefulness of treating the old, including AD – that is, "why intervene, just get old?"
Therefore, the lack of knowledge about clear distinctions between the biology of "aging" and the precise molecular underpinnings of "disease" was a major handicap that impeded the pace of progress. Unfortunately, the need for more precise definitions and precise distinctions between "aging" and "disease" (for example, Alzheimer's disease), as well as persistent vestiges of myths, remain obstacles to overcome. At present, one of the main challenges for the development of therapy is constituted by ongoing work to explain the exact biological links between aging phenomena and Alzheimer's disease.
A little-known or often overlooked historical fact is that 40 years ago national spending on research on aging and AD was practically nil. These topics, as problems to study, have aroused little interest for academic research, with the exception of a handful of researchers. Until the end of the 1980s, the clinical infrastructure needed for systematic longitudinal or clinical studies of well-characterized AD patients was not available. In the early 1990s, the concepts of "cure" and "prevention" were inconceivable. Essential clinical tools such as diagnostic criteria, standardized assessment instruments, specialized professional settings, memory impairment clinics, family support groups or outreach programs did not exist. , even if all these tools are now acquired.
Although research on brain disorders has a long history, the current profusion of knowledge about the neurobiology of complex chronic brain disorders (for example, dementia and AD) has only recently been acquired. Up to 90% of current knowledge about the human brain may have been acquired in the last 40 years. Yet only 30 years ago, information about the genes and / or biological pathways involved in the development of the disease was at best limited. Twenty years ago, animal models of the disease did not exist. At that time, people at high risk for the disease could not be identified, and the idea of clinical trials for prevention or to delay the symptoms was only a dream.
In contrast, a number of genes, as well as a set of possible risk factors, including several susceptibility genes involved in the expression of AD, have been identified. The characteristic brain lesions, as well as several biomarkers associated with the disease, that could not be visualized directly in patients before 2004, can now be detected thanks to new neuroimaging technologies in asymptomatic people in the early stages of the disease. disease.
In short, nearly a quarter of a century has been necessary for the radical transformation of the myths about dementia. For example, breakthrough discoveries, namely that healthy aging nerve cells are able to regenerate themselves and that Alzheimer's disease is a "disease" due to degeneration of neurons, have been essential to combat the aging of the brain. This type of step-by-step construction of a sound scientific base, including the "critical mass" of knowledge and infrastructure, was a critical step in building national R & D capacity in the initial phase of the campaign.
Advances in the early stages of understanding the distinct mechanisms of biology of aging and dementia by neurodegeneration over the past three decades have propelled this area of darkness research to the forefront of science. modern biomedical
During this early period of scientific maturation of the field, we learned how neurochemistry plays a crucial role in neural communications and how changes in this complex signaling system affect the expression of symptoms. We have also discovered many facts regarding genetics, synthesis, degradation, aggregation, toxicity, folding and elimination of abnormal proteins involved in pathogenesis. These two major areas of research; one concerning communication between nerve cells and the other, degradation of protein synthesis; provided the biological foundation and mechanical justification for the drug discovery and development paradigms that have been used up to now.
This brief account highlights some of the achievements, as well as several obstacles, in the development of the first set of treatments in the mid-1990s. At the time, considering that MA was considered a Incurable disease, the approval of these drugs by the FDA was a victory, even though it turned out to be a minor triumph because of a short duration of clinical benefits.
****
Let's talk about the limitations of currently used drugs and the challenges of the second wave of achievements to discover more effective and sustainable interventions. Thus, these questions remain: Why are current treatments not satisfactory? Why have attempts to develop more satisfying therapies failed? What are the obstacles to more positive results? What are the prospects for success?
Until recently, the first therapeutic goal of the first generation of treatments was to obtain symptomatic relief, namely to slow down the cognitive decline functions and to improve other problematic signs of the disease. The general scientific logic of this approach to therapeutic development was based on the global notion of strengthening communication functions between cells by replacing a missing chemical – a neurotransmitter, for example acetylcholine. The basic idea of "alternative" treatment has been a widely used strategy in the development of treatments for a range of neuropsychiatric disorders. This approach, which began to gain momentum in the late 1980s, initially showed promise for the treatment of AD and eventually led to the development of two currently approved drug classes.
Unfortunately, it has turned out that these first-generation drugs are not completely satisfactory, especially because of their relatively short usefulness, 6 to 24 months for symptom relief. The main reason for this short-term benefit of these compounds is not due to lack of drugs, but rather to the gradual deterioration of neurons to benefit from this type of intervention. This means that if we could find ways to formulate different compounds that preserve the healthy functioning of neurons (for example, by promoting the regeneration-repair of nerve cells), currently used first-generation treatments will continue to have certain advantages. Thus, a distinctly different approach is needed to slow the progression of the disease by a distinct, correct aspect of the neurodegenerative process that goes beyond the loss of communication between neurons.
The distinct therapeutic intention of the second generation of drug-development-discovery was not only the relief of symptoms, but also the prevention or slowing down of neurodegeneration. The generic strategy is to block or moderate the toxicity of an endogenous or exogenous agent that kills the neuron. This approach, which has been the general underlying logic for most recent treatment trials, aims to modify or slow the "progression of the disease" by controlling the synthesis or aggregation of "toxic" or abnormal proteins. (eg amyloid, tau).
Unfortunately, despite its universal popularity due to a convincing logic for its scientific basis, this line of attack has experienced sequential failures in efficacy trials of nearly 25 years. The rationale for finding drugs that would maintain or promote the normal and healthy functioning of neurons is solid and many scientists still hope that some of the current clinical trials could still work. However, a growing number of researchers are now beginning to consider alternative approaches to solving the puzzle of AD.
Returning to the fundamentals of this essay, the key questions are:
When will the impressive scientific results, resulting from 40 years of massive investment in R & D, finally lead to sustainable treatment?
What are the reasons for the series of successive failures in clinical trials?
Where do we go from there, based on new emerging knowledge about AD?
What is the next?
These concerns prompted the ongoing formal reassessment of all imaginable reasons for the disappointing results of recent clinical trials. A range of plausible explanations has been unveiled for the failure of some particular tests. For example, an efficacy study could be discontinued due to concerns about the safety of a drug, an unacceptable tolerance, or the number of adverse events. Other reasons may be the wrong "something": molecule or therapeutic target, test plan, subjects, stage of disease, dosage or duration of treatment, etc. The most significant result of the evaluation of these reasons is: failures are the growing recognition that long-cherished theories or assumptions about the origins of AD may not be adequate. Therefore, it will be necessary to reevaluate all known facts about the disease in order to reformulate current theories or to create a new unifying model that will incorporate all known facts leading to new knowledge.
In the history of science, the most thorny challenge has always been to challenge conventional wisdom (that is, "dominant scientific orthodoxy"); for example, examine the shortcomings of existing ideas in a field of study, for example the biology of the disease. This task of modifying the "belief system" or abandoning a "scientific ideology" in favor of a new thinking about therapies for AD will be a very big task for medicine. It will be comparable to a maneuver as difficult as directing a super-tanker in dangerous waters. Yet impartial evaluation of different paradigms or radically new approaches to R & D is an essential step towards solving the problem.
Such an unbiased inventory of all current theories or ideas about AM, which is a work in progress, has begun to identify the new vital challenges facing the field. These evolving facts have begun to highlight some of the limitations of current treatments, as well as some of the reasons for the failures of recent trials. Thus, the reformulation of any "unifying" theory or new paradigm of R & D for the development of therapy must integrate this new knowledge about the clinical features of the disease and its biology. The new understanding of the disease will not only have a significant impact on the design of alternative approaches to the discovery-development of treatments, but will also influence how PCPs could address the clinical assessment of patients to potential risks for the disease.
****
The following brief introduction highlights some of the evolving knowledge about the distinct characteristic of the disease that will change future approaches to treatment R & D and will also provide new information useful for PCP in their interactions with patients with AD.
An important new fact about AD is that it is a clinical entity (heterogeneous state), which means that there is a huge variation among people with the disease in terms of types and clinical patterns. [behavioral] and neuropathological features of the disease. In addition, there are large differences in age of onset, family history, genetics, risk, lifestyle, and other concomitant diseases. This characteristic of the disease explains some of the difficulties encountered in clinical studies and may explain the failure of certain clinical trials; For example, differences in treatment responses in patients. The importance of this information is to sensitize PCPs to "one size fits all" and, therefore, to focus on more individualized case assessment and case management.
Another important new discovery regarding the disease is that the notion of a single etiological factor triggering the disease is no longer valid. It turns out that the disease has a polygenic etiology. This means that we are dealing with a complex brain disorder that represents the culmination of complex connections between several pathogenic factors. The complexity of the underlying biology of Alzheimer's disease not only explains the failure of some trials in the past, but also indicates the need for new paradigms of drug development taking into account the prospects of testing for Alzheimer's disease. several targets or therapeutic agents. Such radical changes in the design and execution of clinical trials, based on the complexity of the disease, will require a better understanding of the relationships between multiple biological processes. This represents one of the big challenges for future R & D on therapies.
The third important feature of Alzheimer's disease is that the exact starting point of neurodegenerations is currently unknown. However, recent findings have shown that an asymptomatic or preclinical stage can precede by almost two decades mild cognitive disorders. [MCI], mild, moderate and severe phases of the disease. These details on the protracted complex mechanisms in progression of neurodegeneration will have a profound impact on the design of future clinical trials as well as on the day-to-day operations of a PCP that must now pay close attention to complaints from older patients or at risk. & # 39; subjective feelings of memory loss. These new findings now indicate the need to reorganize the development of therapy to begin intervention at early stages, perhaps during the preclinical phase, in order to be effective.
The latest field of new information, with important ramifications for the design of future clinical studies, as well as PCP practices, is the discovery of a number of risk factors that have shown a strong association with the expression of Alzheimer's disease. These predisposing factors include several potential susceptibility genes (eg, ApoE), lifestyle, and certain concomitant diseases such as cardiovascular disease, diabetes, hypertension, obesity, and so on. the disease is not yet known. However, these preliminary results have begun to provide promising potential strategies to reduce the risk of AD.
In conclusion, the good news for the PCP is that some innovative strategies are being tested in trials underway for early intervention. For example, new data from ongoing studies have shown that non-pharmacological multidomain interventions have important beneficial effects, such as reducing the decline in cognitive functions or delaying debilitating symptoms. These multidomain interventions, as their name implies, require changes in the "behavioral patterns" of patients in many aspects of their lifestyle, such as diets, physical exercises, and mental exercises. These studies have also shown that the management of comorbid or known risk factors, for example vascular disorders, diabetes, hypertension, obesity, etc., have beneficial effects.
Once these preliminary results have been validated by broader and prospective prevention trials, PCPs will have a number of therapeutic options based on new safe drug applications approved for others. diseases such as stroke, hypertension, etc. or questions about current treatment choices beyond the two classes of medications approved for patients at later stages of the disease (eg, moderate-severe), there will soon be other options to consider.
The campaign to find a cure for a little-known brain disorder began 40 years ago. It was essentially fueled by optimism, even though the battle was considered a crazy race.
Now, the idea of developing interventions to prevent AD is once again considered an impossible dream. But I remain as optimistic as four decades ago about the prospects of winning this renewed crusade.
Zaven S. Khachaturian, Ph.D., is the former director of the Alzheimer's Disease Research Office at NIH, where he was responsible for coordinating all activities related to the disease. Now he serves as the editor of Alzheimer's and dementia, one of the most important journals in neurology. He is also Senior Advisor to the Alzheimer's Association on Medical-Scientific Affairs.
1969-12-31T19: 00: 00-0500
Last update
Source link
