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Finding the Trigger

Although scientists do not fully agree on how, why or what can be done about it, each of us ages every day. Gradually, imperceptibly, we lose hearing, eyesight, taste and muscle mass, while we store more body fat and develop cataracts. While we do not all age at the same rate or in the same way, as time goes by, the accumulation of these biological deteriorations increases our risk and degree of pathologies until death.

As humans live generally longer lives, we see a dramatically higher incidence of pathological conditions associated with ageing, including Alzheimer’s disease (AD), Parkinson’s disease, cancer and atherosclerosis, among others. However, science has been slow to address these conditions because of a lack of emphasis on understanding the underlying mechanisms triggering the onset of these diseases.

For example, several recent clinical development programmes involving promising compounds for the treatment of AD failed during Phase 3 trials and, as a consequence, the R&D programmes were put on hold or suspended by the pharmaceutical companies affected. The problems these compounds experienced in late-stage trials were related not only to efficacy, but also to unexpected toxicity related to organ injury.

Promising drug programmes that fail at late stages of development obviously cause disappointment. Worse, at least 10 years of huge financial investment and effort are lost, while the clock is still ticking for the people who have, or who will develop, these diseases. To reduce the risk of drug attrition, far more basic questions must be answered – chiefly: what are the specific processes that trigger the onset of the disease?

Free Radicals and Ageing


Scientists have long debated whether there is a single mechanism of ageing or whether the ageing process is inherently multifaceted. In the free radical theory of ageing, first postulated in 1956, Denham Harman states that organisms age because cells accumulate free radical damage through oxidation over time (1).

Free radicals are molecules with unpaired electrons in their chemical structure, and can be formed when oxygen interacts with certain molecules, causing them to become unstable. Once formed, they are highly reactive and start a chain reaction that produces a cascade of the same free radical species in the body. The biological danger of this effect comes from the damage free radicals can do when they react with cellular components such as DNA or cell membranes; cells lose function and may die if this occurs.

The creation or suppression of free radicals revolves around the balance of pro-oxidants and anti-oxidants in bodily systems. If an imbalance favours pro-oxidants, the excess of free radical species can trigger cellular damage or death, leading to organ injury – one of the hallmarks of toxicity. As human bodies age, there is an increasing incidence of the creation of free radicals, which is modulated by internal processes or external factors, such as quality of diet.

To prevent free radical damage, anti-oxidants in our bodies work to keep the pro-oxidant/anti-oxidant balance. These anti-oxidants can either be produced endogenously by our organism – as glutathione, the enzyme catalase and the superoxide dismutase are – or incorporated into our diet through, for example, vitamin E, beta-carotene or vitamin C. The antioxidants interact with free radicals and terminate the chain reaction before cellular damage occurs. Humans need a minimum daily intake of dietary anti-oxidants; low levels of these, also called essential nutrients, can cause pathologies such as scurvy to develop.

Mechanism Focus

Although the triggering mechanism of AD is widely debated, the presence of cognitive impairment – together with the formation of senile plaques linked to the β-amyloid peptide and/or neurofibrillary tangles (NFT) connected to the hyperphosphorylation of the tau protein – has long been regarded as a hallmark of the disease.

Research into AD has focused on symptoms in recent years. However, going forward, research must be geared to discover the underlying mechanisms triggering the disease, and to determine whether the onset and progression of AD is due to environmental, dietary, lifestyle, genetic or infectious triggers, or is the result of some other multifactorial mechanism. Oxidation and free radicals must also continue to be considered in the pathology of AD.

In recent studies, two recognised approaches for treating AD were tested: AChE inhibitors and tau kinase inhibitors. Although positive efficacy was demonstrated in transgenic animals in proof-of-concept studies, there was inadequate reproducibility of efficacy in humans, along with unexpected toxicity in Phase 2/3 clinical trials. Animal model studies are designed to predict how humans will respond to specific treatments; so why do molecules that show promise in animal models, and that should have a correlative effect in humans, fail to elicit the same response?

Some question whether it is reasonable to assume that animal models can effectively predict a response in humans. According to the philosopher Willard Van Orman Quine: “Prediction is rooted in a general tendency among higher vertebrates to expect that similar experiences will have sequels similar to each other” (2). If compound X produces result Y in animal tissue of similar characteristics to humans, the assumption is that compound X will also produce result Y in humans. The problem is that it often does not.

Better Science


The development of better animal models is a challenging issue because we do not fully understand the underlying mechanisms causing the onset of neurodegenerative diseases as a hallmark of ageing. In modern research, transgenic animal models are created that have the pathology understudy. In the study of AD, animal models are required that overexpress β-amyloid, models characterised by NFT and/or models for both tau and β-amyloid. Those animal models appropriately validated are used to screen compounds for their observable effect on memory, motor function and behaviour; the drug candidates showing efficacious results will be selected for further profiling and validation before starting the regulatory preclinical development programme.

However, while some drug candidates show promising and significant results in the early proof-of-concept studies, they are still prone to failure in later stages. One reason may be that the animal models used are not reflecting the true natural progression of the diseases and are, instead, focused on only one, two or three pathways involved in the progression of a multifactorial disease.

Another pertinent question is: should we cure or prevent? This debate adds further complexity to the research picture because recent investigations show that Alzheimer’s can start in the late fifties, and even sooner in certain cases. As a result, innovative, curative treatments are applied too late to reverse the progression of the disease in clinical trials. Biomarkers are therefore needed to diagnose the disease as early as possible and, rightfully, there is significant activity and interest in this area of research.

Toxicity Studies


Of particular importance in improving the animal-model-to-human-trial translation in neurodegenerative diseases such as AD is the issue of toxicity. In practice, following identification of a drug target and candidate compounds, activities such as pharmacology, in vivo efficacy, and exploratory absorption, distribution, metabolism and excretion – including drug-drug interactions and exploratory safety studies (target organs, safety pharmacology) – should be performed at an early stage. This is vital to minimise the risk of unexpected toxicity arising during the preclinical safety assessment or, worse, during the clinical development, which would end the programme.

Without sufficient effort to unveil potential toxicity and clearly understand the mechanism of action of the drug candidates, the preclinical safety assessment may appear to be successful, and the drug candidate may be scheduled to progress into Phase 3 where most of the attrition occurs. Drug-induced liver toxicity or unwanted immunogenicity, including anaphylactic/oid reactions are the major causes of attrition at late stages, but could be characterised and predicted at an early stage of drug development.

In a recent conference, K Steinmetz and E Spack added the following observations to the debate:

“In the case of chronic neurodegenerative diseases such as Alzheimer’s disease, the unique medical needs of elderly patients have the potential to affect several aspects of drug design. Alleviation of AD will most likely require long-term treatment and, therefore, the preclinical toxicology program must include repeat-dose administration to mimic the dosing regimen expected in the clinic. Since AD patients are generally well past childbearing age, some delay in safety testing for genetic and reproductive toxicity potential is permitted. On the other hand, it may be important to evaluate the potential for drug-drug interaction much earlier in the drug development program since many elderly patients are likely to be prescribed medications to manage blood pressure, cardiovascular diseases, metabolic and digestive disorders, joint inflammation, diabetes and other conditions associated with aging” (3).

Why Do We Age?

Even if the ageing process is distinct from the diseases of ageing, it is undeniable that the damage associated with getting older increases the probability that such diseases will occur – especially as humans live increasingly longer lives. As science addresses disease, what it has contributed to most, in terms of ageing, is to raise the mean or average lifespan. While the average lifespan in ancient Rome was thought to be around 22 years, the average lifespan in most developed countries today is about 80. Maximum lifespan, however, has remained unchanged throughout recorded history at 115-120 years (4). Curing cancer or heart disease may extend the mean lifespan, but is unlikely to alter the maximum lifespan, unless the underlying ageing mechanism can be found.

The free radical theory of ageing states that organisms age because cells accumulate free radical damage over time, but there are clearly other factors to take into account, including glycation, cellular senescence, and the accumulation of exogenous and endogenous toxins.

Future Success

Whatever the reason for humans growing less robust as we move through life, it lies at the heart of all diseases of ageing. Scientists can only design effective drugs by truly understanding the mechanisms underlying specific pathologies. The pharma industry is only now realising that much more effort must be put into basic science.

One positive response is the number of alliances pharma companies are making with academic groups specialising in the study of specific diseases, such as those associated with ageing.

As a species, we are living longer. In response, pharma must concentrate on producing higher quality drugs that are more likely to succeed in the final stages of development.

References

1. Harmen D, Free radicals: From basic science to medicine, 1993
2. Quine W, Quiddities: An intermittently philosophical dictionary, 2005
3. Steinmetz K and Spack E, The basics of preclinical drug development for neurodegenerative disease indications, from Drug Discovery for Neurodegeneration Conference, Washington, DC, US, 2-3 February 2009
4. Best B, Mechanisms of aging. Visit: www.benbest.com/lifeext/aging.html

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Ciriaco Maraschiello MSc, PhD, is Director of Strategic Initiatives and Deputy General Manager of the Pharmaceutical Business Unit at Harlan Contract Research Services (CRS). Having worked at Harlan CRS for more than 15 years, he previously managed the company’s toxicology and drug discovery and translational medicine operations, as well as holding responsiblility for developing new business streams. For over a decade, Ciriaco has led the design and execution of preclinical toxicology programmes focused on neurodegenerative diseases, vaccines and biologics.
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