| Evotec (24)

Date: 10th - 11th October 2023

Location: Milan, Italy - At Bayer

Attending: Andrea Nizzardo

The next IBIG Forum is coming! #IBIGFORUM2023

After last year's great success, the IBIG Forum looks forward to meeting you again this year to share experiences, address similar statistical issues from different angles, and have fun together!

Our Research Expert Biostatistician • Pharmacometrics, Andrea Nizzardo, will chair a session on "The estimands journey: from theory to practice"

Summary:

The estimands framework has been introduced in 2019 by the Addendum to the ICH E9 guideline on statistical principles for clinical trials to improve alignment between clinical questions, objectives, design, and analysis of clinical trials. Since its release, the addendum has rapidly impacted the drug development world, triggering interest and discussions. Many efforts have been made to clarify the theory behind the framework to strengthen the interaction between relevant stakeholders and between sponsors and regulators. Now that the framework has started to be broadly adopted, several challenges have arisen during its implementation. The session will focus on experiences and case studies on practical issues encountered when adopting the framework in clinical trials.

When?
Pre-Forum courses: 9 October

IBIG Forum 2023: 10 and 11 October.

Where?
Milan, at Bayer (https://lnkd.in/dqUZCMYp)

What?
Five Forum sessions with quality interventions and speakers on current topics and innovative approaches:
·        Artificial Intelligence and Machine Learning
·        Historical data supporting drug approval
·        Decision Making
·        Estimands Application
·        Real World Evidence
Plus two very interesting and applicative pre-forum courses:
·         A pragmatic approach to multiple endpoints resolution
·         R in Clinical Trial Reporting

Registrations are still open at this link: https://lnkd.in/dMsPqq4M

Learn more about the IBIG FORUM 2023

Can we age healthier?

Due to better hygiene and medicines, the aging population has been growing steadily over the last 30 years. By the year 2031 1.4 billion people will be aged 60 or over, comprising one in six of the worlds population.. This figure will reach 2.1 billion by 2050, with 426 million being aged 80 or more. Unsurprisingly, the UN declared 2021 -2030 the Decade of Healthy Aging. The aging global population brings considerable societal challenges. In developed nations, old age increases the financial pressure on healthcare systems because healthcare spending rises sharply with age. This is in part due to the increased use of medications with advanced years, but also the associated support and care costs.

Increasing healthspan

However, the underlying problem is not life span but healthspan. Being of advanced age does not necessarily mean being frail, sick and in need of care. Already today, there are many healthy seniors living an active life. To promote this notion, the WHO set the goal to provide every person in every country in the world the opportunity to live a long and healthy life. This is encapsulated perfectly with the definition of healthy aging being ‘the process of developing and maintaining the functional ability that enables well-being in older age’. Functional ability means having the capabilities to be and to do what people have reason to value, i.e. meeting not only basic needs but also allowing them to learn, grow, and make decisions, to be mobile, to build and maintain relationships, and to contribute to society. This is very different from life extension calculated as accumulation of human years.

What is biological aging?

Aging can be defined as a time-dependent decline in body function and is observed in virtually all living organisms. The accumulation of cellular damage due to dysfunction in multiple biochemical systems increases the susceptibility to disease and ultimately results in death. This is most likely a result of evolution, once an organism has reached sexual maturity to enable reproduction and raising offspring, it makes no biological sense to invest more energy in maintaining the organism. However, the case is more complex for long-lived mammals, with offspring that need to be protected for a protracted time to enable them to reach sexual maturity. Hence mammals have evolved sophisticated and very efficient repair and maintenance mechanisms in order to correct any cellular dysfunction. With this perspective in mind, aging can be defined as the gradual deterioration of this biological maintenance. We can then view improving healthspan through the lens of slowing this decline or improving restorative or regenerative capacity within tissues and organs.

Already, science has identified a number of factors that can contribute or accelerate the aging process and these include genetic predisposition, obesity, smoking and the status of the gut microbiome. Downstream of these drivers is frequently low-level chronic inflammation – ‘inflammaging’ that contributes to the gradual deterioration in cellular and tissue function. The immune system itself is also subject to decline over time, meaning that many of the protective and repair mechanisms of the adaptive and innate immune system become less effective over time. A combination of these factors are thought to contribute to the common diseases associated with advanced age, such as cancer, cardiovascular disease, chronic liver and kidney diseases, type-2 diabetes and dementia. We are all familiar with how these diseases lead to a reduced life expectancy, but also significant impairment in the individual’s quality of life.

At the cellular and molecular level, there are key biochemical mechanisms that promote gradual deterioration of function across all cell types, that we believe underpins loss of physiological performance - consistent with the process of aging. These are well recognized as the classical ‘hallmarks of aging’. These include the emergence of cellular senescence and the senescence-associated secretory phenotype- which drives much of the chronic inflammation in tissues. Telomere shortening, genomic instability and the accumulation of genetic damage which can lead to tumour formation, epigenetic changes, exhaustion of stem cells, altered cell-cell communication, loss of control of proteostasis, aberrant nutrient sensing and mitochondrial dysfunction. In addition there are more generalised drivers of the aging process such as those linked to dysbiosis.

There is therefore no single driver of biochemical and physiological aging, but the concerted influence of an array of many contribuing factors at play. These complex systems can seem daunting to address, but within each of these pathways there are potential points for pharmacological intervention that constitute targets for drug discovery programs. The goal of pharmacotherapy can therefore be viewed as intervening in key node points to slow the accumulation of dysfunctional processes and maintain cellular integrity for longer. Targeting these fundamental pathological mechanisms will be key to providing a systems-wide (i.e. holistic) benefit to the individual.

How to prolong health span?

It is known that medical interventions, good health practice, refraining from smoking, eating appropriately, and exercising, can all help protect our health. But as mentioned above, there are opportunities to improve healthspan, through targeting key points within the pathways that are recognized as the classical hallmarks of aging.

Developing novel senolytics - challenges and opportunities

One of the hallmarks of aging that has been very well characterized is cellular senescence. This occurs when cells reach the end of their ability to divide resulting in stasis, a state associated with the ‘senescence associated secretory phenotype’ (SASP). Under these conditions, the senescent cells release a cocktail of proinflammatory mediators which in the young targets them for removal by the immune system. However, in the aged, where the immune system itself is subject to gradual decline, senescent cells continue to release the cytokines, chemokines, growth factors and other bioactive components which contribute to inflammaging. As such, the use of senolytic agents which are aimed at killing off senescent cells by suppressing the pathways that keep them alive, is receiving significant attention in the aging field. According to a recent report in Nature Medicine, around 20 clinical trials of senolytic compounds are ongoing. Clearly, blocking the ‘keep me alive’ signals in the cell and triggering cell death offers a compelling approach in the treatment of cancer, but such a powerful pharmacological mechanism carries risk. In keeping with this, at present the majority of the ongoing clinical studies are for very severe indications and not aging. However, it seems likely that if the risk-benefit of such a pharmacological approach in man is understood and favourable, senolytics could find utility in aging.

An additional or maybe complimentary approach would also involve the immune system. A healthy lifestyle suppresses pro-inflammatory mediators and at a very simplistic level, agents which inhibit inflammation may prove beneficial. However, inflammation also plays a very important protective function in the body and so such an approach may not prove advantageous for chronic treatment. Conversely, boosting the performance of the immune cells seems like a more viable approach since it would enable the body to fight off infectious agents and correct and repair cellular and tissue dysfunction in a more effective way. The stem cells giving rise to immune cells reside in the bone marrow and their accessibility means their biology is very well understood, especially with respect to stem cell maturation and differentiation. Manipulation of these precursor cells in a positive way could offer the potential to regenerate the immune system and hence slow many of the downstream effects of inflammaging and the damaging consequences of infectious disease, which we know is more prevalent in the aged population.

Before we go in search of completely novel agents to address aging, there may already be therapeutic agents available which may be beneficial. Metformin and rapamycin are generic and widely used in the treatment of Type 2 diabetes and as an immunosuppressant for organ rejection, respectively. However, several clinical studies have suggested that there are health benefits to these agents which seem to be driven by pharmacology that lies outside of that recognized in their primary indications. In the preclinical setting, both compounds have been reported as extending lifespan in mice, but these findings have proven controversial. Metformin improves insulin sensitivity, so it seems reasonable to assume that metformin reduces the risk of cellular damage and oxidative stress by improving cellular homeostasis. On a more global level, improved glycaemic control will reduce the emergence of some cardiovascular disease and peripheral nerve damage. The immunosuppressive effects of rapamycin can be theoretically linked to a dampening of inflammaging, however it seems that the agent may have a more cryptic pharmacological effect associated with improving energy homeostasis in cells.

The bisphosphonates are a group of compounds used clinically in the treatment of osteoporosis, but there are observational studies emerging from the clinic suggesting that they could have beneficial effects on human health beyond that associated with bone homeostasis.

Collectively, these widely used agents may have uncovered key pathways in which to focus efforts to identify more potent or selective agents to address cellular aging. What is required is a deeper mechanistic understanding of the cellular pharmacology of these drugs to determine where best to intervene. A key approach to address this is the possibility of using phenotypic screens in cellular models which capture one or more of the hallmarks of aging, to determine modes of action of known agents. In addition, such models can also be used in a blind fashion to screen libraries of compounds to uncover completely novel pathways and identify agents that may be beneficial.

One of the big challenges in the search for treatments to improve healthspan is having robust endpoints by which to measure efficacy. Clearly extension in chronological time to death provides a very clear endpoint, but it seems likely that clinical trials aimed purely at increasing longevity are a long way off. As such, there is a growing need to accurately measure biological age, as chronological age fails to capture the heterogeneity of signs and symptoms with which people age. For example, we probably all have family members who we think look and behave much younger than we know their chronological age to be. How do we measure healthspan in the context of a clinical setting? How do we define quality of life? These are big challenges but we do have the ability to measure directly improvements in, for example, heart or liver function, muscle strength, mobility, cognition and the performance of the immune system. It seems probable that the identification of pharmacological agents that improve healthspan will be found via exploration in multiple surrogate indications where hard endpoints can be measured and beneficial or detrimental effects become clear.

We need to continue to develop biomarkers and translational strategies which are able to inform us of whole-body cellular ‘health’ and with the gathering interest in this area, we will likely have an increasing array of tools to more accurately assess biological age over time.

However, we should always remember that patients don’t care about biomarkers. They are interested in whether they ‘feel’ better, i.e. can meet their basic needs, whether they can learn and grow and make decisions, can be mobile, build and maintain relationships and contribute to society. That is the patient’s perspective which is encapsulated perfectly in the goals as stated by the WHO.

So, while there is a growing understanding of potential ways we can measure and improve healthspan, there are some challenges in clinical development of novel anti-aging compounds. Study subjects may be aged but otherwise healthy, leading to ethical considerations associated with treating healthy patients in a preventative manner. There is no regulatory path at present, and there is the fundamental question of who is going to pay for agents that improve healthspan. Currently there is an argument over whether old age can be regarded as a disease or not. This is irrelevant as approval of any novel agents or use of an existing therapeutic in an age-related condition will require properly controlled, randomized clinical trials. Given the likely heterogeneity in such a trial population and the differing rates at which individuals age (i.e. manifest the hallmarks of aging), the trials will need to be large and long in duration. There would be parallels to the many trials in Alzheimer's disease, where the cost is enormous and efficacy hard to find. Moreover, it seems probable that like the thinking around AD, treatments should start early before symptoms appear. An additional confounder is the likely variations in ADME in individuals. We know elderly subjects often have reduced hepatic and renal function which could introduce significant variability in the exposure to novel agents.

We can meet these challenges as we believe there is significant will within society to succeed. We all share the common goal of living long and healthy lives.

If you’d like to hear how Evotec has developed capabilities to measure the hallmarks of aging which can support efforts to identify novel agents to treat age-related disease then reach out to us. You can also learn more from our webinar "Therapeutic approaches for aging and age-related diseases" by Steve England, SVP, Head of in vitro Biology and Disease Area Lead for Aging and Senescence at Evotec.

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