Innovative Therapeutics for Ageing Consortium (iTAC)[1] – Written evidence (INQ0042)

This evidence specifically addresses questions 1, 3, 4, 9, 10 and 11 in the call for evidence document.

It is submitted with a focus on the development and testing of novel treatments and markers that target core biological pathways whose age-related decay leads to multimorbidities, which the Academy of Medical Sciences describes as the world’s next major health priority.[2]

Essential biological pathways maintain tissue health, but fail with age and exposure to the environment. Their decline is responsible for many diseases, presented across multiple organs and currently treated separately leading to polypharmacy. This ‘one disease, one treatment’ approach to pharmacy, trials, regulation, and patient pathways is inefficient, suboptimal and contributes to the financial and care burden on the NHS. However its dogma defines how today’s industry chooses to structure itself and invest in future R&D.

A lack of nationally co-ordinated, multidisciplinary effort with a focus on new or repurposed therapeutics aimed at core ageing processes, limits the potential of the UK and its health industry to make a sustained impact on treatments for age-related multimorbidity and frailty within a generation.

We propose that such an approach is now urgently needed to address the largest health challenge in the world today, namely an ageing, multimorbid population. The UK can create the disruptive digital, diagnostic and drug industries that will treat the ageing world but cannot wait for a heavily regulated, incremental industry to make the running.

The UK can choose to industrially harness its national assets of patient data, science-base, industry wisdom, regulatory innovation and entrepreneurship to pioneer in the sector and create new industries here; or await to pay handsomely for the solutions of an emerging disruptive generation of ‘age-management’ firms fostered and funded in the US and Asia.

Rationale

Ageing is not a disease, but the major risk factor for multiple morbidities which include: myocardial infarction; stroke; cancer, macular degeneration, osteoarthritis, osteoporosis, neurodegeneration and many others. Cardiovascular risk doubles every 10 years past the age of 40, even after adjustment for other risk factors—which is the equivalent of adding a major new risk factor every decade[3].

The biology of ageing involves the deterioration of the essential damage repair and limitation mechanisms of cells and tissues and the consequent accumulation of senescent cells and dysfunctional tissues and organs. Complex management systems exist in most tissues and are responsible for cell division, repair and regeneration. Their decline is affected by genetic predisposition, somatic or infectious diseases, and impacts from the environment, which includes prolonged medication and individual lifestyle choices.

Recognised clusters of disease such as cancer have a foundation in cell maintenance decline. Where those sequelae have a specific outcome – such as uncontrolled cell division or tissue specific failures– they are characterised, coded and ‘identified’ as distinct diseases. With age a gradual ‘systems’ failure of tissue maintenance may present first in tissues sensitised by environmental damage, and later in others. This multi-layered presentation of nominally distinct diseases leads to multimorbidity: the burden of failing systems. The chemical (drug) treatment of early manifestations can sensitise other tissues to fail leading to further increase of distinct disease burden, and yet further polypharmacy, literally ad nauseam.

It is understood by the medical profession and lay public that biological age and chronological age are disconnected: a fit retiree may describe themselves as having “the heart of a twenty-year old”, whilst another 65 year old may spend much of the third age in ill health. Rates of tissue ageing therefore are vital to understand and measure as indicators of vitality and prognosticators of the likely order of tissue failure.

Becoming older on its own does not drive healthcare costs. Research supported by the NIHR Guy's and St Thomas' Biomedical Research Centre found that the increasing number of health conditions and age-related impairments along with the proximity to death are more strongly linked to healthcare costs than age alone.[4]

Multimorbidity is increasing globally, likely driven by the ageing population but also by factors such as high body-mass index, increased physical inactivity, urbanisation, and the growing burden of noncommunicable diseases, NCDs (such as type 2 diabetes). [5]

The Lancet’s Taskforce on NCDs and Economics, described how multimorbidity is extremely costly to individuals and health-care systems and recommended identification of the determinants of the acceleration of multimorbidity is crucial.

The multimorbidity perspective adds a timely dimension, suggesting an important window of opportunity to curtail this complex and expanding challenge. Aggressively targeting NCDs as preventable and with identifiable (and treatable) risk factors, whether single conditions or in clusters, could be the first line of offence in addressing the next major health priority—multimorbidity.

A medical system based upon UniMorbidity is suffering from MultiMorbidity

Medical practice and research has understandably developed by taking a disease/symptom centred (phenotypic) approach. Specialisms in disease lead to pockets of excellence, but also boundaries. The impact of taking a systems based approach is therefore profound. It challenges science, structure and status quo. This is now changing. Frailty measures are the most widely used clinical assessments for quantifying the stage of ageing, and to predict risk and mortality in diverse contexts. These, taken together with experimental data from preclinical models, new biomarkers linked with epidemiological patterns of age-related conditions could have broad clinical benefit.

Gerontology (the study of ageing) has to date been regarded by specialist clinicians and disease biologists as a general science, lacking a recognised disease focus and crossing a bewildering range of disciplines including medicine, biology, psychology, sociology, political science, history, anthropology, and economics. The complexity of the ageing process, with a range of biological and environmental influences and a requirement for multidisciplinary research, has impeded progress in mapping the systematic biology underpinning tissue ageing, identifying biomarkers to quantify it, and the core therapeutic arsenal to arrest the decline.

However, advances in our understanding of the biological processes underpinning the ageing process has advanced exponentially in the last decade[6] to such a point that drugs have been tested in animal models and shown to alleviate most age-related conditions and to extend longevity. These drugs have bene termed Geroprotectors. Furthermore, the first feasibility trial in humans with an age-related disease of a drug targeting an ageing process, cell senescence, reported a positive effect on frailty in January 20196 In addition, biomarkers such as the DNA methylation epigenetic clock7are now providing good indicators of an individual’s biological age versus their chronological age, indicating the degree of the ageing process in that person.

The following timeline reflects the recent advances in gerontology

Why Today’s Industry is Slow to Engage in Geroprotection

It is clear that managing multimorbidity, reducing polypharmacy and targeting diseases of ageing is the greatest market and impact opportunity available to the global medicines industry. So why have the pharmaceutical industry not focussed on this with vigour and what is needed to effect change?

As we consider this we must first understand why industry has not ventured into the largest potential global healthcare market of the future and why now is the time for focussed investment in this sector

Whatever therapies are proposed – new, repurposed, precise or multi-disease – industry can argue that:

• Ageing is not a recognised condition for which reimbursement or prescribing is valid;
• Regulatory authorities ask for single disease indications and proofs;
• There are no predictive preclinical models of human ageing;
• The low hanging fruit of repurposing would not deliver acceptable profits;
• Clinical trials in ageing take years and have weak endpoints.

Scientific Barriers

Medicines R&D requires focus on a biological ‘target’: a cellular component or biomolecule whose function can be altered by chemical or biochemical means. The single most risky step in medicines R&D remains the scientific validation of drug targets. Validation is the process by which the target can clearly be seen to directly function differently in patients with, and without the condition. The legacy portfolio of targets associated with tissue ageing contains many that were poorly validated (senolytics), indirect (anti-oxidants, anti-inflammatories) and have been tested in many different guises (telomere length). In addition one tissue disease clearly associated with ageing (dementia) has proven to be the graveyard of investment for big pharma.

There are few animal models that replicate multimorbid ageing in humans, although, aged/frail mice models do exist (Interleukin 10 knockout mouse). However a wide range of animal models of specific diseases have now been shown to be affected by manipulating a single ageing mechanism (such as NAD+) or senescent cells and so this barrier is being lifted.

In order to have industry engage, new biotargets need to be measured in patients succumbing to tissue ageing. A systems based approach must be taken that does not focus on single tissues such as the brain, but addresses the ‘systems’ failure in tissues prone to age-related failure – often linked by the same biology – and that are more accessible to drugs and to therapeutic manipulation (e.g. liver, kidney, muscle etc).[7]

Advances in basic research have now identified certain systems as key nexus of failure.

A range of new validated targets within these systems are currently being progressed by biotech companies with candidate drugs and regenerative technologies. These include; growth and differentiation factor-11–related agents, drugs that selectively clear senescent cells (senolytics), drugs that protect against the proinflammatory senescence-associated secretory phenotype (senostatics), drugs that are related to mitochondrial function, agents that impact protein synthesis or removal of damaged proteins (autophagy), and caloric restriction mimetics.[8]

Clinical Trials Barriers

Successful industrial R&D requires practical, cost-effective, time-bounded clinical trials with definitive endpoints and tightly controlled statistical populations. These endpoints are simply described for single diseases, and statistical power is often maintained by recruiting patients without other morbidities. These features mitigate against performing trials on multimorbid, ageing patients.

The first step on a path to large clinical trials is a series of smaller clinical trials that can provide evidence for the concept that ageing processes can be affected in humans, suggest or validate intermediate outcomes such as biomarkers or surrogate clinical endpoints, and inform the design and scale of larger trials. [9] Innovative trial designs exist in academic research that have shown clear endpoints in aged, multi morbid cohorts and are performed in weeks. These need to be approved and industry stimulated to use them

Biomarker Barriers

Measuring ageing by classical means – mortality, frailty and loss of function do not lend themselves well to effective, agile, clinical trials. Proposed measures of biological ageing may provide a surrogate—a measure that can be tracked over relatively short duration of follow-up and whose response to geroprotective therapy can serve as a proxy for extension of healthy life span.

Recently, several methods have been proposed using algorithms that combine information from multiple biomarkers. These algorithms integrate information from multiple organ systems in the body to produce a single composite measure of system integrity[10]. In observational studies of biological ageing measures, people with “slower” biological aging have lower risk for morbidity, disability, and mortality.

Regulatory Barriers

Regulators are responsible for protecting patients in trials and in clinics. The complexity of using older multimorbid populations, examining multiple endpoints and pioneering drugs carries a risk profile that is higher than the traditional approach. It is therefore challenging for industry to propose and the regulators to accept.

UK Regulators have a high international reputation and are exhibiting a will to innovate. The MHRA’s Innovation Office could have a powerful global impact by focussing on this area, and working with international counterparts to define the future of multimorbidity trials and endpoints that the industry can have confidence will be approved.

The National Institute for Clinical Excellence could create a framework for industry whereby a significant reduction in polypharmacy for multimorbid patients would be a positive aspect for the adoption and reimbursement of a novel therapy, addressing the underlying causes of multimorbidity rather than treating each disease individually. Even if the new cost is higher, the reduction in chemical burden may reduce long term multimorbidity and lead to healthier ageing, with costs arbitraged over time (like a long term loan).

Ageing is not currently an disease indication recognised by regulators, but plausible indications representative of ageing-associated morbidity might include combinations of age-related diseases (multimorbidity) or defined geriatric syndromes such as frailty. Once a precedent is established with the FDA to accept the notion that multimorbidities of ageing can be targeted, larger studies will probably be led by the pharmaceutical industry, realising this opportunity for drug development or repurposing in Phase 3 trials.[11]

The Low Hanging Fruit was not sweet enough

Industry, new start-up companies and VC supported funds are experimenting in this area, almost exclusively in the USA, with known drugs and compounds with some association with tissue ageing and looking at one age-related condition or frailty only. They have been convinced by some scientific, and some apocryphal evidence into trials with for example, Metformin, Rapamycin (Restorbio), Fujimycin (Chronos Therapeutics) and Resveratrol (GSK). Some of these have shown impact on ageing pathways and an associated health benefit, for example an analog of Rapamycin was shown to reduce ageing of the immune system and improve vaccination responses in older adults[12]. Large scale, longterm trials are still awaited.

Competing Market Opportunities

Although industry understands the long term market opportunity, current trends in cancer therapy dominate the industry financing and focus. Today’s industry will not focus on R&D in multimorbidities and diseases of ageing until this cycle of cancer innovation is spent.

International Context

The USA coordinates funding for Ageing research, development and industry stimulus through its National Institute for Ageing, founded in 1974. This has a current annual budget of $3.8bn. In the UK the National Innovation Centre for Ageing was endowed with £20M in 2014, and there are now over 30 centres in the UK claiming to be a Centres for ageing research. The essential science and industry focus lacks co-ordination. In 2018/19 the NIHR Clinical Research Network supported 162 studies on ageing research, 71 of which were new studies, and recruited 16,235 patients to studies. The Medical Research Council and NIHR are due to release new funding calls for research into multimorbidities and have a desire to liaise with major industry.

Since 2000 over $500M has been raised by US biotechnology companies targeting diseases of ageing.

Calico Life Sciences – a US company focussed on ageing therapeutics – recently extended a multiyear £500M R&D collaboration with the international pharma company AbbVie for another three years, bringing an additional $1bn commitment to industrial R&D.

20 of the top 25 geroprotection biotech’s exist in the USA. The remainder are in Russia, Korea and Canada.

In August 2019 the UK investment company Juvenescence Ltd raised $100M specifically to fund age-related therapeutic biotechs: all have so far been US based.[13]

Scientific and clinical research on ageing is also being focussed upon in Japan and Australia.

The UK Opportunity

The UK public sector has a unique opportunity and assets to work together with industry in advance of most industry thinking. It can disrupt the orthodox approaches of industry management and act as an integrated industry player itself, thereby stimulating a next generation national geroprotector industry. This is a new industrial strategy which also answers a national imperative.

The UK has core assets in every sector necessary to deliver this;

• Aged NHS cohorts in UK Biobank/Bioresource; Genomics England; NIHR BRCs
• Proteomic and genomic fingerprinting
• AI and data analytics (public and private sectors, Catapults)
• Real World NHS Data (HDR-UK/CPRD/DIH)
• Target Validation and basic research (public sector, Universities & Institutes)
• Target to Lead discovery (public sector/industry class University groups)
• Lead to Candidate development (private sector contract suppliers, Catapults)
• Advanced Drug Delivery (public and private sectors)
• Innovative Trials (NHS/NIHR/AHSN)
• Innovative Regulators (MHRA)

A Worked Example

A model for this has been developed by the national iTAc consortium, which has brought together all elements necessary to crystallise this effort without the construction of new Institutes, buildings or funding empires.

With leadership and focus, biosamples from UK Biobank, Genomics England and other cohorts can be brought together with proteomics expertise (such as the Stoller Centre, University of Manchester), with AI systems available in public and private sectors, with disease biology expertise at centres like the Francis Crick Institute and drug target testing groups such as the Structural Genomics Consortium at University of Oxford.

These will identify from the real world of ageing UK patients, the biological failures responsible for tissue ageing, and disease. If we are to understand the impact of the environment on this ageing biology we can place specific calls to the national centres to gather around key questions. Sociological research is needed in parallel to address non-drug interventions such as increased physical activity, promote mental fitness in older age and attack issues of loneliness, but focus is needed if we are to make progress in treatment or prevention of age-related ill health.

Industry-class drug R&D can be performed by harnessing academic drug discovery groups such as the University of Dundee and national networks of private sector contract research providers, rigorously metered and managed through the Medicines Discovery Catapult (as described in the 2017 Life Sciences Industrial Strategy). Allied to this can be industrialisation of new drug delivery systems, such as Microbubbles.

Innovative clinical trials models can be discussed with MHRA and performed in NHS multimorbid cohorts (Universities of Birmingham and Oxford) to test those biomarkers and clinical candidates. Additional (nascent) innovations in precision trials for aged patients with renal and hepatic failure can also be deployed (University of Liverpool).

Working as an industrial nation, alongside innovative regulators, enlightened current pharma, data players and technologists, the UK can stimulate a new sector of geroprotector biotechs, diagnostics and AI companies.

The UK can, and must create a co-ordinated national effort to develop new therapeutics for multimorbidities associated with ageing. Without clear focus, funding, goals and industry rigour this will not happen.

On behalf of the iTAc consortium:

Dr Chris Malloy, CEO, Medicines Discovery Catapult, Manchester

Professor Janet Lord, Director of the Institute of Inflammation and Ageing & Director of the MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research

Professor Gary Ford, CEO, Oxford Academic Health Sciences Network and Professor of Stroke Medicine

Professor Chas Bountra, Director, Structural Genomics Consortium, Oxford

Professor Sir Mike Ferguson, Regius Professor of Life Sciences, University of Dundee

19 September 2019