VIENNA – There's a new term gaining attention in the health care sector. Defined as the "constellation of chronic noncommunicable diseases of aging," comprising cardiovascular disease, diabetes, obesity, cancer and neurodegenerative disease, "metabesity" represents a clear opportunity in the quest to extend healthspan, at least if biopharma can succeed in getting investors, partners and regulators on board.

The need is easy to pinpoint. The average life expectancy has increased significantly – it was roughly 35 to 45 years for a child born in 1919 vs. the current global average lifespan of 70 to 80 years – as the leading causes of death have shifted from acute illnesses to chronic diseases and neurodegeneration, explained Danielle Marra, associate principal at Cello Health Bioconsulting, opening a panel on opportunities in the metabesity space at the BIO Europe Spring meeting on Monday.

In the U.S. and Europe, the average lifespan is 79 years; however, the average healthspan – defined as the amount of time living without chronic disease – is only 68, with the decade-plus gap resulting in huge economic costs. Marra cited estimates suggesting direct health care costs of $1.1 trillion in the U.S. in 2016, with costs of €700 billion (US$792 billion) in Europe; indirect costs such as lost productivity were not included, putting the overall cost to society much higher.

On top of that, the number of people over the age of 65 is also increasing, estimated to be roughly 1.5 billion globally by 2050. "So this is a problem that's not going away and is only going to get worse as our population ages," Marra said.

But while the opportunity may be straightforward, the solution is far less so. For one, some of the chronic diseases included in the metabesity category have been slow to see new innovation of late, with big pharma shying away from investment. In a presentation earlier in the day, Dave Thomas, vice president of industry research at the Biotechnology Innovation Organization cited cardiovascular disease, diabetes and obesity in a list of underserved chronic conditions. The reasons for the decline in investment run the gamut from reimbursement difficulties to expensive clinical development – the requirement for large cardiovascular outcomes trials, in particular, put a damper on development of new diabetes therapies.

Another problem is that the terminology itself – "metabesity" was coined in recent years – which Marra acknowledged is not a disease or indication but rather a concept applied to drug development. That takes it beyond the comfort zone of potential investors and big pharma partners, long accustomed to dealing in terms of specific targets and indications.

Yet many of those diseases have common metabolic roots, she pointed out, offering "pleiotropic benefits" via targeting certain pathways.

At the most macro level, Marra added, the approach refers to addressing issues of metabolic aging to extend healthspan and "taking that onset of chronic diseases and shifting it back a few years." She emphasized that metabesity was not the same longevity.

In fact, the distinction between efforts to increase lifespans and efforts to improve healthspans is key. Life Biosciences LLC, for instance, is focused on slowing or reversing age-related decline, explained Sree Kant, head of business development at the Boston-based firm, "and I use each of those words very carefully," he said. The goal is not to "make people live forever," but rather figuring out how to intervene in certain pathways that contribute to aging and answer the question, "Is there a way to slow the progress of these diseases?" he said. "'Metabesity' is one way to phrase that."

Founded in 2017, Life closed a $50 million series B round in January to support its half-dozen "daughter" companies. Each company is focusing on a specific approach that targets aging, such as Senolytic Therapeutics, which is developing therapies by targeting senescent cells, and Selphagy Therapeutics, which is working on treating diseases such as lysosomal storage disorders by restoring autophagy.

"So for us it is about finding opportunities," Kant said. "We're not looking at each of these companies by itself solving the problem."

Educational effort

Metabesity is based on the idea that aging contributes to the decline in metabolic health, which in turn leads to chronic disease. But there is still much that is not understood. For example, "we're still trying to understand certain populations," said Tomas Landh, vice president of innovation sourcing and senior principal scientist at Novo Nordisk A/S, of Bagsvaerd, Denmark, a firm largely focused on diabetes and obesity. He offered as examples healthy obese populations and people living healthily despite nonalcoholic fatty liver disease, though he added he is still "not fully convinced there is a common root," pointing to the fact that type 2 diabetes patients can be subdivided into various groups.

Additional study could also focus on super-centenarians, or those who are 110 or older. The fact that living to 115 or 120 is possible suggests "we're leaving 30 years on the table," said Thomas Seoh, president and CEO of translational research and strategic services firm Kinexum LLC. "I would like all of us to become super-centenarians," remaining healthy and mobile with sharp minds until infirmity, which ideally would be compressed into the last couple months of life.

But all is for naught if regulators cannot be convinced.

To that end, the NIH has proposed the TAME (Targeting Aging with Metformin) trial. Still awaiting approval to launch, the study is designed to demonstrate whether aging can be delayed with pharmaceutical intervention, specifically with the use of metformin, a drug that has been used for decades to reduce blood glucose levels in diabetes patients.

TAME is intended to enroll about 3,000 patients, ages 65 to 80, who have reduce gait speed or age-related disease, Cello's Marra said. A new composite endpoint will evaluate time to incidence of major age-related diseases, including myocardial infarction, cardiovascular disease, cancer, dementia and death, with a composite secondary endpoint of time to incidence of disability in terms of mobility and cognitive function.

What makes TAME unusual is that it doesn't test against a clinical benefit-type endpoint, said Seoh. It's intended to further the "thesis that aging is the cause of the chronic disease and not the other way around."

If successful in proving that thesis and accepted by the FDA, it could serve as a template for regulators for developing other drugs targeting healthspan.

With a regulatory acceptance for TAME, "I think the industry would be encouraged in going in this direction," said Novo's Landh.

Long term, the metabesity will likely expand beyond pharmaceutical intervention alone. "It's going to take a village," said Seoh, bringing in medical devices, socialization, exercise and nutrition. It will have to involve a "completely holistic and multimodal approach."