For a long time, aging biology and research have been enigmatic areas that biotechs hoped to capitalise on due to their market potential. Whether one refers to such research as “longevity”, “anti-aging” or “extending healthspan”, it is clear this area has evolved massively over the last few years with more scientists now eager to get drugs in this area from bench to bedside. However, struggles to prove to regulators the validity of or need for drugs in this realm still serve as a major barrier to success.

In an email to Pharmaceutical Technology, an aging researcher, Dr. Ronald Kohanski, defined aging as “a progressive accumulation of functional deficits, meaning that biological systems do not function as well later in life as they do earlier in life.” Kohanski is the director of the Division of Aging Biology (DAB) at the National Institute on Aging (NIA), a division of the US National Institutes of Health. Kohanski emphasised that researchers at the institute approach their work by focusing on “healthy aging” rather than “anti-aging.” This is often studied using aging clocks, which measure biological age by evaluating different aging processes.

Currently, most drugs being investigated for their healthy aging or anti-aging properties are being repurposed from readily accessible FDA-approved drugs. For example, in the Targeting Aging with Metformin (TAME) Trial, a series of six-year studies, the diabetes drug metformin will be studied for its effects in preventing age-related conditions such as cardiovascular disease, cancer, impaired cognition, and mortality. Dr. Nir Barzilai, the scientific director for TAME and the director of the Institute for Aging Research at the Albert Einstein College of Medicine, New York, says projects like the TAME trial could be what regulators need to see to prove the validity of clinical trials in this area.

Based on preclinical research for their impact on aging, well-known drugs like metformin and rapamycin are already being considered for off-label usage, due to their accepted safety profile and cost-effectiveness. Barzilai hopes that the well-established profile of the drug may allow the FDA to accept the trial more easily and then other aging-related studies can follow.

Aging-related pharmaceuticals and research also need to overcome the barrier of sensational and negative press. “Right now, unfortunately, the aging clocks have gotten a bad name, because there’s been this rush of direct-to-consumer companies that are selling completely unvalidated things to people,” says Dr. Matt Kaeberlein, director of the Healthy Aging and Longevity Research Institute, at University of Washington, Seattle. Concerns exist that headlines touting claims such as “anti-inflammatory drugs turn back time…” and referring to research as a “search for eternal youth” may misrepresent the aims of the field. Kaeberlein says such research is having a harmful effect on the regulatory side: “The FDA is watching this, and they can see it’s not scientific.”

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By GlobalData

What is aging clinical research?

The geroscience industry mostly centres aging research around the “hallmarks of aging.” There are eight hallmarks that define aging, including stem cell dysfunction, inflammation, senescence, and more. The National Cancer Institute (NCI) defines senescence as the “process by which a cell ages and permanently stops dividing but does not die.”

Within these hallmarks, different laboratories have found distinct ways to track and quantify aging. Kohanski highlights that repurposing the drugs like Novartis’ Sprycel (dasatinib) and the flavonoid quercetin to treat cellular senescence “show significant promise.” Traditionally, people are prescribed Sprycel and quercetin for chronic myeloid leukaemia and anti-inflammatory effects, respectively. Dr. Richard Faragher, a professor of biogerontology at the University of Brighton, is looking at a new way to target senescence with a class of small molecules called resveralogues that aim to reverse senescence in cells.

In his studies, Faragher uses biomarkers to track changes in aging clocks. However, Kaeberlein explains, “The challenge with that is I think we’re pretty far away from the FDA recognizing those biomarkers as true surrogate endpoints for clinical trial.” This regulatory issue coupled with others has hindered the clinical development of drugs in the field.

At Kaeberlein’s lab, studies track effects on aging through an approach that is largely focused on genetics, modifying different genes to figure out what affects healthspan and lifespan. “About 2,000 small molecules have been tested for their effects on lifespan,” says Kaeberlein. These are listed in the publicly available DrugAge Database. Furthermore, Kaeberlein explains that, as aging is such a broad area, many studies look at composite endpoints. Thus, rather than looking at a primary endpoint for one disease or condition, studies like the TAME trial may concentrate on multiple measures.

Others have chosen to focus on the functional measures of aging. An example of this is Dr. Ilaria Bellantuono’s lab, which is investigating medicines for frailty, which she describes “as an accumulation of deficits” in organ function. Bellantuono is the co-director of the Healthy Lifespan Institute at the University of Sheffield.

Barriers to regulatory success

Experts are currently debating the key to success for new healthy aging drugs as some logistical issues hold the field back. For example, Kaeberlein says that the length of a clinical study to investigate an entire lifespan is often dismissed for not being cost-effective. Thus far, lifespan studies have only been possible in animals. Kaeberlein is working on a trial investigating rapamycin’s effects on the healthspan of 580 pet dogs. Such issues may have caused hesitance in some drug regulators.

Barzilai predicts that in the future, the FDA will develop an “easier indication” to define aging in clinical research and this may give studies more of a platform to progress through the regulatory system. “Then we’ll extend the use to longevity,” he says.

However, many see possible flaws with this solution. Bellantuono worries that labeling aging as a disease indication could be “agist” and would have social implications. Bellantuono prefers to reference aging as a risk factor for disease, saying, “if you decelerate aging, you have the [potential] of reducing the chance you’re going to get multiple sclerosis or dementia, or cardiovascular disease.”

The UK also faces similar regulatory challenges as some public health officials and drug regulators are slow to collaborate with pharmaceutical researchers on aging-related work. Bellantuono says this may be because they need to consider cost-effectiveness and whether the preventive nature of drugs in the field impacts age-related diseases significantly enough to warrant approval. Barzilai explains that some biotechs are looking at developing drugs for age-related diseases and repurposing them specifically to treat aging, which makes funding for clinical trials easier.

Kaeberlein says efforts to label aging as an indication may be misguided. “It’s not going to change the equation at all in terms of getting a drug approved by the FDA. You still need to have the endpoints that are quantitative, measurable, and tell us something about quantity or quality of life for people,” he says.

Another way to view this would be to consider biological aging as the greatest risk factor for every age-related disease, and that would include almost all the major causes of death and disability in developed countries. “If you can get [the FDA] to recognize that then I think there might be an opportunity for what would fall under the umbrella of a fast track for clinical trials that target the biology of aging,” says Kaeberlein. He goes on to say that this might incentivize more pharmaceutical companies to develop drugs that target the biology of aging. “The incentive from the FDA’s perspective would be the possible larger effect size on multiple age-related diseases compared to that of drugs currently being developed,” he says.

Nonetheless, Faragher has high hopes for the field’s prospects, having coordinated ten UK Research and Innovation’s (UKRI)-funded networks looking at improving healthspan. Faragher is optimistic that regulators will get on board with actively accepting healthy aging pharmaceuticals into healthcare, predicting that in the next century this indication may receive a rush of activity. He says, “The dam hasn’t broken, but there are some very big cracks in it…. We need to act decisively now and start to do the research really diligently.”