I am generally in favor of the sentiment offered in this commentary on recent clinical trial failures for the first attempts to guide anti-aging technologies through the FDA gauntlet, which is that researchers and developers should be aiming to treat aging, not specific age-related diseases. There is likely to be a greater incidence of failure on the way to the clinic, and for entirely avoidable reasons, if everyone is attempting to force a more or less square peg into a more or less round hole.
Following the recent clinical trial failures by Unity Biotechnology and resTORbio, Buck Institute professor Brian Kennedy feels that a change in approach is potentially needed. “I get the idea that you target aging pathways, but then you try to treat disease because you need to get FDA approval and reimbursement from insurance companies – but if that strategy doesn’t work, we’ve got to stop doing it. I think we should actually try to treat aging for a change.”
While Kennedy agrees that effort needs to continue to convince the FDA to recognise aging as a treatable disease, Kennedy also believes that there are alternative approaches that can be employed. “You don’t need the FDA to approve your trial, you need an institutional review board to approve your trial. From an academic standpoint, as long as you can convince people that the trial is safe, you can use biomarkers and study the effects of these drugs. So I think if we start generating that kind of data, then it’ll be a lot easier to get the FDA on board, and hopefully the rest of the world on board. We need to nail down the foundation here and stop giving people excuses why this won’t work. I’m still optimistic about drugs, but if you develop a drug for A and try to treat B, and then you wonder why it doesn’t work – I’m starting to feel like the strategy may not work that well.”
Of course, if companies are going to run trials on aging, then a clearer consensus is needed on the definition of aging, and Kennedy is encouraged by developments in the various clocks that measure biological age. “There’s a bunch of clocks and we don’t really know how they relate to each other yet, and how specific clocks relate to specific kinds of age-related disease. There are a lot of questions to answer, but I think that the most advanced clocks are starting to look like good biomarkers. Some may be better than others but I’m very optimistic about these biomarkers.”
At present the FDA doesn’t recognize aging as a condition that can be treated, so the first generation of companies working on therapies that target mechanisms of aging will all attempt to apply their approach to specific age-related conditions. If successful, the vast majority of usage will then be off-label, as physician networks apply the therapy at their judgement, based upon the extensive literature suggesting that it will be effective for many age-related conditions. It is in the arena of widespread off-label use that the real battle to lighten the regulatory burden will take place. While off-label use is entirely legal, the FDA will likely attempt to shut down providers and manufacturers, in order to force further trials when a therapy becomes widely used in this way.
It would be much easier if we could all just obtain clinical approval by directly assessing the impact of a potential rejuvenation therapy on aging. Or better, obtain clinical approval by demonstrating safety only, rather than safety and efficacy as presently required by the FDA, and letting later studies, reviews, and the marketplace sort out what actually works. It would also be much easier if the FDA was not the bureaucratic monstrosity that it presently is, operating under perverse incentives that cause regulators to have more than doubled the cost of compliance in the past twenty years, at the same time as reducing the number of new therapies that arrive on the marketplace. I don’t see any of this changing any time soon, however. Which is why we will continue to see companies in the longevity industry applying their therapies to specific age-related conditions in order to obtain regulatory approval.
As a sidebar, the trial failures in question were those of UNITY Biotechnology, for senolytics versus knee osteoarthritis, and resTORbio, for an mTORC1 inhibitor versus influenza risk in the elderly. In the former case, the present consensus among observers is that UNITY took a risk on localized senolytic treatment being good enough, and has demonstrated that it isn’t. Senescent cells are present throughout the body, and the inflammatory signals that they generate circulate widely. For an inflammatory joint disease, the background inflammation may well be more relevant in many individuals than the local inflammatory process of joint tissue. In the case of resTORbio, the whisper mill suggests that they were tripped up by a change to the trial endpoint forced on them by the FDA between phase 2 (successful) and phase 3 (failure). Equally, one might suspect that the effect sizes for mTOR inhibition on the immune system are just not that large or that reliable in a general population of humans – this may well be the case for all approaches derived from calorie restriction and stress response upregulation research. We shall see.