Nobody is Counting on the Near Term Emergence of a Regulatory Path to Approval for Therapies to Treat Aging

The article I'll point out today touches on an important point regarding present efforts to develop therapies capable of slowing or reversing the progression of aging. Some of those therapies manipulate metabolism in ways that are known to modestly slow aging, such as upregulation of autophagy via mTOR inhibition, but the full holistic understanding of how they work is as yet lacking. Others target specific causative mechanisms of aging, such as the accumulation of senescent cells and their disruptive senescence-associated secretory phenotype. There, we lack the full picture of how the well-understood cause contributes in detail to the very complex changes of later stage aging, but we can at least be fairly certain that when we see benefits in older animals and people, we know that the specific targeted mechanism is important in aging.

The development of medicine is heavily regulated. Overly regulated. Laboring under such a vast burden of regulation that it is at times surprising that anything is ever achieved. The costs are vast. In some cases the cost is effectively infinite, such as in the matter of aging. At present there is no regulatory path by which the FDA or equivalent regulatory bodies will approve a therapy for the treatment of aging. There is a great deal of discussion as to what it might take to generate such a path, and some pioneering design and persuasion on the part of those heading up the TAME trial initiative, but no signs that all of this will produce the desired outcome at any point in the near future. That won't stop people continuing to invest time and funding into producing this path, of course.

The principals of every biotech company presently developing therapies that may slow or reverse aspects of aging are ignoring the question of regulatory approval for therapies to treat aging. It is irrelevant to them, because it won't happen soon enough. They instead identify the specific age-related diseases that are most likely to respond favorably to the specific mechanisms of aging targeted by their therapies, and seek approval for the treatment of those diseases. This is the standard approach taken by any biotech, is well understood by conservative biotech investors, and is the way that one succeeds in getting a therapy to market as the principal of a biotech company.

This much is said in the article below. What tends to go unsaid by those who are presently engaged with the FDA is that, following approval, one might expect widespread off-label use to emerge for any therapy with sizable effects on a mechanism of aging. There is where the real battle will be fought over the regulatory path to treat aging. The initial approval via the present regulatory system is the wedge applied to the wood, the shoe in the door. This goes unsaid because the FDA has in the past demonstrated considerable opposition to widespread off-label use, and talking about that may prejudice one's chances of success in regulatory approval. Nonetheless, off-label use is legal and in principle in the hands of physicians, not the FDA. If a medicine is demonstrated safe, and physicians have a reasonable expectation that it will produce patient benefits, they can go ahead. At least until the FDA makes earnest efforts to shut things down and force clinical trials; this is something of a political anarchy, well illustrated in practice by the changing regulatory stance on stem cell treatments over the past few decades. The analogous fight over the treatment of aging will be much larger and much louder.

Another point is that the high costs imposed by the FDA are giving rise to a medical tourism industry outside the US that will grow in size and sophistication as the number of customers grows. Medical tourism to treat disease is a small market in comparison to medical tourism to treat aging. The size of that market will inspire, eventually, an entirely distinct medical ecosystem, in which the option will exist to responsibly run trials and treat people at a fraction of the costs presently required. Small elements of that ecosystem exist today, but only the vastly greater number of potential customers created by viable treatments for aging will create the growth and coordination needed to build a viable alternative. That alternative is needed, as present regulatory regimes are holding back progress to chase an ideal of zero patient risk at any cost.

Getting geroprotective drugs to market for specific disease applications is the first step in eventually making them available for healthier aging

James Peyer, the CEO of the New York-based biotech company Cambrian Bio - which seeks to develop therapeutics to lengthen healthspan - says the first geroprotective drug to gain FDA approval may be something that is already known today - perhaps a drug already approved for another indication - and has only to be validated through clinical trials for longevity. "We have actually 80 interventions, of which about 20 are drugs that extend healthy lifespan in mice," he says, referring to all the known drugs on the market that could potentially be repurposed as well as all the experimental compounds in the pipeline not yet approved to treat any disease that look promising as future geroprotective drugs. Probably a handful of the 80 have sufficient evidence to support running a large clinical trial. But therein lies the problem.

Doing clinical trials for longevity is hard. It's expensive. Historically, many have even said it's impossible. "If you took an experimental drug, and I took a placebo, how long would we have to wait to see a real outcome?" Peyer asks me. "Six years. They take six years and they cost $150 million. If you're going to take a drug that has never demonstrated human safety and efficacy before and try to go straight into that six year, $150 million shot on goal, and then maybe afterwards you'll have revenues. It's risky." Six costly years, six risky years - and there's no way around it. That's why people always warned him it couldn't be done.

Instead a preventive medicine is typically tested first for its ability to treat a specific illness. Once it proves safe in humans and effective for that smaller indication, then it moves into the more costly, larger prevention trials. And that's how many companies in the field are moving forward-using what Peyer calls the stepping-stone approach. The idea of targeting treatments for specific age-related diseases is to create value. It avoids the six-year risk of a broader longevity trial and instead tests the drug in well-defined populations, perhaps even people who have a genetic disease and will be highly likely to benefit from the therapy. They may respond more quickly, show results sooner, and allow for shorter, less expensive clinical trials.

The basic idea is simple, says Joe Betts-LaCroix, CEO of the San Francisco-based biotech company Retro Biosciences. "You can start with a disease that has the most acute manifestation in the shortest amount of time with response to some step change in an aging mechanism, produce that as a therapy that gets approved by a health authority, and then slowly expand from there. The idea is that if you can intervene really well in one aging pathway, you can then treat and or prevent multiple downstream diseases at the same time with one therapy."