Thinking About the Pipeline: Getting Therapies into Clinics

A legitimate, actual human rejuvenation therapy is one that repairs one of the forms of cell and tissue damage that are collectively the root cause of aging. By root cause I mean that this damage occurs as a result of the normal operation of cellular metabolism, and is not itself caused by another form of damage. The present list includes a few classes of persistent metabolic waste, such as misfolded proteins and sugary cross-links, mitochondrial DNA damage, senescent cells, cancerous nuclear DNA mutations, and loss of necessary cell populations, such as active stem cells and long-lived cells in the central nervous system. While not directly caused by one another, these various forms of root cause damage do interact with one another. One type of damage can speed up the progression of another independent form of damage by harming quality control or repair mechanisms, for example.

Do any real, legitimate rejuvenation therapies exist yet? Why yes, as it happens. In 2015, Pentraxin Therapeutics and GlaxoSmithKline completed a small trial of a therapy capable of partially clearing transthyretin amyloid in human patients. Amyloids are misfolded protein, a type of persistent metabolic waste that accumulates in all of us with age, and which in this case is implicated in the development of cardiovascular disease, among other conditions. The presence of amyloid in older tissues is a form of damage, and clearing it is a form of repair, and thus a narrow and specific form of rejuvenation. A little way behind Pentraxin is Oisin Biotechnology, a new startup with a working gene therapy approach that selectively destroys senescent cells. That has been tested in rats rather than people, but the only reasons it couldn't be used in humans today, right now, are the heavy hand of regulation on the one hand, and a desire for another year or so of work to underline the proof of function on the part of the founders on the other. Beyond these two, there are a few other cases in which thinner slices of the necessary technologies for rejuvenation are under development. For example Gensight is putting a lot of effort into human trials for allotopic expression of a single mitochondrial gene to treat inherited conditions in which that gene is mutated. There are thirteen genes that need this treatment if the technology is to be used for rejuvenation, to completely block the contribution of mitochondrial DNA damage to aging, so in a sense Gensight is building a 1/13th slice of a rejuvenation therapy.

You can't undertake any of these treatments today, however, or at least not unless you are wealthy, connected, and persuasive, in which case you buy early access to the treatment by funding a company to develop it and becoming an insider. Even that is only an option if the people doing the work are willing to go along with it, which isn't always going to be the case. A lot of developers want to walk the regulatory path with clear compliance, which means that it could take a decade or more from start to finish before anyone other than a qualified trial participant undergoes any version of the treatment. That is clearly the case for the Pentraxin work on transthyretin amyloid, which has been locked up in the Big Pharma development and regulatory process for seven years already, and may well be years yet in getting to the clinic. When it does, the odds are it will be restricted for use for specific age-related conditions in their later stages, and it will take further time to break it out into more general availability. This is how things tend to progress in the formal, regulated development process. It takes a very long time for even spectacularly successful technologies to become available to the general public.

This is not what we'd like to see happen for rejuvenation therapies. Adding five or ten entirely unnecessary years between the first functional, proven therapy and availability of that therapy in clinics seems crazy given the immense cost of aging and age-related disease. Ideally the initial developer of a rejuvenation therapy could license the technology to groups willing to spend the excessive time and money needed to go through the regulatory hurdles put in place - largely for no good reason - by the FDA and their equivalents. Then that developer can focus on putting the therapy into clinics immediately through other channels. This is not a novel idea. It is exactly what happened during the early stages of clinical availability of stem cell therapies outside the US and Europe, in the years immediately following the turn of the century. That produced a great deal more data and beneficial results for patients that would have been the case had everyone followed the demands of regulators. It took the FDA a decade to approve any sort of stem cell therapy in the US, and that only happened because those therapies were widely available in many other countries, making regulators in the US look backward and obstructive. That is really the only way to improve regulation, to work around it, make it irrelevant, and make the actions of the bureaucrats involved appear exactly as foolish and malign as they are.

The first set of narrow rejuvenation therapies capable of repairing a slice of the damage that causes aging either work now or are only a year or two away away from working implementations. What are the paths to getting them into clinics and accessible via medical tourism shortly thereafter rather than locked away in the regulatory process for a decade? Two roads spring to mind. The first is to follow in exactly the same footsteps as the stem cell research and development community: every clinic capable of handling stem cell therapies is only a small step away from being able to deliver infusions of enzymes or even gene therapies. Most of the existing institutions of delivery, manufacturing, certification, and training that have come into being over the past decade could be utilized to deliver rejuvenation treatments alongside stem cell therapies. It isn't a big leap, and there are likely many solid and reputable allies to be made along the way. Stem cell therapies are a big business in many parts of the world now, such as India, China, and other Asia-Pacific countries, and the provision of such therapies is a maturing industry with players at every size, from hospitals to individual practices to associations and advocacy groups.

The second option is to engage with the big networks of the "anti-aging" industry, which currently sells exactly nothing (other than perhaps exercise and advice on calorie restriction) worthy of the name. This large and very vocal industry is the result of enthusiasm for intervention in the aging process that started in the 1970s, well in advance of any ability for medical science to produce meaningful results. It is a great example of the way in which it is possible to succeed in business while failing to achieve any of the original goals that drove the launch of that business. Having produced a pipeline and a network, and finding thereafter that there was no such thing as an "anti-aging" treatment at that time, this space became filled with a mix of nonsense, fraud, and useless frippery, pills, potions, and lies. The nonsense won't magically vanish overnight with the advent of real rejuvenation therapies, but if you go dig through the materials available via organizations such as the Life Extension Foundation or the American Academy of Anti-Aging Medicine, you'll see that there are thousands of physicians involved in this business. Of these, many are associated with clinics capable of delivering mass-produced infusions and gene therapies, and have experience with established mechanisms of provision, training, and certification. More to the point this is an industry with a fair degree of centralization in its points of contact, the conferences and industry groups like A4M are good ways for a developer of actual, real rejuvenation treatments to reach this market.

The question here is whether the intangible costs of the second option are worth the benefits. Is the "anti-aging" marketplace so terrible that it is capable of sinking a legitimate rejuvenation therapy and company by mere association? If plastic surgeons or "anti-aging" clinics start to sell senescent cell clearance injections in addition to their normal wares, is that the good chasing out the bad, or the good being corrupted and confused in the public eye so that support for progress in the medical control over aging becomes even harder to obtain? It is hard to say one way or another - it is one of those things that probably depends on the details.

Comments

Thanks for the update and your viewpoint on where we are at regarding near term rejuv treatments, Reason.

I think medical tourism is going to be the way to go for at least the next 10 years if not more. This country is way too conservative for many issues, not the least for medical purposes. If someone is dying, there is not much for that person to lose. But law makers are very myoptic.

Posted by: Robert Church at March 18th, 2016 6:07 PM

Not all countries have so stringent regulations such as USA (which I find however to be a good thing). It might be easier to receive a market agreement in EU (or another place) and then extend it to US than to start right from the beginning from US, at least because there are international commerce treaties that can smooth things. Why not creating a company in another country and distribute drugs from there at least in a first stage?

For example one could look at Ireland which is in EU. Another excellent place would be the Jersey Isle which is not part of EU but has easy access to EU market either politically or geographically (it is actually much closer to France than to UK), some pharmaceutical companies are already established there (shire plc, Diabetology Ltd)

Posted by: Jean-Pierre Le Rouzic at March 19th, 2016 12:07 PM

I've got to wonder if Liz Parrish and BioViva are looking into offering DMD gene therapy with that micro duchenne gene and AAV down in Colombia?

https://www.duchenneconnect.org/clinical-trials/research-faqs/905-gene-transfer-of-micro-dystrophin-clinical-intramuscular-gene-transfer-trial-of-raavrh74-mck-micro-dystrophin-to-patients-with-duchenne.html

It would create a PR storm, but that is kind of the purpose of BioViva isn't it?

My personal view on the FDA is that they are necessary, but bloody inefficient, as their incentives are currently to set up to delay things. An official's career is ruined if a number of people die on a clinical trial... and that is the only real stick out of all the sticks and carrots of incentives that could be used. How about giving officials bonuses for estimated lives saved, or estimated quality life years added by bringing drugs to market? Get an independent panel of retired judges to do these reviews, much like proposals in the US for retired judges to set electoral district boundaries to avoid gerrymandering.

Posted by: Jim at March 19th, 2016 3:14 PM

"How about giving officials bonuses for estimated lives saved, or estimated quality life years added by bringing drugs to market?"

A very good idea. I wonder if there are any official proposals like this.

Posted by: Claus at March 21st, 2016 3:41 AM

@Claus - I'm sure loads of people have made similar proposals for reforming bureaucracies before, the problem is it only really happens when that bureaucracy is shown to but hurting the public in some fairly obvious way.

Posted by: Jim at March 21st, 2016 8:44 AM

Yes, I know :(

"There is nothing more difficult to take in hand, more perilous to conduct, or more uncertain in its success, than to take the lead in the introduction of a new order of things. For the reformer has enemies in all those who profit by the old order, and only lukewarm defenders in all those who would profit by the new order, this lukewarmness arising partly from fear of their adversaries … and partly from the incredulity of mankind, who do not truly believe in anything new until they have had actual experience of it."

— Niccolo Machiavelli

Posted by: Claus at March 21st, 2016 8:47 AM

Note that Japan now has a fast-track approval process for "regenerative medicine" that allows for marketing authorization based on Phase I clinical trial data that shows the therapy is safe and provides some evidence of efficacy. Both cell and gene therapies are included under RM for the purposes of the law, so many future rejuvenation therapies are likely to fall in this category. A Japan-first approval strategy is already being pursued by a number of companies (e.g., RepliCell) and would be much preferable to trying to simply skirt regulatory systems. Among the many problems with clinics just offering these therapies is that no one has an incentive to do proper data collection and follow-up (least of all the clinics themselves) and to try to figure out whether therapies actually work (since clients are already paying for them).

Posted by: Nick at March 21st, 2016 3:28 PM

Can anyone recommend a particular country with stem cell labs that are both proficient and cost-efficient? Or is it generally the same cost and expertise everywhere in the world? I can't assume such clinics in poor countries would necessarily charge a low fee, given the nature of their work.

Posted by: Eric at March 21st, 2016 3:29 PM

I love your thinking Thank you for sharing

Posted by: timmichael4 at April 20th, 2016 6:37 AM

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