For Senolytics Companies, an Effective Piperlongumine would be a Greater Competitive Threat than Dasatinib
Senolytic treatments selectively destroy senescent cells, and several different approaches have been shown to produce some degree of rejuvenation in mice: reversal of measures of aging; reversal of the progression of specific age-related conditions; extension of life span. Most of these initial senolytics are repurposed pharmaceuticals drawn from cancer research databases, with the exceptions being the engineered peptide FOXO4-DRI, the suicide gene therapy developed by Oisin Biotechnologies, and SIWA Therapeutics' immunotherapy. Where animal study data has been published, the results produced by these varied senolytics are remarkably similar: up to 50% clearance of senescent cells from old tissues in mice, varying widely from tissue to tissue.
One of the repurposed pharmaceuticals is dasatinib, a drug already approved by the FDA for cancer treatment, with a sizable amount of human data by which we can judge side-effects and safety. Dasatinib is a generic drug that is mass produced by numerous manufacturers worldwide, whether with or without approval from the US government, and as a consequence it costs very little. This presents an interesting challenge for those companies attempting to produce senolytic therapies, as new treatments must run through clinical trials at enormous expense. In addition to proving new drug candidates or other classes of treatment, these trials will also provide supporting evidence that will allow physicians to prescribe off-label use of dasatinib at a tiny fraction of the cost that must be charged for new therapies in order to recoup development expenditure.
The principals of senolytic development companies will thus find themselves needing to produce treatments that can clear senescent cells far more effectively than the dasatinib and quercetin combination therapy. Even given the choice between a $100 drug that can clear 50% of senescent cells versus a $20,000 drug that can clear 80% of senescent cells, a company might struggle to obtain the desired level of sales over the long term. Though in fact the situation is more complex than this overly simplistic example, given the variability of results tissue by tissue, and there will be room for senolytics that turn out to be better for the heart, or lungs, or specific other organ than the competitors. But still, you see the challenge. This is particularly problematic for small molecule development, in which it is very expensive, uncertain, and time-consuming to attempt to improve specific aspects of an existing family of drugs. It is by no means certain that small molecule developers such as Unity Biotechnology will be able to produce drugs that are better enough to justify the price premium over dasatinib.
Dasatinib provides a certain degree of sink or swim encouragement to do better, but this pales before the state of affairs that will result should piperlongumine turn out to be senolytic to much the same level in mammals. Which may well be the case, given recent data, but nothing is yet proven in certainty. If piperlongumine is in fact approximately as good at removing senescent cells as the dasatinib and quercetin combination, then this discovery will unleash the dietary supplement industry and in short order allow them to become the major players in the senolytic marketplace, rather than merely a gaggle of hopeful onlookers. Piperlongumine is a plant extract, a natural product that is regulated in a completely different way from small molecule drugs and other medical biotechnologies. It costs far less in time and funding to bring a new natural product to the marketplace, and the resulting supplements are as a result far cheaper than medicine. Given effectiveness for piperlongumine, established dietary product concerns will be selling low-cost senolytics to much of the world well prior to the point at which the first expensive senolytic therapies emerge from the FDA regulatory process.
One could argue that this particular vision is unlikely to come to pass on the basis that the other potentially senolytic categories of natural product are not in fact capable of killing enough senescent cells to be worthy of the name. The flavonoid quercetin, for example, doesn't do much on its own. Certainly not enough to be an alternative to a real senolytic, no matter how cheap it might be. Is this a valid argument to direct at piperlongumine? Maybe so, maybe not. We shall see when the data arrives. Anyone with a few hundred thousand dollars to invest could run the necessary mouse studies to prove or disprove the senolytic capacity of piperlongumine, and that is not a large number in comparison to what it requires to build a new supplement manufacturing and distribution business. Given this, one might wonder whether or not anyone in the industry is already working on this project.
I wonder if a significant piperlongumine study could be entirely crowd funded by lifespan.io.
As I said above I believe small molecule approach is not good in rej bio, because -- in contrast with "big" molecule approach -- one is not adaptive! If you wish to make change in small molecule -- you have a big problem, if you wish to change your enzyme -- you have very well established programme for protein engineering. You just can look at nature, after all!
Look at any small molecule senolitic -- and compare one with gene therapy framework from Oisin which can make nearly everything just by changing pair -- promotor / effector which can be easily printed via synthesizer and amplified in bacteria!
I have thought about what it would take to sell Ganthoda, the Piper Longum root, as a standardized extract the same way St Johns Wort is sold. And conducting some mouse tests for marketing. The conclusion I came to was that after developing a market one or more big supplement makers would mimic the extract and use their superior marketing stance to destroy any profit potential.
>Look at any small molecule senolitic -- and compare one with gene therapy framework from Oisin which can >make nearly everything just by changing pair -- promotor / effector which can be easily printed via >synthesizer and amplified in bacteria!
Is it achievable on an individual, DIY level? Hard to see how this drugs would be accessible to a public less than a 15 years from now, yet it would be tempting to try it.
Didn't Oisin's treatment have an effect in pre-cancerous cells where the dasatinib and quercetin combination had no effect?
Recently Vincent Giuliano in his new blog pointed to research indicating that senescent cells play a much more positive role in the body than previously thought. He sees no problem in senescent cells itself but in having a too great amount of them.
If so, the good news is that a relatively weak plant extract will give better outcomes than a cancer medicine. The bad news: the amount of bad senescent cells will vary tissue per tissue.
@Peter
The modern thinking is that the senecent cells are bad because of the SASP, and secondarily because they have a reduced tissue functionality. If the harmful section can be moderated then having senecent cells would be less of a problem.
The truth is that we don't really know how well a senolitic treatment would work with humans. The mouse studies suggest very promising results. And I do hope they work as well in humans. But it might turn that the benefits are not so large in general, and help only in narrow cases.
As everting in biology, senecent cells have positive and negative roles. We will know better when we can effectively reduce their numbers in humans. For now it is all speculation...
@Andey, you are wrong! Makeing new gene therapy -- computer, using special software, synthesizer, sequenator, thermostat, PCR machine, kit for extracting plazmids from bacteria -- are much more achievable on personal or garage level than personal chemical factory. Moover, what Oisin are doing may be done in any normal university lab ( even in Russia ), because they have no own lab and outsource much of their research in such a way.
@Jim, exactly! I cannot say on small molecule, but Oisin's combination of therapy p53 + p16 is much more valuable than they are used alone. Also from my inerview with Hary Hudson:
-- Can we use your therapy for not only treating cancer but also for preventing one? If people have pre-cacenrous cells using your therapy will be very useful!
-- We do believe that our p53-based treatment will have beneficial effects to prevent malignancies, but we have yet to demonstrate this in vivo.
https://medium.com/@arielf/the-rise-of-oisin-d4664ed7e9
@JohnD
I sent suggestions to both Herb Pharm and Gaia Herbs to make a standardized extract; perhaps one will pick up on it.
I see no real reason to believe that piperlongumine would make dasatinib/quercetin obsolete. None of these three are particularly potent senolytic treatments; and each of the three likely have a different mechanism of operation.
Unless piperlongumine's effect is a nearly complete superset of the effect of the other drugs, you'd want to use all three together for maximum clearance (if it's possible to do so without serious side effect.)
These are by no means concerns for today
There is always going to be room for quality products in both products classes - remember how GSK took a cheap commodity like fish oil and made Lovaza a billion $$$ product in a matter of 2 years
Most important is creating a product that has efficacy, safety, and tolerability and worry about marketing strategy down the line
A very recent (Sept.11, 2018) related USPTO patent was just approved --
Compositions and methods for selectively depleting senescent cells
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.htm&r=1&p=1&f=G&l=50&d=PTXT&S1=piperlongumine.ABTX.&OS=abst/piperlongumine&RS=ABST/piperlongumine
Interesting that topical applied formulations are also proposed.
@Lou Pagnucco: Well that somewhat squashes the argument in this post, if the patent holder can be expected just sit there and refuse to license for uses of plain piperlongumine, or otherwise make things expensive for a potential supplement business.
Patents are a great evil. They act to slow progress and make things more expensive. A few benefit at the expense of everyone else. Investors in biotech are absolutely fixated on them; you can't get funding without them. So the wheel keeps turning.
Hi Reason,
you are right about the patents. And the practice of having broad and definitions opens the possibility of lawsuits. On the other hand a patent that expires and is overly broad, could probably explicitly allow a lot of actions. Now , i am not sure how enforceable this patent can be. But nobody wants to spend a not so small fortune on trials...
But there is a good part here too. It means that the investors are waking about about the anti-aging and senolitic markets. So, while the exact patent might be a bad thing, the trend is positive...
Can someone explain how a phytochemical like piperlongumine can be patented? It it a micronized preparation or some such?
@CD: It isn't patenting the natural compound, it is patenting the use of it as a senolytic. Just as bad, really.
What's to stop someone from selling a piperlongumine supplement for 'joint pain and gastric troubles* *these statements have not been evaluated by the FDA'?
I only glanced through it, but that patent is a joke. No doubt that group has dozens of similar BS patents intended only to ne used to extort money from real innovators.
@CD You do not need to make any claim to sell a natural supplement, in facr making such a claim would likely be against fda regs
Fisetin is as powerful as Dasatinib + Quercetin (or more), but does this alone. I see references on longevity forums to dr Green using protocol Dasatinib+Fisetin (D+F), instead of D+Q. Anyone has references how much of each component it uses and how effective it is compared to D+Q?
There are 6 distinct SCAPs in senescent cells. F hits 4 of them. P (as far as I can tell) hits 3, but one of those is a SCAP that is hit by D, but not by F or Q (the Dependent Receptor/Tyrosine Kinase SCAP). So there is a chance that a F+P or Q+P combination would be particularly effective.