$54,000
$15,970

How Would One Go About Building a Company to Bring Cheap Senolytics to the World?

Let us for a moment choose to believe that the dasatinib and quercetin combination is a senolytic treatment that does as well in humans as it does in mice. This is to say it kills about 25-50% of senescent cells in the tissues usually most affected by oral medications, meaning the kidney, liver, and cardiovascular system, and some unknown but lower fraction elsewhere. Whether or not this is the case has yet to be determined; the first pilot studies are still running at Betterhumans, and they likely won't tell us the size of the effect in terms of fraction of cells removed. Viable assays for cellular senescence that can be used in human medicine are in short supply - there is only the one that I know of that is ready to go, and even that has just reached the final stage of laboratory proof of concept. If it is the case, however, that treatment with dasatinib and quercetin works in much the same way in humans, then it should have a notably positive effect on the state of health for older individuals, given that the accumulation of senescent cells is one of the causes of aging.

The distinguishing feature of dasatinib and quercetin are that they are cheap. A senolytic therapy would be undergone perhaps once every few years at most; it kills the unwanted cells it can kill, and it is pointless to do it again before there has been enough time for new senescent cells to emerge at their slow pace. Quercetin is a widely used supplement, and enough of it for a single treatment costs less than a dollar. Dasatinib can be purchased from manufacturers for between $20 and $150 for a single dose suitable for senolytic therapy, depending on where the manufacturer is based. The FDA approved packaging of dasatinib, called Sprycel, costs $300-600 for the same amount, assuming you can find someone willing to break down a bottle of tablets to sell you the small amount needed. It is certainly possible to purchase Sprycel for less than this by ordering from outside the US.

If this pharmaceutical does work in humans as imagined above, then at these prices it is a therapy that would be affordable for a sizable portion of the world's population. It isn't the only candidate senolytic drug that is cheap enough to consider in this way. Once the first of these treatments are proven to be at least passably useful in human patients, what is the path to putting these low-cost rejuvenation therapies into the hands of hundreds of millions of people, the majority of which are not wealthy, as soon as possible? We should give this some thought, as it is a opportunity that will likely arrive much sooner than most of us expected it to. This is a big deal: early senolytics could provide a gain in health for much of humanity if the opportunity is managed correctly. That makes it worth consideration even prior to proof arriving in human studies.

There are always roadblocks. Like all such matters, the use of dasatinib is tied up by patents and regulation. No-one can build a large-scale business selling a pharmaceutical where the intellectual property and regulatory approval are owned by a large and influential concern - in this case Bristol-Myers Squibb (BMS). It is certainly the case that there is a healthy marketplace of scofflaws outside the US who sell directly from manufacturers, but they are not a single target, and it is hardly worth BMS's time to try to squash them while dasatinib is generating only the level of revenue possible for a cancer drug. That economic calculus may well change if it suddenly becomes a viable treatment for every older individual, and physicians show interest in off-label use - that is a vastly larger potential market. Certainly, BMS exerted their influence to block attempts to produce a cheaper generic version in India. That was associated with the Indian government and thus had a convenient single point of attack, unlike the manufacturer marketplace.

Dasatinib is still patent protected, at least until 2020, which means that any earnest effort to make dasatinib a household term in the near future would have to engage with BMS and gain at last tacit approval in order to grow. After 2020, no permission is needed. BMS will continue to tinker with their formula to extend patent protection on the versions of Sprycel that they sell, but they will no longer be able to directly make life difficult for those who wish to manufacture and sell dasatinib per the original formulation. The price will likely drop considerably at that point. So how could a group proceed if willing to found a company to work on distribution of low-cost senolytics?

The Non-Profit Approach

The most obvious option is to build a non-profit that focuses on education and partnership. The goal would be to deliver low-cost dasatinib and the understanding needed for widespread use to less wealthy regions of the world. The non-profit would focus on building relationships with physicians, medical organizations, manufacturers, and the product owner, BMS. There is considerable precedent for this sort of endeavor, and many larger pharmaceutical companies carry out in-house programs of this nature. It can benefit the pharmaceutical company considerably even if they make little to no revenue from the use of their product in those markets. It is usually the case that they wouldn't have been able to sell at profitable prices there anyway, and the program can be very good for their public image - something that Big Pharma entities are always in need of, for some strange reason.

The For-Profit Scofflaw Approach

Prior to 2020, one would require deep pockets and to be based outside the US, preferably in a country that doesn't regard the US with any great favor, in order to build something large that undercuts BMS, or even simply to sell into markets that BMS chooses not to serve. Being a small company that ships dasatinib at low cost from China to other parts of the world is probably viable, but growth to any significant size would bring a quick end to the endeavor. As mentioned, an attempt was made in India, where there is a history of threatening to break international intellectual property agreements in order to bring low-cost medications to that part of the world. That failed, and I'd say that India is probably the most likely region to successfully host a defensible patent breaking exercise.

The For-Profit BMS Enabler Approach

The enabler approach runs something like this: establish a path to obtain Sprycel in bulk at a workably low cost, and in an approved manner for the regulatory framework, and then build a revenue stream based on selling wrapped packages of services and Sprycel to physicians, nursing home operators, and other interested groups. Businesses and other organizations are better customers to start with in less wealthy regions, as there is a greater chance of being able to gain sufficient revenue to expand. Optionally, partner with BMS, though this is typically hard to do without connections.

The packages sold might include: educational materials and classes; professional services to assist with insurance and other regulatory concerns for prescribing off-label usage; membership of a network that helps bring in patients interested in the treatment and thus contributes to a physician's bottom line; tests and organization of testing services to evaluation results; and so forth. Everything is carried out in a such a way that it benefits BMS, such that the company has incentives to allow the business to grow. There are many possible variations on this theme, some of which are similar to the promotional activities carried out by the pharmaceutical companies themselves, while others look more like patient or physician associations or service organizations.

The Wait Until 2020 Approach

In either non-profit or for-profit models by which dasatinib might be distributed to the less wealthy regions of the world in volume, the prospects look a lot better once BMS is no longer the gatekeeper. The price of manufacture will fall precipitously, and an enterprising group with a good approach and competent execution might be able to do quite well in markets traditionally neglected by large pharmaceutical concerns. "Quite well" in this case would mean - under the assumptions at the top of this post - a significant number of people living incrementally longer in better health at a cost that is reasonable for them, considering the benefits achieved. That seems a worthwhile goal to aim for.

Comments

I hope they figure out the dosages, and if it needs to be repeated several times or not. I'm eager to try.

Posted by: bmack500 at February 21st, 2018 2:36 PM

Sorry, but I don't understand the point of this whole argument. Since D+Q and any other antiaging treatments are still far from finishing any clinical trial, what's the point of these plans (apart from making money, of course)? Isn't it like the old antiaging supplements marketplace?

OTOH, would you do this when Oisin finishes their product? I'm not a big fan of patents but, isn't this like shooting ourselves in our feet?

Posted by: Antonio at February 21st, 2018 3:55 PM

@Antonio: The point is thinking out loud. Dasatinib is not the only cheap senolytic candidate. The odds are good that at least one of them will prove to be useful enough at the cost for most people to use it. Once one is proven, what next? Beyond personal use, what should be done to help make it widely known and available? How do you get it into the hands of a hundred million people? What steps need to be taken to get to that point?

Posted by: Reason at February 21st, 2018 4:11 PM

How do you want to make money out of such a business model? Once enough clinical data is available the friendly physician at your local hospital can prescribe it to you. They're also used to splitting up packages and probably even have Sprycel in stock. And if it's paid for by statutory health insurance (might be a cost savings on other treatments for them) it's basically for free.

It might work in the US if you keep the costs down, but still I think there are easier ways to make a buck.

Posted by: Matthias F at February 21st, 2018 4:24 PM

@Matthias F: The point of for-profit for this goal of widespread and more rapid adoption in less wealthy areas is not to make money, it is to speed up the process of that adoption by making money. For-profit can in principle pull in a lot more funding to get the job done, in the form of investment, and seed a broader industry of competitors, outcomes that will likely take much longer to achieve via a non-profit path.

Posted by: Reason at February 21st, 2018 4:46 PM

So, if I understand this well, this is for drugs that:

(a) have human clinical data against aging
(b) are repurposed from other indications
(c) their patents for the original indication will expire in a few years
(d) their company refuses to sell them in 3rd world countries
(e) are relatively affordable in developed countries but not so much in developing countries

in order to make them available in those countries, no?

Posted by: Antonio at February 21st, 2018 5:08 PM

@Antonio: I've made some edits to the post that hopefully clarify my thinking here. Basically yes. I think ten years ago we all expected the first therapies worthy of mention to be expensive, and thus take time to work their way through mass manufacture and widespread use in order to become cheaper, but it seems very likely that for senolytics that will not be the case. Some of the early repurposed drug candidates may well be good enough at the price to pass the cost-benefit equation for most people, even though they will only provide a fraction of the benefits of more engineered and expensive therapies.

Posted by: Reason at February 21st, 2018 6:18 PM

@Matthias F
"Once enough clinical data is available the friendly physician at your local hospital can prescribe it to you."

That is unlikely to be the case unfortunately.
Using senolytics or any treatment which has been shown to alleviate aging in a prophylactic manner is probably not going to happen any time soon. You're not getting it from your GPs office anyway.

Posted by: Anonymoose at February 21st, 2018 9:13 PM

@Reason. You have on occasion made the assertion that Senolytic chemotherapy (my term) would be a once every few years endeavor. I have run the numbers, and it seems to me that one would have to have at least 5 treatments a year, possibly a lot more. Depending on how you define SC, I have read that as many as 10% of cells in an old human could be described as senescent (a noteworthy lack of data and consensus on numbers of SC in humans). I think it is self evident you can't remove even a significant fraction of all those SC in one treatment without killing the patient. And even with highly selective Senolytics, as many healthy cells are going to be killed in a treatment as SC, because there are 10+ times as many healthy cells as SC.

Posted by: JohnD at February 21st, 2018 9:59 PM

@Reason
did you said cheap ?
its thirty three thousand and one thirty six for 10 tablets In India.
I can buy all my supplements in 30 thousands for 10 months supply

Posted by: Salman at February 21st, 2018 10:04 PM

FOXO4-dri doesn't have human data yet, but once it does it should be somewhat straightforward for overseas labs to manufacture and ship it as it is a peptide.

Also it may have a much more favorable side effect profile than re-purposed lower dose chemotherapeutic drugs.

Peptides that mimic testosterone for bodybuilding and performance enhancement in sport are already manufactured and distributed from overseas illegally on a fairly large scale. So this isn't without precedent.

Posted by: Jim at February 21st, 2018 10:16 PM

Many of the richest people in America are people who had a crazy idea, then managed to convince a bunch of people with related skills to go along, and then also convinced investors to invest with them. I think your number of $100 million is a good target.

I would be willing to join in the effort, alas I only have useful skills for the effort in the accounting/finance.

As someone who has spent 10 years reading about the pharmaceutical/biotech industry what I would recommend is the plan would be to create our own chemicals. With $100 million I would bring in people with serious experience in the pharma industry who can run projects. The first step once those people are in place is to recruit chemical scientists who can create the first compounds targeting the receptors we want.

It would be hard to match the big pharma companies salaries, but the upside in an early stage company and in a whole new field could attract some big thinking young(in spirit) scientists. Its not hard to see a 100x upside on their stock options.

Our first chemicals would have like a 0% chance of success. But with those we could go back to investors with 'early stage candidates'. 'Fight Aging Senolytics Inc.' FAS-0987, FAS-1023, etc.

Step 2.. Link up with organizations like universities, SENS, etc. doing the research. We pay for some of their research.. but the main think we want here is their expertise in the area. Meantime now with new bigger investor money we are engaging in a serious scientific effort in our laboratories.

Step 3.. Now we are getting somewhere and have a number of chemicals showing some promise. Here is where we interact with the FDA asking what they want to see, and what theoretically could get approval - like should the trials be against a certain disease, biomarkers, etc. You hire people like retired FDA experts/people with experience doing this.

Step 4.. Phase 1 trials just check carefully escalating doses to check for safety.

Step 5.. Phase 2 trials are where you have small trials to try to show some benefit. You have to hire statistics people and scientists with experience running trials.

Step 6.. If the corp got promising results in a phase 2 trial here is where you sell to a mega pharmaceutical corporation.

You see Phase 3 and beyond costs run into the billions and small corporations are not set up to do this.

Posted by: aa3 at February 21st, 2018 10:58 PM

@Anonymoose
> Using senolytics or any treatment which has been shown to alleviate aging in a prophylactic
> manner is probably not going to happen any time soon.

Depends on how you define soon. A lot of people are on beta blockers, blood thinners or statins already. To alleviate age related diseases in a prophylactic manner. What's different for senolytics? They're new and there's not much data available.

Posted by: Matthias F at February 22nd, 2018 10:00 AM

Dasatinib has promise as a senolytic agent, but the bioavailability of quercetin, while adequate in rodents, is horrible in humans. This renders quercetin likely a useless senolytic agent for humans. Perhaps the Betterhumans trial will generate some data, but I don't have high hopes for quercetin.

Posted by: niner at February 22nd, 2018 4:45 PM

Niner, what do you base your assertion that Quercetin has horrible bioavailability in humans? This 1997 study reports a 24% +-9% absorption for Quercetin aglycone, the type of Q found in OTC supplements. https://s3.amazonaws.com/academia.edu.documents/40037687/559b998808ae99aa62ce5e8f.pdf20151115-68247-1fmqkzf.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1519352508&Signature=QeNLeG2HSjM92aTarW3ObPTT5mw%3D&response-content-disposition=inline%3B%20filename%3DBioavailability_of_the_dietary_antioxida.pdf or here http://www.cancerletters.info/article/S0304-3835(97)04644-2/abstract Not great absorption, but at 40 cents per gram who cares.

Posted by: JohnD at February 22nd, 2018 7:36 PM

@JohnD: The assumption here is that dasatinib will kill only a fraction of senescent cells, but repeating it multiple times a year will not kill that same fraction each time. The first treatment kills near all that dasatinib is capable of killing. Repeating it won't help much until a sizable number of new senescent cells have emerged. The only way to do better is to use a better senolytic, or multiple senolytics with different characteristics for the senescent cells they are capable of killing.

This all needs to be validated in human studies, of course.

Posted by: Reason at February 22nd, 2018 7:49 PM

Dasatinib price would drop dramatically after 2020. I would estimate $6 per tablet.

Posted by: Tj Green at February 28th, 2018 7:17 AM

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