Biopharma has abandoned antibiotic development | Hacker News Reader

Biopharma has abandoned antibiotic development

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106 pointsrefurb66 comments

From the article, "Public measures designed to incentivize development of new antibiotics are woefully inadequate."

This is the issue. Relying on private entities to provide (R&D, clinical trials) for what are ostensibly public goods (antibiotic resistant bugs puts every person at risk) brings the real risk of market failure.

The NIH is making some progress on this front.

https://aspe.hhs.gov/system/files/pdf/258516/ProgressYears1a...

It appears that overprescribing existing antibiotics to people and livestock is a leading cause of rising drug resistance, both of which can be addressed by policy changes.

> It appears that overprescribing existing antibiotics to people and livestock is a leading cause of rising drug resistance, both of which can be addressed by policy changes.

I worry that any changes in that area will be too little too late.

It seems like overprescribing to a cow is such low hanging fruit.

I understand that if my 5-day-old child marginally needs antibiotics, that the doctor may prescribe to appear active.

But couldn’t sensible legislation end over-prescription to livestock overnight? Is this really an issue of beating the cow lobby?

The "cow lobby" is large multinational corporations... so yes it's an issue beating their lobbyists. Also, a side effect of antibiotics is weight gain in livestock - so even legislation that ostensibly outlaws use for the direct purpose of directly adding to profits, language in regulation is generally kept for medical purposes of "reducing disease" among herds. Disease that is at a high rate because of high density feedlot practices...

I think a weight loss factor could be added to legal antibiotics to remove the benefits of their overuse.. Caffeinated cows on a rampage might correct the industry.

> a side effect of antibiotics is weight gain in livestock

Original article in Nature: https://www.nature.com/articles/nature11400

There have been quantitative calculations for antibiotics taught for years in ag departments, and known among industry practitioners. Farming is a highly quantitative industry, and any agent of growth promotion is tracked carefully along with feed energy & cost inputs. Today you may have to go back to older documents to see talk about it in a more open manner though.

Here's a more industrial type of analysis paper (2003)

https://www.cambridge.org/core/journals/journal-of-agricultu...

Overprescribing antibiotics to animals helps keep meat cheap. Politicians have a hard time with the headwinds caused by ads like “Evil big-government libs are raising the price of your steak!!” So it doesn’t happen. You’d probably be surprised how cheap some feed antibiotics are — Tylan powder being a good example.

In short, yes, it is beating lobbyists and opportunistic political opponents. Even if this issue is important to you, political capital is not limitless, so it has to be weighed against a whole host of other issues.

> It appears that overprescribing existing antibiotics to people and livestock is a leading cause of rising drug resistance, both of which can be addressed by policy changes.

About 80% of antibiotics sold in the US are used in agriculture[1], where they are given to animals not to treat infections, but to prevent them and to stimulate growth.

Over 60% of infectious disease in humans are spread from animals, and 75% of new diseases in humans are spread from animals[2].

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638249/

[2] https://www.cdc.gov/onehealth/basics/zoonotic-diseases.html

Back in 2017, the FDA banned the use of medicinally important antibiotics in livestock.

https://www.cdc.gov/drugresistance/food.html

That's good to know, thanks for the link. However, up until recently, you could buy 55-gallon drums of antibiotics without a license on sites like Alibaba.

This line item for allowed uses from that link:

* Prevent disease in animals that are at risk for becoming sick

Is pretty much a giant loophole.

If those animals are treated, they then need to be pulled out of the food supply until the antibiotic washes out.

It’s not in a farmers best interest to use an antibiotic in those circumstances unless the animal needs it.

That’s often irrelevant. If a cow is going to be slaughtered at 36 months, you can use antibiotics for 95% of their lifetime and still have a 50 days window at the end.

>until the antibiotic washes out.

This is part of the problem. If animals are given the antibiotics, then their waste products contain them, and piles of manure or water runoff/storm drains/wastewater ponds form a giant evolutionary experiment for development of drug resistant organisms.

They're not just a problem while they're in animals, they're a problem if they're used at all.

Apparently, most antibiotics don't undergo metabolism in animals, and 40-90% of ingested antibiotics in livestock are excreted in urine and feces[1].

Those antibiotics go on to contaminate groundwater, and as you say, contribute significantly to antibiotic resistance[2].

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220964/

[2] https://en.wikipedia.org/wiki/Antibiotic_use_in_livestock#An...

Does that make any practical difference for animals meant for consumption like beef cattle, hogs, or chickens? You can give them all the antibiotics you want until a few days before slaughter.

It does. The animals will be colonized by bacteria that have "learned" to deal with all those antibiotics you gave. That resistance is easily transmitted.

I understand the problem with antibiotic resistance, but telling a farmer that an animal treated by antibiotics can't enter the food supply until after treatment ends doesn't really solve the problem when it comes to animals raised as food -- the farmer can treat the animal with antibiotics for nearly all of its life, only stopping the treatment just before slaughter.

Totally agreed. I'm naive to much around Ag/Husbandry. If that's what farmers do, that is a concern. From a microbiology point of view, the concept that "washing out" the drug before slaughter improves anything is flawed. It will be a reservoir of smoldering antibiotic resistance as long as that practice persists.

> until the antibiotic washes out.

while I don't want surprise antibiotics in my food, I'm probably more concerned about the antibiotic resistance that antibiotic exposure generates. The flora of those animals _will_ have drug resistance genes that doesn't just "wash out". That resistnce can be passed to other animals or human by direct contact, environment or otherwise.

Much of the emerging evidence is that while the amount used in livestock makes for flashy numbers, it's likely medical overuse in humans is the main driver of the problem.

Recent mini-thread on it by Marc Lipsitch, a Harvard epidemiologist who does a lot of work in the area: https://twitter.com/mlipsitch/status/1206419839872569346

Including use in urban poverty: https://www.nytimes.com/2019/04/07/health/antibiotic-resista...

Where antibiotics are handed out without prescription and people live in squalid conditions.

"70 percent of salmonella infections in Kenya had stopped responding to the most widely available antibiotics, up from 45 percent in the early 2000s."

"Even when the drugs are authentic, many poor Kenyans try to save money by buying just a few tablets instead of the full course — not enough to vanquish an infection but enough to allow bacteria to mutate and gain resistance."

The current population of Kenya is 50m, forecast to increase to 95m by 2050, and 156m by 2100.

Kenya also currently has the scientific output of Serbia, a country 14% the size. Its likely that Kenya will continue to import drugs developed in advanced nations, and internally produce only antibiotic resistance.

https://www.natureindex.com/country-outputs/generate/All/glo...

SO I do a little work in Kenya, and it's really hard there. Because you do have rampant resistance, but you also have lack of drug availability - especially in rural parts of Kenya.

We've got some data suggesting there that stewardship is, relatively speaking, less impactful there than decreases in transmission. Because the environment is heavily contaminated, which is itself conducive to the spread of resistance.

I've seen this in sports and games. Sometimes everybody know they should make a move to catch up with the current leader but if they do they probably spend too many resources and lose from the others close to them. So they wait for somebody else to self sacrifice and the leader eventually wins. The leader here are the superbugs and I'm afraid that no normal market rules can make us win this race.

There is a tragedy of the commons problem as well: from massive over-use of the same antibiotics in farm animals. Antibiotic susceptibility is a asset of the commons. And there are farmers who are incentivized to ruin it for everyone else.

I would interpret this as roughly equivalent to the biomedical industry telling Congress they need to put the meat industry in its place. Stopping use of antibiotics in animal husbandry will raise the price of meats, decreasing the market for them. It seems that Congress is, by neglect, accepting some human deaths in exchange for cheap meat and a few animal husbandry jobs.

I work in this area, and a couple notes:

- The free market is actually doing a really good job driving down antibiotic use in livestock.

- There's not a huge amount of evidence that livestock use of antibiotics has as big an impact on human resistance patterns we see. Overuse in human populations is a big enough problem on its own. Medicine has, in some ways, been really eager to abdicate its own role in developing resistance by pointing at veterinary use.

- There are a number of policy changes already in effect, but all they can do is kick the can down the road a little. Bacteria will develop resistance to antibiotics - it's what they do. Some more easily, some less easily. This is a treadmill you can never get off - all stewardship does is control the speed. Even with good stewardship programs, we'll still need new classes of antibiotics.

A reminder: Poor sanitation in underdeveloped countries is part of what is breeding antibiotic resistant infections which then get exported to more developed countries thanks to the modern ability to get from pretty much anywhere on the planet to pretty much anywhere else on the planet that people typically reside in about 24 hours (or less).

The last time I said this, someone apparently thought I was being racist and classist and saying mean things about "those people" overseas. I'm not.

I'm saying there are other ways to tackle this issue and one is by supporting hygiene programs worldwide, including here in the US when the revival of sometimes deadly Medieval Diseases is associated with the homeless crisis we are having.

Gates foundation is working on toilets to remediate this exact problem.

https://www.gatesfoundation.org/what-we-do/global-growth-and...

> Poor sanitation in underdeveloped countries

It's not just poor sanitation. It's that in underdeveloped countries antibiotics are completely uncontrolled, available without a prescription for almost nothing. This availability promotes misuse.

Better sanitation and hygiene would help with that as well, though. People would no longer get sick with lots of infections that can easily be prevented in other ways, and the habit of overprescribing antibiotics would disappear.

People take antibiotics prophylactically all the time even here in the US. They'll do so in the developing world too unless stopped with regulation restricting use of antibiotics to cases where they'll be effective.

Poor sanitation is a separate, important and usually overlooked issue that contributes to this issue in its own right. It isn't all about how antibiotics are used.

That's my primary point: Antibiotic resistance is not just about antibiotic use.

"An ounce of prevention is worth a pound of cure."

Open defecation is still widely practiced in sometimes densely populated parts of the world where it is known to cause and spread illness. Building toilets (and the infrastructure that goes with them) is known to reduce incidence of illness.

It's not just the availability that's the problem. Generic antibiotics sold in markets with little to no effective government oversight are often highly defective, with incredible variance between the active ingredient dosage listed on the label versus what's actually in the product itself. In most cases, the active ingredient contents are much lower than the label indicates, meaning that patients don't actually receive a therapeutically effective treatment unless they gamble on taking larger or more frequent doses than are indicated. Under-dosing in this manner creates excellent conditions for breeding resistant strains of bacteria.

>Achaogen ($AKAO) and Paratek ($PRTK) both had NDAs approved for novel antibiotics and saw their stock prices drop sharply in response to the news, as investors anticipated all those pesky expenses related to commercialization.

I was around for most of Achaogen's implosion. Some key points not mentioned in this blog post:

1.) In the ~12 months leading up to FDA approval, Achaogen started burning their capital at a rate that was, frankly, insane. Financial decision-makers were definitely counting their chickens before they hatched, and this ultimately seems to have resulted in massive cuts to opex (e.g. sales positions) that snowballed into abysmal revenue once Zemdri hit the market.

2.) The FDA approved Achaogen's product, Zemdri, indication for complex UTIs (cUTI), but not for bloodstream infections (BSI). The latter indication is much more lucrative. My personal opinion is that this factor alone wasn't responsible for the poor sales numbers, but it was certainly a huge contributor to the problem.

There's no guarantee that there even are further broad spectrum antibiotics possible.

As far as I understand, what's needed here is (first) fundamental research, then discussion of promising ideas, then maybe you can rely on private companies to perfect and bring to market new molecules.

Thats a far cry from other drugs for other diseases where there is a futile set of fundamentals to pick over and small research groups spinning off from universities regulatly.

Every time I've heard of new prospects, it's either been reexamining old methods (like plagues) or new fundamental work (sampling and sequencing new bacteria, studies on fungi).

So instead of "incentives", we should just man up and fund some biology and stop wasting what we have already on farm animal fattening programs and the worried well etc.

If the public knew about this problem, if it were marketed to them there might be a solution. You'd likely need some policy changes too. But if I could choose between an insurance that supported and supplied new antibiotics I'd jump at that insurance over one that did not. I'd happily pay more to be covered for something so fundamental.

Obviously there would be a lot to iron out but I think there is an opportunity for health insurance companies to make a good amount of money off of that.

I'm guessing however that existing policy would make this impossible.

So much of the modern corporation has been outsourced...including nearly all research. Most animal research today and Phase II trials are done...in China/India.

The evidence that these studies are largely faked due to the pressure put on the staff and management there has been piling up for years. I would recommend “Science Mart: Privatizing American Science” by Philip Mirowski for more on this.

> and that larger players would correspondingly re-enter the market, hungry to pick up first-in-class antibiotic programs.

Does this mean their business model is basically always going to be getting acquired by one of the big pharma firms?

Yes, This is essentially the only model in Pharma and bio-med.

Public fund, public production. Take antibiotics research out of the IPR domain, and put it back into public health funding.

Tldr: privately funded research is not working.

I don't understand why antibiotics research can't be done at (publicly funded) universities?

> Approval incentives were not the only policy included in the GAIN Act. There were also measures designed to promote stewardship, or appropriate use, of new antibiotics. In short, when a new antibiotic becomes available, it should only be used as a last resort to prevent new resistance from arising. This kind of responsible use is a good thing! But stewardship severely limits the number of patients who will receive a new antibiotic and, correspondingly, the potential sales volume.

Privately funded research is unable to overcome the well intentioned regulations that are preventing use of the antibiotics that are developed.

Instead of hoarding the few antibiotics we have, we should be moving faster and keeping ahead of the problem, but the current regulations essentially prohibit that.

It's comparatively difficult to do applied research with grant funding, which is what most "publicly funded" universities tend to rely on. For this sort of high-value research, what you want is prizes so that success can be rewarded after the fact, even when the usual "market" mechanism of selling drugs is not working very well for whatever reason. Current policy approaches provide 'development incentives' of some sort as OP mentions, but clearly these are not enough.

Or crazy thought, expand the number and duration of grants to research this area...

You can't rely on researchers to make a product out of their findings (running trials and getting approval) and that's were the big costs are.

That's precisely where the difference between grants and prizes would be clearest. If there is a big fat prize for, e.g. getting approval of a new antibiotic, people will be incented to push it through the pipeline.

That's the thing about applied research, in biotech/med and elsewhere: it doesn't get much interest from researchers, but the results are comparatively easy to evaluate for an uninvolved third party.

Not in the current job climate, but if (say) successfully shepherding something through FDA approval were treated like a Nature paper, I bet you'd see a lot more researchers trying it.

The problem with the prize idea is that this stuff is expensive. Most academic institutions don't have a mechanism for doing something "on credit" and hoping to win a prize that covers the costs and then some. Some companies can, but the optics of giving prizes to BigPharma also aren't great.

> Most academic institutions don't have a mechanism for doing something "on credit" and hoping to win a prize that covers the costs and then some.

Some do, actually. It's called an "endowment". Unless by mechanism you meant an internal policy to allow for this - but that's the sort of stuff that can be changed with relative ease.

I chuckled a little at "relative ease" (nothing involving university legal stuff is easy) but ran some numbers to see how feasible that would be.

The median Phase II trial costs about $10M and has a 30% success rate; Phase III costs a lot more (say 2x that), but has better odds (58% advance to approval, and 85% of those get approved). Neglecting Phase I and everything before it, the expected cost is therefore about $16M (over ~3 years) and gets you an approved drug 15% of the time.

There are only 11 individual universities (plus three university systems) with endowments over $10B, but a surprising number with endowments in the $1B range. The draw rate on endowments is usually capped at 5% so that the principal remains intact, giving you around $50M for the entire university's endowment income.

A single trial would therefore consume about 10% of the endowment income per year--and with a 15% success rate, it's probably not going to win anything. There's no way a university president is going to let a group of researchers make a gamble like that.

One thing at a time, first uncover more promising avenues to antibiotics. Maybe they get private investment, maybe not, if not then go ahead and publicly fund the next stage.

None of this kind of thing stops say defense spending. We say hey our defense experts say we need x vehicle to defend our nation. Let's build x.

Our medical experts say we will need antibiotics in the future. It's a nice optimization perhaps to use crossover private profitability to fund the path to more drugs, but if the path isn't there privately, no one says, well we needed a new Aircraft carrier to defend the nation but none is available on the private market, oh well, guess we just live without.

It’s already being done.

The question is, what do you do when you identify a new antibiotic? Who pays for the clinical trials and manufacturing?

Academic centers don’t have experience in doing either of those for an FDA approved drug.

The other side of high health care costs in America is that the wealth from overleveraged and dead Americans is absolutely needed to cover drug research and development for the rest of the world

A University can never develop a drug. Pharma companies are very large organisations with a great deal of embedded expertise, and have discipline born out of having to sell a highly regulated product in competitive markets.

Universities are... not that.

The healthcare and pharmaceutical industries sure seem to have a lot of market failures.

A typical failing of short term economic thinking:

Superbugs are virtually certain to kill a huge number of people, because virulent resistant strains gonna Black Death.

But we can't get a payoff within a quarter or whatever the payoff window for the seed money is? Eh, don't bother investing.

This is where the government must step in. Oh right, gubberment baaaad.

Seriously, if these have promise they should be funded for 10 years by a multinational conglomerate.

I mean, maybe the Chinese government will step in. You know, the only forward-thinking major government in the world? What a world.

I would not be surprised if DARPA were already in this space. They have been researching the affects of Sulforaphane on reversing autism in children. Surely they must have teams of people working on antibiotics.

Are there any scientists here from DARPA that can chime in?

The DoD has the DTRA (Defense Threat Reduction Agency) Chemical and Biological Technologies Directorate, which throws funding at things like antibiotics development. Achaogen, mentioned in the blog post here, has received DTRA funding in the past.

BARDA (a US HHS program) is also a huge player in this space.

You're missing the main point of the article.

If you invent a great new antibiotic, it won't be used unless absolutely necessary.

This is a great summary of the article and should be the top comment.

If you write less obnoxiously you would be more likely to convince people of your ideas. Otherwise what's the point?

Ah, reminds me of investing (poorly) in Amplify Biosciences in late 2017...

Since acquired by Armata pharma, which trades around 4 a share, cap of 40M.... I lost 90% of my investment, oh darn, was a bad investment in hindsight.

Looking at that chart in the article, not too surprised the rest of the market in big red territory.

> Under the Affordable Care Act, hospitals must pay a penalty for each hospital-acquired-infection (HAI) occurring within their in-patient population. As a result, if a patient dies from a superbug contracted during a procedure such as surgery, the official cause of death may be instead listed as “Complications from Surgery.” Consistent and systemic undercounting of illnesses and deaths from resistant infections further discourages the development of new antibiotics as the number of patients who need these medicines may appear to be very small.

Sounds like the regulatory environment is overriding any market forces or customer needs.

> Consistent and systemic undercounting of illnesses and deaths from resistant infections

That's not "regulatory environment goes too far", that's "regulatory environment doesn't go far enough".

Pick any problem that regulation causes and you'll find some people saying that the real problem is that the regulation doesn't go far enough. You can listen to these people and expand regulation an indefinite number of times until you end up with a full command economy --- and we all know how well command economies work.

Poorly crafted regulation tends to cause more harm than good. That's why turning to regulation as the solution must be done with care.

On the other side. Unrestrained markets tend to do more harm than good. That's why turning away from regulation must be done with care.

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