Preventive drugs may be the best solution to the antibiotic resistance crisis
By Brian Finrow│This piece was originally published at STAT NEWS on October 18, 2023
The antibiotics crisis is a silent pandemic that threatens to knock modern society back into the medieval age of therapeutic leaches and serum therapy. A world where an accidental scratch in the rose garden can kill.
Why is the supply of new antibiotics so thin, and growing thinner? A high-profile Wall Street Journal article recently highlighted what everyone knows: There is huge need but no market demand.
There are many interrelated causes. Doctors prefer to keep novel antibiotics in reserve, as a last-resort option, limiting sales volumes. Insurance companies like novel antibiotics that prevent costly ICU stays, but they’re used to the cheap price of older generics and balk at any price that allows recoupment of the full cost of development. Low prices and small volumes are a great recipe for insolvency as Achaogen’s experience showed.
The second order effects are pernicious, too. VCs and big pharma companies see the commercial failure, and — acting as good custodians of their investors’ capital — they naturally look to other, less risky opportunities. In today’s environment, even cryptocurrency might be a better bet.
All these choices are individually rational, but together they yield a tragedy of the commons — the “commons” here being our limited pool of cheap, generic antibiotics.
What’s to be done? Subsidizing supply is surely part of the solution — and the PASTEUR Actand CARB-X are great initial steps — but they are a drop in the bucket relative to the need. Far better to unleash the larger and more dynamic efforts of private enterprise, and this means finding new business models that can stand on their own, solvently.
But there’s an underappreciated solution to the broken market for antimicrobials: preventive biologic drugs. These are therapeutics that act directly on the causal organism like most drugs, but, like vaccines, they aim to prevent infection rather that treating it after it has already set in. In fact, Lumen Bio, where I am CEO, is among the research groups working on this approach, alongside other companies including Astellas Pharma, Provention Bio, and Leyden Labs. Lumen Bio did not invent the idea of preventive biologics, but we’re doing our part to help make it a reality.
Preventive biologics can address the anti-infectives market failure while simultaneously improving patients’ lives and reducing health care costs. Here’s how.
To appreciate the potential impact of preventive drugs relative to conventional treatments, consider the situation from the perspective of various stakeholders in the health care system. Would patients prefer a new drug that rescues them at death’s door, or a preventive drug that saves them from reaching death’s door in the first place? Would caregivers prefer a drug that puts their loved one on the road to recovery, or one that keeps them off the wrong path in the first place? As an insurer or Medicare, would you prefer a new drug that gets people out of the ICU, or one that keeps them out of the ICU in the first place?
Most importantly from an investor perspective: Preventive drugs are among the most profitable in industry history. Examples include statins like Lipitor (to prevent heart attacks and strokes), HIV cocktails (to prevent AIDS), and incretin therapy (to prevent diabetes, NASH, heart disease).
They do so while simultaneously providing greater benefits to patients and caregivers and saving the health care system money.
In Economics 101, we learn that products are subject to economies of scale, and drugs are no different. Novel antibiotics lack scale, so they lack economies of scale. Antibiotics are not atypical in this regard. In fact, the market sizes of newly launched drugs have been shrinkingfor years — it’s one of the major causes of the biopharma industry’s R&D productivity crisis.
The trend is especially pronounced in the antibiotics field, but antibiotics makers can’t raise prices to compensate as commonly done in other disease areas. The retail price of a typical antibiotics course is around $40, but even pricing its novel antibiotic 100 times higher didn’t save Achaogen from bankruptcy in 2019.
Preventive drugs are one way to reverse this trend: They’re generally sold at much higher volumes and lower unit prices. For example, more than 100 people must take statins for five years to prevent a single heart attack. This is a straightforward way to measure the difference between treatment and prevention markets. Compared with a notional “heart attack treatment” drug, the market for a “heart attack preventive” drug is at least 100 times larger.
There are some catches, however. Preventive drugs for AMR must be extremely safe and well tolerated because they will be administered to many patients who, in a statistical sense in retrospect, didn’t need it. This is one reason why conventional chemical antibiotics cannot be used this way — most are unsafe for routine use. (Broad prophylactic use of conventional antibiotics would also accelerate antibiotic resistance.)
Another catch is that each dose must be very inexpensive — by definition cheap enough for mass-market consumption. The FDA-grade manufacturing must also be massively scalable — scalable enough for global use because, like Covid-19, antibiotic-resistant bacteria do not respect national borders.
These are tall orders for our industry because of a tension inherent to the two main kinds of drugs made today: small-molecule (chemical) pharmaceuticals and injected biologics. The former are cheap and scalable to make and distribute, but they come with higher safety risks (consider Vioxx and fen-phen). Injected biologics like monoclonal antibodies are much safer but they’re also far more expensive, particularly for infectious diseases because they tend to require much larger dose sizes. They’re also not very scalable.
These barriers are daunting, but they’re merely technical in nature so should be much easier to solve than the market structure problems above. The former can be rationally tackled with technology; the latter are rooted in societal values, government policies, and human nature, all of which are more intransigent.
Our own experience at Lumen Bio is encouraging. Tuesday we announced $16.2 million in new funding from the U.S. Department of Defense, which will allow us to execute the REPREVE Study, a late-stage clinical trial assessing an orally delivered cocktail of four biologic drugs, called LMN-201, and its ability to prevent recurrence of C. difficile infection, or CDI. It’s worth looking at this program in some detail because it illustrates many of the key themes in action.
CDI is a common and extremely serious hospital-acquired bacterial infection. With as many as 8.4 million people (see graphic below) at significant risk each year in the U.S. alone, there is a vast need for a safe, affordable, scalable CDI preventive drug. By one estimate, U.S. hospitals spent over $8 billion managing this one disease in 2009–2.3% of all U.S. hospital spending that year; the problem has only grown since then. Assigning value to the death, pain, and suffering of patients and their caregivers, the fully accounted economic burden is far higher. There is also a significant and growing community-acquired CDI burden in the U.S., which may comprise more than half of all CDI cases. The global economic burden is larger still.
In short, all stakeholders — patients, caregivers, and the health care system itself — stand to reap enormous savings from a safe, affordable, scalable CDI preventive drug.
The CDI preventives available lack the scalability and affordability needed to help most of these patients. Start with scale. There are approximately 9 million episodes each year in the U.S. where a patient experiences a fairly high risk (about 10% or more) of contracting a new bout of CDI within a short period (about 12 weeks or less). In a terrible irony, the main cause of CDI is, in fact, antibiotics, but this makes it easy to find those at risk.
The monoclonal antibody now on the market (bezlotoxumab) is made with traditional CHO-cell fermentation and IV administration. The fecal microbiota transplant (FMT)-based preventives (Vowst, Rebyota) are reliant on human donors, which is even more costly than monoclonal antibodies. They also require extensive safety testing due to the prior patient fatalities associated with past FMT treatments and the risk of accidentally transferring pathogens with the stool donation. (Convincing patients to ingest the fecal material of strangers is another adoption barrier.)
In health economics terms, a 10% risk means that roughly 10 patients must be treated to prevent one case of CDI. Current preventives carry list prices between $4,000 and $20,000 per treatment (higher when delivery costs are included — IV infusion, enema administration, or bowel prep). Even if these products were 100% effective, the effective cost per prevented CDI case would be $200,000. (In reality they’re only 34% to 68% effective, so the true economics are significantly worse.) This is too high for the health care system to absorb, so these products will likely continue to see very limited update uptake outside of the extremely high-risk patients where CDI recurrence risk can be as high as 50% (implying a number-needed-to-treat as low as 2).
The figure below shows how sensitive preventive markets are to scaling and cost considerations in practice. My colleagues at Lumen Bio and I asked two health economists to assemble all the available epidemiological data on U.S. CDI occurrence/recurrence rates and their respective associations with various antibiotics. This data was collated to generate a model of CDI recurrence risk by tier, with Tier 1 corresponding to a 12-week CDI case risk in excess of approximately 40%, Tier 2 approximately 25%, and Tier 3 approximately 12%. Total at-risk patient populations were calculated on this basis. Each CDI preventive product’s addressable market was then assessed by comparing its volume-weighted acquisition price to the average cost of a CDI case in U.S. hospitals ($34,000) adjusted by the reported CDI prevention efficacy rate for each product.
Intuitively, an oral pill that requires no IV infusion, enema administration, or bowel cleanse, cheaply made in a scalable way, can be made available to many more patients (large green circle) than a cumbersome, costly intervention (the orphan indication “multiply-recurrent CDI”, red sliver).
LMN-201 shows how this vision can be realized with technology available today. It is massively scalable; easily distributed, stored, and administered (oral capsules; no needles, enemas, or bowel preps); and affordable even for patients at more modest risk of recurrence. In contrast to those existing preventives now on the market, LMN-201 is produced using the same basic methods used to make the spirulina sold affordably and in vast quantities through supermarkets today. This means it is scalable and cheap to make in large enough quantities to serve the entire global market. The drug will be delivered orally in tablets or capsules; no needle, bowel cleanse, or enema required. And according to preliminary stability data, it is expected to be shelf-stable at room temperature, obviating the need for costly refrigerated storage and distribution. It was built from the ground up for universal, global-scale adoption.
Preventive drugs have an important and underappreciated role to play in keeping antibiotic-resistant microbes from dominating our lives as they did a century ago. By expanding the customer base and improving the value delivered (an ounce of prevention is worth a pound of cure), preventive drugs can sidestep the failure of the commons issues that plague conventional antibiotics developers. Working out how to make many more drugs with the safety and scalability for broad-usage preventives are nontrivial technical challenges, but the potential impact on human flourishing is profound.
Brian Finrow is founder and CEO of Lumen Bioscience, a clinical-stage biotechnology company in Seattle.
