Q&A: Nonprofit model for antibiotic development ‘overdue’

Travis B. Nielson, PhD 
Travis B. Nielsen
Brad Spellberg 
Brad Spellberg

The antimicrobial market is broken and not everyone agrees on how to fix it.

In a recent perspective published in The New England Journal of Medicine, Travis B. Nielsen, PhD, an MD/MPH student at the Loyola University Chicago Stritch School of Medicine, Brad Spellberg, MD, chief medical officer of Los Angeles County-University of Southern California Medical Center, and colleagues argued for the establishment of a nonprofit model to sustain antibiotic development.

Infectious Disease News asked Nielsen and Spellberg about the approach and how it would work. – by Caitlyn Stulpin

According to the perspective, there were 42 antibiotics in clinical and preclinical development as of March this year, and the number of new antibiotics approved by the FDA over the past 6 years has tripled. We always hear that the world needs new antibiotics, so these would seem to be encouraging figures. What is the “dark lining” in all of this, as you described it?

The silver cloud is that we’re starting to produce more antibiotics. The dark lining is that we’re mostly producing new “me too” antibiotics that we don’t need. We need more antibiotics that treat infections caused by extremely drug-resistant (XDR) gram-negative bacilli (GNB) and Mycobacterium species. Instead, most antibiotics in the pipeline and approved in the last decade have targeted gram-positive pathogens. Such drugs do not provide meaningful benefit to our patients. Those few antibiotics that DO target XDR GNB are primarily focused on carbapenem-resistant Enterobacteriaceae (CRE) and are redundant with drugs already on the market — again, offering minimal clinical advantage. We don’t need any more CRE drugs right now. Clinicians don’t need more of the same, and industry focusing on more of the same does not help our patients.

What are the strengths of a nonprofit approach to antibiotic development, and what are the potential weaknesses?

The development of antibiotics is no longer a profit-making venture — our article proves this. Recent sales of all antibiotics approved in the last decade have been disappointing, resulting in falling market capitalizations of the companies that developed them. The best-selling antibiotics sell in the range of tens of millions of dollars per year, which is a catastrophic failure for for-profit ventures but would be a lifeline to nonprofits. Unlike for-profit companies, nonprofits don’t have to satisfy insatiable shareholder demand for year-over-year growth. This is a particular problem at venture-backed small companies, which dominate antibiotic development. Venture capitalist firms require very high rates of return over short periods of time, and antibiotics simply can no longer sustain such demand. The antibiotic market has become a commodities market, where high returns on investment are unrealistic. In contrast, nonprofits are capable of pursuing smaller market opportunities that specifically focus on critical, unmet needs and don’t have to demonstrate high rates of return on investment to satisfy shareholder demands.

The biggest obstacle to setting up such a model is establishing the seed capital necessary for starting nonprofit institutes. Calling for recurrent, multibillion-dollar market entry awards for venture-backed for-profit companies amounts to corporate welfare and will be very unpopular with the public. Instead, investing a billion dollars in two or three nonprofits with the mission to sustainably discover and develop new antibiotics is a much better long-term societal investment. Furthermore, if designed correctly, a very carefully targeted pull incentive can help make this model of antibiotic development both sustainable and palatable to the public. This could be done by earmarking revenue from transferrable market exclusivity extensions that allow large pharmaceutical companies a one-time, short-term extension of data exclusivity, funneling some of the additional revenue back into nonprofit institutes to help sustain development of truly needed antibiotics, as deemed by clinical experts.

How feasible is the approach?

The nonprofit approach is not only feasible but has already been proven. The first drug approved to treat tuberculosis in over half a century was brought to market by Johnson & Johnson, with participation by the TB Alliance in a public-private partnership. The TB Alliance is developing multiple other TB drugs as well. This is an excellent model for the future of nonprofit discovery and development of antibiotics.

Have we given existing incentives enough time to work?

Existing incentives have actually worked, if the read-out is volume of new antibiotics in the pipeline and approved. But this expenditure of publicly funded economic subsidies has been poorly targeted. We’ve been spending public money to subsidize development of drugs that do not help our patients in meaningful ways. When it comes to incentivizing antibiotics development, we need less of a shotgun approach and more of a sniper approach. We need better targeting of existing incentives before we consider throwing more money at the problem. We need to advocate for our patients, rather than for venture-backed for-profit companies. These interests are partially aligned but not parallel, so it is important for clinicians to speak up and tell our elected officials and medical societies what we need to care for our patients.

Is the world really approaching a “post-antibiotic era,” as some have suggested?

The world has been approaching a post-antibiotic era since the first use of these miracle drugs. We need to stop thinking of the problem as a winnable race. Bacteria have been adapting to antibiotic selective pressure for billions of years. Antibiotics are their weapons. Humans are only borrowing them. After 2 billion years of evolutionary warfare, it is safe to assume they’ve invented poisons to block every biochemical pathway imaginable and subsequently developed resistance mechanisms to survive such onslaughts. As such, resistance mechanisms already exist throughout nature to any antibiotic we come up with. There will never be a “gorillacillin” that comes along and ends the race against bacteria.

We have a special moment in time right now. Because the latest surge in antibiotic development, we have numerous agents to treat gram-negative bacteria recently approved and in the pipeline. Does this mean all of our problems are solved? No. We could use new antibiotics to treat Acinetobacter, Stenotrophomonas and atypical mycobacteria. But we have enough agents for most bacterial infections in the coming few years. This is the time to stop throwing money blindly at the problem, to stop bringing multiple new antibiotics to market all at once and to take our time to redesign our antibiotic discovery and development enterprise and make it sustainable. The next 5 to 10 years aren’t the problem; the next 500 years are the problem. Assuming artificial intelligence and climate change don’t wipe out humanity, there will be humans in our solar system half a millennium from now, and they’ll want to have effective antibiotics at their disposal. We should stop rushing so many new antibiotics to market all at once and start to intentionally release new ones slowly, one at a time, in a targeted fashion. This will ensure the sustainability of antibiotics effectiveness over time.

Disclosures: Nielsen reports owning equity in BioAIM and ExBaq. Spellberg reports receiving consulting fees from Acuryx, Alexion, Bayer, Cempra, Forge, GlaxoSmithKline, Merck, Paratek, Peptilogics, Pfizer, Shionogi, Synthetic Biologics and Tetraphase, and has owned equity in BioAIM, ExBaq, Motif, MycoMed, NovaDigm Therapeutics and Synthetic Biologics.

Travis B. Nielson, PhD 
Travis B. Nielsen
Brad Spellberg 
Brad Spellberg

The antimicrobial market is broken and not everyone agrees on how to fix it.

In a recent perspective published in The New England Journal of Medicine, Travis B. Nielsen, PhD, an MD/MPH student at the Loyola University Chicago Stritch School of Medicine, Brad Spellberg, MD, chief medical officer of Los Angeles County-University of Southern California Medical Center, and colleagues argued for the establishment of a nonprofit model to sustain antibiotic development.

Infectious Disease News asked Nielsen and Spellberg about the approach and how it would work. – by Caitlyn Stulpin

According to the perspective, there were 42 antibiotics in clinical and preclinical development as of March this year, and the number of new antibiotics approved by the FDA over the past 6 years has tripled. We always hear that the world needs new antibiotics, so these would seem to be encouraging figures. What is the “dark lining” in all of this, as you described it?

The silver cloud is that we’re starting to produce more antibiotics. The dark lining is that we’re mostly producing new “me too” antibiotics that we don’t need. We need more antibiotics that treat infections caused by extremely drug-resistant (XDR) gram-negative bacilli (GNB) and Mycobacterium species. Instead, most antibiotics in the pipeline and approved in the last decade have targeted gram-positive pathogens. Such drugs do not provide meaningful benefit to our patients. Those few antibiotics that DO target XDR GNB are primarily focused on carbapenem-resistant Enterobacteriaceae (CRE) and are redundant with drugs already on the market — again, offering minimal clinical advantage. We don’t need any more CRE drugs right now. Clinicians don’t need more of the same, and industry focusing on more of the same does not help our patients.

What are the strengths of a nonprofit approach to antibiotic development, and what are the potential weaknesses?

The development of antibiotics is no longer a profit-making venture — our article proves this. Recent sales of all antibiotics approved in the last decade have been disappointing, resulting in falling market capitalizations of the companies that developed them. The best-selling antibiotics sell in the range of tens of millions of dollars per year, which is a catastrophic failure for for-profit ventures but would be a lifeline to nonprofits. Unlike for-profit companies, nonprofits don’t have to satisfy insatiable shareholder demand for year-over-year growth. This is a particular problem at venture-backed small companies, which dominate antibiotic development. Venture capitalist firms require very high rates of return over short periods of time, and antibiotics simply can no longer sustain such demand. The antibiotic market has become a commodities market, where high returns on investment are unrealistic. In contrast, nonprofits are capable of pursuing smaller market opportunities that specifically focus on critical, unmet needs and don’t have to demonstrate high rates of return on investment to satisfy shareholder demands.

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The biggest obstacle to setting up such a model is establishing the seed capital necessary for starting nonprofit institutes. Calling for recurrent, multibillion-dollar market entry awards for venture-backed for-profit companies amounts to corporate welfare and will be very unpopular with the public. Instead, investing a billion dollars in two or three nonprofits with the mission to sustainably discover and develop new antibiotics is a much better long-term societal investment. Furthermore, if designed correctly, a very carefully targeted pull incentive can help make this model of antibiotic development both sustainable and palatable to the public. This could be done by earmarking revenue from transferrable market exclusivity extensions that allow large pharmaceutical companies a one-time, short-term extension of data exclusivity, funneling some of the additional revenue back into nonprofit institutes to help sustain development of truly needed antibiotics, as deemed by clinical experts.

How feasible is the approach?

The nonprofit approach is not only feasible but has already been proven. The first drug approved to treat tuberculosis in over half a century was brought to market by Johnson & Johnson, with participation by the TB Alliance in a public-private partnership. The TB Alliance is developing multiple other TB drugs as well. This is an excellent model for the future of nonprofit discovery and development of antibiotics.

Have we given existing incentives enough time to work?

Existing incentives have actually worked, if the read-out is volume of new antibiotics in the pipeline and approved. But this expenditure of publicly funded economic subsidies has been poorly targeted. We’ve been spending public money to subsidize development of drugs that do not help our patients in meaningful ways. When it comes to incentivizing antibiotics development, we need less of a shotgun approach and more of a sniper approach. We need better targeting of existing incentives before we consider throwing more money at the problem. We need to advocate for our patients, rather than for venture-backed for-profit companies. These interests are partially aligned but not parallel, so it is important for clinicians to speak up and tell our elected officials and medical societies what we need to care for our patients.

Is the world really approaching a “post-antibiotic era,” as some have suggested?

The world has been approaching a post-antibiotic era since the first use of these miracle drugs. We need to stop thinking of the problem as a winnable race. Bacteria have been adapting to antibiotic selective pressure for billions of years. Antibiotics are their weapons. Humans are only borrowing them. After 2 billion years of evolutionary warfare, it is safe to assume they’ve invented poisons to block every biochemical pathway imaginable and subsequently developed resistance mechanisms to survive such onslaughts. As such, resistance mechanisms already exist throughout nature to any antibiotic we come up with. There will never be a “gorillacillin” that comes along and ends the race against bacteria.

We have a special moment in time right now. Because the latest surge in antibiotic development, we have numerous agents to treat gram-negative bacteria recently approved and in the pipeline. Does this mean all of our problems are solved? No. We could use new antibiotics to treat Acinetobacter, Stenotrophomonas and atypical mycobacteria. But we have enough agents for most bacterial infections in the coming few years. This is the time to stop throwing money blindly at the problem, to stop bringing multiple new antibiotics to market all at once and to take our time to redesign our antibiotic discovery and development enterprise and make it sustainable. The next 5 to 10 years aren’t the problem; the next 500 years are the problem. Assuming artificial intelligence and climate change don’t wipe out humanity, there will be humans in our solar system half a millennium from now, and they’ll want to have effective antibiotics at their disposal. We should stop rushing so many new antibiotics to market all at once and start to intentionally release new ones slowly, one at a time, in a targeted fashion. This will ensure the sustainability of antibiotics effectiveness over time.

Disclosures: Nielsen reports owning equity in BioAIM and ExBaq. Spellberg reports receiving consulting fees from Acuryx, Alexion, Bayer, Cempra, Forge, GlaxoSmithKline, Merck, Paratek, Peptilogics, Pfizer, Shionogi, Synthetic Biologics and Tetraphase, and has owned equity in BioAIM, ExBaq, Motif, MycoMed, NovaDigm Therapeutics and Synthetic Biologics.