The Critical Fix We Need To Rebuild Our Broken Antibiotic Pipeline
Recently, a Ukrainian soldier in his 50s suffered terrible burns in a vehicle fire. After he was transported to a U.S. military hospital in Germany with infected wounds, his doctors tried to find him an effective antibiotic. But startingly, they discovered that his bacteria were resistant to multiple drugs, including one highly mutated strain resistant to all 27 antibiotics they tested.
This tragic story is not relegated to the front lines of war. Life-threatening infections with superbugs can affect all kinds of people, from cancer patients and laboring women to those hospitalized, undergoing surgery, facing organ transplants, or suffering from diseases like cystic fibrosis.
In 2019, antimicrobial resistance was directly responsible for an estimated 1.27 million deaths worldwide and linked to close to 5 million total. The pandemic didn’t help. In the U.S., Covid reversed years of progress on hospital-acquired drug-resistant infections. Rates of carbapenem-resistant Acinetobacter, one of the highest priority pathogens for the WHO and CDC, jumped 78% from 2019 to 2020.
Not only is the problem worsening, but we also don’t have an adequate arsenal of drugs to fight it. A completely new class of antibiotics has not been developed for over 30 years. The result is the global crisis we find ourselves in today.How We Got Here
Antibiotics are a miracle drug. Penicillin, which was discovered in the 1920s and brought to patients during World War II, revolutionized medicine and have added 20 years to our overall life expectancy.
But antibiotics are fundamentally different from other drugs like insulin or aspirin that remain as effective as when they were first developed. The catch is that the more we use antibiotics, the less useful they become, as bacteria gain mutations that allow them to sidestep our drugs. It’s already well established that antibiotics are overprescribed in primary care, which accelerates resistance, but even if we were to use them judiciously, bacteria would still evolve resistance over time.
“Bacteria are evolutionary machines. They divide every 10 minutes. They really progress fast, and that means we will always have a constant need for innovation in this space,” says Marc Gitzinger, founder and CEO of BioVersys, one of a rarified group of biopharma companies still developing new antibiotics today. “The timelines are hard to predict but every 20–30 years certainly, you need a totally new generation of antibiotics.”
That pipeline is critical, yet ours has become perilously thin.
It’s not the science that’s the main problem — there are academic researchers and some companies working on new approaches to tackle resistant pathogens, from novel antibiotics to phage therapy.
The challenge is the current market incentives — or rather, the lack thereof.
Consider the standard use of antibiotics. You get prescribed a course for 7–10 days and then you’re done. But most markets for drugs depend on volume of use. Here, the volume is purposefully small to forestall resistance. Given the reality that antibiotics can cost more than $1 billion to develop, it’s clear that developers face a difficult path to making their investment back. In fact, of the last nine antibiotics approved for use in the U.S., the companies behind seven have gone bankrupt or experienced significant financial headwinds.
Without a viable model, drugmakers and investors have turned to other areas of high unmet need, like cancer. The numbers tell the story: venture capital investments in oncology over the last decade in the U.S. topped $26.5 billion, whereas the funding invested in antimicrobials was only $1.6 billion.
On top of these stark realities, some of the antibiotics we already have — and still very much need — are facing their own struggles. Pfizer recently warned clinicians about a shortage of a long-acting form of penicillin for kids. Part of the problem is that generic drugs have become very inexpensive, as hospital systems, insurance, and governments exert downward price pressures. Razor-thin margins mean fewer manufacturers, so if a supply chain hiccup hits one, a shortage can result. Possible solutions for these manufacturing issues are currently being discussed in U.S. Congress.
On the pipeline side, what can be done to incentivize much-needed R&D? Fortunately, there are interim solutions and a critically needed long-term one.
“Noah’s Ark” Venture Funds
Several venture capital funds have been established out of necessity in recent years to rescue innovation in antimicrobial therapy development. (Antibiotics, synthetic compounds that target bacteria, fall under the broader category of antimicrobials, which encompass all therapeutic approaches that target bacteria, like phage therapy, as well as medicines that counter viruses, parasites, and fungi.)
The AMR Action Fund launched in 2020 with support from pharma and biotech companies, charitable foundations, the World Health Organization (WHO), the European Investment Bank, and the Wellcome Trust. (Bayer is among the investors.)
Its purpose is to act as a stopgap measure to fund the best of innovation in the space and thus “buy time for policymakers to fix the market and provide the necessary incentives to bring capital naturally back into the sector of health care that has abandoned it over the last 25 to 30 years,” says Henry Skinner, CEO of the AMR Action Fund.
It invests in biotech companies that are developing new antimicrobials for drug-resistant pathogens that are considered by the WHO and CDC to pose the most urgent threats to global health. The fund has about a billion dollars committed to invest over ten years, with a public goal of helping to get two to four new antimicrobials approved in the coming decade. By the end of this year, the Fund expects to have committed approximately $200 million in investments to at least six companies.
Gitzinger’s BioVersys, based in Basel, Switzerland, is one of the companies the Action Fund has invested in.
“Currently we are one of the very few companies out there still actually innovating in this space — we call ourselves the persistent survivors — but it’s tough and it’s totally inadequate to the problems we are facing with antimicrobial resistance,” Gitzinger says. “Purely based on the reimbursement front.”
He is frank about the challenges of being in his shoes: “It’s a disaster to run a company in the AMR field. If you thought biotech fundraising is hard, try antibiotic resistance. However, the drug development costs the same as any other drug, so we have to do this stuff.”
The good news is that BioVersys has two programs in phase 2 clinical trials, and two preclinical stage assets in the pipeline. One of the clinical programs is for a novel mode of action and formulation of an antibiotic directed against one of the highest priority bacterial pathogens: Acinetobacter baumannii. Patients hospitalized with severe infections tend to be susceptible to this resistant pathogen and current survival rates for resistant A.baumannii lung infections are only 50 percent. The program is recruiting adult ventilated patients at multiple sites, including in Hungary, Georgia, and Greece.
The other clinical program, which is recruiting in South Africa, is a first-in-class new molecule for tuberculosis given in combination with an old TB drug, to treat pulmonary tuberculosis. The program will also be investigated in extra-pulmonary tuberculosis, like meningitis in patients who have no or very limited treatment options.
“You have diseases like Acinetobacter where physicians are actually crying out loud for new drugs because they don’t have appropriate therapies in hand today,” Gitzinger says.
Another bridge fund is the REPAIR Impact Fund, commissioned by the Novo Nordisk Foundation. It launched five years ago to advance early-stage therapeutics and vaccines for resistant bacteria and fungi.
Aleks Engel, the fund’s director who is also a partner with Novo Holdings based in Boston, explains that its goal is to advance innovations through human proof-of-concept results, with the intent that such programs would be “de-risked and attractive for other investors.”
REPAIR has so far deployed about half of its $165 million across 10 investments, two of which have progressed through phase 1 clinical trials.
But earlier this year, the fund was put on pause because policymakers have still not advanced reimbursement reforms for developers.
“When we started this five years ago, we recognized the broken business model of the space, but said given our nature and very long-term investment horizon, we can stomach that risk and at the same time hope something will happen over the next few years,” Engel says. “Well, it’s been a few years and not a lot has happened.”
The Critical Long-Term Fix
There’s no doubt that the AMR Action Fund and the REPAIR Impact Fund are essential bridges, but without financial viability for drug developers and investors, the updated wave of medicines we need in the coming decades won’t come fast enough.
That’s why experts in the field are unanimous and vocal in their support of a proposal now in front of U.S. Congress called the Pasteur Act. If this policy passes, then the reimbursement of antimicrobial drugs would change. Instead of drug developers being paid per volume used — the problematic status quo — the government would commit to pre-purchasing a proven new antibiotic at a fixed sum. Like the Netflix subscription model, physicians would be able to decide how much or how little to prescribe the drug to their patients. Limited use would no longer conflict with economic sustainability.
“If that was done [across] wealthy countries, there would be a guarantee of financial return on antibiotics and patients would have a guarantee of accessibility,” Skinner says.
The Pasteur Act has bipartisan support and has been introduced three times in Congress, most recently in April, but it’s unclear whether it will pass. Its total price tag would be $6 billion over ten years.
Engel agrees that the Pasteur Act and other international policies like it, such as a leading one in the UK, would revive the ecosystem of innovation. Sweden and Japan are also running pilot programs and Canada may be next.
If the Pasteur Act passes Congress, Engel says the REPAIR fund would come back: “Those types of reimbursement reforms that Pasteur represents are exactly what we’re looking for, which is to change reimbursement from a per-volume reimbursement to access for working antibiotics.”
The time is now to build up our armamentarium of new medicines for antimicrobial resistance — before a highly resistant pathogen like the one that infected the Ukrainian soldier causes an outbreak. Drug-resistant bacteria don’t respect borders, and every year their numbers are growing.
The need for a policy leap now goes beyond incentivizing innovation. As Gitzinger says, “It’s about preserving our style and way of life.”
“One of the challenges with drug-resistant infections is that we all take antibiotics for granted,” echoes Skinner, describing how he could always count on amoxicillin to help his kids’ ear infections after 24 to 48 hours. “And yet we’re just that one bad pathogen away from effectively being back in Civil War medicine where there’s nothing physicians can do except hope and pray.”
Special thanks to Kira Peikoff for her additional research and reporting on this article.
The article was initially published on Forbes.com on August 10th, 2023