In the not-too-distant future that we could be facing — one with rampant, uncontrollable, multidrug-resistant microbes — a seemingly inconsequential infection could have the power to kill. Being admitted to a hospital may do more harm than good, as hospital-acquired infections become incurable. Modern medical procedures, such as organ transplants, chemotherapy, and even surgery, might no longer be possible.
For many patients and physicians, this future is already a reality.
If an individual in the U.S. is infected with a drug-resistant strain of Acinetobacter — a species of bacteria my company is working on that is widely found in hospitals and that has one of the highest rates of resistance to antibiotics — there is a 50% chance he or she will die. An alarming 50% of Acinetobacter infections in the U.S. are drug-resistant; in other parts of the world, rates are as high as 90% with reports of resistance even to drugs of last resort. The treatment for such infections is isolation — and hope.
Today’s reality of resistance to antimicrobial drugs presages the future if we do not make changes to the way we develop, prescribe, and pay for these drugs. These are issues that affect the dwindling number of companies like mine that are working to develop new ways to treat the growing number of pathogens that have become resistant to existing antimicrobial drugs.
In the first half of 2019, this industry witnessed events that would have been unthinkable a few years ago. And while world leaders, organizations, and governments are taking notice, we have a long way to go to achieve a long-term solution.
Earlier this year, Achaogen, a company that overcame the innumerable technical and scientific challenges that face developers of antimicrobial drugs and created a new FDA-approved, commercialized antibiotic, filed for bankruptcy. Other biotechnology companies with recently FDA-approved antibiotics are terminating their research and development efforts in an attempt to survive an unsustainable commercial market.
The majority of large pharma companies, including AstraZeneca — which spun out my company, Entasis, in 2015 — terminated its anti-infective R&D programs and exited this space because of the lack of profitability of novel antibiotics despite positive changes from regulatory agencies (including the FDA), and sizable incentives (especially in the U.S.) that have significantly reduced the R&D costs of developing new antimicrobial drugs.
As the field is reduced to a select few companies, the threat of antimicrobial resistance continues to grow. If we are to stay ahead of it, we must create a sustainable market for new antimicrobial drugs.
As a drug developer for the last 25 years, many of which I spent developing products to fight infectious diseases, I see an urgent need for a multifaceted solution that encompasses a new paradigm for development and commercialization as well as recalibrated incentives and payment models. The solution will require coordinated action between industry, regulators, prescribers, payers, governments, and more. The good news is that there’s progress being made in achieving this alignment.
In the U.S., the Centers for Medicare and Medicaid Services recently released its final rule for a prospective payment system for inpatients that aims to remove reimbursement barriers to the appropriate use of new antibiotics. Under the rule, CMS finalized a new technology add-on payment pathway for antimicrobial drugs that the FDA has designated as qualified infectious disease products. This is important because it is very difficult, and usually impossible, to demonstrate that a new antibiotic is superior to existing ones. Under the new rule, a new qualified infectious disease product will not need to demonstrate that it meets the FDA’s “substantial clinical improvement” criterion, but must meet only cost criteria, which significantly lessens the burden for drug developers.
CMS also increased the level of reimbursement to hospitals from 50% to 75%, and introduced a number of other measures which, in aggregate, should result in hospitals recovering more of the cost associated with treating patients with newly developed antibiotics.
Policymakers are also taking notice and proposing change through legislation. The Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act, first introduced by Sen. Orrin Hatch (R-Utah) in 2018, was dusted off, reinvigorated, and reintroduced in June 2019 by Sens. Johnny Isakson (R-Ga.) and Bob Casey (D-Pa.), and again in July by Reps. Danny Davis (D-Ill.) and Kenny Marchant (R-Texas). DISARM aims to improve access to innovative antimicrobial drugs by removing the reimbursement challenges created by the diagnosis related group, which sets a fixed payment for patients being treated for infections in hospitals. That approach to payment biases physicians toward choosing inexpensive but frequently ineffective and unsafe older medicines.
The bipartisan DISARM Act introduces a much-needed and timely incentive that allows physicians to select newer medicines when needed for the sickest patients and get paid for doing that, effectively leveling the prescription field to ensure appropriate access to new antibiotics that fight serious and life-threatening infections in the inpatient setting.
While I believe that changes in policy and reimbursement will benefit patients in the short term, a greater long-term impact will emerge from antibiotic companies adopting a business model and market approach that are distinctly different from standard approaches.
Antibiotics have traditionally been low-margin/high-volume products broadly prescribed for multiple infection types, even when the specific pathogen isn’t known. Over time, using antibiotics when they aren’t needed, or using the wrong one for the job, has led to widespread antibiotic resistance. Since broad-spectrum, largely generic antibiotics will continue to work for the majority of patients, physicians and pharmacists will rightly want to preserve newer drugs for only the most serious infections that cannot be treated with older antibiotics.
This principle of antibiotic stewardship preserves the effectiveness of new antibiotics by limiting their use and the inevitable emergence of resistance to them. But it also means that new antimicrobial drugs will be used in fewer patients and in a much more targeted way, which means prescribing them only for the sickest patients with the highest medical needs in whom infection with a specific pathogen has been confirmed and for whom older drugs won’t work.
This approach requires companies to develop new antimicrobial drugs that overcome resistance mechanisms and that are made available through a targeted commercialization model. In this way, the majority of patients with drug-sensitive infections will continue to be effectively treated with older, inexpensive, but still-effective antibiotics and physicians will reach for the newer ones that target resistant microbes only for patients who need them. While prices for the new antimicrobials will be higher, their effectiveness and safety will also be greater for the few patients who require them.
Antimicrobial stewardship sets a high bar for new drugs, which need to be clearly differentiated from currently marketed products, address patients with the highest medical needs, and be backed by pharmacoeconomic data demonstrating their benefits to patients and the health care system. With the removal of the artificial diagnosis related group, such novel antibiotics should be priced based upon the value they provide to patients and to society, rather than artificially capped to compete on volume with older generic drugs.
The DISARM Act of 2019, if signed into law, would enable my company and others like it avoid an antimicrobial Armageddon and lead the change, empowering physicians and pharmacists — not spreadsheets — to choose the right medicines for their patients. It would strengthen antimicrobial stewardship and reinvigorate antimicrobial research and development. It would also unleash innovation from small and large companies still committed to this space, and perhaps bring new players into the field.
Policy change can be slow and painful at times, but it is necessary if we are to stay ahead of antimicrobial resistance and preserve medicine as we know it — for ourselves and the generations to come.
Manos Perros, Ph.D., is a co-founder of Entasis Therapeutics and serves as its chief executive officer and director.