Antibiotics
Aina Abell
Last August, FDA approved pretomanid, a new antibiotic used in combination with bedaquiline (Sirturo—Janssen) and linezolid for treatment of patients with multidrug-resistant and extensively drug-resistant tuberculosis (TB). Pretomanid, which was developed by the nonprofit organization TB Alliance, is the third anti-TB drug approved by the agency in more than 40 years.
In recent years, many pharmaceutical companies have abandoned the development of new antibiotics because they can cost up to $1 billion to bring to market but yield much less revenue per dose than drugs used for chronic conditions, such as antidepressants, beta-blockers, statins, and cancer therapies. This is because most antibiotics are inexpensive and are taken for only short durations. Add the rise of antibiotic resistance, which is increasingly making existing antibiotics obsolete, and the push for antibiotic stewardship, which encourages antibiotic use only when necessary, and the market finds itself in a precarious spot.
This also puts patients at an extremely vulnerable position. Tuberculosis, for instance, is the world’s deadliest infection, claiming 1.6 million lives in 2017, according to the World Health Organization. About half a million new cases of TB that same year were drug-resistant and unresponsive to existing first-line treatments.
Push and pull
To address these market issues, “push” economic incentives, which provide funding to the few small companies left attempting to create new antibiotics, were established in recent years. Federal agencies like the National Institutes of Health and the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, as well as public–private partnerships like the internationally-funded CARB-X, have helped fund antibiotics companies like Achaogen, whose first drug, plazomicin (Zemdri) was approved by FDA in June 2018.
But this doesn’t seem to be enough. Despite their initial success, Achaogen filed for bankruptcy in April 2019—just 10 months after plazomicin’s approval—because of insufficient profit.
Part of the issue is that most new antibiotics approved are “me too” drugs, wrote Brad Spellberg, MD, chief medical officer at the Los Angeles County USC Medical Center, and Travis Nielsen, PhD, MD/MPH candidate at Loyola University Chicago Stritch School of Medicine. Spellberg and Nielsen co-authored a recent New England Journal of Medicine paper on sustainable discovery and development of antibiotics.
These drugs are often approved to treat similar indications to antibiotics already in the market and therefore directly compete with each other. This was the case for Achaogen’s plazomicin, which was a promising treatment for carbapenem-resistant Enterobacteriaceae infections yet was only approved for resistant UTIs.
Some believe that “pull” incentives, which include, among other ideas, giving companies a one-time monetary “market entry reward” for bringing a drug to market, could be the solution because it would offset research and development costs. But these would involve significant policy reforms and public buy-in.
A nonprofit future?
Some health professionals like Spellberg and Nielsen are looking to the potential of nonprofits to fill the vacuum in the antibiotics market.
“The current model for developing antibiotics is broken,” Spellberg and Nielsen told Pharmacy Today. “For-profit companies have a fiduciary responsibility to their shareholders to drive up their stock prices. … Nonprofits suffer from neither the need to answer to shareholders nor the need to continuously increase sales year over year. An antibiotic that generates a net income of $10 million is a catastrophic failure to Big Pharma but a lifeline to nonprofits.”
Governments or rich donors need to step in and fund these nonprofits, said Spellberg and Nielsen. “If the government spent $1 billion to seed three nonprofits, that would allow sustainable antibiotic discovery and development in perpetuity. This one-time investment … is a much better use of taxpayer dollars than throwing recurrent billion-dollar prizes or advance market commitments at for-profit companies to develop new antibiotics.”
Education and collaboration
While the cost of these new antibiotics and their development is a huge concern, “that’s not the whole story,” said Kerry LaPlante, PharmD, FCCP, FIDSA, infectious diseases pharmacotherapy specialist, professor of pharmacy at the University of Rhode Island, and director of the Rhode Island Infectious Diseases Fellowship and Research Programs at the U.S. Department of Veterans Affairs Medical Center in Providence, RI.
“There is an understandable and significant knowledge gap across prescribers on how and when to use these new agents,” said LaPlante. “Prescribers are often overwhelmed with the differences between these new agents and the antibiotics they use every day, which to their knowledge seems to work for a large majority of their patients.”
“In the end, cost is only one component. Education and understanding of how and when to use these new agents correctly are also extremely important,” she added.
For LaPlante, the best way to move forward is to bring industry, academia, and the government together.
And this seems to be TB Alliance’s approach. The nonprofit received funding from various donors, including USAID and the Bill & Melinda Gates Foundation, for research and development and basic operations. It also collaborated with laboratories at academic institutions for their resources and has partnered with the generic pharmaceutical company Mylan to manufacture pretomanid in the United States.
“[TB Alliance’s] success is a sign of the future,” said Spellberg and Nielsen.
While many disagree on the right path to sustainable antibiotic development, one thing is clear—something needs to change, and now is the right time.
“We already have the public’s attention. We already have the government’s attention. We need to harness it and see if we can move forward together,” said LaPlante.