Ethics of Antibiotics

Ted Schroeder

Nabriva Therapeutics’ CEO Ted Schroeder heads one of the few small commercial-stage biopharma companies engaged in the development of innovative anti-infective agents to treat serious bacterial infections. Nabriva Therapeutics currently markets Xenleta® (lefamulin), its semi-synthetic pleuromutilin designed to inhibit the synthesis of bacterial protein in oral and IV-administered formulations, which FDA approved in August 2019 for community-acquired bacterial pneumonia (CABP). Ed Cox, MD, MPH, director of FDA’s Office of Antimicrobial Products, said in a press release at the time, “For managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics.”

New antibiotics is the key phrase here. Most people may be familiar with the term bacterial resistance or antibiotic resistance. As Schroeder points out, this “resistant” situation has been evolving throughout the entirety of his career, which has been mostly in antibiotic marketing and sales. Schroeder entered the industry with Bristol Laboratories, a division of then Bristol Myers, selling antibiotics to both hospitals and outpatient settings. Schroeder says, “This is when they actually still manufactured antibiotics in Syracuse, N.Y.” But soon after this heyday, there was a dearth of innovation in the antibiotic market, for numerous reasons.

For example, says Schroeder, it may have seemed evident to people in the 1980s and 1990s that the war on bacteria had been won. A large part of the gains in life expectancy achieved over the past 70 years can be attributed to vaccines and antibiotics. And antibiotics is one of the few classes of drugs that “cure” something at the end of five, seven, or 10 days, or other short courses of therapy. “Because of that, the economics of antibiotics are difficult, and that drove a lot of people out of the market,” explains Schroeder.

Apparently, resistance wasn’t factored into the exodus equation. Bacterial resistance had been noted as early as 1947, with the first case of penicillin resistance. Discovered in 1928, penicillin wasn’t mass produced for use in people until the early 1940s. But after penicillin, more antibiotics were developed and used—and overused—in the years since. But, as Schroeder points out, “The organisms antibiotics are trying to eradicate are smart. They evade the product that’s trying to kill them, so they create their own defense mechanisms, and they continue to survive.”

An article from 2010 in Microbiology and Molecular Biology Reviews painted a grim picture for the overall success of global interventions to limit antibiotics overuse in all settings—agriculture, animal husbandry, pharmaceutical access, and healthcare systems. However, it did point positively to research: “It is vital that there should be absolutely no letup in the search for new antimicrobial agents. Despite the negative attitude of Big Pharma, the microbial parvome is nowhere near being exhausted in the search for new antimicrobials. Likewise, many uninvestigated drug targets exist in bacterial pathogens.”

And here we find Schroeder.

“Quite honestly, I have grandchildren, and I really feel like they’re going to need effective antibiotics. The way the world was going, I wasn’t convinced they were going to get them,” says Schroeder.

He looks at the innovation dearth as proof that it’s just not easy to find new classes of antimicrobials. “There’s a reason why all the antibiotics tend to be from just a few classes…because they worked when other attempts didn’t work. It wasn’t being lazy, it wasn’t lack of trying for the past 30 years. They are not any easier to discover than say a new immuno-oncology product or a new gene therapy, and they’re not any less expensive to develop,” he explains.

Schroeder saw his chance to make strides in antibiotics when he founded Cadence Pharmaceuticals in 2004. The company started pursuing a topical antimicrobial for central venous catheter-related infections but did not make it past Phase III. The company then acquired IV-acetaminophen from Bristol Myers Squibb for development in the US market. The product, OFIRMEV®, was approved for the management of mild moderate pain, as well as severe pain with adjunctive opioid analgesics, and the reduction of fever. Cadence was acquired by Mallinckrodt for $1.4 billion in March 2014.

Again, Schroeder saw an opportunity to form another company to try and change the narrative and help advance the development of antibiotics. In 2015, he founded Zavante Therapeutics. “I will admit, I might seem a little crazy, but I didn’t do this because I wanted to get beat up every day by investors,” he says. “I did it because I really believe that the world needs what we’re doing and that the rewards will come.”

In 2016, Zavante entered clinical trials for ZTI-01 (fosfomycin for injection), or CONTEPO™, as a first-line treatment for complicated urinary tract infections (cUTI) suspected to be caused by multidrug resistant (MDR) pathogens. It is a first-in-class broad spectrum IV antibiotic to treat MDR strains, with the goal of improving anti-infective options in the hospital setting. In 2018, Nabriva acquired Zavante, thus broadening its portfolio, which included Xenleta. Schroeder became Nabriva CEO and led the FDA submissions for both Xenleta on Dec. 20, 2018, and Contepo on Jan. 4, 2021.

Policy solutions

Schroeder, seeing another opportunity to influence the antibiotic narrative, became the chair for the Antimicrobials Working Group (AWG) in May 2021. The AWG was formed in 2012 and works with both government and private stakeholders to implement policies that will sustain the antimicrobial innovation infrastructure to combat the urgent threat of antimicrobial resistance (AMR).

“What is needed most,” says Schroeder, “is for the remaining companies in the antimicrobial space, mostly small companies, to get the ear of policymakers to make the kinds of changes that will ensure that we have an antibiotic infrastructure as we move forward. My day job is running the company but also advocating for the kinds of policies that will facilitate continued development in this area.”

He related a recent discussion he had about a friend whose wife was in the hospital for multiple weeks and her family was afraid she would die. The woman, around 50 years old with no underlying conditions, developed an infection, and the antibiotics she was treated with were two of the oldest and least expensive antibiotics that are used commonly in hospitals. “There are better antibiotics than the two she received. Fortunately, she survived. But not without weeks of being in the hospital with the pain, as well as the emotional suffering that families experience. But, had she been treated with the more advanced antibiotics, her recovery may have been quicker and almost certainly resulted in a shorter hospital stay with a less painful experience—maybe days instead of weeks, for all involved,” says Schroeder.

Because of what he calls perverse incentives, mostly at the hospital reimbursement level, as well as hospital administration bonus plan structures around pharmacy use, the situation won’t change without government intervention. “There is almost no legislator that I’ve met with that doesn’t know that antibiotic resistance is a problem,” says Schroeder. “It’s not just a looming problem, it’s a problem now, but there are so many other priorities on either side of the aisle that not enough are stepping forward.” However, Schroeder believes that serious people with real concerns about AMR are turning it into a national security issue. A recent study published in January 2022, estimated nearly 5 million deaths were associated with bacterial AMR in 2019, including 1.2 million deaths attributable to bacterial AMR. These data are alarming and reinforce the urgency of antibiotic stewardship.

There is a long history policy-wise in the US on how we got here, one in which Schroeder is very well-versed, and a long history in the healthcare system around the reimbursement conundrum of antibiotics, also in which Schroeder is well-versed. He explains why he is working so hard to change that system. Antibiotic stewardship in healthcare, according to the CDC, is “the effort to measure and improve how antibiotics are prescribed by clinicians and used by patients. Improving antibiotic prescribing and use is critical to effectively treat infections, protect patients from harms caused by unnecessary antibiotic use, and combat antibiotic resistance.”

Anecdotally, Schroeder mentions research that asked hospital stakeholders, including administration, pharmacy, nursing, and infectious disease physicians, what they thought defined stewardship. “The only group that thought that stewardship was about matching the right antibiotic to the right patient were infectious disease physicians,” he says. “Every other group thought it was about saving costs.”

Schroeder, again, stresses that a cost-first approach is not good stewardship. On the outpatient side, he says they suffer more from a lack of information about which the bacteria are most prevalent in the local area and how resistant they are. This lack of information can drive inappropriate use. Research in 2018 from Pew Research estimated that one in three outpatient antibiotic prescriptions were unnecessary.

On the ground

Xenleta became commercially available in the US through major specialty distributors for both the oral (600 mg every 12 hours) and the IV (150 mg every 12 hours) dosage forms indicated with a short five-to-seven-day course of therapy. And in November 2019, Nabriva launched a focused commercial effort for Xenleta tablets in the community treatment setting. “We launched, starting with a small sales team to target the hospitals, and two things became obvious very early,” says Schroeder. “The first was the access into hospital pharmacies was harder than any of our combined experience had seen before. We attributed that to the decline in margins and the financial pressure that hospitals are under.”

However, on the positive side, Schroeder saw significant uptake in managed care plans. “We got better positioning on more plans than we had thought would be possible early on, and about 93% of all commercial lives in the US have access to Xenleta,” he says. “On most of the plans, we’re at the third-tier copay, so most people have to pay a $50 copay to get the drug, but it’s not $500—it’s not $5, but it’s not the worst copay­—and there aren’t a lot of prior authorizations where the doctor has to call and justify the prescription.” Here, Schroeder believes, the plans’ acceptance is based on what they see as an opportunity to keep a patient out of the hospital. An opportunity that may be even more relevant during the COVID-19 era when hospitals are overburdened.

By January 2020, Nabriva started promoting in the outpatient setting and was clearly gaining traction, until March 2020. To stem losses to access during COVID, Nabriva laid off its Xenleta salesforce and subsequently signed an agreement with Merck to market its drug, Sivextro, for acute bacterial skin and skin structure infections, in July 2020. Nabriva partnered with Amplity Health to field a 60-person salesforce to educate doctors in the community about its products. Nabriva has since received EMA and Canadian approval for Xenleta for the treatment of community-acquired pneumonia (CAP); approval for Xenleta in Taiwan in September 2021; and most recently filed an NDA in China on Nov. 29, 2021, with its partner Sumitomo Pharmaceuticals. With improved physician access, the company expects to see Xenleta growth in 2022.

Leadership and the future

Schroeder admits that he likes to create companies, as well as high-functioning teams, based on a positive culture and core values. “I think with smaller companies you can really focus on what makes a difference,” he says. “When you sit down with a team and embark on defining core values and culture, like we did at Cadence, it might seem like a waste of time or money. But I fully believe that while we couldn’t outspend our larger competitors, we could outthink and outmaneuver them by having a team that fundamentally understood each other and worked well together.”

Schroeder says his philosophy worked, and he continues to have a strong belief that a sense of belonging for the people in an organization is important. “When I came into Nabriva, it was already an established organization,” he says. “But we’ve worked very hard to build on the years of research success by bringing a common language into the company.”

Clearly, Schroeder brought all his knowledge—of science, policy, healthcare, business, and pharma—to bear in this interview, however, he’s quick to add that he doesn’t have a science background; he’s just very interested in the science and learning all he could about these topics throughout his career. “No one would ever accuse me of being a scientist. They might accuse me of being a marketer. And I might be a better scientist than I am a golfer, so there’s that,” jokes Schroeder.

He views COVID as a tipping point for pharma, as it has brought vaccines, and antiviral and bacterial infection issues to the fore of the public mind. At the same time, he says, “People feel like there was some kind of magic, and all of a sudden we had a vaccine, but [they] don’t realize it was 30-plus years of good, hard scientific effort to get there.” The same holds true for antibiotics. “We need to be constantly innovating with antibiotics because the target infection continues to change,” he adds.

And how can industry and government strike a balance between what’s affordable and what will continue to incentivize the sustained effort over decades to bring advances in antibiotics?

“I guess it’s hard to really put into words how passionately I feel about the need that we have right now,” remarks Schroeder. “We still use the same worn-out antibiotics that in large part have contributed to the antibiotic resistance we have now, because they’re the least-expensive options. But doing that over and over doesn’t seem like a good solution to me, and ultimately it doesn’t seem to be very patient-friendly.”

Lisa Henderson is Pharm Exec's Group Editorial Director. She can be reached at lhenderson@mjhlifesciences.com