Agencies push bug drug pipeline but development lacks market pull

Efforts to improve the treatment of multidrug-resistant bacterial infections begin with the pipeline, and pipelines emerge from scientific prowess and dealmaking. Despite public rhetoric about confronting the superbug threat globally, experts contend that the cupboard of innovative treatments to address these pathogens is meager and the supply of scientists needed to restock the shelves is scarce.

The reasons are legion, and failure to address them promptly could lead to a public health disaster.

One of the biggest challenges is a common bugaboo: funding, or lack thereof. Unlike most drug classes, antibiotics have not generated big profits. Instead, most have struggled to break even. Since antibiotics development didn't fit the traditional biopharma revenue model, which links regulatory approval to the prospect of growing sales, the class failed to attract steady investment to keep pipelines flowing.

For the most part, big biopharma turned to other, more lucrative drug classes. Small companies, which were most likely to pursue innovative science in the field, couldn't find partners or capital, and many shut their doors. The chain of events created a void in scientific discovery and scattered researchers, who often left antibiotics to pursue other fields.

Government agencies and not-for-profits have stepped in to plug those holes as best they can. Some are providing mechanisms to push antibiotics toward market by underwriting the cost of early stage research and helping to advance pipelines in the space. In the U.S., for instance, the NIH funds grants and contracts while the Biomedical Advanced Research and Development Authority (BARDA) funds public-private partnerships, "and the whole system works pretty well," said Joe Larsen, BARDA's acting deputy director. "Push is an effective incentive because you're subsidizing development."

However, third party constraints, in terms of budgets and stakeholder agendas, are insufficient to move the entire class forward in a stable and consistent manner.

"What's missing is a strong pull incentive," Larsen acknowledged. "Pull incentives only reward successful research, but they also guarantee a known return on investment to companies developing in the space."

Lack of pull incentives in antibiotics is strongly correlated with lack of candidates and companies in the field.

"The profitability of developing a new antimicrobial agent is not there," Larsen maintained. "Increasingly, we need to look at alternative economic models that reward innovators for developing new antibiotics."

'THERE'S A HUGE INNOVATION GAP'

Numbers tell the tale. Antibiotic discovery peaked in the 1950s and subsequently dropped precipitously, according to data from the Antibiotic Resistance Project developed by the Pew Charitable Trusts. Nearly every antibiotic brought to market over the past 30 years has been a variation of an existing drug, and every antibiotic currently on the market is a derivative of a class discovered prior to 1984, experts agree.

FDA approvals in the class fell from 29 during the 1980s to nine in the decade following 2000. Of 37 antibiotics that have moved into the clinic, according to Pew's count, most are still variations on existing drug classes. Assets tracked by Thomson Reuters Cortellis bump the number of therapies targeting serious bacterial infections to nearly 70, including non-traditional approaches such as monoclonal antibodies, lysins and vaccines. (See Drugs in Development to Treat Serious Bacterial Infections, below.)

Still, the number of compounds in the antibiotics pipeline – in particular, agents with new mechanisms of action – contrasts sharply with the growing global resistance to approved drugs. Two years ago, the first output from the U.K.'s Antimicrobial Resistance (AMR) Commission warned that, left unchecked, antimicrobial resistance would cause more deaths than cancer by 2050. (See BioWorld Today, Dec. 11, 2014.)

"If you look at what's in the pipeline now, it's absolutely clear that there's not nearly enough in antibiotics – not enough diversity and not enough new mechanisms of action or chemical structures to meet even today's need, never mind the certainty of emergence of resistance down the road," said Allan Coukell, Pew's senior director of health programs.

Larsen agreed.

"Think about the oncology pipeline 40 years ago compared to today," he pointed out. "Currently, there are over 500 drugs in phase II/III development in oncology, and there are about 40 antibacterials. There's a huge innovation gap."

In part, he blamed the technical challenges, such as undertaking the medicinal chemistry to move compounds across the gram-negative outer membrane. But the challenge of surmounting biopharma's revenue-driven economic model also has curtailed the segment's growth, leading to the exit of talented researchers.

"Every time one of these companies folds up its antibiotics shop, the people in that area go off and do other things," Larsen told BioWorld Today. "If we're going to invest in this area for the long term, we need to be thinking about how to build up a brain trust of scientists who understand the nuances of antibiotic drug development."

Merck and Co. Inc.'s 2014 acquisition of Cubist Pharmaceuticals Inc., nearly on the eve of the PDUFA date for its ceftolozane/tazobactam, branded Zerbaxa, was a rare billion-dollar-plus deal in a field dominated by small biopharma. And a good case in point: Merck summarily dumped scores of researchers following the $9.5 billion deal. (See BioWorld Today, Dec. 9, 2014.)

In May, Pfizer Inc. ponied up $5.2 billion to acquire Anacor Pharmaceuticals Inc., but the company's lone antibiotic, epetraborole, wasn't a big factor in that deal. What will happen to the phase II asset, which targets gram-negative bacterial infections, and the company's R&D work force remain to be seen. (SeeBioWorld Today, May 17, 2016.)

Speaking at the 2016 annual meeting of the American Society for Microbiology (ASM) Microbe in Boston, Ankit Mahadevia, CEO of Cambridge, Mass.-based Spero Therapeutics LLC, whose assets remain in preclinical development, maintained that drug development skill sets are fungible.

"If I'm a chemist, whether I become an oncology drug developer or an anti-infective drug developer depends on the incentives in those fields," he said. "The last four or five drug approvals were all invented at small companies. Don't forget them in your incentives."

'WE NEED TO JOIN UP THE DOTS'

Organizations are paying attention to incentives, and efforts to transform the economics around antibiotics, expand pipelines and boost partnering are gaining momentum. Structurally, emerging models are focusing on milestone-driven research rather than conventional grants and publications. Antibiotics development also is trending toward an interdisciplinary approach that allows scientists to pursue high-risk challenges and change direction, as needed, to achieve a common mission.

"There's a whole body of work that hasn't been done that could lower the barriers to antibiotics discovery and sustain companies in the field," Coukell told BioWorld Today. Although balancing push and pull incentives is a necessary part of the equation, he also cited elements such as pre-competitive collaborations to tackle fundamental questions that could accelerate research efforts across the field.

"We're not set on any particular model," Coukell said, "but it is crucial that – to the extent work is done outside industry, through academia or other settings – governing bodies need to be very involved in setting priorities and funding mechanisms need to be very focused on outcomes and milestones. This must be a multidisciplinary, semi-industrial model of science."

Coukell cited New Drugs for Bad Bugs (ND4BB), launched in 2012 by the EU's Innovative Medicines Initiative (IMI), as one example of a program that shows early promise. The IMI is joint venture between the European Commission and the European Federation of Pharmaceutical Industry Associations. (SeeBioWorld Today, July 18, 2012, and July 17, 2013.)

Pierre Meulien, who was tapped last year as the IMI's new executive director, told attendees at the BIO International Convention in San Francisco that "we need to join up the dots where they're not joined today." He emphasized the need to improve clinical studies, address the scientific challenge of penetration barriers and efflux, translate early discovery into the clinic and create an economic model of antibiotic development that has buy-in across stakeholders. Multiple initiatives in drug discovery and development are underway under the ND4BB framework. (Look for additional details on the IMI program as BioWorld's superbug series continues this week.)

In the U.S., BARDA's antibacterial initiative, modeled on the agency's funding of drugs and devices for potential use as medical countermeasures, has provided the resources to move five programs into phase III development. The drugs – all broad-spectrum agents – include plazomicin (ACHN-490), an aminoglycoside from Achaogen Inc. that won its first BARDA funding in 2010; Carbavance (carbapenem/RPX-7009), a carbapenem/beta-lactamase inhibitor developed by Rempex Pharmaceuticals Inc., which was nabbed in 2013 by The Medicines Co.; solithromycin (CEM-101), a fluoroketolide from Cempra Pharmaceuticals Inc.; eravacycline (TP-434), a synthetic tetracycline from Tetraphase Pharmaceuticals Inc. that joined the BARDA queue in 2012; and ceftobiprole medocaril, a cephalosporin from Basilea Pharmaceutica Ltd. already launched or approved as Zevtera in certain countries outside the U.S. (See BioWorld Today, Aug. 31, 2010, Feb. 17, 2012, Dec. 5, 2013, and June 26, 2013.)

In terms of setting priorities, "we've really tried to fund and support antibiotics that address unmet medical need," Larsen said, explaining the portfolio's emphasis on therapies targeting gram-negative bacteria. Rather than targeting broad- or narrow-spectrum candidates, per se, BARDA keys in on the downstream benefit to patients.

"We look for features that provide substantive benefit over currently marketed products," Larsen said. "Many of them overcome current resistance mechanisms, or a majority of the resistance mechanisms, to a given class of antibiotics."

'THE DRIVER OF INTEREST IS THE QUALITY OF THE ASSET'

BARDA's first five initiatives – all one-off partnerships – led to even more ambitious collaborations with Glaxosmithkline plc (GSK) and Astrazeneca plc, both of London. Through those portfolio deals, BARDA is funding multiple antimicrobial compounds in various stages of development.

Lessons learned from the early days of BARDA's antibiotics program led the agency to consider the approach. Setting up individual partnerships, previously focused on a single asset, required nearly a year of due diligence and hand-holding. When a candidate subsequently ran into technical problems, BARDA was forced to end the program, which also meant ending the relationship with the company.

"Putting together any one of these partnerships is not a trivial affair," Larsen observed. "It takes time. It takes resources. It takes energy. We thought, 'There has to be a better way to do this.'"

The portfolio approach allows BARDA to commit to a "deep strategic alliance and ensure a definitive long-term commitment to companies that are dedicated to this space, outside the bounds of technical attrition of any specific molecule," he explained.

Congress empowered BARDA to engage in flexible arrangements through Other Transaction Authority, or OTA, cooperative agreements, originally granted to the Defense Advanced Research Projects Agency, or DARPA. The agreements are constructed outside the confines of other acquisition regulations, "so we come up with terms that are suitable to BARDA and suitable to the company," Larsen explained.

Each BARDA portfolio is overseen by a joint oversight committee comprising top officials from both partners, who meet about twice a year to assess the health of the portfolio and allocate resources for the ensuing six months. Those bodies also determine whether and when to bring assets into a portfolio or to terminate a program.

Importantly, the portfolio approach involves cost-sharing with industry partners, which have the option to form additional collaborations and in-license assets that can be integrated into the program. Within the Astrazeneca portfolio partnership, for example, BARDA has a direct relationship with the COMBACTE trials network in the IMI's ND4BB program. BARDA is funding the ex-EU portion of the pharma's phase III program for its avibactam/aztreonam combo candidate, designed to treat multidrug-resistant gram-negative infections.

BARDA expects to award two additional partnerships with portfolio structures within the next 90 days, according to Larsen.

The agency has won praise from industry partners for the approach. For GSK, the first company to be awarded a BARDA portfolio agreement and also a founding member of the ND4BB program, BARDA's model is "exemplary, because it gives us the flexibility that is essential to progress a portfolio of antibiotics and maximize the probability that we will be able to address the medical need for new antibacterial medicines," said David Payne, vice president for the company's antibacterials discovery performance unit. "We are able to collaborate with BARDA to respond quickly to emerging data that is the hallmark of drug discovery and progress a portfolio of new antibacterial assets. This provides us with a framework for a truly collaborative partnership that will maximize the probability of success."

GSK saw troubles in the field begin to emerge a decade ago and turned to public-private partnerships "as a way of sharing the risk and sharing the funding," Payne told BioWorld Today. GSK worked directly with the Defense Threat Reduction Agency, a unit of the U.S. Department of Defense, before inking the portfolio deal with BARDA, which Payne called "the flagship antibiotic R&D driver here in the U.S."

He was more circumspect about the likelihood that GSK might extend its antibiotics effort with BARDA upstream to other partners.

"We are consistently looking at opportunities that are outside of GSK, and there are some interesting opportunities out there," Payne acknowledged. "But we have a considerable focus on progressing our internal portfolio, and that's an important consideration when we consider potential in-licensing opportunities. The main driver of our interest in external assets is the quality of the science and data package and the likelihood of success. Funding from the BARDA agreement could help progress the asset, but the driver of interest is the quality of the asset."

GSK evaluates "a lot of companies," Payne added. "Personally, it's frustrating as a scientist but this is not an area where we can invest in a huge way. A major driver of what we do is the public health need, but, frankly, there's an anticipation that an improved commercial model will come together by the time molecules get approved."

'ANTIBIOTICS ARE LIKE THE FIRE DEPARTMENT'

Though the GSK and Astrazeneca portfolio programs are still in their early days, BARDA is already preparing to embark, in partnership with the National Institute of Allergy and Infectious Diseases (NIAID), on an even more ambitious portfolio initiative: its Carb Accelerator, which will tap the talents of outside experts to identify antibacterial assets from different organizations that BARDA can fast-track to the clinic. The concept for the funding vehicle emerged from BARDA's desire to "repopulate the pipeline" of early stage antimicrobial candidates by seeding promising agents from the discovery/hit stage through phase I development before "graduating" them.

NIAID and BARDA will jointly establish the program using a cooperative agreement and expect to name the first awards in late July or early August. And Larsen doesn't plan to stop there. The accelerator will seek to recruit other partners, including international agencies, "to create an infrastructure that ultimately will represent a global innovation fund to support antibiotic R&D," he said. "Looking at emerging infectious diseases more broadly, BARDA is recognizing that, to have the partnerships we need at the scope and scale to address these public health issues, we're going to have to think about ways to finance them more creatively."

The key to long-term sustainability in antibiotics development, many say, is to de-link return on investment (ROI) from sales volume.

"Antibiotics represent the only drugs whose utility decreases with use," Larsen pointed out. Post-approval market-entry reward payments that subsidize ROI for successful antibiotics developers could help them to survive and continue to conduct research without trying to saturate the market with product. Discussions about that type of incentive mechanism have gained more traction in the EU than in the U.S., however.

The final Review on Antimicrobial Resistance report and recommendations, Tackling Drug-Resistant Infections Globally, was released in May, concluding that developers of new antibiotics should be given $1 billion market entry awards, paid on the condition that the drugs are available as required but not overmarketed to render them ineffective. (See BioWorld Today, May 19, 2016.)

Jeremy Knox, private secretary to the director general of public health and international health at the U.K. Department of Health, served as deputy head of the Review, which was commissioned by the U.K. government and the Wellcome Trust. Speaking at ASM Microbe, Knox emphasized the need to "rewire the incentive system to make sure the proper incentives are in place" for antibiotics development. The pipeline, he said, "doesn't contain enough products, and it doesn't contain the right products."

The 80-page Review on Antimicrobial Resistance report, also known as the O'Neill report, added to the call for change in the field, according to GSK's Payne.

"When you look at all of the other medicines that are out there, I don't know of another medicine that you can take for one or two weeks and increase your expected life expectancy not by months but by decades," he said. "We all thrive by the fact that our bacterial infections can be managed effectively."

The need for creative thinking is especially urgent considering the agencies that provide the lion's share of push incentives in antibiotics R&D are fraught with their own challenges. Continued flow of BARDA funding – ever at the whim of the U.S. Congress – has been the topic of contentious debate. (See BioWorld Today, June 15, 2016.)

And the IMI last year faced its own political battle over allegations that its activities disproportionately benefited the biopharma industry. (See BioWorld Today, April 14, 2015, and July 9, 2015.)

"We need to fundamentally change the economics of antibiotic development," Larsen said. "Ultimately, our antibiotics are like the fire department. We don't pay the fire department by the number of fires they put out."

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