Antibiotics: Officially Encouraged, Increasingly Precise, Still Risky

Anti-infective start-ups getting funded these days say they can boost the odds of clinical success, and reduce the cost of achieving it. Profiles of EnBiotix, Nosopharm, and Spero Therapeutics.

It's official: fighting antibiotic-resistant bacteria is now a national security priority for the US. On September 18, 2014, President Barack Obama issued an executive order requiring the National Security Council to develop and implement federal policies for combating antibiotic-resistant bacteria (CARB). Under the order, the Council must collaborate with at least a dozen other agencies including the Departments of Defense, Justice, Veterans Affairs, Agriculture, and Homeland Security. A task force representing all the collaborators will present a five-year strategic action plan by February 15, 2015.

The president's order comes none too soon, as statistics reveal. The Centers for Disease Control & Prevention estimates that two million Americans acquire serious infections caused by antibiotic-resistant bacteria each year, and 23,000 people die as a direct result of these infections. The prevalence is high enough that 63% of infectious disease doctors have treated patients with infections that did not respond to any antibiotics. The speed with which bacteria spread is a major cause of alarm, as evidenced by the proliferation of carbapenam-resistant Enterobacteriaceae. This pathogen, which the CDC called a “nightmare bacteria” and an urgent threat,was reported in just one state in 2001, but found in 47 states in 2014.

While the bugs are bad and getting worse, the supply of drugs to combat them is aging and shrinking. In the 1980s, 29 new antibiotics were approved, and in the 1990s, another 23. By the 2000s, just nine new antibiotics came to market. The drop-off came about because major drugmakers simply stopped doing R&D on infectious diseases. They chose instead to focus development efforts on chronic conditions like cardiovascular disease and diabetes, where medications command higher prices and are typically taken for years, versus a few days or weeks.

Recognizing the need, Congress took action in July 2012 to help spur development of new antibiotics and antifungals for treatment of life-threatening infections caused by drug-resistant pathogens. The Generating Antibiotic Incentives Now (GAIN) Act makes “Qualified Infectious Disease Products” (QIDPs) eligible for accelerated review by the Food and Drug Administration, requires the regulatory agency to provide written guidance, and extends drug-patent exclusivity by five years.

For small start-up companies, the GAIN Act is a decidedly positive change, asserts Eszter Nagy, MD, PhD, an immunologist who co-founded Arsanis Biosciences GMBH andnow serves as its president and chief scientific officer.The firm's research facility is based in Vienna, Austria, while the corporate office calls Lebanon, NH, home. Arsanis is developing a “cocktail” or mixture of antibodies to treat ventilator-assisted pneumonia caused by Staphylococcus aureus and other pathogens.

More Talk, Less Data

The biggest benefit of the GAIN Act, Nagy says, is that it allows companies to test their anti-infective drug candidates in just one pivotal trial, instead of two, which was the requirement before. The shorter development path means regulators have less data on which to base their appraisals, but it also means that drugs can get to market years sooner.

Under the new law, the less data a company presents to FDA in support of a new anti-infective, the greater the commitment the developer must make to post-approval monitoring. Phase IV trials are expensive, but at least they occur when companies have the drug on the market, generating revenues. That's a better deal than paying for a large Phase III trial years before the product is sold.

The GAIN Act is also bringing companies more interaction with FDA officials than ever before. In a standard review, Nagy explains, a company meets with regulators after about 10 months, and is permitted to ask questions to which the FDA responds simply yes or no. “But if you have priority review you meet them in only six months, and you can request a written document of their guidance,” she points out. “It's much more grounding, and it saves time for you.”

By now FDA has approved three antibiotics underthe GAIN Act, all treatments for acute skin and skin-structure infections. The first was Dalvance (dalbavancin), approved in May 2014 just eight months after Chicago-based Durata Therapeutics Inc. submitted it for review. Durata was able to show that dalbavancin can clear acute skin infections with just two once-weekly intravenous injections. The drug had previously been rejected by FDA in 2007 when submitted by Pfizer Inc., because regulators were unconvinced of its efficacy. Durata picked up the compound in 2009 for just $10 million, only to realize it would require two new Phase III trials to pass muster.

Some Investors Enthusiastic, Others Not

The story of Dalvance explains why some investors are now enthusiastic about antibiotics, and others are not. The drug's promise was not enough to rally much support for Durata's initial public stock offering in July 2011. Now it appears all the time, money, and effort will benefit a new set of investors.

Even though Durata won approval for Dalvance relatively quickly under the GAIN Act, the success was too little, too late to sustain the company. On October 6, 2014, Durata announced that it had agreed to be acquired by Allergan PLC for $675 million. [See Deal] Stakeholders would get $23 cash per share, well above the previous record high of $18.17 in July, and contingencies could add up to $5 per share. That's nice as it goes, at least for public shareholders that had bought Durata stock recently. But it's not great for the original investors, nor for those who had bought looking for longer-term growth.

If the Activis acquisition goes through, Durata will never grow up to be a long-term value generator like Cubist Pharmaceuticals Inc. Cubist was able to generate significant revenues from one life-saving hospital-based antibiotic, Cubicin (daptomycin for injection), and use the profits to acquire and develop additional products. In August 2013, Cubist bought Optimer Pharmaceuticals Inc. and with it Dificid (fidaxomycin), a first-in-class treatment for Clostridium difficile infections that cause severe diarrhea. Cubist had been co-promoting the drug since its launch in 2011. In June 2014, Cubist saw Silvextro (tedizolid phosphate) approved for the same skin indications as Dalvance, also under the GAIN Act. Cubist exemplifies a specialty pharmaceutical firm built around novel drugs that solve serious problems and can therefore command a premium over standard-of-care therapeutics. It's a great business model, but not easy to achieve.

Investors acknowledge that anti-infectives remain risky to develop, and even when they do win regulatory approval, confront some unattractive market dynamics. Anti-infectives are never administered chronically, and because many good antibiotics have been long available at generic prices, there is the expectation they all should be cheap. Although some few cost more than $10,000 for a course of treatment (e.g., a couple for cystic fibrosis), antibiotics' life-saving ability is seldom rewarded by high prices. Developers increasingly point out the discrepancy with cancer drugs that cost hundreds of thousands of dollars while extending life only three to four months. But it is what it is: new anti-infectives are typically given as a last resort, only after pathogens have become 30% to 40% resistant to existing drugs. Hospital hoarding policies arise for good reason: to keep costs down, and to keep a reserve of medicines for the most severely ill patients.

Anti-infective start-ups getting funded these days say they can boost the odds of clinical success, and reduce the cost of achieving it. “We think it's a great time to be investing in novel anti-infectives,” declares Ankit Mahadevia, MD, a venture partner at Atlas Ventures, now serving as CEO of Spero Therapeutics LLC, profiled in this issue. Spero, founded in April 2013, aims to use a small molecule to inhibit a transcription regulator called MvfR (Multiple Virulence Factor Regulator), which appears to control production of numerous toxins in gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Theoretically, inhibiting MvfR will not kill microbes directly, but will render them less capable of secreting proteins harmful to the human body, and also less able to evade existing antibiotics by “hibernating.”

To defray development costs, Spero has given Roche an option to buy its lead drug candidate for a predetermined price, once it is ready to request FDA's permission for human testing. [See Deal]

Atlas expects Spero to generate the data necessary for IND filing for less than $20 million in equity capital, within two to three years. The GAIN Act is helping to save money and time, Mahadevia declares: “Previously FDA was a hard sell on new antibiotics. Now there is a fresh attitude, open and collaborative discussion.”

The Promise Of “Precision Medicine”

Until recently, drug developers have sought and sold mostly “broad spectrum” antibiotics capable of killing many phyla of bacteria, such as gram-positive or gram-negative bacteria. The goal there was to find a common mechanism, a common weakness, and exploit it to, for instance, block cell-wall synthesis. The approach created antibiotics that doctors could and did prescribe routinely, seldom bothering to diagnose specific organisms and not thinking much if at all about what else beyond the symptom-causing pathogen was being killed. Awareness of this problem, and fear of it, is one factor shifting interest toward “precision medicine.” The term describes treatments that target and kill or somehow influence only specific things, and nothing else.

Combining anti-infectives with antibodies is one approach: Merck & Co. Inc. is close to wrapping up a Phase III trial to see whether MK-3415A (actoxumab + bezlotoxumab), and these components separately, can when given with standard antibiotic therapy prevent recurrence of infection with C. difficile. The candidate’s approval would smooth the path for other antibodies in development at Arsanis, MedImmune LLC, and elsewhere.

Advancing abilities in molecular biology and genomics, and a growing host of new technologies from bioinformatics to cell sorting are opening new doors for treatment of infectious diseases resistant to current drugs. Cambridge, MA-based EnBiotix Inc., profiled here, is applying systems and synthetic biology methods from the lab of James J. Collins, PhD, at Boston University to revitalize existing antibiotics with waning potency. Collins and his collaborators figured out how P. aeruginosa, which causes persistent infections in people with cystic fibrosis, can evade frontline antibiotic tobramycin (TOBI), and come back stronger after treatment with that drug.

Insight into a sort of triggering mechanism sparked an idea to “feed the bacteria something it likes,” so that it will simultaneously take up drug that can kill it. EnBiotix' co-founder and current CEO Jeff Wager, MD, says experiments with the approach made TOBI 10,000 times more potent against persistent organisms than TOBI alone. He says EnBiotix could have its candidate molecule in the clinic 12 to 18 months from obtaining funding for it. It's one of several programs underway at the start-up, which was founded in January 2012.

Nosopharm SAS, also profiled here, thinks existing sources of antibiotics have been overused. It is bioprospecting to find new classes of anti-infectives using a drug discovery platform that exploits the microbial diversity of the bacterial genera Xenorhabdus and Photorhabdus. “Our natural products approach means that we can discover more diverse druggable first-in-class antibacterials. Theoretically, this route evades the current mechanisms of resistance in the clinical pathogens," says CEO Philippe Villain-Guillot, PhD.

Scientists and investors who respect them are increasingly excited by the concept of thwarting disease by treating specific bacteria in precise ways. “If we can subtract a single organism from an otherwise healthy human biota, and prove a causal effect, then we can use that concept to prevent disease,” declares David Martin, PhD, CEO of AvidBiotics Corp. in South San Francisco, CA. Right now there is no such thing as species-specific, let alone strain-specific antibiotics on the market, he points out. But those are precisely the sorts of drug candidates, called “avidicins,” the company is readying for clinical testing. The AvidBiotics approach involves a chemical scaffold derived from proteinaceous toxins known as R-type bacteriocins. “Bacteria have been using these for half a billion years, as defense mechanisms against other bacteria,” Martin explains. If the plan works, the start-up's lead drug candidates will prevent recurrence of C. difficile infections, and urinary tract infections caused by pathogens in the gut.

If current efforts to eliminate specific strains of pathogens show clinical benefit, then the field of antibiotic R&D that Big Pharmas largely abandoned could again be deemed fertile ground, and this time for more than infectious diseases. Relationships between bacteria and the human body are being examined afresh, as mounting evidence suggests that chronic disorders such as rheumatoid arthritis, asthma, cancer, diabetes, and coronary heart disease are influenced or perhaps even caused by gut bacteria. Obesity is also one of the diseases that scientists and clinicians increasingly suggest could be due in part to certain populations of organisms that might be treatable.

Researchers now know that there are 100 times more unique genes in the gut microbiota than there are within the human body, and there are 10 times as many bacterial cells in the gut, as cells in the human body. Many of these gut organisms cannot yet be cultured, and so have been assigned no phyla. But researchers can already get some idea of their function by studying genomic sequences. That capacity will only grow as sequencing becomes less expensive. Already, companies such as AvidBiotics and others have shown that even unknown organisms can be selectively eliminated with novel compounds that can be manufactured relatively quickly. The science is enticing, and is spurring related research into diagnostic methods to quickly identify bugs. For those who can stomach the risks, there is surely plenty to investigate and commercialize.