The Struggle to Get Anti-Infectives on a Faster Track to Commercialization

Medical leaders have been sounding the clarion call for over a decade: Something has to be done about the rising resistance of infectious agents to existing drugs, combined with the dearth of new anti-infectives to combat them. So far, however, there has been little movement. The death toll from drug-resistant pathogens keeps ticking upward worldwide. And the number of new anti-infectives passing through clinical trials remains a trickle.

Unlike oncologics or cardiovascular drugs, where substantial R&D efforts show intermittent advances, anti-infectives suffer from both little funding and few promising research directions. At the root of this are two confounding problems in commercializing anti-infectives: a new, more powerful agent would be held in reserve for only the most recalcitrant infections, limiting its commercial potential; and nearly all anti-infectives are being restricted in use (particularly in agriculture) in order to slow the development of more drug-resistant strains of infectious pathogens. Add to these the problem that anti-infectives typically are administered as an acute-care regimen for a week or a few months, rather than to treat a chronic condition, and the commercial promise of any anti-infective begins to look unpromising.

A year ago, the Infectious Diseases Society of America (IDSA; Arlington, VA), together with a handful of other medical societies, kicked off a “10 X ‘20” campaign: to get 10 significant new anti-infectives on the market by 2020. But the campaign (which also engages with health authorities in Europe) appears to be another victim of the gridlock caused by the debate over healthcare reform legislation of the past year. The STAAR (Strategies to Address Anitmicrobial Resistance) Act legislation has been kicking around Congress for at least three years, having been re-introduced into the current Congress in 2009; this September, Rep. Phil Gingrey (R-GA) introduced the Generating Antibiotic Incentives Now (GAIN) Act, which was referred to committee where it still sits.

“We’re supportive of these initiatives, and they seem to enjoy bipartisan support in Congress, but clearly there’s work to be done in realizing them,” says Robert Guidos, director of public policy at IDSA. He notes that since the 10 x ’20 initiative started, one new drug (Forest Labs’ Taflaro; see below) has been approved.

At October’s 48th IDSA Annual Meeting (Vancouver, BC; Oct. 21-24), Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) of NIH, presented a familiar list of action items (increased surveillance; fast-track drug development and review) that have been recommended for years; even so, these recommendations are merely being “reviewed” by HHS as part of its Medical Countermeasures (MCM) initiative. But Fauci might be excused for doing the best he can under the circumstances; the portfolio of NIAID includes influenza, malaria, bioterrorism, HIV/AIDS and other sexually transmitted diseases, allergies and other thorny, high-profile public health issues.

Proponents of a more substantial commitment to infectious diseases might be pigeonholed as just another medical advocacy group, except for this fact: anti-infectives are the single-most successful lifesaver among drugs in the past century. As pointed out by Brad Spellberg, an IDSA task force member, in Congressional testimony last June, penicillin and sulfa drugs introduced in the 1940s reduced mortality by 220 per 100,000 lives over the next 15 years; by comparison, all other drugs introduced since then have reduced mortality by roughly 20 per 100,000 lives. Today’s pharma industry is still enjoying the afterglow from this signal accomplishment—and it is this legacy in danger of being lost today.

How bad is it?

“Infectious agents” include bacteria, viruses, fungi, protozoa, prions and parasites. Anti-bacterials are the largest segment of the anti-infectives market (see figure) and within this segment, drugs for resistant bacteria are of most concern. Bacteria are either Gram-positive or Gram-negative (based on a test that differentiates them); the Gram-negative appear to be the most resistant to treatment.

Today, the Most Wanted list of drug-resistant bacteria — which are currently to blame for the majority of US hospital infections — have collectively been dubbed the ESKAPE pathogens (based on an acronym of their names):

• Enterococcus faecium (Gram-positive)
• Staphylococcus aeurus (Gram-positive)
• Klebsiella pneumoniae (Gram-negative)
• Acinetobacter baumanii (Gram-negative)
• Pseudomonas aeruginosa (Gram-negative)
• Enterobacter (Gram-negative).

Commonly encountered drug-resistant strains within this group include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and fluoroquinolone-resistant Pseudomonas aeruginosa.

According to the Centers for Disease Control (CDC), in the US alone, nearly 2 million patients acquire an infection in the hospital each year, and nearly 100,000 of them die annually as a result of drug-resistant infections (making this the sixth leading cause of death in the US). This figure is up from 13,000 such patient deaths in 1992. Another 94,000 are infected, and 19,000 die, from MRSA infections outside the hospital, according to a 2007 JAMA article (Fridkin, 2007 JAMA 298:1763-71).

And the problem is global. In a 2009 survey, 50% of 14,114 patients in 1,265 intensive-care units (ICUs) in 75 countries were infected, and infected patients had twice the chance of dying in the hospital than patients without infections.

In the European Union, an average 25,000 patients die from antibiotic-resistant infections annually, according to a 2009 report released from the European Centre for Disease Prevention and Control and the European Medicines Agency. The report estimates that Gram-negative infections account for two-thirds of these deaths.

Only 2% of Staph infections in the US were drug-resistant in 1974. The percentage jumped to 63% by 2004, according to CDC, which says that Staph infections now kill more people in the US than HIV/AIDS. And, when Staph bacteria spreads to the bloodstream, sepsis can occur. The incidence of sepsis has increased by more than 90% over the last 10 years, and is expected to kill 215,000 people in the US alone this year.

This medical disaster drives up healthcare costs. Recent data suggests that resistant infections prolong the length of the hospital stay by 25% and increase costs by 29% compared to treatable infections (Maudlin et al., Antimicrob Agents Chemother, 2010, 54:109-115). In the US alone, drug-resistant infections have been estimated to result in 8 million additional hospital days, and cost the healthcare system between as much as $34 billion/yr (Roberts et al., Clin. Infect. Dis., 2009, 49:1175-84).

Meanwhile, potential non-drug therapies, based on, for instance, anti-Staphylococcal vaccines or immunoglobulin antibodies, would seem to be another promising option for the prevention or treatment of infections. However, according to IDSA, “studies to date have failed to demonstrate efficacy for these agents.”

“There’s no doubt that there’s a critical need to develop novel anti-infectives — but the economics are hard to justify,” says Jeffrey Besterman, EVP of R&D and chief scientific officer for drug developer MethylGene, Inc. (Quebec). “The last major class of novel antibacterials—the oxazolidinones—was introduced ten years ago with a lot of fanfare, but it turned out to be a financial failure.”

Similarly, says one industry insider: “New technologies, such as combinatorial chemistry, high-throughput screening and molecular modeling have not been as successful in identifying new antibiotics as hoped. Even genomic data has failed to deliver an expected flow of novel targets.” He adds: “Even if a novel target is identified, the challenge remains of finding a chemical entity that can reach the target site and inhibit growth without being too highly toxic to patients.”

Powering the development engine

Many would argue that the biopharmaceutical industry has a moral obligation to devote its considerable expertise and resource base to developing novel anti-infectives, and critics charge that drug makers have been slow to do what it takes to regain the upper hand in the epic struggle of mankind versus microbe. But the industry counters these claims, saying that drastic measures are needed to re-balance inherent market inequities that are at play in the anti-infectives arena and help them to justify redirecting their finite R&D resources to the pursuit of these high-risk, low-return products.

“Serious educational and lobbying efforts are needed to bring the lawmakers to understand the ramifications of this trend on national security and public health,” says Besterman of MethylGene. “Considering the speed at which you’d have to respond to a bacterial pandemic, we can’t wait for a crisis. More vigorous discovery and development efforts — which can take a decade or more to come to fruition — need to be happening now.”

“It is much more difficult to discover new antibacterials with activity against Gram-negative pathogens compared to Gram-positives,” explains Steven Gilman, PhD, EVP of R&D and chief scientific officer for Cubist Pharmaceuticals (Lexington, MA). “While there has been some success, most notably with newer anti-MRSA drugs, novel therapies to combat increasing resistance in Gram-negative infections remain elusive,” says Siddharth Agrawal, a principal consultant at IMS Health. “Any anti-infective that has potent activity against Pseudomonas and is safe has the potential to become a blockbuster.”

Further complicating the picture is this paradox, unique to the anti-infectives sector: Antibiotics and other antimicrobials are the only drugs that lose their efficacy over time (particularly with widespread or inappropriate use) and thus must be replaced. These factors increase the R&D burden for committed drug developers and sharply curtail the long-term market potential of any given anti-infective agent.

Meanwhile, when anti-microbials are used incorrectly — for instance, for too short a time, at too low a dosage, or for the wrong disease (such as bronchitis, sinusitis and other common viral infections against which antibiotics have no efficacy) — the likelihood is greatly enhanced that the exposed microbes will adapt and replicate, conferring greater drug resistance on the next generation. Unnecessary antibiotics are often prescribed as a result of patient pressure on physicians, which is said to be particularly acute in pediatric-care settings.

To slow the emergence of drug resistance and keep the most powerful agents in reserve, conscientious “antibiotic stewardship” efforts are underway throughout the medical community to actively discourage and even withhold the use of both proven and newly marketed products.

While such stewardship protocols (which often involve strict hospital formulary designations) are lauded from a clinical standpoint, this approach further blunts the market prospects for these drug franchises and gives drug developers even more reason to pursue more lucrative prospects elsewhere. “Medically, this might be the right decision, but financially, for drug companies, it’s been a disaster,” says Besterman of MethylGene. “It creates a belief among drugmakers that the market opportunity just isn’t going to be there for their product.”

Many antibiotics are now available as inexpensive, generic products. “If you are a hospital administrator with a limited budget, you are going to mandate that all patients get the cheap agents first (even if they only have a 40—50% response rate). Patients who relapse or don’t respond can then go on the new expensive therapy. This can cut the commercial potential for those new agents in half,” says Andy Smith, an industry consultant and former fund manager at AXA (London).

Industry experts looking at this situation have several fairly straightforward recommendations to improve the economics of anti-infectives development:

• extended patent exclusivity, which has worked well for orphan drugs
• streamlined clinical trial protocols, recognizing that it is very difficult to find trial patients who are both infected yet healthy enough to sustain a treatment regimen
• financial incentives, which can range from tax credits beneficial to large pharma companies, to outright grants to startups who are not profitable enough to make tax incentives meaningful.

“Applying extensions of market exclusivity — a proven and effective incentive in the rare diseases arena — to correct the narrow and well-documented market failure in the area of antimicrobial would send a strong signal to scientists, entrepreneurs, venture capitalists, and new markets, and greatly encourage more R&D and commercialization of new drugs to treat resistant infections,” says Gilman of Cubist.

“Without some form of cost-sharing mechanisms, rebates, extension to patent life to motivate a company to put compounds through the clinical process because of low incidence of success — so much risk is involved that in many cases it’s simply not deemed being worth the gamble,” says Besterman of MethylGene.

“There’s a lot to be learned here from how Congress handled the development of push (to decrease developmental costs) and pull (to increase market value) mechanisms for treatments for rare and neglected diseases through the Orphan Drug Act,” says says Allen Coukell, Director of Medical Safety for the Pew Health Group (Washington, DC).

Accelerating approvals

Equally important are bottlenecks created by the regulatory-approval process. “Given the fact that there is a pressing need for new drugs against resistant strains, the existing regulatory process is far too long and far too time-consuming,” says Agrawal of IMS Health. “The increased hurdle for new anti-bacterials to demonstrate success ranging from the need to demonstrate superiority in some circumstances to demonstrating a mortality benefit rather than a clinical or microbiological cure is discouraging many companies from pursuing new therapies and new indications.”

“Finding large numbers of patients infected with a particular resistant strain to enroll in a trial is not an easy task, and sometimes investigators have to wait for an epidemic to break out in hospitals,” says one industry insider. “Predicting such an event impossible. As a result, it can take up to five years to complete a clinical study. This is unacceptable.”

Stakeholders are calling for FDA to address some of the persistent regulatory uncertainty — in terms of a lack of both clear guidance from FDA and consistent approval pathways — that remains a major disincentive to development efforts in anti-infectives.

Borrowing a page from the orphan drug playbook (Pharmaceutical Commerce, Sept/Oct, p.1), stakeholders are urging FDA to allow for more flexibility in clinical trial design — for instance, to allow for a model that allows for FDA approval based on a relatively small sample size (<100 patients) with infections in multiple organ systems.

Advocates are also asking the agency to more clearly define acceptable surrogate markers (such as clearance of bacteremia, animal models and analytical methods that could be used as appropriate endpoints to accelerate clinical trials related to drug-resistant bacterial infections. Fast-track review for antibiotics developed for high-priority pathogens would also help.

“FDA has acknowledged the challenges of revising the standards as the science has changed, and the agency has acknowledged that it has not gone as fast as the industry would like it to,” says Coukell of Pew Health. “While FDA has been meeting with many stakeholders and seems committed to addressing these issues—and that’s encouraging&mdash;everyone would like things to move a little more quickly here.”

Another obstacle is the lack of adequate rapid, point-of-care diagnostic tests and devices that could help physicians and drug developers to more rapidly confirm a bacterial infection and identify pathogens. Such rapid-identification capabilities right at the point of care would help prescribers to select the most appropriate, narrow-spectrum antibiotic or to shun antibiotic use altogether if the infection turned out to be viral not bacterial (again, in an effort to curtail inappropriate antibiotic use that promotes the development of drug resistance).

Improved diagnostic tools would also help drug developers to increase efficiency and reduce costs associated with clinical trials, by helping researchers to more effectively identify patients whose particular infection might make them eligible for their studies. Existing test methods (which rely on culture tests) requires days or weeks to identify bacterial organisms, often prompting the prophylactic overuse of antibiotics. In all types of inpatient and outpatient healthcare settings. Better diagnostic tools would also make it easier to track the spread of new and dangerous drug-resistant pathogens, enabling better interventions to be put in place to slow the spread.

“The failure of antibiotic R&D has occurred along the entire spectrum of drug discovery and development — there is no single rate-limiting step to overcome,” Spellberg told Congress. “Therefore, adopting a single type of incentive will not solve the problem.”

Combining therapies

An alternative approach to new therapies is to combine new or existing agents with a beta-lactamase inhibitor (BLI). BLIs (clavulanate, sulbactam, tazobactam and others in development) have little antibacterial activity themselves, but do target the enzymes produced by some Gram-negative bacteria that degrade antibiotic effectiveness.

“Combination therapy is more the rule than the exception these days,” says Gilman of Cubist. “However, the problem is that some strains are now emerging that are resistant to essentially all anti-bacterials and it doesn’t matter if they are given individually or in combination — the bacteria are still resistant.” His company already markets the antibiotic Cubicin (daptomycin for injection) as a therapy for Staphylococcus aureus bloodstream infections (bacteremia). Now, Cubist is developing CXA-201, which could become a first-line intravenous therapy for the treatment of Gram-negative bacterial infections, including those caused by the multi-drug-resistant Pseudomonas aeruginosa. CXA-201 combines the company’s novel anti-Pseudomonal cephalosporin (CXA-101) with the existing BLI tazobactam. Cubist expects to file an NDA for two indications by the end of 2013.

Another promising anti-infective is TD-1792, which is being developed by Theravance (San Francisco). “It inhibits two key bacterial cell wall synthesis functions (transpeptidation and transglycosylation) and is active against Gram-positive bacteria, including certain multi-drug resistant Gram-negative strains,” explains Agrawal of IMS Health. “Data shows that the covalent attachment of the two active antibacterial agents is synergistic, and results in a higher efficacy than an equimolar combination of cephalosporin and vancomycin.”

Mergers and acquisitions

Over the past year or so, a variety of strategic partnerships and acquisitions between major pharma companies and smaller startups have been announced — a move that clearly helps all participants to share costs and reduce exposure in anti-infective ventures.

For instance, last January, KaloBios Pharmaceuticals (San Francisco) partnered with Sanofi-Pasteur, the vaccines division of Sanofi-Aventis Group, to develop and commercialize its antibody fragment KB001 (created using the company’s “Humaneering” technology platform), an investigational biologic for the treatment or prevention of Pseudomonas aeruginosa infections, initially for mechanically ventilated patients and those with cystic fibrosis.

Sanofi Pasteur is also collaborating with Syntiron (St. Paul, MN) to develop a vaccine to prevent Staphylococcus infections, and is developing a vaccine (now in Phase 2 trials) to prevent Clostridium difficile (another prevalent source of hospital-acquired diarrheal infections).

Meanwhile, in December 2009, AstraZeneca bought Novexel, a French research company dedicated to infectious diseases, and the pair will collaborate with Forest Laboratories (New York) on the future development and commercialization of two late-stage antibiotic-development programs that are aimed at helping two anti-infectives (one on the market, and one just approved) to become more effective by overcoming antibiotic resistance in a growing number of infections that have become resistant to existing therapies.

Specifically, these two products are:

• Ceftazidime/NXL-104 (CAZ104) — a combination of ceftazidime, a third-generation cephalosporin to which resistance has recently emerged, and NXL-104, Novexel’s novel investigational BLI called NXL-104). It is expected to move into Phase III development in late 2010 and will be filed with US and EU regulators in 2012
• Ceftaroline/NXL-104 (CEF104) — a combination of the BLI called NXL-104 and ceftaroline, Forest’s just-approved, broad-spectrum cephalosporin with MRSA coverage, to enhance the activity of ceftaroline against resistant Gram-negative pathogens. It is expected to move into Phase II development by the end of 2010.

According to the companies, the addition of NXL-104 to these antibacterials helps to extend their coverage of resistant Gram-negative pathogens including bacteria that produce extended-spectrum beta-lactamase enzymes.

In October, Forest Laboratories received FDA approval for Teflaro (ceftaroline fosamil), an injectable antibiotic in the most widely used class of anti-bacterials, the cephalosporings, to treat adults with community-acquired bacterial pneumonia (CABP) and acute skin infections from MRSA and others. The product is expected to hit the market next month.

Last December, Cubist Pharmaceuticals announced it would spend more than $92 million up-front and as much as $310 million more in future milestone payments to buy Calixa Therapeutics (San Diego), which has been developing CXA-201 (as discussed, this product combines Cubist’s newer broad-spectrum cephalosporin called CXA-101 with the widely used BLI tazabactam in a fixed 2:1 ratio). CXA is in Phase II to treat complicated urinary tract and intra-abdominal infections, and later trials are planed for nosocomial (hospital-acquired) pneumonia.

CXA-101 has demonstrated excellent in vitro potency, especially against multi-drug-resistant Pseudomonas aeruginosa, which differentiates it from existing cephalosporins, says the company. “It’s right in our sweet spot, right in our strike zone,” said Michael Bonney, president and CEO of Cubist, at the time of the announcement. Cubist expects to file an NDA for CXA-201 with FDA by late 2013. Because the candidate drug CXA-201 provides enhanced spectrum activity, it is being pursued as a first-line therapy for serious Gram-negative infections in hospitalized patients. In addition to the IV development program for CXA-101 and CXA-201, the same cephalosporin has also been evaluated (pre-clinically) for inhaled administration by cystic fibrosis patients to address multi-drug resistance to Pseudomonas aeruginosa infections (this investigational product is called CXA-301). PC