Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Regulatory constraints and lower ROI have been impeding investment.

On April 7, World Health Day, the Infectious Diseases Society of America (IDSA) issued a report that recommended ways to encourage pharmaceutical companies to reinvigorate anemic pipelines for new antibiotics. As antibiotic pipelines have all but evaporated, bacteria resistant to existing drugs continue to emerge.

“The way we’ve managed our antibiotics for the past 70 years has failed,” said IDSA president James M. Hughes, M.D. “Antibiotics are a precious resource, and we have a moral obligation to ensure they are available for future generations.”

During the past three decades, IDSA’s report pointed out, the number of new antibacterials approved by the FDA has dwindled from 29 between 1980 and 1989 to 9 between 2000 and 2009. It noted that in 2003, of 89 approved drugs, none were antibiotics.

GlaxoSmithKline (GSK) along with AstraZeneca are the only major pharma players still in the antibiotic space. GSK said it can take 15 years for such drugs to come to development and can cost up to $800 million, which includes the cost of many failures.

“The current model does not provide industry with a good return on investment,” GSK commented. “Experts today will advise that any newly created antibiotic be kept in reserve, for use against infections that have failed to respond to other antibiotics.” Also, the relatively short courses of antibiotics needed to treat bacterial infections make these drugs less financially rewarding than longer-term treatments like diabetes and heart diseases drugs.

Beyond poor prospects for financial gain, antibiotic developers also face potential rapid obsolescence of drugs that have taken enormous amounts of money and time to develop as well as significant regulatory hurdles as the FDA struggles to define a clear path for clinical development.

Dropping Antibiotic Development

As far back as 2003, industry analysts and scientists noticed companies exiting antibiotic development. Pfizer was one of few large pharma companies that had maintained an antibiotic development program, which it now plans to relocate to China.

“You can imagine what that means functionally when you have project teams with specific expertise who live in Groton, Connecticut,” remarked Brad Spellberg, M.D., of the University of California, Los Angeles, and a member of IDSA’s antimicrobial availability task force. “Do you think those people are moving to China? Highly unlikely.”

Dr. Spellberg suggested that antibiotic research will be starting essentially from scratch in the new location. Expertise gained in U.S. and British labs may never be recovered or duplicated. “Although it’s possible that Pfizer will attempt to keep up the same level of effort in Shanghai, the results are likely to lag.”

Pfizer’s change comes amid the firm’s decision to lay off thousands of R&D personnel, close its research facility in Sandwich, U.K., and shrink its central lab in Groton. The cutbacks, planned for 2012, are designed to preserve the company’s profits as Lipitor, its biggest-selling drug, loses U.S. patent protection.

The latest company to cut antibiotic development loose is Johnson & Johnson’s Janssen Pharmaceuticals. It opted out of its deal with Furiex Pharmaceuticals on April 19. The firms were co-developing JNJ-Q2, a fluoroquinolone antibiotic. A Phase II study in acute bacterial and skin and skin structure infections (ABSSSI) reportedly proved its efficacy.

Janssen said that it has decided to direct its R&D investments toward antiviral and vaccines. Furiex will evaluate partnering and financing options to fund Phase III trials.

Regulatory Uncertainty

In testimony before Congress in 2010, Michael Flavin, Ph.D., CEO and chairman of Advanced Life Sciences, said that lack of a clear regulatory path created a major disincentive throughout the R&D-focused biopharmaceutical industry and is a prime reason that so many companies have abandoned development within this therapeutic area.

For example, Advanced Life Sciences will have to carry out a new Phase III trial for Restanza, its lead antibiotic, in community-acquired bacterial pneumonia (CABP), because the late-stage study on which the NDA was based was deemed to be insufficient by the FDA. Restanza was acquired from Abbott Laboratories when that company backed out of antibiotic development.

On July 2009, the agency issued a complete response letter asking for additional clinical data. Last August an agreement under the SPA process was reached regarding the new Phase III study. According to the company, it will be the first prospectively designed superiority study to be conducted in CABP. The double-blind trial will compare the efficacy and safety of once-daily oral administration of 300 mg of Restanza over seven days of treatment to azithromycin. The primary efficacy endpoint will be the clinical cure rate in a macrolide-resistant Streptococcus pneumoniae (MRSP) population.

Mark Leuchtenberger, president and CEO of Rib-X Pharmaceuticals, told GEN that the regulatory climate had become more encouraging for antibiotic developers with the revision of guidelines for serious skin infections. It began with the agency replacing rules on primary endpoints with the new endpoint of lesion-spread cessation and fever abatement.

“With this change, we believe it becomes very important to validate the performance of a drug candidate against active comparators using these new endpoints before progressing to a pivotal trial,” Leuchtenberger noted.

For that reason, he added, Rib-X has chosen to perform such a trial with delafloxacin, its lead product candidate. In February a Phase IIb trial evaluating delafloxacin, linezolid, and vancomycin for the treatment of ABSSSI including infections caused by MRSA was started.

Trying to Change the Tides

Both Leuchtenberger and Rib-X CMO Scott Hopkins, M.D., added that from their perspective, companies are still out there and are more encouraged than in the past. This is partly due to an improving regulatory climate and also because the discovery process is finally bringing forth some interesting compounds.

“The large companies are desperate for compounds,” Leuchtenberger remarked. Rib-X was in late-stage discussions with companies for in-licensing of its early-stage compounds, including companies that don’t have a historical stake in antibiotics, he added. “With some companies deemphasizing antibiotics and others moving in aggressively, what we’re seeing is really a changing of the guard.”

As for the FDA, at World Health Day, FDA commissioner Margaret A. Hamburg, M.D., said, “We need better, more advanced strategies for evaluating the effectiveness of new antimicrobials once they are in development. This includes new clinical trial designs that reflect the need for important and robust scientific answers but are realistic about constraints such as the number of patients, the size and length of studies, and the cost of the trials.”

She further remarked that the agency would continue its efforts to streamline and modernize regulatory pathways “so that we can expeditiously review applications for new antimicrobial drugs, diagnostics, and vaccines when they come before us.”

Given the current funding climate it will definitely take time to work out the details. Scientists close to the antibiotic crisis say the U.S. cannot afford to wait, as workhorse antibiotics become useless in the fight against emerging resistant infectious organisms.

Some companies are indeed not waiting, leveraging innovative methods to combat the super-bugs. Their path to approval may not be simple, but the novel techniques provide some hope that developing antibiotics to fight against drug-resistance bacterial strains has not completely been forgotten. A future article will delve into some of these approaches.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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