Translating validated targets into clinical candidates is the major hurdle in discovering new antibiotics to combat resistance, Lilly VP-Scientific Affairs Gail Cassell, PhD, suggested in a presentation to FDA's Center for Drug Evaluation & Research Jan. 7.

"The thing I'm most worried about is getting those validated targets to a clinical candidate...What about the gray zone between the validated target and the clinical candidate? Who's going to take responsibility for that and bring it across the finish line?" Cassell said during a CDER seminar on antimicrobial resistance in Rockville, Md.

"I don't think you can argue you need more validated targets or more targets in general. After all, we have the entire genome sequence of most pathogens, and not only one sequence but for multiple strains," Cassell added.

Despite increasingly sophisticated technologies to assess candidates, antibiotic discovery is in crisis, Cassell maintained, pointing to rising cases of multi-drug resistant tuberculosis and the dearth of new antibiotic classes.

"I think that most of us have been a little bit surprised that there was not more of an epidemic of discovery in terms of new antibiotics, because during this decade, there was an enormous increase in expenditures within the pharmaceutical industry to try and develop new antibiotics using the new technologies," Cassell said.

Referring to industry's vast expenditures on high through-put screening and validation of targets, Cassell said, "I think it is fair to say it has not been as successful as we all had imagined that it might be, or wanted it to be."

Cassell noted that many companies have eliminated or sharply curtailed their antimicrobial research capabilities. "Most companies no longer have their natural product libraries, but I would say in many cases kind of disbanded them after they realized that the return from those was not very significant after all."

Antibiotic research has been so disappointing that "I think it's time for us to ask the question of where are we going to go from here, what is going to be required," Cassell said.

Only two new antibiotics were approved in 2003: Cubist's Cubicin (daptomycin) and GeneSoft's Factive (gemifloxacin).

Aventis hopes to receive approval for its antibiotic Ketek (telithromycin) in April.

FDA has taken a number of steps to address antimicrobial resistance, including a November 2002 joint workshop with the Infectious Diseases Society of America and the Pharmaceutical Research & Manufacturers of America (¹ Also see "Antibiotic Resistance, Drug Prescribing Trends To Be Tracked By Database" - Pink Sheet, 25 November, 2002., p. 17).

FDA is developing a priority list of drug-resistant pathogens that would allow for resistance claims in labeling and expedited review (² Also see "Pathogen List Development Guided By Limited Therapy Availability – Cmte." - Pink Sheet, 24 March, 2003., p. 43). An FDA working group is developing an exposure-response database for antibiotics to speed future drug development (³ Also see "Antibiotic Indications For Resistant Pathogens Could Rely On PK/PD – FDA" - Pink Sheet, 2 December, 2002., p. 25).

Cassell stressed public-private collaboration as key to developing new drugs to combat resistance. "I think we need to be working together more closely and having very frank discussions about how we can realistically try and address the problems," she said.

"Taking a look at the big picture, what is it going to take? And certainly I would argue it's going to take the private sector, but also the public sector and government working together with the best minds...to succeed scientifically," Cassell said.

Cassell also emphasized that the effort should have a broad focus that includes naturally occurring infectious agents as well as neglected organisms and bioterrorism agents. "No longer should it be focused on only neglected disease or countermeasures," she said.

Cassell contributes to PhRMA's bioterror work and strategy (⁴ 'The Pink Sheet' June 17, 2002, In Brief).

FDA Principal Associate Commissioner Murray Lumpkin, MD, suggested that a different marketing paradigm for antibiotics could slow the emergence of resistant organisms.

Lumpkin noted that historically the antibiotic market "has been based on large sales of product. So you get into this never ending circle of we need large sales of antibiotics to generate the funds to develop them, that give us the resistance that brings us right back to where we started from."

"Do you see domestically a different economic paradigm or a different use paradigm, or some way to break this cycle of having to have large use of a product as the economic force to give us the funds to develop products?" Lumpkin asked.

Cassell responded that charging more was not necessarily the answer.

"Certainly this question comes up a lot: why not just charge more, and then you have to sell less to be able to pay for development. But will that really be tolerated?" Cassell asked.

The high cost of newer antibiotics like Aventis' Synercid (quinupristin/dalfopristin) and Pfizer (formally Pharmacia)'s Zyvox (linezolid) has been cited as a major barrier to their use (⁵ Also see "Synercid, Zyvox Drug Pricing Discourages Use, IDSA Rep Says" - Pink Sheet, 11 March, 2002., p. 27).

At the September Interscience Conference on Antimicrobial Agents & Chemotherapy, Wyeth Antibacterial Research Director Steven Projan, PhD, suggested that the incentive structure for antimicrobial development needs to be changed (⁶ Also see "Antibiotic Trial Without Comparator Would Lower R&D Cost, Wyeth Exec Says" - Pink Sheet, 29 September, 2003., p. 18).

Companies have proposed strategies including wild-card exclusivity and revised requirements for clinical trials to spur antimicrobial drug discovery.

Cassell suggested that companies discontinued their antimicrobial research in part because marketers were reporting a low interest in new antibiotics. "I think a lot of effort went into trying to establish what that market really is, with a lot of focus groups, with different types of physicians out there in the field...When you keep hearing, there is no need for antibiotics, then when you marketers hear that, that is all they need to hear."

She noted that there was not enough understanding about the problems of resistance.

"We, as scientists and physicians, have maybe not done a good enough job explaining the issues around resistance and the fact that there is not another new antibiotic just waiting to be delivered to your doorstep, and, by the way, it will be eight to 15 years before another one is."

"So I think most people are really shocked when they hear there are not a ton of new antibiotics coming down the pike, because in the past, resistance develops, fine, there's a new one on the way....That is not going to be the case anymore," Cassell said.

Antibiotic Research Stalling In Conversion Of Target Into New Drug

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