There was a period during the mid-1990s when biotech companies focused on infectious diseases were hot. According to the mantra, it was going to be a slam dunk to develop new antibiotics because preclinical work was highly predictive of human efficacy, clinical trials would be straightforward, and companies could piggyback onto known classes of antibiotics.

The argument was that if a compound killed a bacterial infection in animals, it would kill it in humans. Thus the productivity metrics for companies developing antibiotics were supposed to be better than for companies working in other diseases.

The reality has turned out to be far more complex, and developing new antibiotics has not been any easier than developing other new drugs. Some of the new targets have proven to be intractable, good animal models only exist for a limited set of infections, clinical trials are complicated, and compounds often must be tested in comparison with existing antibiotics.

Keeping the faith

Antibiotics are typically directed against a microbial target that has no human counterpart, such as a bacterial cell wall, or against a microbial target that significantly differs from its human counterpart so it can be selectively targeted, such as the ribosome. The point is that the host is not affected by the treatment while the infectious organism is killed, or at least cannot continue to proliferate.

Indeed, researchers remain optimistic about the infectious disease space, despite the problems encountered in the 1990s, in part because it remains an area in which products can be reasonably well tested prior to clinical trials, and where the success rate in the clinic is higher than elsewhere.

Thus George Miller, executive vice president of R&D at Essential Therapeutics Inc. (ETRX, Waltham, Mass.), argued that once a therapeutic blood level has been identified in animal models, "it should scale up to man." ETRX was formed by the merger this year between Microcide Pharmaceuticals Inc. (MCDE, Mountain View, Calif.) and Althexis Co. Inc. (Waltham, Mass.) (see BioCentury, Aug. 6).

Moreover, Barrie Haskin, senior medical director for infectious diseases at Pharmacia Corp. (PHA, Peapack, N.J.), noted that the majority of antibiotic failures in the clinic are due to safety or pharmacokinetic issues, not to problems with efficacy. "There have been a few extraordinary glitches with products that had problems with efficacy" in late stage trials, but even those products had antibacterial activity if used at high enough doses, he said.

Finally, Ken Kelley, CEO of IntraBiotics Inc. (IBPI, Mountain View, Calif.), argued that compared to other therapeutic areas, antibiotics that make it to Phase II testing have a better chance of reaching the market. "By Phase II testing, this area offers a higher chance of success than other therapeutic areas."

Kelley, who recently announced he would step down in January, asserted that more than 50% of products entering Phase II testing and over 80% of products entering Phase III trials ultimately reach the market (see "Selected Antibiotics in Clinical Development", below).