James Netterwald, PhD, MT (ASCP)
Emerging pathogens are still a threat, but their lack of staying power has caused big drug companies to lose interest in combating them.
Ebola, anthrax, bubonic plague, MRSA—these words strike fear into the hearts of all of us. They are some of the deadliest diseases known to man, and some of the toughest diseases to treat, mainly because people who get them die quickly. These are emerging diseases—those that have either recently become known or have re-emerged as a result of antibiotic resistance or the threat of bioterrorism. But don’t take my word for it.
“There are two ways to think about emerging pathogens,”says Joseph Blondeau, PhD, head of clinical microbiology at Royal University Hospital, Saskatoon,
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Source: Tufts Center for the Study of Drug Development
Saskatchewan, Canada. One way is to look at the emergence of infectious microorganisms that had not previously been recognized as problems, he says. And a second way is to look at pathogens that have become a problem as a result of a number of conditions, including antibiotic resistance. It’s the latter kind that interests Blondeau.
Some of the pathogens Blondeau studies include methicillin-resistant Staphylococcus aureus (MRSA); penicillin- and multidrug-resistant Streptococcus pneumoniae; and Pseudomonas aeruginosa. Although Blondeau is not developing drugs against these bugs, his lab does test a lot of drugs already developed by pharma.
One of the tests he has set up is an in vitro system for assessing the likelihood that a pathogen will become resistant to a certain antibiotic. Specifically, the system determines the mutant prevention concentration—the threshold of a drug necessary to inhibit the growth of the most resistant organism present in a high-density population. This new technology is being groomed
to improve antibiotic-susceptibility testing in clinical labs. Current assays focus on testing the susceptibility of a bacterial inoculum of 1 x 105 cells. “This number may not reflect what actually happens in bacterial populations present in infections, where the number of organisms might be 1010,”says Blondeau.
He will also be investigating how bacteria develop drug resistance, in the hopes of developing new antibiotics. “Most of the intracellular targets for antibiotics are known, but there may be some novel targets,”he says. “In the absence of novel targets, we may have to realize that the antibiotic era as we know it could be ending. And that is a scary prospect.”
But are drug companies concerned about developing new antimicrobials?
In and out
In 2003, Wyeth Research terminated all of its drug-discovery efforts for antimicrobials, says Steve Projans, PhD, vice president of biological technologies, Wyeth Research, Cambridge, Mass. “We are making a very heavy investment in vaccine development, antibacterial development, and antiviral agents, but what we are not doing much of is trying to discover new vaccines, antibacterials, and antivirals.”He concludes by saying that there are already good drugs on the market for bacterial infection, and that if it weren’t for resistance, there would be no need to develop any more.
So Wyeth is out of the front end (discovery) but in the back end (development). Is this a trend in the industry? “Actually, what is pretty much common now is to be out of the front and the back end—out of discovery and development [of antimicrobials],”says Projans. And there are many reasons for this trend, he says. Wyeth Research felt a degree of futility prior to closing down their antimicrobials program. “We have not really discovered any great new [antimicrobial] drugs to put into development.”And this is a major reason many companies shut their antimicrobial programs down, he says.
Another reason, according to Projans, is that after antimicrobials are discovered, they are much more difficult than other types of therapeutics to develop. And this, he says, is due to the fact that the regulatory hurdles for bringing these drugs to market keep getting “higher and higher.”The hurdles are so high that drugs approved 20 years ago would not be approved under the current US Food and Drug Administration regulations.
More than regulation
There is more to the story than just regulatory hurdles and feelings of futility. And there are some companies working on new antimicrobials; one of them is SRI, Menlo Park, Calif. SRI is an independent research and development (R&D) company contracted by businesses and government agencies to do R&D. Jon Mirsalis, PhD, DABT, director of preclinical development, Biosciences Division at SRI, says that the company has a long history of developing drugs for infectious diseases. “Halofantrine for malaria was discovered by SRI in the 1970s, and AraA, an antiviral, is also an SRI drug,”he says.
But much of the current infectious disease work by SRI is for the National Institutes of Health (NIH) because “infectious disease is not an area that big pharma is diving into right now because there is not much money in it.”The problem, according to Mirsalis, is that the major infectious diseases such as malaria and schistosomiasis only affect people in developing countries, who generally cannot afford to buy the therapeutic pharmaceuticals they need. And although big pharma has reluctantly worked with these countries, the pressure to make a profit there is still an issue.
There are some exceptions of emerging disease that big pharma and large biotech companies in the United States still care about, with MRSA and human immunodeficiency virus type 1 (HIV-1) being just a few examples. Companies care because there are still very sizable markets for these diseases in the US and Europe, where they count on making most of their profits. “The market for potential HIV vaccines is very healthy, but look at Chiron and the flu vaccine and how the bad press they got outweighed the money they made on the vaccine,”says Mirsalis. “If I were a ruthless shareholder in a pharma company, I would say ‘don’t waste your precious R&D on doing infectious disease research. Put it into cholesterol-lowering, diabetes, obesity, schizophrenia, erectile dysfunction, and GERD’ —you know, diseases of rich people.”
If the risk of losing money from developing an unprofitable drug were taken away, would bail-out drug companies consider coming back into the game? Probably not, and that’s where contract R&D companies like SRI and small biotech companies come into the picture. Most of these companies put the work in to discover and develop the drugs that they later sell or license to big pharma and big biotech.
“If we take all of the risk out, if we got the drugs through clinical trials, and solved all of the manufacturing problems, big pharma would be happy to make it and sell it for us,”says Mirsalis. And that’s the model some biotech companies are using right now to develop drugs against biodefense bugs using government funds. Their hope is to get the drugs through phase I clinical trials and then sell it to a Merck or Pfizer, he says.
Emerging pathogens: too flaky?
Obviously, the fact that big pharma and big biotech have jumped ship when it comes to antimicrobial drug discovery is not news. In fact, there are people in academia keeping track of such trends. “I don’t actually work with emerging pathogens. I keep track of what the companies are producing in terms of therapeutics; anti-infectives are a very small part of what I do,”says Janice Reichert, PhD, senior research fellow at the Tufts Center for the Study of Drug Development, Tufts University, Medford, Mass. Databases at the center track the number of ongoing clinical trials, the amount of development time, and time to approval for a given drug, even the fast-track status or orphan designation for a drug (see table).
In her job, Reichert notices all of the trends. “There was a flurry of activity when the government gave the allure of potential bioterrorism defense money,”she says. This did not come to fruition because working with the government was difficult, she says, “because they did not promise to buy anything the biotech companies were contracted to create for them.”Without a promise of an eventual purchase, companies felt they would have to sink a decade or more of work into developing anti-biodefense agents and not make any money from it, so nothing happened.
Drug discovery for some non-biodefense pathogens has also fallen by the wayside. “There is a big uproar over [these pathogens], then they fade away. A good example of this is SARS. It was big deal for a while, but then started to recede,”says Reichert. And the biotech sector is paying little attention to this bug because it’s not an issue at the moment. Reichert added this about the biotech sector: “When you’ve got an R&D timeframe of a decade, you can’t decide to work on a new anti-infective and then say ‘this pathogen has gone away, and, therefore, there is no need for the drug.’”In contrast, diseases like cancer have greater staying power, and, therefore, companies have more incentive to develop drugs against them. And of course, drug companies have their perennial favorite bugs. Pathogens like HIV-1, hepatitis B virus, and MRSA have a stable market and, thus, provide greater incentive for big pharma and small biotech companies alike to develop new anti-infectives. But of course, they won’t be the ones doing the work.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 5, May, 2007, pp. 22-25.
Filed Under: Drug Discovery