The Dilemma of Antibacterial R&D
On the face of things, working in antibacterial R&D should be a “no-brainer.” After all, you can never fully eradicate any pathogen. The reason for this is bacterial resistance. If you get an infection and are treated with an effective antibiotic, it is likely that the drug you take will wipe-out as much as 99% of your infection. This impact is sufficient for you to feel fine and to return to your daily routine. But the small percentage of bacteria that survives does so because it is resistant to this medication. A drug designed to kill them can be extremely effective, but a small subset will be unscathed because they are genetically resistant to the way the drug exerts its lethal effects. As a result, some bacteria survive, multiply over a finite period of time, and emerge as a drug-resistant pathogen.
This field of research, therefore, should be eternal. Infectious diseases can’t be “cured.” Furthermore, doing clinical trials is relatively easy. Unlike R&D for conditions like heart disease or Alzheimer’s Disease where thousands of patients need to be treated for years to measure the true effectiveness of a new medicine, a new antibiotic is used acutely. Generally, patients are dosed for 2 – 4 weeks and a physician can measure via blood samples whether the bacteria has been eradicated. Thus, the need for long and expensive clinical trials doesn’t exist in this therapeutic indication.
Why, then, are fewer and fewer large pharmaceutical companies investing in antibacterial R&D? Why are companies like Johnson & Johnson and Pfizer either scaling back their efforts or getting out of this field entirely? According to the Infectious Diseases Society of America (IDSA), of the 20 major companies doing R&D in this area 20 years ago, only two remain. How can this be? After all, according to the IDSA, antibiotic-resistant pathogens cost the US healthcare system more than $20 billion a year. This treatment is clearly a major medical need. Yet, there are only a handful of new antibiotics currently in clinical trials, as opposed to nearly 1,000 exploratory new drugs for cancer.
While there are a lot of attractions to doing R&D in this area, there are significant downsides. Although clinical trials for a new antibiotic are not daunting, the discovery of a new drug is very difficult. The resistant bacteria have evolved to such an extent that finding a new way to penetrate their defenses is much harder now than it was decades ago. Making modifications to existing classes of antibiotics is no longer fruitful; totally new molecular approaches are needed. Thus, just getting a new compound to test in the clinic may be more difficult in this therapeutic area than any other.
Just as important, however, is the fact that the commercial return on a new antibiotic would pale in comparison to a new treatment in areas like cancer or Alzheimer’s Disease. This is attributed to the fact that an antibiotic is generally used acutely, not chronically, and so profits are diminished by short-term use. However, a truly effective antibiotic against a life-threatening infection such as methicillin-resistant Staphylococcus aureus (MRSA) would likely receive very favorable pricing. The commercial issue really centers on the highly limited use of such a life-saving antibiotic. In order to prevent overuse of such an important new medicine, federal agencies would limit its use so that it was the last line of defense. This would slow down the potential for drug-resistance to the new antibiotic and prolong its effectiveness. This narrow use of the drug would limit its commercial viability, making it unattractive for a big company.
Last week, the GAIN (Generating Antibiotic Incentives Now) Act was introduced by Senators Blumenthal (D, Connecticut) and Corker (R, Tennessee). A similar bill had already been introduced in the House last June. Its purpose is to incentivize companies to carry out antibacterial R&D. Among other things, the GAIN Act, when passed, will extend the patent protection for a new antibiotic by 5 years and streamline the FDA approval pathway and allow for rapid NDA review – welcome changes. But this reform probably isn’t sufficient for the major companies to re-enter this area. The GAIN Act should, however, be a boon to small companies that are seeking novel antibiotics. In fact, this problem seems ideally suited to the expertise of biotech companies.
Also, this may be an area where the NIH can make a major contribution. Dr. Francis Collins, the Director of the NIH, has been seeking areas where the NIH can be more involved in quickening the drug discovery/development process. Perhaps using NIH resources to seek new ways to understand the genomics of resistant pathogens can lead to better insights into how best to kill them. More innovation is needed and the NIH can help fill this gap.
This problem is only going to get worse. It’s great that Congress is taking steps to help work on this. Back in the 1980s, the FDA, academia and pharmaceutical companies all worked together to discover new drugs that converted AIDS from a death sentence to a manageable disease. One would hope that it will not take a similar major disease outbreak to galvanize all parties to recommit to this field of research in a big way.