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Where have all the antibiotic patents gone?
Martin L Katz, Lisa V Mueller, Mark Polyakov & Steven F Weinstock
Patent and regulatory hurdles combined with low returns on investment are stifling antibiotic R&D
in the pharmaceutical industry.
.com/naturebiotec
Since the discovery of penicillin by major pharma companies are still players in Of the companies examined, only eight Alexander Fleming in 1929, many bacterial the antibiotics market, it seems that they are seem to be currently conducting antibiotic infections that were once fatal have become losing interest in these drugs. A 2004 study R&D: Pfizer, Merck, Johnson & Johnson, treatable with antibiotics. Although Fleming reported that out of more than 506 drugs GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, never patented penicillin, virtually every newly in development, only five were new antibi- Sanofi-Aventis and Schering-Plough. Of these, http://www
discovered antibiotic since 1929 has been pat- otics1. We have updated this analysis using Pfizer is the leader, having obtained FDA ented. These include erythromycin, vancomy- company websites, annual reports and infor- approval for three antibiotics since 1998. Of oup cin, rifamycin, clarithromycin, ciprofloxacin mation available at the website of the US the three, only two represent new mechanisms
and azithromycin. The vast majority of pat- Food and Drug Administration (FDA) and of action: Eraxis (anidulafungin) and Zyvox ents related to antibiotics are assigned to phar- other sources. Since 1998, only nine antibiot- (linezolid). The third antibiotic is an extended- maceutical and biotech companies. However, ics or new uses of old antibiotics have been release formulation of an oral suspension of lishing Gr recent years have witnessed a marked slow-
approved by the FDA, and only six antibiotics an existing drug, Zithromax (azithromycin). down in the development of new antibiotics. are in phase 2 or phase 3 clinical trials (Table
Currently, Pfizer has two antibiotics in phase 2 Accordingly, there are fewer patent applica- 1). In contrast, there are approximately 313
or phase 3 trials. In addition, since 1998, only tions filed with the US Patent and Trademark non-antibiotic drugs in phase 2 or phase 3 four other companies—Merck, Wyeth, Bristol- Office (USPTO) for new antibiotics, and fewer trials. Moreover, of the approved antibiotics, Nature Pub
6 patents issuing from these applications. This only four are truly novel: that is, either exhib-
obtained approval for any antibiotics. These article examines some of the reasons why there iting a new mechanism of action or exhibiting data strongly imply that pharma companies 200
is less antibiotic research and suggests some
a structure different from that of antibiotics are developing fewer antibiotics in comparison solutions that may alleviate this problem.
Shifting research priorities
One possible reason for the slowdown in
Table 1 Antibiotic development at selected major pharmaceutical companies
antibiotic research may be the advances in New antibiotics
Number of
Approximate total
healthcare that have prevented the occur- or new uses of old
New antibiotics
antibiotics in
number of drugs
rence of epidemics requiring new antibiotics. antibiotics approved
approved
phase 2 trials
in phase 2 trials
At the same time, there are still no satisfactory since 1998
since 1998
or beyond
or beyond
treatments for many chronic diseases such as arthritis and cancer, and for some relatively recent diseases, such as AIDS. Faced with relatively little societal pressure to develop new antibiotics, companies have shifted their resources to developing other, more profitable ceutical firms reveals that the pipeline of new antibiotics is fairly scarce. Although the Martin L. Katz, Lisa V. Mueller, Mark Polyakov
and Steven F. Weinstock are at Wood Phillips,
500 West Madison Street, Suite 3800, Chicago,
Illinois 60661-2562, USA.
e-mail: mlkatz@woodphillips.com
NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 12 DECEMBER 2006
by Replidyne and Forest Laboratories. In December 2005, Replidyne submitted a new drug application for four adult indications, based on the results of eleven phase 3 clini- cal trials and a safety database of more than 5,000 patients treated with the antibiotic6. In October 2006, the FDA issued a ‘non-approv-able’ letter recommending further clinical studies for all indications. Replidyne and Forest estimated that it would take at least two years to complete the additional clinical studies. Further, the FDA stated that for two of the indications, superiority studies may be needed. Whereas the current criterion used by the FDA for evaluating new antibiotics is non-inferiority (that is, the manufacturer must demonstrate that the new antibiotic is .com/naturebiotec
not inferior to currently available antibiotics), there seems to be a shift by the FDA towards Figure 1 Antibacterial sales forecasts from 2005 to 2015, and key patent expirations. The patent
a requirement of demonstrating superiority. expirations of some of the leading antibacterial drugs will inevitably lead to further incursion into the Although superiority may be a better indicator market by generic drugs. Although the degree of generic incursion following patent expiration tends of the usefulness of a drug, such a requirement to vary considerably between different countries and also between individual products, most brands may very well lead to even less research in the experience declining sales following the launch of cheaper copies. Source: Datamonitor. Report: http://www
Commercial Insight: Antibacterials, December 2006.
Lost profits
A raised utility bar
Development, the cost of developing a new Other factors affecting companies’ decisions Although it seems that antibiotic R&D has drug rose from $231 million in 1987 to about regarding antibiotic R&D programs include become a low priority for many pharma and $802 million in 2001, with one of the major the difficulty in improving upon the efficacy lishing Gr biotech companies, another possibility for the reasons for the increase being the rising cost of of currently available antibiotics and the low
decline in the number of patent applications clinical trials3. Some antibiotics may be subject return on investment compared with invest- being filed and issuing may be the US patent to particular scrutiny by the FDA because cer- ing in the research of non-antibiotic drugs. process. In order to obtain a US patent, an tain antiobiotics, such as grepafloxacin, have Assuming the costs of developing antibiot- invention must be new, useful (namely, possess been found to cause cardiac problems, such as ics and other drugs are about the same, it is Nature Pub
6 ‘utility’) and nonobvious. In response to the the prolongation of the QT interval, which is inherently more profitable to develop non-
criticism that prior utility guidelines were too a measure of the time between the start of the antibiotic drugs. Whereas one patient might 200
liberal, in January 2001 the USPTO issued new
Q wave and the end of the T wave in the heart’s require a full year of therapy for a chronically guidelines2. Although these guidelines were electrical cycle. QT prolongation is known to administered drug (such as an anticancer stated to be applicable to all inventions, spe- cause ventricular tachyarrhythmia, which can drug, antiarthritis drug, etc.), most antibi- cific examples were included for biotechnol- cause sudden cardiac death4. If a new antibi- otic drugs are administered for about a week, ogy and large generic chemical applications.
otic is found to cause QT prolongation dur- and therefore, it would take 52 patients to Under the new guidelines, an examiner is ing preclinical testing, millions of dollars in achieve a similar financial return. In other required to review an application to determine additional R&D costs will be needed if the words, from a commercial perspective, it is whether or not the applicant has asserted a antibiotic is to have any chance of receiving more profitable for companies not to engage “specific” and a “substantial” utility for the FDA approval.
claimed invention. If an asserted utility is spe- The risks inherent in developing new anti- As with other therapeutic areas, the com- cific and substantial, the examiner must deter- biotics are further demonstrated by two recent mercially successful development of some mine whether or not the asserted utility would cases. The first surrounds Sanofi-Aventis’s antibiotics is often a result of the discovery be “credible.” For example, patent applications Ketek (telithromycin), which was approved by of a new use of an existing drug. However, claiming recombinant proteins that assert that the FDA in 2004. In June 2006, an FDA offi- companies may not be as likely to invest in the such proteins are useful for treating certain cial warned that Ketek might cause severe liver development of a drug for a new use, as patent types of bacterial infections may be receiving damage, blurred vision, loss of consciousness protection for new uses is not as effective as and even death. Moreover, the official stated for the drug itself. Although US patent laws that there was no evidence that Ketek worked allow one to obtain a patent for the discov- Regulatory hurdles
any better than any of the other, safer drugs ery of a new use of an existing product, such Another factor contributing to the low number already on the market5. Although Ketek is patents are hard to enforce. Once the patent of antibiotics in the R&D pipeline may be the still on the market, this incident underscores for the drug itself expires, generic companies significant time and cost involved in discover- the risks companies face in developing new are free to market generic versions for a frac- ing and developing a new drug and obtaining tion of the cost of the brand name compound marketing approval from the FDA. According The second case relates to faropenem (Fig. 1). Although there may exist a pat-
to the Tufts Center for the Study of Drug medoxomil, a novel antibiotic being developed ent protecting a second indication for the VOLUME 24 NUMBER 12 DECEMBER 2006 NATURE BIOTECHNOLOGY
decisions made by pharmaceutical companies. accelerated review process at the FDA and to sue doctors who may still prescribe it for Clearly, pharmas are assigning a lower prior- providing financial incentives to companies the second use. Additionally, because doctors ity to antibiotic R&D programs or eliminating engaged in antibiotic research. These incen- and patients may often use a formulation them altogether. Contributing factors include tives could include extending market exclusiv- approved for one use to treat another indica- higher R&D costs associated with developing ity for antibiotics (especially when second uses tion, pharma companies may not be inclined new antibiotics and then guiding these drugs are discovered) and providing longer patent to develop a new dose, dosage form or brand through the FDA, difficulties in improving term extensions to compensate for longer and name for a second use (which would have pro- the efficacy and safety of new antibiotics, and costlier developments of antibiotics as com- vided more effective protection). Therefore, difficulties in discovering new drugs effective there are fewer incentives for companies to against multiple strains of bacteria.
invest in a product for a second use as com- According to the Infectious Disease Society 1. Bad bugs, no drugs: as antibiotic R&D stagnates. a pared with a new drug. One possible solution of America (IDSA), one of the main problems public health crisis brews (Infectious Diseases Society for this problem may lie in extending market with currently available antibiotics is the rise of America, Alexandria, Virginia, 2004).
2. Utility Examination Guidelines, 66 Fed. Reg. 1092 exclusivity for the compound once a second in antibiotic resistance. In 2004, more than http://www.uspto.gov/web/officer/com/sol/notices/ 70% of pathogenic bacteria were estimated 3. Tufts Center for the Study of Drug Development pegs to be resistant to at least one of the currently cost of a new prescription medicine at $802 mil- Conclusions
available antibiotics1. It is therefore crucial lion. http://csdd.tufts.edu/NewsEvents/RecentNews.
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There seems to be less antibiotic R&D, and that new antibiotics be developed. Although 4. Fermini, B. & Fossa, A.A. Nat. Rev. Drug Discov. 2,
accordingly fewer patent applications being there is no impending silver bullet, some of filed for antibiotics and even fewer patents the IDSA’s recommendations seem advisable, 5. Harris, G. Approval of antibiotic worried safety officials. issued. The reasons for this are wide-ranging such as simplifying the FDA’s approval process New York Times (19 July 2006).
6. FDA rejects Replidyne drug application. Denver and relate to both patent law and business for antibiotics, granting priority antibiotics Business Journal (23 October 2006).
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Source: http://www.woodphillips.com/documents/Nature00042497.pdf