The New England Journal of Medicine last week published the results of a Phase 3 trial of a new antibiotic called fidaxomicin, made by a company called Optimer Pharmacuticals. Fidaxomicin is the first of a new class of antibiotics called macrocycles; it’s a narrow-spectrum drug aimed specifically at Clostridium difficile, the bacterial, toxin-producing, potentially fatal infection of the gut that occurs when broad-spectrum antibiotics have killed off the other populations of bacteria that normally live in the intestines.
Fidaxomicin’s existing competition is vancomycin, the 50-year-old broad-spectrum big gun used for MRSA and many other serious bacterial infections. As compared against vancomycin, fidaxomicin was “noninferior,” in industry jargon; its selling point was a lower rate of recurrence of C. diff among patients who received it compared to those getting the older drug. From the paper:
A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P = 0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. (NEJM Louie et al.)
Fidaxomicin has been in the works for a while — it was given Fast Track status by the Food and Drug Administration back in 2003 — and it has faced some criticism for not being different enough from vanco to justify the price that a new drug can charge. Nevertheless, on the basis of this and other trials, Optimer has completed its New Drug Application, and the FDA’s Anti-Infective Drugs Advisory Committee will review it at a meeting in April.
An accompanying editorial in NEJM explains the rationale:
Since 1996, the incidence of Clostridium difficile infection has more than doubled. Some estimates suggest that there may be up to 3 million cases each year in the United States. If that statistic is correct, it would make C. difficile infection the most common bacterial cause of diarrhea in the United States. With the rising incidence, we are seeing higher mortality associated with the disease, related to at least two factors: increasing virulence of the C. difficile strains and increasing host vulnerability. C. difficile infection is particularly problematic when three factors are aligned: coexisting conditions, including advanced age; disturbed intestinal microbiota as a result of antibiotic therapy or antitumor drugs; and exposure to vegetative cells or spores of C. difficile…
A disturbing number of people have multiple recurrences over many months or years and are exposed to many courses of expensive and potentially toxic antibiotics. The frequent occurrence of intestinal C. difficile colonization in hospitalized patients and in patients with acute and recurrent infections results in an important pathogen reservoir that leads to secondary infection among other exposed patients…
If studies with fidaxomicin confirm a favorable clinical response and a significant decrease in the rate of recurrence after treatment, this new agent could become a recommended therapy for C. difficile infection. (NEJM DuPont)
To me, here’s what’s most notable about the fidaxomicin news: That it is big news, even when it is not a paradigm-changing breakthrough. That speaks to how few antibiotics are coming through the development pipeline now. And that is happening because, for the most part, pharma companies have decided that antibiotics are not a cost-effective investment.
You could see this in the news last week that Pfizer Inc. is closing major plants and cutting back on its antibiotics business. Dr. David Shlaes, formerly an executive at Wyeth and Idenix (and author of Antibiotics: The Perfect Storm), blogged:
While traveling this week I received a surprising and frightening email from a colleague at Pfizer. He said that Pfizer had just announced that they were moving their antibacterial research and development from Groton, CT in the US to China. They move cardiovascular research to Massachusetts, but antibiotics go to China. Their (2,400-employee) facility in Sandwich, UK, the origin of Viagra and, if I’m not mistaken, Diflucan, will be closed. This was announced as part of an almost 25% cut in research and development overall within Pfizer…
It is important to understand that once a company abandons antibacterial research, they lose their internal expertise in the area. This makes it difficult if not impossible for the company to evaluate opportunities in this space from external (i.e. biotech) sources. Therefore, it further erodes opportunities for biotech. This then leads to a ripple effect where no one can work on antibiotics because of a lack of partners with big pockets to support the late stage research required to get the products registered.
A few experts and health authorities have been warning for years — mostly without being listened to — that the lack of new antibiotics is a crisis. Representatives of the Infectious Diseases Society of America (IDSA) wrote last year in Clinical Infectious Diseases:
The antibiotic pipeline problem may change the practice of medicine as we know it. Advanced interventions currently taken for granted—for example, surgery, cancer treatment, transplantation, and care of premature babies—could become impossible as antibiotic options become fewer. Resistance to the current library of antibacterial drugs is a serious problem in all parts of the world including the Asia-Pacific region, Latin America, Europe, and North America. Accordingly, the regulatory, financial, and scientific challenges/impediments to antibacterial drug development are a global problem.
Truly new antibiotics are critically needed because bacteria, having no experience of them, cannot immediately mount resistance to them — something that does happen with me-too compounds featuring some slight molecular change. But they’re rare. As this chart from the research group Extending the Cure shows, antibiotic development has slowed dramatically over the past 30 years, and among the few drugs being brought forth, most share the mechanisms of already-existing classes.
How bleak is the situation? The online journal Knowledge@Wharton (from University of Pennsylvania’s Wharton School of Business) has a special report out this week, In Search of Faster Cures. It’s hard to imagine on-the-other-hand economists indulging in alarmism, but they feel comfortable calling the situation a crisis. The report sounds an R&D warning:
The year 2011 marks the end of an era for the pharmaceutical industry, which has long relied on blockbuster drugs to keep it financially healthy. But with best-sellers like Pfizer’s cholesterol-lowering Lipitor — the world’s most prescribed medicine — losing patent protection this year, drug makers are feverishly seeking new prescriptions for profit. No fewer than nine of the industry’s 10 biggest blockbusters will go off-patent and face low-cost generic competition within five years, according to the consulting firm Bernstein Research.
There is little in the pipeline to replace these top sellers. The number of new drugs has been steadily falling despite rising public and private spending for research and development. Approval of new treatments by the U.S. Food and Drug Administration (FDA) has dropped from an average of more than 35 a year in the mid-1990s to just 20 in 2009, according to the Tufts Center for the Study of Drug Development.
So what’s to be done? Various voices, including IDSA, have been arguing for breaks for drug companies, from extending patent life from 20 years to 25 or 30, to granting market-exclusivity rights — also known as wild-card patents — to other drugs made by the same company. (So that, for instance, a company that made a new antibiotic would get a secondary patent that it could apply to an existing drug, in order to extend the period in which it could be sole manufacturer.) But in a paper in Health Affairs that I’m just catching up to now, Boston academics Aaron S. Kesselheim and Kevin Outterson argue that such supply-side solutions could harm public health rather than help:
Because future spending on pharmaceutical products is unpredictable, patent owners may choose to maximize short-term revenues, wasting antibiotic resources. For example, they may encourage the broad use of an antibiotic so they can sell more of the drug. If there are other manufacturers with antibiotics in the same class, this anticonservation pressure will spread to those competitors. The damage in terms of resistance may then be even more acute, because bacteria may develop cross-resistance among drugs with similar mechanisms of action.
Instead, they recommend linking the supply side to explicit public health goals:
[W]e suggest a conservation-based market exclusivity strategy, whereby the FDA would set specific effectiveness targets for each antibiotic. Just as the FDA consults with expert advisory committees on the approval of new drugs, it could consult with appropriate experts from the NIH and the Centers for Disease Control and Prevention (CDC). Ideally, these experts would be free from substantial conflicts of interest.
In the deliberations, factors such as disease morbidity, the effectiveness of current treatment strategies, and the rate of emerging resistance would be used to set the public health goals. If the observed data met the target and equitable access to the drug was observed, the company would continue to enjoy marketing exclusivity.
Setting up such a system would face a number of hurdles, from finding unconflicted experts, to require improving funding for surveillance for resistance, to potentially even loosening price-fixing rules to allow collaboration among manufacturers who make different drugs the same antibiotic class. So, not a quick remedy. But as the news from Pfizer and the lack of news over new drugs underlines, something has to be done.