Tigecycline Bittersweet

I recently attended a large infectious diseases meeting in Europe.  There I saw a booth advertising for “Pfizer’s” tigecycline.  On my way to the posters, I stopped by the booth .  To my chagrin, I saw nobody I recognized.  And no one there knew me.  As some of you may know, I helped direct the preclinical and clinical development of tigecycline through Ph. II and into early Ph. III during the time I ran infectious diseases at Wyeth (now part of Pfizer).  I am still very proud of tigecycline because I think, now as back then, that it offers an important therapeutic alternative to patients with serious infections who have little other choice.  Some, possibly many, might say that tigecycline has so far failed to prove its efficacy in the most serious infections like hospital acquired and ventilator associated pneumonia.  I don’t argue with this.  Nevertheless, there is precious little else available for those with the most resistant infections and such patients can almost never be included in any significant numbers in our usual non-inferiority trials of antibiotics. 

I also saw a number of old colleagues from Wyeth who have scattered to the four winds.  Our last colleague standing from infectious diseases finally retired last month.  A number have found positions in the Pfizer/Wyeth vaccine group.  Luckily, my friends told me that, in fact, a few of the old Wyeth tigecycline people were actually at the meeting and that I just didn’t stop by the booth at the right time.  So I stopped again, and sure enough, several of the old tigecycline folks from the early 2000s were there and were working for Pfizer.

I happened to see an old colleague and friend from France at the meeting.  He always gives me a hard time about tigecycline.  He’s not a big fan.  He said that it is not used in France.  I responded that tigecycline brought in about $400 million last year – without France.  Like most antibiotics, tigecycline has had a slow uptake in the marketplace, but there is no arguing that it will be a commercially important product.

So the meeting brought me bittersweet reminders of tigecycline and the pharmaceutical industry in general.  I was reminded that tigecycline is an important product for patients and their physicians.  At the same time, it is achieving reasonable commercial success.  But most of the team who worked so hard and fought the good fight against all the naysayers in order to bring this product to the market in the first place, are long gone and are certainly under-appreciated by the new Pfizer/Wyeth.

For those interested in some of the history of tigecycline, Steve Projan wrote a wonderful reminiscence of Frank Tally’s days at Wyeth when he developed the concept for tigecycline and when the first compound related to tigecycline was tested in the clinic.

Clin Infect Dis. 2010 Jan 1;50 Suppl 1:S24-5.

Francis Tally and the discovery and development of tigecycline: a personal reminiscence.

Paying the piper

One of the major problems in the fight against antibiotic resistance is how we will pay for the required solutions.  Even though we stand to gain money through prevention of death and sickness and all the additional costs engendered by resistant infections, to prevent these infections or to treat them with new, as yet undiscovered antibiotics, is going to require an investment. As in money (to say nothing of time, energy, dedication . . .).   Of course, this investment would be nothing but good for our economy. Below is an incomplete list of things that have been proposed along these lines.

·      Ban the use of those antibiotics used for growth promotion in animals where resistance might result in resistance in human pathogens.

o   This seems like a no-brainer.  But the large food producers argue that this will slow time to market, increase their costs and increase costs to consumers.

·      Increase infection control efforts in hospitals.

o   Good luck on billing insurance companies for this! 

o   Not only that, but quality improvement measures are now forcing hospitals to eat the costs of certain hospital-acquired infections even though not all of them might have been prevented by good infection control measures. This is because of recent Medicare reimbursement policies where care for some of these infections is no longer reimbursed.  But somehow, these costs will have to be covered.

·      Carry out additional basic and epidemiological research to better understand the origins of resistance in bacteria and how resistance spreads among bacteria.

o   Again – a great idea and necessary.  But as the recent NIH budget suggests, we aren’t willing to pay for this either.

·      Provide incentives for pharmaceutical companies to produce new antibiotics active against resistant pathogens.

o   I think this is a great idea.  But no one who might have to pay for these incentives agrees with me.

o   I noted the European initiative in an earlier blog and I hope that they will actually DO something along these lines – but I’m skeptical.

·      Provide financial disincentives for companies who have abandoned antibiotic research.

o   This is an idea put forth by Dr. Louis Rice.  He feels that since pharmaceutical companies have marketed antibiotics for what some might consider inappropriate use, and that this use led to the more rapid emergence of resistance, they should pay the price.

o   But the fact is that even if we could implement and enforce such a policy, someone would still have to pay and it is not clear that it would be the pharmaceutical companies or their shareholders.

What are the consequences of doing none of the above?  Well, the fact is that infection control efforts will continue to improve since hospitals know that nosocomial infections are not good for their bottom line in any case.  This improvement will simply be at our current slow pace instead of the more urgent pace we could accomplish with additional funding. The same is true for research.  We will keep plodding along with a minimum number of investigators while failing to attract new investigators to the field. As far as incentives (and disincentives) for the pharmaceutical industry – I predict that we will continue to lose large pharmaceutical companies either through continued consolidation or through cost-cutting and prioritization which will always favor chronic diseases over acute bacterial infections.  I predict that the biotech industry will continue to struggle because of an ever-decreasing number of potential large pharma partners for antibiotics.  One potential bright spot for biotechs and biotech-watchers is that innovation there is starting to improve (see my previous blog).   Another potential bright spot is that biotechs are starting to do their own deals – e.g. Cubist and Calixa.  We certainly live in interesting times. 

Novel Drugs Need Novel Regs

 This week as I was catching up on journals, I was struck by the number of potential novel approaches to anti-infectives being considered in academia. Many of these ideas target the microbe’s ability to invade the human body.  Some target functions that weaken the microbe’s ability to deal with a threatening environment such as the presence of life-threatening antibiotics.  These compounds or proteins would not actually work like an antibiotic in that they would not kill the microorganism in a test tube. Such a product, when combined with an antibiotic, might make the antibiotic more powerful and might reduce the likelihood of resistance.  Some experts think that our traditional antibiotics work so well because they not only inhibit one essential life function of the bacteria, but they also target a second or even third essential function or they hit additional non-essential functions that might otherwise help the microbe survive in humans.  In fact, I see ideas to target non-essential functions of microbes all the time at grant review sessions, in print, and in start-up companies that are trying to exploit these ideas to make new products.  But there is always one large stumbling block that stops me in my tracks.  How can we actually develop such products? 

The problem is that antibiotics work very well.  In most indications, cure rates are somewhere between 75 and 95%.  Go try and do that in treating arthritis!  Many of the novel ideas being generated in academia would probably only be viable as part of combination therapy.  It seems unlikely that something that inhibits one portion of the bacterial invasion mechanism, since the bacteria uses multiple such tools, would clear, all by itself, an infection once it has taken hold.  On the other hand, in very serious infections, which are frequently not studied in clinical trials leading to approval of antibiotics, such an addition to an antibiotic might provide an additional edge.  The question is, how can we demonstrate this in clinical trials?

This conundrum has led me to be very negative about these novel ideas.  I feel torn since they are frequently based on good science. But I see no way to bring these novel nascent products forward in today’s regulatory environment.  This leads me to my question.  Are the novel ideas not worth pursuing or do we need a new regulatory paradigm that allows us to pursue them?

What would a new regulatory paradigm look like?  I can think of several approaches that we might explore.  Dr. Janet Woodcock at the FDA has been pushing us to identify biomarkers that correlate with infection and with resolution of infection such that these could be used to support our clinical trial data.  This is now done all the time for HIV/IDS where the number of viruses present in the blood is used to predict clinical success.  Of course, at the end of the day, the drug has to show ultimate clinical success – but marketing can be conditionally approved based on viral load data.  There are, as yet, no such markers for bacterial infection.  It turns out that bacterial load data is not so predictive either of success or failure for a variety of reasons. But obviously this is something we should be pursuing vigorously. 

Another approach, for example, would be to study the combination of drug X plus an appropriate antibiotic in a very small number of patients with very serious disease comparing it to the antibiotic alone or to standard of care.  The problem is that, even in such patients, you might not be able conduct a superiority trial since this might require large numbers of hard to find patients. A non-inferiority trial could not be large enough to provide reliable statistical power.  Thus, we would end up having to accept a smaller, less statistically conclusive clinical trial with supportive in vitro, animal model and pharmacokinetic/pharmacodynamic data.  The regulators might then grant conditional approval while these more difficult but definitive trials are carried out.  This would allow a company to earn money on the new product selling in a limited patient population while pursuing their additional data.

I think that a new approach such as this, or others that I have not considered, would be worth discussing.  There are many very smart people out there who have been thinking along these lines for a while.  Lets get them together with the regulators and start thinking about a new way forward.  Only by providing a feasible path forward for the development of these novel compounds that do not, by themselves, actually kill bacteria in a test tube, can we expect to have any to help deal with our most serious and antibiotic-resistant infections.  In the meantime, I guess I’ll continue to be skeptical about their chances of success.

Skin infections - follow-up.

Sometime in early March, the FDA let it be known through the Infectious Diseases Society and others that they no longer knew how to set a non-inferiority margin for designing trials in serious infections of skin and skin structures.  As I wrote at the time, because this indication is such an important one for the development of antibiotics, this has shaken the world of large pharmaceutical companies, biotechs and investors alike.  Forest Laboratories completed their two pivotal trials of ceftaroline in the treatment of complicated skin infections back in 2008.  If the FDA changes the accepted endpoints or the non-inferiority margin or both at this point, Forest may be obligated to carry out additional costly trials. Paratek announced the initiation of their Ph. III trials in complicated skin infections early in 2009 before their antibiotic was partnered with Novartis. Presumably, these trials are ongoing.  A mid-stream modification, if it occurs, would be costly, but probably better than having to repeat everything.  For those companies who have just completed their ph. II trials and who want to progress their compounds into phase III, they will probably have to wait for the FDA to make up its mind what they want.  Investors waiting to gauge the risk and to see whether further investment is indicated are doing just that – waiting.  In the meantime, company finances are being further strained. For many companies contemplating entering into Ph. II trials, they too are trying to understand how to design these trials such that they will be well positioned to enter phase III when the time comes.  All of this is now in limbo.

I spoke with the FDA this week.  They understand the urgency of the issue.  They believe that they have legitimate concerns around the scientific validity of the traditional endpoints of trials in skin infection – cure at 10-14 days.  The FDA seems to want to tie everything to some 80-year-old placebo-controlled trials so that they clearly understand the treatment effect that, in turn, determines in large part what the statistical margin should be in the design of the trial.  In this regard, they have focused on cellulitis and erysipelas where the 80-year-old data seem to be the most robust.  So it looks like, to register an antibiotic for the treatment of skin infections, there will have to be cellulitis involved.  Wounds will have to have surrounding cellulitis.  Same for abscesses.  There will continue to be significant questions around everything without cellulitis unless we can come up with more placebo-controlled trials to establish a robust treatment effect. This seems highly unlikely at this time.

There are many other ways to approach the question of endpoints other than the 80-year-old endpoints the FDA wants to use.  The other approaches should be a topic of public discussion.  But I fear that this is where we are likely to end up.

In the 80-year-old data, the endpoints examined were early.  The FDA is concerned that antibiotic effect wanes with time of therapy. So our modern endpoints will likely have to be early.  The FDA would like help in refining exactly what those endpoints should be and how they should be measured.  In other words, they would like the NIH or sponsors (guess who will do this better and faster) to incorporate these experimental questions into their phase ii studies. 

During our telecon with the FDA, we discussed the importance of providing a way for companies that have completed trials, have ongoing trials or need to rapidly start trials, to go forward with reduced risk.  The idea is to provide a mechanism for them to bridge to a new endpoint either by a post-hoc analysis if possible or by carrying out a smaller bridging study of phase ii size.  Whether the FDA will agree to this or under what particular circumstances is as yet unclear – but we were not laughed out of the room.

I went into the discussion believing that the FDA lived in some space-time warp where they were the only beings present.  After our discussion, I have a better understanding of their scientific concerns and I even agree that there is a scientific discussion to be had. I still completely disagree with their questioning of whether antibiotics work and how well to the point that they are willing to stop the world turning on its axis while they figure out what we already know.  As the IDSA asks consistently, what ineffective antibiotics have we approved?

I can only hope we can find a way to resolve the urgent issue of allowing clinical development to progress while we address the scientific questions the FDA is posing.