FDA Antibiotics Task Force!

The FDA recently announced the formation of a new task force to support innovation in antibacterial drug development.  I have received a number of calls about this and have recently been misquoted.  So I thought I would try and let you know my perspective on all this myself.

The one good thing about the GAIN act is that it requires the FDA to review and revise as necessary its guidance on the development of antibacterial drugs such that drugs active against important resistant pathogens (the ESKAPE bacteria) can be brought forward to patients and physicians in an expeditious manner. The FDA says that this task force was formed based on this clause in the GAIN act.  But, in fact, the FDA came to realize that the strategy that they have been trying to implement for the last 12 years – that of increased stringency of non-inferiority trial designs for antibacterials – is not only not working, but is actually driving the industry out of the business.  This is something I have been preaching all this time and something Bob Moellering and I predicted would happen way back in 2002! And since 2002, things have only gotten worse.

An advantage of this clause of the GAIN act is that it provides congressional cover for innovative approaches that might be viewed by some as increasing risk.  It is clear that trial designs where we only study small numbers of patients will increase the risk of seeing unpredicted adverse events once the drug achieves wider use.  But my own calculations suggest that large trials have been unable to detect rare events in any case.  These events have been rare enough that they are no different than many marketed antibiotics and other drugs in any case.  Therefore, to me, and I think to patients who are infected with these resistant pathogens, the slightly increased risk is clearly worth it since the alternative is no therapy.  But for the FDA – the cover from congress, especially after the Ketek debacle of 2006, is clearly important.  Its important since it is very likely that a new antibiotic, at some point, will result in some adverse event that is rare and was not predicted by prior data.  When that happens, rest assured, congress will once again rise to the occasion to try and make votes out of the fact that no drug is 100% safe and FDA scientists, clinicians and staffers will pay the price.  I just hope the GAIN act is enough cover for the FDA folks. 

Back in May, when the FDA asked the Brookings Institution to help them review their stance on antibacterial drug development, Janet Woodcock stated that the FDA was going to reboot.  Janet, Rachel Sherman and others at the FDA finally got it.  They finally understood that we were going backwards and that it might be true that new antibiotics active against resistant pathogens could be available everywhere BUT the US if they continued down their current path.

Another fascinating aspect of all this is that the FDA obviously recognizes another problem they face.  Their normal advisory committee process is fatally flawed because of overly restrictive conflict of interest rules.  This puts them in a position of relying on people who have insufficient experience and expertise regarding the FDA’s key questions to provide reasonable advice.  For this reason they turn to think tanks like Brookings.  And it’s a good thing, too!

I firmly believe that this process will work!  I believe that we will end up with feasible designs and innovative approaches to getting urgently need antibiotics to Americans who need them.   I am singularly impressed by the determination of Janet Woodcock, Rachel Sherman and the anti-infectives division to finally tackle this problem head-on.  The big question for me is when will we get something on the table.  At the last Brookings meeting, I suggested that we use the European Draft Guidance as a starting point and go from there.  I think there was much support for this idea since Europe is way ahead of the US in its thinking in this area.  Their non-inferiority trial designs are feasible and use clinically relevant endpoints.  They have listed a number of innovative new approaches to the rapid development of antibacterial products meeting areas of high medical need – like resistant infections. 

So – FDA – lets get going!  I am ready, willing and able to do anything needed to get this moving quickly!

Antibiotics, ICAAC and Bronchitis

I am writing this blog on the last day of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.  As someone whose living depends on the pipeline of new antibiotics coming through, I am depressed.  I always attend the poster review session the first day of the meeting where the 10 best data sets on new products are briefly reviewed.  This year, as in the past few years, there have been precious few gems among the 10 best.  The two most interesting to me were the presentations by Rempex where they are developing a combination (Carbavance) between an old Japanese carbapenem, biapenem, and a new B-lactamase inhibitor, RPX7009 – a boronate.  Although this class of inhibitors has a bad reputation from the past, the data on this molecule and on the combination look encouraging.  Merck – you may get a run for your money! 

The other interesting presentation was from Trius on a topoisomerase inhibitor with a very broad antibacterial spectrum.  It targets Gyrase B and ParE and is a completely novel class.  Its actual binding site is the ATP site.  Unfortunately, many compounds targeting this site have died a toxic death – so the jury is still out – but the data are encouraging so far. The remaining presentations were quinlones or quinolone relatives offering no particular advantage to existing products either marketed or in late stage development.  It seems unlikely that any of these will get off the ground even though at least one has serious investor money behind it.  So – two out of the 10 best . . .I’m depressed.

On a totally separate note, an interesting study of antibiotics in the treatment of exacerbations of bronchitis was recently published. (A caveat – I was unable to get access to the actual article since I would have to pay $$$ – so I am relying on the abstract and news reports for my information).  The investigators in Spain, Dr. Lior and colleagues, studied over 300 patients with diagnosed chronic obstructive lung disease who had acute worsening of their symptoms (exacerbations).  These patients were only moderately ill.  The point of the study is that while it is clear that such patients with severe exacerbations benefit immensely from antibiotics with reduced mortality rates, it is not at all clear that those with milder disease benefit. This study attempted to answer that question.

Half of the patients were treated with an antibiotic, amoxicillin-clavulanate, and the other half received placebo in a blinded fashion.  Those that received antibiotics were 14% more likely to achieve cure of their symptoms within 8 days and showed a longer time to their next episode – 233 days vs. 160 days.  The study provides strong evidence for a treatment effect of antibiotics in moderate exacerbations.  I believe that by altering the design of the study focusing on those most likely to have new bacterial pathogens as the cause of their exacerbation would have led to an even more impressive treatment effect.  This is important because both in Europe and the US, to study a new antibiotic in the treatment of this disease, we would have to run such a placebo controlled trial.  But, as was the case for otitis media in children, equipoise may be lost.  It may no longer be ethical to run such a trial and, it is going to become harder to convince physicians and patients to participate (rightly so!).

I know that I am running up against the pundits who only want us to develop antibiotics for “serious” infections who believe that misuse and abuse in the community breeds resistance.  And I agree with their view in this regard.  But at the same time, new antibiotics for community acquired pneumonia should be developed – most of us agree on that.  So the only thing that will happen is that they will be used “off-label” for "milder" infections like bronchitis.  (By the way - if you are the patient with lung disease experiencing such an exacerbation - I wonder if you would consider the disease to be mild). Further, if antibiotics work, which I think they do for some patients, and I think we can identify those patients, we should be able to develop new antibiotics and get them approved for use in this condition. 

New Antibiotics? Go Public!

I am now contemplating a talk I have to give at ICAAC this year (Intersciences Conference on Antimicrobial Agents and Chemotherapy for the uninitiated – the biggest infectious disease meeting of the year in general).  My topic is New Antibiotics – what should PhRMA be doing?  In my view – they should either spin off what assets they have, or form independent business units with their antibiotics franchises or just get out of the way. As I have been saying for years – for antibiotics in PhRMA companies – smaller is better.  A product with peak year sales of $300 million is not even a rounding error for a company like Pfizer that brings in $67 billion a year in sales.  As they and many others have demonstrated since 1999 – they couldn’t care less.  In the battle of public health vs. shareholders – guess who wins?  Of course – I don’t argue that this view is somehow perverted – its not – its just the way business is run.  These companies exist to provide a return on investment for their shareholders and not to run a public health non-profit. 

Amazingly – some companies like Astra-Zeneca and perhaps GSK and now, maybe even Sanofi-Aventis, are apparently convinced that antibiotics can still provide enough of a return that they can justify an effort to advance the cause of the public health.  Bravo! I am still not exactly sure what is going on at Merck – the other company that is (at least sort of) in the antibiotics R&D business.

But take heart.  There are other ways to bring antibiotics to market.  Look at Cubist and Cubicin (daptomycin), their anti-MRSA and -VRE (superbugs) drug.  After being unable to find a partner to finance their late stage trials, Cubist went to the public markets and raised enough money to get them to an approval for a single indication, serious skin infections for their antibiotic. They then went on to obtain approvals for other indications like blood stream and heart valve infections all of which increased sales.  Cubicin is on its way to be a billion dollar seller – the gold ring for an antibiotic. Cubist has even in-licensed a new antibiotic, ceftolozane, for the treatment of severe infections caused by resistant Gram negative bacteria like Pseudomonas aeruginosa (another superbug). Ceftolozane is now in phase III trials in preparation for registration for market.

When Cubist went public in 1996 it raised $15 million.  Of course, at this price, Cubist’s investors and the after-market must have had to put in more money to allow Cubist to move forward.  Not much has changed. Nevertheless, this remains a viable strategy for biotech – especially in the US market.  I say this because the IPOs recently have still been meager in terms of ultimate share price but the after-market has remained robust.

Trius, with their new oxazolidinone, tadezolid, was, like Cubist, unable to find a partner to take the compound into phase III development in preparation for an application for market approval.  Tadezolid is a compound similar to linezolid from Pfizer that has garnered a $1.4 billion market.  Linezolid goes generic in 2015. There are many reasons for the fact that Trius was unable to partner their product. The FDA was lost (and still is to a certain extent), thus raising the regulatory risk for antibiotics.   In addition, in my view, their early proof of concept trial was flawed and may not have provided the kind of risk reduction that potential partners wanted. So Trius bravely went forward to the public markets since they obviously had confidence in their product. Trius was forced to cut their offering price by over 40% and raised only $50 million. This forced them (I think) to take a stepwise approach to phase III by running one phase III trial at a time (two are required for registration).  They have now completed both trials. Tadezolid now has a partner in Bayer. Trius was, with all this, able to maintain a discovery effort and now has drugs in the preclinical phase of development.

Cempra is a biotech with two products in clinical development.  Solithromycin is a compound for the treatment of community-acquired pneumonia so far only available in oral form.  It is active against resistant pathogens and so far looks quite safe. Taksta is fusidic acid – an antibiotic that is marketed in every country in the world except the US and is used primarily for skin and bone infections. Like Trius, Cempra has been unable to partner either product.  And, like Trius, Cempra was forced to shave their IPO asking price – this time from $11-13 down to $6 per share.  They ultimately raised $48 million.  But they will have to go to the after-market, their investors and may have to prioritize which trials they do when in order to make it to market with their first product.  Nevertheless – they are on their way and at least one, if not both, of these antibiotics may ultimately find their way to patients and physicians around the world.

Finally, there is Durata.  I love telling this story.  George Horner was the CEO of Vicuron, a biotech that was acquired by Pfizer for $1.9 billion!  Pfizer acquired two products from vicuron one of which was dalbavancin for the treatment of skin infections.  Dalbavancin’s differentiating feature was that it could be given once a week instead of daily. But the trial package submitted to the FDA was not satisfactory to the agency and Pfizer halted development.  George Horner offered to take the asset off the hands of Pfizer and complete development.  Thus Durata was formed and is back in George’s hands (or at least sort of).  Again – Durata was apparently unable to partner dalbavancin and decided to go to the public markets. Like everyone else, they had to take a bit of a haircut but still raised $68 million.  Dalbavancin is now in phase III trials and headed to market.  Durata, with a revenue stream, may then be able to in-license other products to expand their hospital presence. 

So – PhRMA – get out of the way!  These small companies can afford to market niche products and accept lower returns than the giant conglomerates that are PhRMA today. They can bring needed antibiotics to market and, in my view, they can frequently do it faster and smarter than the large, bureaucratic behemoths of PhRMA.