IDSA 10, USA 0.

I thought that this would be an appropriate title for a blog during March Madness (which I do not follow at all).  I recently attended a Gordon Conference on New Antibacterial Discovery.  I saw lots of cool science and hot technology, but came away disappointed with how far we are stuck in the muck of political complacency, scientific denial and regulatory inertia. 

Bob Guidos (pronounced Gidos, not Gweedos) gave a nice presentation on the Infectious Diseases Society of America’s (IDSA) 10 by 20 initiative where they are pushing for 10 new antibiotics to be approved by 2020 for the treatment of infections caused by one or more of their ESKAPE organisms.  For a complete explanation of these resistant bacterial pathogens and their initiative, see their website at www.idsociety.org.  The crowd was generally critical because they felt that this goal of 10 new antibiotics by 2020 was unrealistic given the current status of antibiotic discovery and development.  I agree with that view.  Nevertheless, I applaud the IDSA for continuing to push this concept.  If nobody fights for new antibiotics, we will surely have none.  So, realistic or not – go for it IDSA!  What can I do to help?

During his talk, Bob noted some disturbing realities about our most important funding agency for our national basic science effort on antibiotics and antibiotic resistance, the NIH.  I noted in a previous blog that the NIH had recently established a new study section specifically to provide expert review of grant requests for studies on bacterial resistance and the discovery and development of new antibiotics called DDR.  I even participate from time to time. Bob showed an analysis carried out by the IDSA which demonstrated that the NIH spends between $9.7million and $38million of research directly in ESKAPE pathogens or in other pathogens but at least relevant to ESKAPE pathogens.  Great! You cry.  But wait – that comes to a paltry 0.03 – 0.13% of NIH’s total budget! 

So – earth to NIH – where are we going to train new investigators in antibiotic research?  How will academia contribute to the discovery of new antibiotics if we don’t fund the research?  Where are your priorities?  I know, they are where they have always been – in TB, malaria, biodefense and vaccines.  This is laudable – but not enough.

In response, the NIH says that they are offering an array of services from support for screening, toxicity testing and even early clinical trials.  I applaud this effort and await another audit to see how much they are dedicating resources to antibiotics and the ESKAPE organisms in this effort.

Of course, antibiotic discovery and development in academia does not have a stellar track record.  This is partly because much of the expertise required to drive this process forward lies within the pharmaceutical industry and academics are not trained in industry.  This is another area where NIH could help by providing training opportunities for academics within industry (that is, within the few companies left still doing antibiotic research).  Even if we can train folks in antibiotic development and discovery, we still need a way to bring these needed drugs to FDA approval and to the marketplace.  We now seem farther from achieving that goal than ever before.

Between the NIH with its chronic lack of support for antibiotic research and the FDA’s current position somewhere between confused and outright hostility to antibiotic development, I think the score is IDSA 10, USA 0.

EARTHQUAKE!

The FDA has just set off what could be an earthquake of 9.5 on the Richter scale!  This apparently came to pass during discussions between the FDA and a sponsor (I do not know who, but we can all try and guess).  They were discussing an end of Phase II proposal and preparing for their pivotal trials to register a new antibiotic for the treatment of serious infections of skin and skin structures.  The FDA apparently informed them that they no longer understood how such a trial should be designed because they decided that they did not understand the effect of antibiotics in these serious infections.  When I first heard this, I was dumbfounded since the data showing that antibiotics have a dramatically beneficial effect in skin infections was just reviewed with the FDA publicly in 2008 and the issue seemed to be settled with consensus among all involved.  The data that was reviewed again came mostly from the pre-antibiotic era and was sparser and less consistent than the data we reviewed for pneumonia.  Nevertheless, all present, including the FDA’s advisory committee, seemed convinced that antibiotics worked extremely well in the treatment of these serious infections.  So what happened since 2008?

We reviewed pneumonia and decided that the greatest clinical effect of antibiotics in the treatment of pneumonia occurred early in the treatment course – in the first 72 hours or so.  After this time, the antibiotic effect diminished.  What I surmise from discussions with Ed Cox of the FDA and others in the infectious diseases community is that the FDA then went back to re-review the old data on skin infections.  They became concerned that, like pneumonia, the greatest clinical effect occurred early.  If so, they reasoned, then the current endpoints looking at cure much later, usually after two weeks or so, were inappropriate.  They further worried that the old data, comparing to placebo where the time to response was studied were so limited as to preclude their ability to actually define the extent of this response in a reliable way.  So they are now saying that since they cannot define the response to treatment compared to placebo, they certainly cannot define how to run a trial where two antibiotics are compared to each other.  What should the acceptable potential difference be between the new agent and the comparator antibiotic they wonder?  So they are telling industry that if a company starts a pivotal trial before the FDA can understand the science, they do so at their own risk.

Of course, companies have been on their own for the past several years anyway – so what is new here?  What is new is that there is really no way of knowing where the FDA will go here and therefore that an investment of $70 million in two pivotal trials could well be money down the drain to say nothing of exposing so many patients to experimental therapy unnecessarily.

To me, and virtually every infectious diseases clinician that I have spoken to about this, the FDA seems to be living in a different dimension where huge amounts of data and our own experience can no longer be believed. The FDA seems to think that they can stop the world from turning on its axis while they try and understand the science that the rest of us already think we understand well, and that they can do so in the name of science with no ill effect.  But this time, given the number of companies small and large that are counting on approval for use of their antibiotic for the treatment of skin infections, this will be the end of the world as we know it.  This approach will devastate biotech and undermine large pharma to the point where we seriously risk our ability to have any new antibiotics in the next decade or so.  How can the FDA possibly contemplate such a step?

“Just say no” vs. “The Champion”

In the pharmaceutical industry, it is always (almost) less costly to say no.  It is also more costly to continue a program that is almost certain to fail.  These competing tensions are constant in the industry and I thought I would take this opportunity to explore this dynamic a little today. 

Starting with the naysayers – they take almost no risk in saying no.  A program that is halted is one where we are very unlikely to know whether it would have ultimately been successful or not.  The only time that occurs is when another company wants to license the program or compound that the naysayer has killed.  If the other company is successful and makes it to the market with a good selling product, then the naysayer at the original company might be in trouble.  But the way things work in the industry, that naysayer has most likely gone on to bigger and better things by the time the product he/she killed hits the market for the competing company.  Look at daptomycin.  It was discovered at Eli Lilly in the early 1980s, killed by them in the mid 1990s and marketed by Cubist in 2003.  Where is the naysayer at Lilly?  I have no idea.

I have personal experience with this.  Back in the 1990s, we at Wyeth wanted to license a penem B-lactamase inhibitor from Glaxo-Smith-Kline.  They seemed very surprised that we would be interested.  They claimed that the compound was unstable and difficult to make.  We, at Wyeth, at least wanted to see for ourselves, but also we thought we could use their knowledge of the chemistry to improve on the compound. Then GSK started to waffle.  They said that maybe they would develop the compound themselves.  I suspected some internal strife for the naysayer there.  After working with them for over 6 months, we gave up and started our own program.  GSK never progressed the compound or the series further and they never outlicensed the program.  Meanwhile, we at Wyeth were able to weave our way through the GSK patents to make compounds that were active, stable and could be manufactured (with some difficulty).  (Rumor has it that this program has now been killed at Pfizer . . .another naysayer at work?).

This experience is typical.  The naysayers assume that everyone would agree with their reasoning in killing the program including outsiders.  Of course, that is not always the case and when such a prospect arises, the naysayer gets nervous.

On the other side of the naysayer is the scientist who cannot understand why his/her favorite project is being killed by the company. This inability or unwillingness to understand or agree with the corporate decision frequently leads to subterranean efforts by the scientist and their buddies to continue the project.  Their hope is that they will discover something new that will change the corporate mind.  I don’t know how often this actually happens – I suspect it does rarely.  But I never saw it.  In my experience, the naysayers usually win and the scientists end up like Quixote until they reach a dead end or finally realize the futility of their pursuit.  Of course, sometimes it is these very scientists who are the program champions that we so desperately need to move programs forward in spite of the naysayers.

For program champions, on the other hand, the risk rises exponentially as the compound advances later and later into development.  Why?  Because that’s when things start getting really expensive.  At least $30 million per phase 3 trial (for an antibiotic anyway).   Program champions (sometimes the champion is more than one person) have to continue to point out every reason why the compound or program should go forward.  They have to speak about the medical need, the market prospects, how the trial strategy is well informed, etc, etc.  They have to continually keep the positive aspects of the program in front of the eyes of top management.  If the program champion is “wrong,” and there is a late stage failure – they are the most visible image of that failure in the company.

But without these brave souls, program champions, I am convinced that few or no drugs would ever be developed in large pharmaceutical companies.   Why?  Because there is little or no risk in saying no.

Innovation in Biotech?

In examining the late stage pipeline for antibiotics in biotech, I have been disappointed.

Antimicrobial Compounds in Development by Biotech.
Compound		Manufacturer		Company of origin		Status
Dalbavancin		Pfizer from Vicuron		Merrell Marion Dow		Unknown
Iclaprim		Arpida		Roche		Failed in US
Oritavancin		Targanta		Lilly		Failed in US
Telavancin		Theravance		Theravance		Approved
Ceftibiprole		Basilea-Johnson&Johnson (J&J)		Roche		Delayed in US
Cethromycin		Advanced Life Sciences		Abbott		Failed in US
Doripenem		Peninsula J&J		Shionogi		Approved
EDP-420		Enanta		Enanta		Ph. II
Faropenem		Replidyne		Daiichi Suntory		Failed in US
Ceftaroline		Cerexa/Forest		Takeda		Submitted for approval
NXL-104		Novexel		Aventis		Phase II
NXL-103		Novexel		Aventis		Phase II
PTK-0796		Paratek - Novartis		Paratek		Phase III
Torezolid		Trius		Dong-A		Ph. II
Radezolid		Rib-X		Rib-X		Ph II

In this table, the Ph. II or later stage systemic antibacterial compounds in bold are those that were actually discovered in biotech and not in large Pharma. I only count four out of the 15 total, from Theravance (now approved in the US), Enanta, Rib-X and Paratek. (I have not included Optimer whose OPT-80 for CDAD is apparently home grown. Nor have I included several quinolones being developed in biotech – all licensed from larger pharmaceutical companies).

But – I finally have something to be optimistic about. Several biotechs are nearing Ph. II development with compounds actually innovated within their biotechs. Nabriva has a series of pleuromutilins ready for Ph. II trials. They are active against Gram-positive skin pathogens and both typical and atypical respiratory pathogens. Tetraphase has a lead molecule with broad-spectrum activity that comes out of a novel and exciting method of synthesis of tetracyclines also poised for Ph. II trials. Achaogen has a lead aminoglycoside that they discovered which is ready for Ph. II. Maybe innovation in biotech is going to actually produce some new antibiotics active against resistant pathogens. This would be welcome news for us all. I just hope that when these companies are ready, there will still be a few large pharmas around as potential partners.

In examining the late stage pipeline for antibiotics in biotech, I have been disappointed. 

In this table, the Ph. II or later stage systemic antibacterial compounds in bold are those that were actually discovered in biotech and not in large Pharma.  I only count four out of the 15 total, from Theravance (now approved in the US), Enanta, Rib-X and Paratek.  (I have not included Optimer whose OPT-80 for CDAD is apparently home grown.  Nor have I included several quinolones being developed in biotech – all licensed from larger pharmaceutical companies).

But – I finally have something to be optimistic about.  Several biotechs are nearing Ph. II development with compounds actually innovated within their biotechs.  Nabriva has a series of pleuromutilins ready for Ph. II trials.  They are active against Gram-positive skin pathogens and both typical and atypical respiratory pathogens.  Tetraphase has a lead molecule with broad-spectrum activity that comes out of a novel and exciting method of synthesis of tetracyclines also poised for Ph. II trials.   Achaogen has a lead aminoglycoside that they discovered which is ready for Ph. II.  Maybe innovation in biotech is going to actually produce some new antibiotics active against resistant pathogens.  This would be welcome news for us all.  I just hope that when these companies are ready, there will still be a few potential large pharmas around as potential partners.