Antibiotics - Looking Backward and Forward.

This year, looking forward, I thought that looking back would be the best way to start.  I dug out the blog I wrote a year ago trying to predict what I thought would happen this last year and then going on from there.  I didn’t realize how humbling the experience would be.

The FDA –

In December, 2011, I said,  “the FDA has finally understood that they cannot continue to issue guidance documents requiring infeasible trial designs.  What is less clear is whether they understand what “feasible” means to clinical developers and to industry"  I was RIGHT here. But I was WRONG when I said, " I am going out on a limb in predicting that rather than issue design requirements that are unworkable for urinary tract and intraabdominal infections, the FDA will delay guidance documents on these indications until they have a more clear idea of what will and will not work.”   The FDA came out with guidance on complicated urinary tract infections prohibiting the use of prior antibiotics and with a margin, although feasible, is small for the size of the treatment effect (as always) and is simply impossible to achieve if all prior antibiotics are prohibited. On the other hand, their guidance on complicated intrabdominal infection changed our current practice very little and those trials are feasible.

In 2011 I said, “I also predict that the FDA will try and achieve some understanding of pharmacometrics and how these methods can be used in various ways including as methods to define treatment effect for clinically relevant endpoints in various infectious disease indications.”  WRONG!!!  Although the FDA has given lip service to this idea, I see no concrete evidence that they are moving forward in trying to understand how to use pharmacometrics either to set margins for clinically relevant endpoints or to use these methods to establish control levels of response.

I was RIGHT when I predicted that the FDA would not come forth with a re-evaluation of generic antibiotics in terms of their risk to benefit ratios in spite of their promise to do so in 2006.  

In 2013, I predict that the FDA will achieve a “reboot” but that it will focus on “unmet needs” or infections with highly resistant organisms for which other therapies are limited. I think they will remain stuck in providing feasible guidance for traditional indications – but I really hope I am wrong here.

Innovative clinical trial designs –

I was a little optimistic when I said, “I predict that the first truly innovative trial designs for antibiotics will be implemented in 2012 including superiority trials possibly even using adaptive Bayesian designs. “  But I was right on when I said that pharmacometrics will play an important role in the design of such approaches and that these novel designs will be negotiated first in Europe with the US playing a distant second fiddle to the European regulators.  This has actually happened in 2012.   As noted above, in 2013, I am hoping the FDA will catch up with Europe at least for the situation when we are talking about new therapies for patients with limited options.

The markets -

Another area where I believe I was correct was when I said, “2012 will be the year where the payor in mature markets begins to understand the value of antibiotics compared to high-priced drugs that only prolong lives weeks to months.  Whether this will result in price adjustments for antibiotics already on the market – I doubt it.  But prices for new drugs that offer clear advantages over generics or other marketed brand antibiotics will achieve higher prices.  If these are supported by superiority data, such value will be easier to justify.”  I know that such discussions have occurred and will continue to occur – so far mainly in Europe.

I hope I was wrong when I predicted that 2012 would also see continued if slowing growth of antibiotic revenues in the emerging markets.  Pressures from the global recession and internal economics will provide a braking of the rapid growth of the middle class in these economies and therefore will slow the growth in demand for branded antibiotics.  Unfortunately 2013 may be held hostage to the US “cliff” negotiations.  A worldwide recession will probably not be good for the antibiotic markets.

The pharmaceutical industry and antibiotics –

I was mostly on target when I said, “I predict that 2012 will see a continuing equilibrium at our current low point of only three large pharma companies truly engaged in antibiotics R&D. The three today are AZ, GSK and Sanofi (just getting back into the game).  Novartis will remain schizophrenic with their discovery group fully engaged and their pharma group not so sure.  Merck will continue with their slow, small program that is not large enough to really count.”  I am now convinced that Merck, even with its small effort, must be considered a player given their ongoing phase II trials of MK7655.   

I also predicted that we will see continued emergence of small pharma along the lines of the Cubist model.  Examples will be Trius and possibly Rib-X.   Was this right?

Biotechs developing antibiotics have continued to struggle.  Those that have novel compounds active against resistant Gram-negative pathogens are in the best position.  Those with newer versions of older antibiotics targeting mainly Gram-positive or even Gram-positive and respiratory pathogens are having a more difficult time providing an exit for their investors. I was right here and this will continue to be the case in 2013.

Calling All Large PhRMA

As we begin to look towards 2013, I thought this would be a good time to reach out to a number of neglected but large pharmaceutical companies.  I’m talking about Lilly, Abbott, BMS, Roche, and others who do not have ongoing research in the antibiotic space. If my memory serves, Roche was the first of the large pharmaceutical companies to abandon the area way back in 1999.  They were closely followed by Lilly and BMS.  Abbott gave up a few years later. J&J and Pfizer were more recent departures – but hey – its not too late to admit you made a mistake.  Just look at Sanofi-Aventis.  Sanofi got back in shortly after they had spun everything out to Novexel.

These companies have been gone from the area for so long, they probably do not have the internal expertise to even follow current developments.  But I am addressing this blog to help them see clearly.  THIS IS THE TIME! Global resistance is rising and, in parallel so is the medical need for new antibiotics.  With medical need comes market opportunities.  Emerging economies are sustaining dollar volume growth in the antibiotic space and the world’s population has not started to shrink yet – so there are increasing numbers of patients in need of new antibiotics. The world economy, in spite of our global recession, provides a growing number of patients that can afford to pay for new antibiotics and that prefer branded products over home grown generics. 

Of course, without a regulatory path forward, there is no way to enter this market.  But hold the phone!  There already are feasible regulatory paths in Europe and, believe it or not, the FDA will find a way.  Not only that, but on both sides of the Atlantic, pathways for the rapid (and less costly) development of antibiotics to fill the most desperate medical needs already exist or are coming on line quickly. 

In spite of the last advisory committee meeting where the FDA sat on their hands and covered their mouths and ears, I know that they will get there. Besides, by the time you build up a new antibiotic research effort, the FDA will have caught up to you.

Antibiotic discovery remains hard.  But somehow a fair number of small biotechs have been able to find a way forward.  Check out Polyphor, Tetraphase, Nabriva, Durata, Cempra and Trius.  Look at what happened with Novexel and avibactam. If they can figure this out – so can you!

And, for those of you who are interested in speaking about this opportunity, I am offering a free (except for expenses) consultation.  This comes with no strings attached since I am no longer accepting any new clients. I may not be easy to find since my website will go down on December 31 – but I figure you will find a way . . .

Yours truly – the pessimistic optimist – or is it the optimistic pessimist?

Writing Grants - Antimicrobial Screening - 3

Guest Blogger Lynn Silver of LL Silver Consulting, LLC 

The three main screening paradigms are 1) in vitro screens for enzyme inhibition, ligand binding, interruption of protein-protein interactions, etc. 2) phenotypic whole cell screens that select for inhibitors or effectors of specific cellular targets and 3) empirical, whole cell kill-the-bug-screens.  

To start with the last - for most grants I’ve seen, empirical screening seems mostly applied to natural products – but this is very inefficient if not coupled with a rapid dereplication system that can identify knowns, since a very high percentage of Actinomycete and fungal fermentation broths contain antibacterial agents and a minuscule number of those will be novel.   Note that most Pharma chemical libraries, and, likely, most other publicly available libraries, have been screened empirically already.  Empirical screens could still be useful if libraries were previously unscreened, or, for natural products, if the producing organisms are themselves novel.  But any empirical screening will require extensive follow-up to establish mechanism and safety.

In vitro assays for inhibition of enzyme activity (or other readout) are prevalent in grant applications.  Standard rules for HTS obtain (in establishing z-factors, etc.), but also important is setting up assays to reflect as well as possible intracellular conditions. For example, if ATP is present in the cell at 2 mM and you use 100 ?M in the assay – you may find ATP-competitive agents that will not show activity intracellularly.

With many screens there will be no true positive control – but that shouldn’t stop you.  It is very important, however, to run many negative controls,  antibacterials, possible interfering compounds – as false positives and high hit rates will complicate screening and require a good deal of counterscreening to eliminate.   In writing the grant, discuss planned controls, possible pitfalls and remedies.  As Dave noted in his initial write-up, many in vitro screening hits will not have the physicochemical properties necessary to enter the cell and will lack antibacterial activity.  This is especially true for Gram-negatives which have a tougher permeability barrier and more contribution from efflux pumps than do Gram-positives.  What will you do about it?  How do you plan to optimize in vitro hits to gain antibacterial activity – and, importantly, show that any antibacterial activity you do develop is related to enzyme inhibition?  In the same vein – you may find that your hit has antibacterial activity – but you must, very early on, establish that the antibacterial activity is indeed due to inhibiting your selected target – because this is very rarely true with screening of synthetic libraries.  Some pointers on connecting in vitro to whole cell activity may be found in O’Neill and Chopra (2004. Exp. Opin. Invest. Drugs 13:1045-1063) and Silver (2011. Clin. Microbiol. Rev. 74:71-109). 

One way of making the connection is to have a phenotypic assay which will give a whole cell readout that indicates a specific kind of effect on cellular physiology.  For example, inhibitors of cell wall synthesis should cause Gram-negative bacteria to form spheroplasts in osmotically stabilized medium.  And extraneous toxic properties of the hit should prevent spheroplast formation – so spheroplast formation is a good indication that a step (or steps) in cell wall synthesis has been inhibited.  In fact, the spheroplasting assay was used at Merck and at other pharmaceutical companies from the early 1960’s as a primary screen for cell wall inhibitors.   Thus phenotypic assays may be used as secondary to primary in vitro screens but also as another primary screening paradigm.  And primary screening with a whole cell phenotypic assay has the great benefit of selecting for compounds with activity against the whole cell.

Other phenotypic screens may use engineered bacterial strains to turn on a reporter gene if a specific target or pathway is inhibited – for example by taking advantage of stress regulons (see Fischer et al. 2004. Genome Res. 14:90-98), by specifically downregulating a desired target (for example by turning on antisense; see Singh et al. Curr. Opin. Drug Disc. Devel.  10:160-166) in order to sensitize to inhibitors or using a pair of strains engineered so that one should be sensitive to an inhibitor while the other is resistant (see Testa. 2003. Curr. Pharm. Biotechnol.4:248-259 for a screen for inhibitors of the non-mevalonate isoprenoid synthetic pathway).  Concepts of cell based screening are discussed in Mills and Dougherty (2012. pp. 901-929. In Antibiotic Discovery and Development.  Eds. Dougherty and Pucci. Springer.)  As with any antibacterial screening methodology, hits must followed up with tests of specificity (hitting the desired target[s] only), selectivity (hitting bacteria and not their hosts) and testing and optimization for the many layers of necessary pharmacological requirements for development (which presumably Dave or another guest blogger will discuss.

In writing screening grants, first read as much of the literature on screening as you can and recognize that there has been much of it done over the past 50 or more years.  It raises the reviewers’ hackles to read a dismissive introduction that says antibacterial screening has always been done empirically and now you will do it rationally.  It has been done rationally – BUT it must be noted that almost all the classes of antibacterial drugs in clinical use were FOUND by empirical and not rational methods.  Thus it would behoove us all to consider why such approaches haven’t worked so well (see Silver. 2012.  Clin. Microbiol. Rev. 74:71-109 and Gwynn et al., 2011. Ann. N. Y. Acad. Sci. 1213: 5-19) and approach new projects and grant-writing with an aim of improving on the past.