Antibiotic Incentives - Old is New

The Office of Health Economics just released a report on incentives to stimulate antibiotic research and development( I was unable to connect to their website to provide you a link to the report - but you may have better luck at ohe.org).  They focused on pull incentives in particular, and they focused on what would work in Europe while noting that the European contribution to any incentive should align with Europe’s contribution to the antibiotic marketplace in general. The report is very well done and well considered.  I recommend a careful read of this work.

At the same time, John Shimkus (R-IL) and Gene Green (D-TX) have introduced legislation in the House of Representatives

Sub-Committee on Energy Commerce and Health that proposes a 1 year transferable exclusivity extension as a pull incentive for antibiotic research and development. This is an idea that first came up in the Infectious Diseases Society’s original Bad Bugs No Drugs White Paper in 2004 and the IDSA still supports the idea today.  In this plan, a company the successfully achieve approval of a needed new antibiotic would receive an extension of their exclusivity (one year in this case) for a product of their choice. This could either be used by the company bringing the antibiotic forward or sold to another company.

Back in 2004, those of us working on the IDSA white paper were convinced that this would work as an incentive.  Investors also indicated they supported it. The idea was declared DOA in congress because of fears that it would raise drug prices and delay the entry of cheaper generic drugs to the marketplace.  According to Barret Thornhill of the Antimicrobial Innovation Alliance, the Democrats are once again digging in their heels with the same objections.  But look, Democrats (I’m one of you, by the way), someone will have to pay for a pull incentive somehow.  The choice is direct taxpayer dollars, a tax on drug companies that would be passed through to consumers anyway or a delay in generic entry. In the best of all possible worlds, I would prefer using tax dollars since this money is at least obtained relatively progressively or less regressively. (My latest understanding from Barrett is that the legislation seems dead - there is not even a working link to the proposed bill anymore.  Thanks, Democrats.)

In the OHE report, the concept of restricting rewards or scaling rewards based on the importance of the new antibiotic to society is raised. Bringing another anti-staphylococcal drug that is only available in intravenous form and that is not superior to other such drugs should probably get less of a reward than a product shown to be active against highly resistant Gram-negative pathogens. Another idea that has been discussed for transferable exclusivity rewards is providing a revenue cap.  For example, if 10 years ago such a reward had been available for a needed new antibiotic, and Pfizer had brought such a product to market, it could have gained  $15 billion dollar reward with a one year exclusivity extension for its lipid-lowering statin Lipitor. Clearly this is way beyond the reward that is thought of as necessary ~$2 billion. None of this exists in the current proposed legislation by Shimkus and Green.

Another question that I continue to consider is – Whom are we incentivizing? Do we want companies that have left antibiotic R&D and who no longer have a sales force capable of handling a new antibiotic to get back into the area?  Such companies might be Abbvie, Bristol-Myers Squibb, Lilly, and others. It seems unlikely that any incentive would drag them back.

What about companies that recently departed the area but are having second thoughts like J&J? Then there is Pfizer that seems committed to antibiotics as an add-on for their hospital sales force but, as far as I know, has not yet committed to re-establishing their antibiotic discovery research effort (an email to Pfizer went unanswered).

What about small companies and Biotech?  Here I think the transferable exclusivity extension is the most efficient award being discussed today either in Europe or the US.  Think about a biotech that is discovering and developing antibiotics like Entasis or Achaogen. The potential for them to be able to sell an exclusivity extension to a large pharma or even to use this possibility to leverage a buyout for their investors would be enormous. Investors were enthusiastic about this idea in the past – I see no reason for them to have changed their minds.  None of the other pull incentives that are being discussed have such a clear and immediate advantage for biotech and its investors as far as I can tell.

What can you do?  Write your congressional representatives and senators and tell them you support transferable exclusivity as an incentive to fix the broken antibiotic marketplace and reboot antibiotic research and development. 

A Giant Step Forward for Antibiotics for Gram-negatives

Last week, a remarkable paper was published in Nature (subscription required – sorry). The paper is remarkable because it takes a simple, practical and elegant approach to understanding how drugs penetrate Gram-negative bacteria.  This problem has confounded antibiotic discovery for decades.  The penetration problem has recently been highlighted by the Pew Charitable Trust Roadmap for antibiotic discovery and by the proposed OMEGA project. The problem has been so challenging that many scientists, including yours truly, did not believe that there were universal rules that one could follow to achieve penetration of antibiotics into Gram-negatives. While we may not be 100% wrong, it is now clear that there are a few important such rules for E. coli, an important Gram negative pathogen.

 

Richter et. al. from the Department of Chemistry and the Institute for Genomic Biology at the University of Illinois used a very sensitive method (tandem mass spectrometry) to actually measure the penetration of various molecules into E. coli. They then studied a collection of 100 molecules including antibiotics with known activity against E. coli and those that were active against Gram positive bacteria but not against Gram negatives. Based on these data, the authors were able to show a strong correlation with the presence of a positive charge at neutral pH or primary amine. They also realized that even though a positive charge might be required, it was not sufficient since not all such molecules were able to penetrate E. coli.

To further explore the requirements for penetration, the authors carried out a search of compounds with primary amines for 297 different molecular characteristics. Those characteristics that were associated with penetration could be identified.  The authors then went further and measured the penetration of compounds where specific characteristics differed – one at a time. In this way, they showed that rigid compounds penetrated better than flexible ones and that flat compounds were better than globular compounds. Using this information, they were then able to take a natural product that was active against Gram positive bacteria, and by altering it chemically along the lines of their predictive model, they were able to create a new compound with activity against both Gram positive and Gram negative bacteria.

What is surprising to many of us is that the data provided by the authors differs considerably from the conclusions we had surmised based entirely on retrospective analyses of marketed antibiotics. The great thing about science is that progress means change and with progress more questions always arise. Its perpetual.

So, Hermione, there are at least some rules after all. While the paper by Richter and coworkers is a breakthrough – no question about that – it is not going to be the whole story. And the authors clearly recognize this. How about Klebsiella?  It is closely related to E. coli. What about E. coli that are resistant already either via increasing their ability to efflux compounds out of the cell or by limiting the ingress of compounds? Then there is the problem of Pseudomonas – a pathogen with not only the ability to radically limit ingress of molecules compared to E. coli, but also one that more readily pumps them back out again. What about Acinetobacter? – a complete unknown here. Will these rules apply to all Gram negatives or are they specific to E. coli?

Richter and coworkers have shown us a way forward. We now have to fill in the rest of the blanks.

Antibiotic Development - the IDSA Stands Up!

I take pen (computer keyboard) in hand today along with John Rex who has agreed to be my co-author of this blog. Because John is currently very busy, the retired guy (me) gets the last word.

Last week, the Infectious Diseases Society of America (Boucher et al) published a white paper on the development of antibiotics for resistant pathogens, narrow spectrum indications and unmet needs.  An editorial by George Drusano accompanies the paper. These are important discussions that are based on the myriad of workshops and advisory boards held by the FDA over the last several years. The white paper represents clearly the views of the IDSA. We are grateful that the IDSA has taken this step (full disclosure – JR is a co-author).

A summary (credit to JR here) of core concepts of the paper might be –

1.       AMR continues to advance and narrow-spectrum drugs could be valuable tools to address this problem.

2.       But, developing narrow-spectrum drugs is surprisingly difficult when you want to do so for less common pathogens or forms of resistance – and these are precisely the settings where we most need new drugs.

a.       There are a few (but only a few) settings where narrow-spectrum is / would be pretty easy: S. aureus (skin) and GC (STDs).

b.       Everything else is / will be hard.

3.       ALL approaches to the general problem of narrow-spectrum drugs have significant flaws.

a.       There is no simple approach: 100+ people attacked this for a day during July 2016 and failed to generate any strong alternatives.

4.        We thus must find ways to use a collection of relatively flawed tools as the basis of registration.

5.       The alternative action of not finding this pathway is also a form of action and would be unacceptable.

6.       In this/the/an alternative plan, comparative clinical data will be needed on each new agent but generating these comparative data is (and should be!) very hard.

a.       The needed patients are uncommon … and we want this to remain true, as if they are common then we’ve failed with infection prevention.

b.       Neither non-inferiority-based nor superiority-based approaches are routinely tractable.

c.       Diagnostics will not solve the problem in that they don’t create patients with the target pathogen – they only help spot them.

d.       That said, screening for such rare patients would be facilitated by layering study of such drugs on top of a clinical trial network that is actively running UDR-focused studies.

7.       Excellent preclinical PK-PD programs are now possible and need to be better leveraged.

a.       Multiple isolates and models.

b.       PK in patients with the target syndrome.

c.       Is there a way to use these as an informative Bayesian prior? Not clear, but perhaps worth further study.

8.       To resolve these issue, and despite their flaws, we will need to use elements from these two categories of clinical research tools:

a.       The concept of validated Animal Models (approaching the ideas of the Animal Rule to the extent possible).

b.        Validated external controls (e.g., reasonably contemporaneous controls who could actually have been enrolled).

9.       At a practical level, we need to validate ertapenem for HABP-VABP

a.       This appears to be the best way to provide a companion for a  narrow-spectrum anti-pseudomonal.

b.       There is a paper coming out on this from the Ambrose group.

10.   And to succeed in a sustained fashion, we must make pull incentives work.

One quibble – (see this prior blog)  the paper uses the term “superiority studies” in a very specific way.  They mean prospective randomized controlled trials designed to determine if one treatment is superior to another. The IDSA argues that such trials are not feasible outside a large outbreak of infection caused by virtually pan-resistant bacteria – something we work hard to avoid.  They also point out the difficulty of randomizing patients to treatments that, in that situation, are likely to be inferior. We agree. But there are other ways of running superiority trials. As the paper also points out, the use of validated external controls (something I have been pushing for the last two years) can help here. Whether or not such a trial will be able to enroll sufficient patients to achieve statistical superiority or not is not yet clear – but the external controls will clearly increase the power of such a study. (On a personal note, I am very gratified that the idea of validated external controls seems to have taken hold among my colleagues).

The other aspect of the paper we would like to emphasize involves the use of animal models.  We agree with the FDA and the IDSA that exploring models that might more clearly reflect the human situation as compared to our current mouse models is a good idea.  But to achieve the validation of any new model, as clearly stated by both the IDSA and Drusano, will take years of effort and is not a guaranteed result. All agree that the existing models are well validated and are likely to provide reliable dosage predictions when combined with appropriate human pharmacokinetic studies.