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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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October 31, 2007

Resistant Little Creatures

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Posted by Derek

The post here the other day on resistant bacterial infections prompted some readers to wonder why the drug industry isn’t doing more to come up with compounds in this field. It’s not like there’s no money to be made, and it’s not like there’s no history of antibiotic research, after all. But since my industry doesn’t have a history of knowingly leaving money on the table (what industry does?), you’d figure that there’s more to the story.

Money aside, there’s a real problem with finding good targets. For as long as I can remember in the industry, the infectious disease field has suffered from a relatively small target landscape. Almost all the known drugs in the area work through just a handful of basic mechanisms, and adding new ones to the list has been very difficult for at least the last twenty or thirty years.

That was supposed to change, in theory, starting about ten years ago. I interviewed around then at a company that was working in the field, and everyone was quite excited about the bacterial genome sequences that were starting to appear. Surely this would open the sluice gates and let that long-delayed swell of new targets come washing down the flumes. Hasn’t happened. Not yet, anyway.

I have the impression that the same problems that have affected the translation of human genomic data to new drugs have been the problem here as well. In some cases, not as many genes came out as some people were hoping for. And of these, the function of many of them was (to put it mildly) obscure. Of the ones whose use was at least partially known, many of them have proved not to be useful targets for killing the bacteria or limiting their growth. And of the ones that made that cut – and we’re down to an all-too-manageable set by now – screening hasn’t turned up much chemical matter for people like me to work on.

In fact, there’s a persistent feeling among many people in the field that bacterial and fungal proteins have a lower hit rate than you’d assume they would. Even enzymes that are fairly homologous to those in higher organisms, so the story goes, don’t turn up as many hits in the screens as expected. I’m not sure if this is true or not, but as folklore it’s pretty well known. The combination of all these factors with the perceived lack of opportunities for profits (even if you do find something) has made for slow going.

In recent years it’s become clear that the medical need has grown to the point that antibiotic research can indeed be financially worthwhile – but there are any number of financially worthwhile drug outcomes that we haven’t been able to realize. (See obesity, Alzheimer’s, and many other therapeutic areas for examples of multibillion-dollar opportunities waiting for a good idea to come along. Resistant bacteria have their name on one more sword stuck in yet another stone.

Update: there's clearly another reason why developing good antibacterials is hard, and it's the same reason we need more of them. Bacteria are well-stocked with efflux pumps to get rid of molecules they don't like (and with other weapons as well), and they evolve so fast that you can watch them do it. I wrote about efflux on the site a while back - another post is well worth doing soon.

Comments (15) + TrackBacks (0) | Category: Drug Development | Infectious Diseases


COMMENTS

1. Matt on October 31, 2007 9:35 PM writes...

I'm sorry to be nit-picky, but my bioinformatics professor went out of her way to drill this into our heads: two proteins can only be homologous, not very homologous, nor fairly homologous. They can, however, be fairly similar, and on the basis of that similarity it might be reasonable to conclude that they are homologous.

Okay, I'll get off my high-horse now...I think your meaning was pretty clear, even if the terminology was slightly off.

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2. weirdo on October 31, 2007 10:24 PM writes...

The excitement of the genomics revolution just never made any sense to me as it relates to anti-bacterials.

Either your compound kills the bugs, or it doesn't. Either your compound stops the bugs from growing, or it doesn't.

Screen on the bugs.

Spending years determining "essential" genes in bacteria don't mean sh** if your molecules don't kill bacteria or stop bacteria from growing.

Many people seemed to have lost sight of that.

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3. drugsforbugs on October 31, 2007 11:43 PM writes...

GSK recently opened the curtain on the results of their genomics-driven antibacterial HTS campaigns. It was a paper that any of us in big-pharma antibacterial research could have written. Lots of targets, many screens, few hits, and no drugs.

One of many frustrations is that when you do get potent enzyme inhibitors, they often don't translate into activity against bacteria. When they do, rapid resistance development, efflux, and/or limited activity against a 'marketable' set of organisms is observed.

Some advances that I think would benefit antibacterial drug discovery:

1) Develop an understanding of the physicochemical properties that favor bacterial cell wall penetration and understand what drives efflux of small molecules from bacteria

2) Understand how to succeed with combination approaches - novel agent + existing agent – acknowledging that significant regulatory hurdles exist to these sorts of approaches

3) Exploit the potential for 'polypharmacology' - one compound inhibiting 2 essential enzymes in the same pathway

4) Pursue fragment-based approaches to work around the bias towards kinase/GPCR/ion channel agents that dominate pharma compound libraries

5) Make a serious effort to expand known natural products using molecular evolution / biosynthetic pathway engineering approaches

6) Seek out new natural products that meet the usual PK/efficacy requirements and are amenable to synthetic (or biosynthetic) modification.

7) Learn to work with target mutation-driven resistance by avoiding inhibitors that derive their binding energy from interactions with non catalytically / structurally essential residues.

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4. LNT on November 1, 2007 5:21 AM writes...

Derek, you failed to mention one important problem with antibacterial research: cell permiability & efflux pumps. This is similar to the problems faced in cancer research, but I believe to a greater degree in the antibacterial field. Those bugs just love to actively pump out any unnatural small molecule that you throw at them. Moreover, they have a cell wall that is fall less permiable than the typical eucariotic cell membrane is. Combine those factors with the ones you mentioned, and you have an incredibly tough project to work on....

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5. Kay on November 1, 2007 5:30 AM writes...

Large pharma companies DO leave money on the table if money or risk is involved and if the profit potential is small. The short duration of therapy makes it impossible to build a business case. Please correct the record here so that you can maintain your high credibility.

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6. Derek Lowe on November 1, 2007 7:38 AM writes...

Kay, I think we're talking about the same thing. Your comment seems to boil down to "Pharma companies do leave money on the table if it's not much money", which I'd certainly agree with. But I've had comments from people about how come no drug company is raking in the big bucks on MRSA, etc. I guess the two answers are "Because we don't know how to" and "Because the bucks aren't as big as you think". That second one probably isn't as true as it was a few years ago, though.

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7. Ross on November 1, 2007 8:06 AM writes...

Derek,

Another possible reason why this much-needed area is underpopulated by new drugs might be the way we use new antibiotics. Unlike other new drugs, novel antibiotics are kept back until all other options have been used. This obviously means that any new-to-market antibacterials will not have huge, instant financial returns, and time-to-patent-expiry ticks on and on. One way around this, it has been suggested, might be to offer longer periods of market exclusivity for new antibiotics.
Thanks for the blog, by the way-long time reader

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8. GATC on November 1, 2007 8:14 AM writes...

I am mainly with Drugs-for-Bugs on this commentary string. I was part of the then SKB Manhattan-Micro Project (1996-2002) searching for new antibiotics and it was a blast having pre-public access to so much bacterial genomic data together with the fun of developing and using new HTP knock-out technologies on the fly. Of course in the end it all comes down to whole-cell activity and good PK/PD in appropriate animal models but the last time I looked, the agency still requires that we know something about the MOA of new agents and that is where the essentiality testing and in vitro assays were key. Can you say “spectrum”? Genomics revolutionized our ability to gauge and predict antimicrobial activity spectrum before going to whole-cell screening; the FabK fiasco in S. pneumoniae being a prime example.

We were not looking for follow-ons but entirely new classes of molecules for entirely new targets. But aside from all of the blown sun-shine of the recent Payne article (Nature Reviews-Drug Development, 2007. 6:29-40), and thank God we didn’t have to bear yet another lecture on the wonders of the GSK program at this year’s ICAAC, it still comes down to the economic and tox realities as described eloquently by Projan, Shlaes and others. As I see it, the failure of the GSK enterprise was due to 1) lack of effective management and target prioritization, 2) lack of serious chemical diversity and med-chems who understood bacterial physiology, 3) lack of bioinformatics appreciation for the complexity and diversity of the bacterial target space, 4) lack of technologies that allowed for the pursuit of the really cool targets (integral membrane proteins!), and 5) a complete disconnect between discovery and preclinical development. With antibacterials, we are blessed to have wonderful in vitro and in vivo models that can predict clinical outcome. Except for Lorian’s text how many books on antibiotic development realistically address the unique PK/PD parameters of this drug class?

The antibacterial target space is immense and we haven’t even scrapped the surface yet. So where are all of the new antibiotics? Why has nature, for the most part, only selected for cell wall and ribosome agents? Why are the group-A streps still so exquisitely sensitive to the betalactams after decades of use? Who will take the psychic risks to get this field moving again?

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9. Hap on November 1, 2007 10:36 AM writes...

GATC,

What is the FabK fiasco? I have heard of the enzyme before and Googling gets a bunch of papers/patents on its inhibitors - what is the problem with FabK inhibitors in S. pneumoiae that they don't work (I assume)? Thank you.

Permalink to Comment

10. JEK on November 1, 2007 2:23 PM writes...

How about polyclonal antibodies produced in transgenic animals? We aren't there yet, but in pre-antibiotic days antisera were used to treat things like diphthera. Getting rid of the immunogenicity problems of this approach through the production of human polyclonals in an animal species could be interesting. It certainly is to Roche, who bought THP and their rabbits.

Permalink to Comment

11. MTK on November 1, 2007 3:48 PM writes...

Kay,

Your statement, "The short duration of therapy makes it impossible to build a business case." is not true at all.

First, there is a lot of activity by Big Pharma in anti-infectives so clearly they have built a business case for it or they wouldn't be investing the money into R&D. GSK's failing as described by GATC, came down to lack of execution, not lack of will or effort due to a perceived small market.

Second, I'm pretty sure that Zithromax, Cipro, and vancomycin are all making, or have made, their Big Pharma producers plenty of money.

Third, the short treatment duration also means a short clinical trial period with easily definable endpoints. This is a critical part of the business case. It's about ROI, so even if the return may not be as great since the treatment is acute, not chronic, the investment isn't as great from a clinical standpoint, which is easily the most expensive part of development. The short clinical timeline can translate into longer exclusivity which adds to the ROI.

All of this means a company may pass on a particular antibacterial indication as too small of a market, but to state that the short duration period is the reason is just not true. The need, and the will, is there. It's just a tough nut to crack.

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12. The Pharmacoepidemiologist on November 1, 2007 7:40 PM writes...

Kay's got the right idea. Antibiotics started becoming a difficult sell in the late 80s, when hospitals started pinching on use of 3rd gen cephalosporins. JCAHO didn't help matters by insisting that hospitals limit use of such antibiotics. The pharmaceutical industry got the message that there were higher returns on invested capital in places like diabetes and high cholesterol rather than infections. It's that simple. That there is a need no one questions. But is anyone willing to pay for the investment needed to bring an antibiotic to market? Nope. Look at what happens to Tegrin and moxifloxicin. I don't think the former is even on the market anymore, and there were safety issues with both antibiotics. As always, if you wonder why an American company isn't investing in something, it's probably because it doesn't think it can make enough money off of it to justify the risk of the investment.

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13. Micro Dude on November 1, 2007 8:52 PM writes...

What about lytic bacteriophage therapy? i know the Russians used to do it but there wasn't any great clinical data on it. Fischetti at Rockefeller has been working on it for awhile. I know they work great in vitro and I thought they worked in mice as well. One problem is that the phages are immunogenic so that the patient develops antibodies to them reducing their effectiveness, but maybe they can engineer out the antigenicity.

I'm a Micro Ph.D., so I certainly hope there will be lots of antibiotic research in the future!

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14. k on November 2, 2007 8:06 AM writes...

I see a lack of agreement regarding whether a business case can be built. It's nice, however, to see the harmony of opinion expressed above indicating that drug development is just too darn difficult for today's industrial participants. Instead, maybe we should focus on line extensions.

Wait ... who said "KSR?" What's that?

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15. bob on November 3, 2007 6:23 PM writes...

The answer to the business question depends on how you look at it. If you come up with a new class that bypasses existing resistances, it's going to get locked away where nurse practitioners can't dispense it for viral infections. Most hospitals now actually forbid treatment with carbapenems without authorization from a committee of appropriate physicians (which is a Good Thing).

If you're just coming up with a slightly different cephalosporin, ironically you're probably better off from a business standpoint. On the other hand there will be almost zero tolerance for side effects with these knockoff drugs, which has been a real problem for them.

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