Monday, September 29, 2014

New Antibiotics = New Targets?

I am about to go to a meeting in Europe where one of the topics of discussion will be where Europe should spend its money on antibiotic discovery research. Of course, geographically – in Europe – sorry Americans.  But what kinds of discovery research should they support with their Euros? I’ve had this conversation so many times now that I am starting to sound like a broken record even to myself.  Every time this topic is raised (with academicians) the first two words out of their mouths are “New” and “Targets.” In theory – this is a great idea.  If the antibiotic hits something entirely new and different than what is hit by existing antibiotics, at least the resistant strains that exist today won’t be resistant (at least mostly) to the new product – until they become resistant that is. And every time I hear these arguments,  I get a little less tactful in my response.  But who cares?  I’m retired – right?  I can say what I want (mostly) – right?

My thoughts run as follows.

Every pharmaceutical company in the world already investigated a very large number of new targets during the 1990s and early 2000s. Just read David Payne’s wonderful exposition of GSK’s efforts in this regard (assuming you have a subscription to Nature or you want to pay). We certainly went through the same trauma at Wyeth and so did Schering and many many others.  Unfortunately, much of the billions of pages of resulting data were never published because the results were, almost 100%, negative! And those of you in the academic world know how hard it is to publish negative data. There were some interesting scientific observations that were published based on this research – but little of the kind of data noted by David Payne and colleagues made it to press. So what will the academic community bring to this table?

First on my wish list would be a way to understand how we can make small molecules enter Gram-negative cells and avoid efflux. This is a basic science research effort that can be separated to a large extent from drug discovery per se. Hans Moser has already published some fascinating work on this topic and additional research is already being funded to some extent by IMI. 

Then, even if we identify a novel target – what makes us think we can find a drug that will work against that target?  Academic researchers in general are not trained to carry out drug discovery research. And when they try to enter the area without adequate training, the results are not good.

So – what do I say to people who ask me if they should spend money on research into novel targets for antibacterial drug discovery in academia?

1.     First – get academics trained in antibiotic discovery research.  They must understand many aspects of translational research that they currently have not even considered. This includes everything from biophysical properties of small molecules to PK/PD to toxicology to chemical manufacturing. This seems like the highest priority to me.
2.     Get people to think about new approaches to existing antibiotic classes.  This is less risky and might well provide more bang for the buck.  How about some additional B-lactamase inhibitors targeting the class D carbapenemases.  Lots of people (Merck and AstraZeneca among others) have worked on this class of inhibitors known fondly as DABCO.  Why not focus efforts on a set of enzymes where there is high medical need?  Are other companies working on this?  Of course.  Have they gotten anywhere? – not to the stage of clinical trials at least according to
3.     Encourage research on known targets using new approaches.  Look at all the binding sites in ribosomes that have not yet been explored.
4.     Finally, if you plan to spend taxpayer money on research in novel antibacterial targets, require researchers to provide a chemically tractable ligand that binds the target and gets into bacterial cells and avoids efflux before you throw too much money at the project. Seed money OK.  Small projects with high risk – OK.  But that’s it.

For more on this topic, my blog contains a number of articles on writing grants for antibiotic discovery (1, 2, 3, 4, 5).  I have also previously discussed the issue of training for academics in antibiotic drug discovery.

Friday, September 19, 2014

PCAST and Antibiotics - Show me the Money!

Well boys and girls, ladies and gentlemen, the long-awaited PCAST (President’s Council  of  Advisors on Science and Technology) report  on antibiotic resistance has been released.  The report is much better than I expected in some areas and disappointing in others.

Highlights of the report are –

·      The President should task the National Security Council, in coordination with the Office of Science and Technology Policy and the Office of Management and Budget (OMB), with oversight and coordination of Federal efforts to combat antibiotic resistance, and appoint a member of the National Security Council staff as White House Director for National Antibiotic Resistance Policy (DNARP), supported by adequate professional staff, devoted fully to ensuring integration and accountability and annual reporting. The President should also establish an interagency Task Force on Combating AntibioticResistant Bacteria (TFCARB) cochaired by the Secretaries of Agriculture, Defense, and Health and Human Services or their designated deputies and having members from all relevant agencies and establish a President’s Advisory Council on Combating AntibioticResistant Bacteria composed of nonFederal experts.
o   Although this kicks the current Interagency Task Force on Antimicrobial Resistance to a much higher level – I remain skeptical given the difficulty for all these agencies to speak to each other much less actually work together.  The fact that they all compete with each other for funding doesn’t help.
·      Strengthen State and local public health infrastructure for surveillance and response. ($90 million per year).
·      Establish a national capability for pathogen surveillance based on genome analysis. A multiagency effort that will require $190 million per year.
·      Expand fundamental research relevant to developing new antibiotics and alternatives for treating bacterial infections (NIH, FDA, DARPA, DITRA).
·      Develop alternatives to antibiotics in agriculture. (USDA, NIH - $25 million per year to fund an Innovation Institute at USDA).
·      Establish a robust national infrastructure to support clinical trials with new antibiotics (NIH, FDA - $25 million).
o   The NIH is already doing this.  It involves developing a network of hospitals to serve as centers for clinical trial research on new drugs and other approaches to antibiotic-resistant infections.
·      Develop new regulatory pathways to evaluate urgently needed antibiotics.
o   Here PCAST notes that in spite of the FDA’s call for new legislation to support this effort, the FDA already has sufficient statutory authority to carry out this task without congressional action.  This is something I have been saying for the last several years as well.  In fact, the FDA has already started down this path anyway.
·      The Federal Government should significantly increase economic incentives for developing urgently needed antibiotics.
o  Here PCAST again agrees with my view and that of many experts that the GAIN Act was entirely insufficient to provide the kind of return on investment that pharmaceutical companies require to invest in antibiotic R&D.
o  PCAST recommends that BARDA’s brief be expanded beyond bioterror threats to the overall threat of antibiotic resistance.  They recommend and additional $400 million per year in funding for BARDA to fund antibiotic R&D.
o  They recommend support for the higher prices that these new antibiotics will command by authorizing CMS (Center for Medicare/Medicaid Services) to provide reimbursement to hospitals when required. Other insurers usually follow CMS.
o  PCAST supports a delinkage approach where government provides a guaranteed purchase of product upfront upon approval. This could either be a complete buyout of around $1 billion or a smaller amount that would then serve to decrease the price of therapy.  They recommend that BARDA be given this responsibility with an additional $400 million annually.
§  Sound familiar?  See my previous blogs on antibiotic pricing.
o   Tradable vouchers – this is PCAST lingo for wild card patent exclusivity – something I suggested in the context of the IDSA report Bad Bugs No Drugs back in 2004.  Still a good idea that is sure to be rejected by all.
o   Antibiotic usage fee – by adding a fee to the price of antibiotics already approved some of the above might be funded.  Good luck on that one.
·      Improve Antibiotic Stewardship – expand to settings like long term care and outpatient care.
·      Establish a prize for breakthrough point of care diagnostics.
o   Great idea.
·      PCAST calls for more research on whether the use of antibiotics in animals contributes to the resistance threat to humans.
o   Are you kidding me? To me, and I’ve only been working in the area for around 30 years, the answer is already established.  Even if one has doubts, the benefits to producers cannot possibly be outweighed by the more cautious approach of restricting antibiotic use in agriculture.  This is a great disappointment in the report.
o   By the way – the FDA has already responded to the PCAST report emphasizing their voluntary approach to restricting antibiotic use in agriculture.
·      PCAST calls for international cooperation.
o   Yes.  Good luck on this one.  Are you listening FDA?  Harmonize with Europe?

President Obama has already issued a set of executive orders aimed at implementing the recommendations of PCAST. There is just one thing missing here.  PCAST has recommended spending several billions of dollars.  Where is the money?  Show me the money! Without congress – and we are definitely without congress – much of this is arm waving.  To me – that is the most disappointing aspect of this well conceived (mostly) report.

Thursday, September 18, 2014

PhRMA - Good and Not So Much

Two recent articles caught my eye.  Neither had anything to do with antibiotics per se – but both are relevant to the pharmaceutical industry overall.  When I was at Wyeth, the product champions – frequently both scientists and marketing folks, the chemists and the finance people – would spend countless hours wringing their hands over the approaching patent cliff for their favorite product. Yes, its true.  When your exclusive rights expire – which actually usually occurs some years after your patent expires - the road is open to generic companies.  Revenues for the branded product can then be expected to drop at least 70% in the first year of generic competition and much more after that. This system seems fair to me – as a company you get to make up for your development costs and provide a return on your investment to your shareholders within the time frame of your exclusive rights.  After that – you’re done and consumers can still benefit from your miraculous (or not) product at a much lower price (hopefully).

But this system has been twisted and subverted such that there are myriad ways to avoid the loss of your precious revenues even after 15 years or more of exclusive sales around the world. One of the most egregious tricks is to legally collude with the generics companies to keep them from entering the market.  I don’t pretend to understand the legalities here – but it is very common for Pharma companies to reach an “agreement” (read money) with generics manufacturers to delay their entry into your market. 

One trick that I was not really aware of but that I just learned about after reading an article in the New York Times is drug hopping.  In this scenario, a rather common tactic of formulating your drug in some new way and then patenting your new formulation is taken to extremes.  The idea is, for example, to take your drug that is normally taken two or three times a day and to repackage it in a way that allows you get the same drug effect with a once-a-day pill.  Scientifically this is challenging and can give you an advantage over the generics when your patent on the drug itself expires.  You now have a new patent on the once-a-day formulation and can still sell that at a higher price than the generics since they cannot copy your new formulation. But in the case of Forest (now Actavis), prior to their loss of market exclusivity, they actually stopped selling the older version of the drug – Namenda – used for Alzhemier’s disease.  This forced all current users to switch to the new formulation.  This way, when the generic versions of Namenda come out, everyone will be on the once-a-day version and will be more reluctant to switch to a twice- or three-times-a-day version that the generics would provide. This tactic is called drug hopping.  Forest-Actavis is the subject of a lawsuit by the State of New York over this practice.
On the other side of the coin, Gilead is showing us how we should all behave.  My idol as a pharmaceutical company CEO is Roy Vagelos and Merck during the heyday 1980s and early 90s. Dr. Vagelos is a physician-scientist who rose to become the leader of one of the greatest expansions of a pharmaceutical company in history.  He also led a company-based philanthropic effort to deliver a Merck product (Ivermectin) to areas of the world ravaged by river blindness in a remarkably successful effort to all but eradicate the disease.
Today, Gilead has announced that they have reached an agreement with India and six other developing countries to market Sovaldi, their remarkable new anti-Hepatitis C drug that sells for $80,000 per 3 month course of therapy here in the US at a price of les than $1800 for a 6 month treatment course.  This turns out to be a 100-fold difference in price per pill. The Indian versions of the drug could ultimately reach 91 countries around the world offering help to the 100 million or more infected individuals in those countries.  The move also forces generic manufacturers in India – where a patent for Sovaldi is unlikely to be granted in any case - to charge an even lower price.  Gilead, in this way, will appeal to the growing middle class in India and other developing nations who can better afford branded treatments and who mistrust (with good cause) their home made generics. Gilead also will provide a humanitarian service and still provide a return on their investment to their stockholders.  Talk about win, win . . . .

So – compare and contrast – drug hopping by Forest-Actavis vs. low cost, effective, branded drugs for the developing world by Gilead . . .