Antibiotics in 2020 - A Vision - Reporting from the Pew Charitable Trust

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This is the first installment from a fascinating meeting at Pew Charitable Trust, September 22, 2011. 

• ·      Revenues from Antibiotic sales in Asia-Pacific (not Japan), Russia, Brazil and South America will exceed those in the US by at least 200%. We might even meet the IDSA goal of 10 by 20 – just not in the US.
• o   The medical need for therapies for multi-resistant Gram negative infections are as great or greater than the need existing in the US.
• o   There is a growing middle class who will be able to afford these new therapies.
• ·      Driven by these sales revenues, there will be six large pharmaceutical companies actively pursuing antibiotic R&D by 2020 compared to just 2-3 today.
• ·      This growth is made possible by a flexible and balanced regulatory environment in Europe where approval for antibiotics in key indications such as respiratory infections remains feasible. These approvals then drive approvals in the rest of the world outside the US.
• ·      This bright future leaves the US in perpetual antibiotic darkness.  While the Chinese, Koreans, Russians and South Americans have access to approved new antibiotics active against resistant infections, Americans do not.
• ·      In the US there remains no feasible regulatory path for key infectious diseases indications where there is a high medical need such as hospital-acquired pneumonia. 
• ·      If the new antibiotics are approved in the US for an indication where the trials are feasible, Americans would only have access to therapy for pneumonia via off-label use. 
• o   The off-label use, however, would be paid for by Medicare and other payors in the US based on medical need.
• ·      The lack of a significant market in the US in 2020 has led to an innovation drain.  Much of the antibiotic R&D has moved to Asia where the revenues are and where a growing entrepreneurial class has taken hold.
• o   Antibiotic research in biotech and academia is flourishing with ample opportunities for partnering with large pharma and even for accessing the public markets.  But these companies do not flourish in the US – but rather in Europe and especially in Asia.
• ·      At the beginning of the decade (that is, today), BARDA showed that they could support even phase III trials providing a very important incentive for the industry to continue or even restart antibiotic R&D. But that effort fizzled before 2020 since no novel therapies could be approved by the FDA even though the same drugs were approved in Europe.
• ·      But this vision might just be a nightmare.  We could wake up to a different future.  The first step must be that the FDA must provide a feasible regulatory path for antibiotics in key indications such that new products can be approved here in the US.  No amount of monetary incentive can overcome this regulatory roadblock.
• ·      If we do not act now, the US will be left on the sidelines.  Antibiotic R&D in the US and in fact the US antibiotic market altogether will be irrelevant compared to the rest of the world.  And Americans will pay a high price for our lack of foresight today.

Related articles

• Visualizing Antibiotic Resistance With a New Online Tool (blogs.wsj.com)

Hope from ICAAC 2011

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Hello out there in blog-land.  I am writing from the 51^st ICAAC here in Chicago.  David Livermore gave an opening address where he reviewed antibiotic resistance in Gram-negative bacteria – focusing on common Enterobacteriaceae like E. coli, a frequent cause of urinary tract and other infections. David pointed out the rapid emergence not only of resistance to our latest cephalosporin antibiotics, but also to our last line antibiotics for these bacteria, the carbapenems. He ended his talk by noting the regulatory hurdles (FDA) that are stifling development of new antibiotics and by also stating that the pipeline of new antibiotics to address the resistance problem is woefully inadequate.  The only compound David recognized as possibly addressing the emerging resistance was the boron-containing GSK-052 that has a strong Gram-negative profile and which is in phase II development. While I agree with David’s view of the threat of resistance emerging in Gram-negative pathogens on a global basis, I take slight issue with him on the promise of the late stage antibiotic pipeline to address this threat. 

I will be giving a talk myself tomorrow afternoon focusing on new Beta-lactam-beta-lactamase inhibitor combinations in the late stage pipeline for Gram-negative infections. I will cover CXA-201, a combination of the anti-pseudomonal cephalosporin, CXA-101, with the older beta-lactamase inhibitor, tazobactam. This antibiotic is very active against resistant strains of Pseudomonas aeruginosa that can cause very serious infections in our hospitals – especially pneumonia .  These infections are associated with a high mortality.  There are more and more of these infections caused by strains resistant to all or almost all currently available antibiotics.  CXA-201, being developed by Cubist, is active against many of these strains.  Phase II trials in urinary tract infection and in intra-abdominal infections have already been completed with promising results.  Phase III trials in urinary tract infection have been initiated.

A new class of beta-lactamase inhibitor, called the bicyclo-diaza-octanes, was discovered at Aventis.  These compounds were spun off into Novexel in 2005 (the lead drug was called NXL-104). In combination with ceftazidime, the drug (now called avibactam) inhibits most organisms resistant to our last line carbapenem antibiotics including Pseudomonas.  The only exception is those emerging but still rare bacteria carrying a metalo-beta-lactamase that is resistant to the new class of inhibitors.  Novexel developed the inhibitor in combination with ceftazidime through phase II trials in intraabdominal infection and in urinary tract infection.  These trials demonstrated that the combination works in the clinic and is able to cure infections caused by ceftazidime-resistant Gram negatives.  Avibactam is now being developed by Astra-Zeneca. Phase III trials are hopefully imminent.

Avibactam + ceftaroline is being developed by Forest/Cerexa.  Ceftaroline is a cephalosporin that is active against MRSA – a rarity.  When combined with avibactam, the drug can inhibit an extremely broad spectrum of Gram negative and Gram-positive pathogens – but is not very active against Pseudomonas. This combination just entered phase II development in urinary tract infection.

Merck is developing its own version of avibactam combined with their carbapenem, imipenem.  It is called MK-7655. Imipenem-MK7655 is active against many imipenem-resistant Gram-negatives and is still in phase I development.

Finally, even though the beta-lactamase inhibitor avibactam inhibits most beta-lactamases causing resistance to cephalosporins and carbapenems, it does not inhibit the metallo-beta-lactamases as I noted above. But, certain beta-lactam drugs, like the monobactams, themselves are not hydrolyzed by the metallo-beta-lactamases.  Therefore, a combination of a monobactam with avibactam should be active against these types of superbug (like NDM-1).  I have mentioned this in a blog after the last ICAAC. In fact, David Livermore’s lab has shown that this prediction is accurate. Currently, no such combination is under development – but what a great idea.

It is true that these antibiotics do not cover all the resistant pathogens that are emerging today.  Note that I have not mentioned Acinetobacter.  But there are new products for them too – like TP-434, a novel tetracycline from Tetraphase that is now in phase II clinical trials and which is also the subject of a presentation tomorrow afternoon.

So my message is one of hope for patients and physicians confronted by these highly resistant pathogens.  There are antibiotics in the late stage pipeline that will address many but not all of our current medical needs in this regard.  If a company would/could develop a monobactam-avibactam combination, we could treat most infections caused by even the most resistant of the superbugs. I am hoping that this will come to pass . . .

BARDA "Pushes" the Envelope

In several previous blogs, I noted how important funding Phase III trials would be to incentivize the industry to work on new antibiotics.  I had criticized BARDA specifically stating that they excluded Phase III funding from eligibility for support.  They then wrote to me indicating that was not true and that they did not exclude phase III support from funding, but they also admitted that, at least up until that point, no applicant had been funded for phase III.  I corrected my blog with a follow-up comment.

Now, the proof is in the pudding.  A recent press release shows that GSK has received a grant of up to $94MM to fund development of a broad spectrum antibacterial compound under a new program aimed at just such a public health need at BARDA.  This funding includes support for phase III trials in intraabdominal infections.  In their press release, BARDA specifically requests additional applications under this program.  You can access the application instructions through this link.  Of course, not everyone has an antibiotic in their back pocket that might qualify for such support – but there are definitely a few out there.

I believe that this is a major breakthrough in our ability to incentivize industry, large and small and academia.  The lack of support for phase III trials has constituted a major roadblock, especially for small companies that are privately funded through venture capital.  The venture investors cannot afford the costs of phase III.  Thus those companies have always been dependent on either large pharma (deep pockets) partners or on the public markets.  The availability of BARDA support for phase III opens up a number of new opportunities for such small companies. Academia would also be able to benefit from such support.

In addition, such funding constitutes an incentive for large pharma (like GSK) where phase III contributes heavily on the negative side of the NPV ledger.  Funding for these trials will clearly improve the NPV calculation for large companies.  Will this be enough for large companies?  I think it will help those companies like GSK, who are already committed to the area.  It will provide a way for them to stay in at a time when the environment otherwise might not be favorable.  But I doubt that, by itself, such funding will be enough to entice those companies that have abandoned antibiotic R&D to re-commit the resources required. For those companies, the pull incentive, such as some sort of guaranteed market post approval would also be required. 

Nevertheless, the inclusion of phase III support in BARDA funding is an important step forward.

Related articles

• BARDA backs GSK antibiotic with $94M in R&D support (fiercebiotech.com)

Conundrum

I have been invited to participate in a meeting later in September  where the FDA, congressional staffers, the pharmaceutical industry large and small, clinicians and finally, the press will gather. The purpose of the meeting is to expose for congressional staffers the special nature of antibiotics and the challenges currently faced by society in bringing needed new antibiotics from the research laboratory to patients and clinicians.  I need to explain that I have been invited not as a participant from industry, not as a clinician or scientist, but as a member of the press.  I don’t know if I should be grateful to have been invited at all (I am!) or if I should be insulted.  What do you think?

The draft agenda I have seen suggests that there will first be a discussion of antibiotics and areas of current urgent medical needs for new products.  This will be followed by a discussion of the regulatory challenges for antibiotics followed by a discussion of the economic challenges for companies and academics wanting to bring new products to market. Of course, there is nothing in this meeting that has not been discussed previously ad nauseum. There have been multiple reviews from IDSA and others summarizing the dire threat of rising antibiotic resistance both in our hospitals and our communities.   The clinical needs are clear and are becoming more urgent with time, especially for treatment of Gram-negative infections.

The regulatory situation, especially in the US, has been the subject of countless FDA advisory committee meetings, IDSA-FDA workshops, and has been discussed publicly in a variety of other forums.   There have been many appearances on Capitol Hill by infectious diseases clinicians, the IDSA and industry discussing the medical need, regulatory environment and economics of antibiotic development.  So, while I welcome the opportunity for another shot on goal with Congress, I don’t understand what it is that they don’t get. Are they not listening?  Do they not care?  If it’s the latter, let’s not waste more time. If it’s the former, what makes us think they will listen now – especially in the current political and economic climate?

I recently had a discussion with a colleague on incentives in regard to this upcoming meeting.  I have been contemplating once again the various economic incentives that could be used to encourage industry to get back in the antibiotics game.  But you know what? Effective incentives for industry will never be passed in the current political and economic environment.  Lets face it. But, even though I find that disappointing, I disagree with my colleagues who are prioritizing incentives over regulatory reform.  As I have stated on multiple occasions, without a clear regulatory path for antibiotic development in the US, no amount of money will suffice to attract industry back into the business.

As I see the ongoing evolution of the state of antibiotic research and development within industry, we have probably reached bottom.  The number of large pharmaceutical companies exiting the area will now be balanced by those getting back in to one extent or the other.  I see the imminent departure of Novartis balanced by the arrival of Sanofi-Aventis and the toe-dipping exercise of Bayer with Trius.

We should learn from the companies who are getting back into the business, Sanofi-Aventis and Bayer.  I believe that both, but most certainly Bayer, are targeting Asia.  Why?  There is a clear regulatory path forward and a growing market – especially for antibiotics. The clear regulatory path, so far, is coming from Europe where one can leverage a European approval to win approval in most emerging economy countries. The US has a clear regulatory path for skin infections – period.  The pathway for respiratory infections no longer exists.  The FDA has promised new guidelines for intraabdominal infections and for urinary tract infection. This does nothing but increase fear and uncertainty in industry given what has already happened with respiratory infections.  So the US market is being wiped off the map by our lack of a clear and feasible regulatory path for key antibiotic indications. Companies see this clearly but they also see the rising market opportunities in the merging economies especially in Asia-Pacific (see figure - Antibiotic sales in dollars last 5 years 2006-10).  This leaves us n a situation where needed new antibiotics will be developed and will be available for patients and physicians in China and India but not for Americans here in the US.

So – here’s my suggestion for Congress.  It won’t cost taxpayers a dime.  Ask the FDA in public hearings why we do not have feasible regulatory paths for the development of needed new antibiotics and why India is a more attractive places to develop and sell antibiotics than the US. In my view, at this point in time, this is the only practical starting point in the real world.  Of course my caveat is that Congress doesn’t really know what it’s doing either . . .

Now – my conundrum.  I want to participate in the meeting I mentioned earlier.  But as a member of the press, I probably can’t get up and make statements.  I will actually have to ask questions to make my points.  I’m not sure I know how to do that.  So – any suggestions are much appreciated.

Dysfunctional Large Pharma

In the July 28 edition of Fortune magazine online there is a fascinating report by Peter Elkind and Jennifer Reingold with Doris Burke on Jeff Kindler’s rise to power at Pfizer and his subsequent fall from grace.  The reporters spent four months interviewing over 100 people including current and past Pfizer employees as well as colleagues of Kindler from his previous jobs at McDonalds where he rose from General Counsel to President of Partnered Brands. Kindler joined Pfizer at the beginning of its end as the pharmaceutical giant with Lipitor. When Kindler’s predecessor, Hank McKinnell took over as CEO in 2001, Pfizer’s stock price (corrected for splits) was $31. McKinnel was a businessman who took the reins from Bill Steere.  Bill Steere got his degree in biology and worked his way up through the Pfizer sales organization.  Under Steere, Pfizer acquired and marketed Lipitor and marketed azithromycin (Zithromax). Pfizer stock went from $2.00 to over $30.00. Under McKinnel, Pfizer brought in Zyvox through its acquisition of Pharmacia-Upjohn. The Pfizer stock went from $31 to $49 to $20.  Today, six years after Kindler took over, the stock sits at $18.

It is interesting to me that the successful CEO (Steere) was trained in science and worked in sales.  The two successors, neither of whom could be described as having advanced Pfizer from a business perspective, were a businessman and a lawyer – neither with any science background.  While this is not necessarily a detriment, I always worry about that in the key leadership position of a science driven business like pharmaceuticals.  My pharmaceutical CEO idol is Roy Vagelos the ex-CEO and chairman of Merck – a trained physician scientist.

The Fortune article goes into great detail exploring the political machinations behind the replacement of Steere by McKinnel and then McKinnel by Kindler.  Steere is characterized as the Wizard of Oz pulling strings behind the curtain to manipulate the characters involved and get the result he wanted.  These sorts of politics seem rampant in large corporations where the powerful frequently have large egos that overmatch their abilities.

One counter-example is Iain Buchanan.  Iain is still one of the best CEOs with whom I have had the pleasure of working.  He led a small biotech, Novexel.  Iain learned the science enough to make key strategic decisions and, more importantly, he understood his limits and listened to the advice of the experts he brought in for that very purpose.  Listening is frequently not a characteristic of heads of large corporations and was certainly not among the descriptions of Jeff Kindler in the Fortune article. I am sure there are also people like Iain in key positions in less dysfunctional large corporations.

Of course, we can’t blame the CEOs for the failings of an entire industry.  The large pharma model just seems to be outmoded.  Blockbuster drugs are now coming too infrequently to support the bottom lines of any of these behemoths.  Most of these giants are making their numbers by slicing divisions, including large segments of R&D, and even by selling off large parts of their business.  Pfizer, for example, now plans to sell off a number of non-pharma businesses like animal health and consumer health to bring down their bottom line and concentrate on ethical pharmaceuticals.  Whether this will be enough remains to be seen.  But clearly, shrinking is, from my viewpoint, the only positive way forward for these large companies.  If they shrink enough, maybe antibiotics will be an attractive business for them again.  Getting small might also help avoid the kinds of political shenanigans and manipulative behavior that apparently went on at Pfizer and was reported in such detail by Fortune.

Looking at all this from where I sit, in order for us to think small about antibiotics, we still need to solve the phase III problem.  Outside of mid-size companies (Cubist, Shire) with the cash on hand to support phase III trials, the smaller, private companies are still stuck having to partner with a larger company or with going to the public markets to fund these trials. A number of new and valuable antibiotics are being discovered and developed at such small companies. I don’t think we should count on large pharma to pull us out of this hole.


Pictured below are Jeff Kindler, Hank McKinnell and Bill Steere.

Related articles

• LaMattina gives insider's view of R&D 'upheaval' at Pfizer (fiercebiotech.com)

FDA Guidance for Antibiotic Development - A Cautionary Note

As I understand it, the FDA will soon be releasing a series of new Draft Guidance documents for the development of antibiotics.  The subjects that have been under consideration include quite a number as noted below.

Community-acquired bacterial pneumonia – hopefully a modification of the previous draft that will now provide for feasible designs.

Hospital-acquired and ventilator associated bacterial pneumonia – again hopefully a modification of the previous draft that will now provide for feasible designs.

Complicated urinary tract infection (cUTI).

Complicated intraabdominal infection (cIAI).

The utilization of superiority trial designs for antibiotics.

Rumor has it that the FDA will be releasing a number of these new guidance documents over the next six months or so starting in September.  I am writing this blog as a cautionary note.

Since the list of commercially interesting indications for antibiotics in the US has now shrunk to skin infections, intraabdominal infections, urinary tract infections and perhaps infection in neutropenic patients, the above list includes some blockbuster topics. The potential indications for much needed drugs to fight Gram negative bacterial infections are all in the above list.  Hospital-acquired and ventilator associated pneumonia frequently involve Gram negative pathogens, but the development of antibiotics for this indication is no longer feasible in the US (thanks to the FDA). cUTI and cIAI trial designs based on guidance dating back to the 1990s remain feasible for now.  A number of companies, including Cubist, Forest, Astrazeneca and others are targeting these indications for their new Gram negative antibiotics.   If the Draft Guidance documents for cUTI and cIAI require infeasible designs – that will quite simply be the end of antibiotics for Gram negative infections in the US. No more no less. So, before releasing any new Draft Guidance in these indications the FDA needs to get the proposed designs vetted for feasibility by people who actually know what they are doing in this regard.  Given performance on recent guidance documents, we can assume that this does not include the FDA folks.

Who can advise the FDA on feasibility? FNIH? FNIH includes all stakeholders and as such will provide comments written by committee – always challenging and may not be the best representation of  key issues.  Industry?  Clearly those in industry can tell the FDA about feasibility, but they are “biased.” Consultants? We never agree.  In this area, to a certain extent, I sympathize with FDA.  What is required is an FDA insider who can actually make these judgements and parse the advice received by FDA.  Even a key consultant would help – but the FDA seems not to have such a consultant specifically tasked to evaluate trial design feasibility. This key individual or group seems to be entirely missing from the anti-infectives group at FDA. I wonder if that situation can be repaired  . . . .

Points of View on Antibiotic Development: FDA and Infectious Diseases Clinicians

   

                                 

In the current issue of Clinical Investigation, four interviews focused on the development of antibiotics are featured.  From left to right - Brad Spellberg, the Rib-X CEO, Mark Leuchtenberg, Rib-X CMO Scott Hopkins and Joseh Kuti, are interviewed along with Sumathi Nambiar of the FDA. 

Dr. Nambiar states that, “ The non-inferiority margin should be prespecified, based on historical evidence of treatment effect for the active comparator and be reliable and reproducible.”  Drs. Spellberg (especially) and Kuti note that the endpoints found in today’s guidance documents are anything but that. In discussing the guidance for skin infection trials, Brad notes, “Given that sulfon­amides were clearly greatly less effective than modern antibiotics and yet had a >95% success rate with this end point, how can this end point possibly distinguish less effective drugs from more effective drugs? This end point has no assay sensitivity according to the very data used to justify the end point. It is ironic that the statis­tical concern that non-inferiority studies could lead to approval of inferior therapies has led to selection of a new end point for future studies which, according to the very historical data used to justify it, can’t distinguish inferior from superior therapy. Finally, recent experience suggests that the cessation of lesion spread end point has much lower success rates (e.g., 70%) in modern studies than in the Snodgrass and Anderson data. This is another example of lack of constancy.”

Dr. Nambiar also notes that the trials should be feasible.  While that is the case for trials in skin infections (even though that guidance document might have lots of other problems), it is certainly not so for any respiratory infections.  The FDA has stated this before – that trial designs required by guidance must be feasible.  So where are the feasible designs?  Dr. Nambiar’s response when challenged on this point by the interviewer was to say that trials must be scientifically rigorous.  Good – who could disagree with that?  But if you can’t actually conduct the trial – what’s the point?

In discussing endpoints, luckily, Dr. Nambiar recognizes that a physicians assessment is valuable, even beyond specific data on how a patient feels, functions or survives. In conclusion, Dr. Nambiar discusses the fact that the new, scientifically rigorous approach by the FDA, along with guidance being provided by the Foundation for NIH, is important in thisw time of difficult challenges for antimicrobial chemotherapy.  But both Drs. Spellberg and Kuti question the scientific rigor of the FDA’s approach as exemplified in recent Draft Guidance documents on several fronts.   It seems that from the clinicians’ point of view, the FDA has developed a “pseudoscience” (my interpretation) around non-inferiority.  In my own view,  this restrictive view of non-inferiority design is impeding development of new antibiotics and is chasing companies out of the field.

Of interest, the Rib-X interview was very focused on the data gathering they are doing to be able to do in order to argue their case before the FDA.  They also addressed issues of running global trials when the FDA and EMA do not agree on endpoints.  There were no questions for R-b-X inviting them to challenge the FDA on trial feasibility.  I suspect that Rib-X, like most companies, did not want to get into that discussion – certainly not publicly.  But as I suggested in my last blog – I hope they will get into that discussion vocally when they do meet with the FDA privately.

The bottom line for me from these very interesting interviews is that infectious diseases clinicians and the FDA live on different planets or in different dimensions – I’m not sure which.  Scientific rigor for the FDA is not at all that for the clinicians.  Feasibility of trial design is another point of clear disagreement. So here we are – back where we started in 2006-8. How will we find a way forward?