Antibiotic Uppers

I was inspired this week by a few news articles and blogs that appeared recently.  One in particular was a piece by Maryn McKenna, author of Superbug.  She writes about the frustration of activists dealing with political and social inertia. I have spent the last several years discussing the perfect storm of factors working against the discovery and development of new antibiotics needed in our fight against antibiotic-resistant pathogens. It is fair to say that the last 10 years have been mostly downers in this regard.  So I can certainly empathize with the difficulties of trying to move boulders uphill. 

But I also have my own moments of optimism (perhaps misguided) – like now.  Over the last year we have seen the European regulatory agency, EMA, leading the way to the feasible and rational design of clinical trials to support the approval of new antibiotics.  The FDA has said they will reboot their entire process (which probably cannot get worse) (famous last words).  Since regulatory reform was one of the key potentially reversible roadblocks to the development of new antibiotics, I believe these developments are very positive and I am becoming optimistic about the future of antibiotics.

We have recently seen very significant government investments in antibiotic R&D including funding through BARDA to cover at least a portion of the expensive phase III trials to get antibiotics to market approval. GSK was awarded  nearly $100 million in support of its ‘052 antibiotic active against many resistant pathogens  (unfortunately, those trials have now been halted).  Tetraphase was awarded up to $67 million in support of TP-434 (see below).  The Innovative Medicines Initiative in Europe has also just announced similar important investments in antibiotic R&D (see the last blog). These very important investments provide additional, clear incentives for the continued discovery and development of new antibiotics.

Another source of optimism to me is the continued rapid growth in antibiotic sales in the emerging markets. Antibiotic sales in these markets have already outpaced the US market by over 30% and are rapidly approaching the point where they will be equal to Europe and the US combined.   These markets will become more and more attractive to companies who are poised to exploit them.  This indicates that more companies will re-enter the antibiotic R&D arena as Sanofi-
Aventis has recently done.  To me, this makes the patent extension included in the GAIN act (recently signed into law by President Obama) totally irrelevant except for those small companies who are developing products with otherwise short patent lives.

We now have a number of antibiotics that will be effective against at least some of the most fearsome resistant Gram-negative pathogens in the late stage pipeline.  These include ceftazidime-avibactam from Astra-Zeneca which will be active against KPC-producing organisms resistant to carbapenems and virtually all other antibiotics and ceftolozane from Cubist – a drug active against many highly resistant Pseudomonas strains. Tetraphase should soon be completing their phase II study of TP-434, a tetracycline active against many multiply-resistant Gram negative pathogens including Acinetobacter and which is available orally as well as IV. There are other antibiotics about to enter late stage development with complementary activity against other multiply-resistant pathogens as well. 

So, I am now in one of my more optimistic moods regarding the future of antibiotic R&D.  But of course this all depends on; a successful FDA reboot; a large PhRMA industry that sees an advantage in rising antibiotic sales in emerging economies in spite of their continued need to slash and burn to make up for patent losses; and perhaps, even on welcoming public markets for small biotechs desiring to go it alone.  So, I guess I am a somewhat cynical optimist after all.

Innovative Medicines Initiative Explained

GUEST BLOGGERS - DAVID PAYNE AND KIM BROWN of GSK. 

When David sent us an email with ‘does anybody understand IMI ?’ we felt we needed to put this opportunity into better perspective. The New Drugs 4 Bad Bugs (ND4BB) project (6th Call for proposals) came about from high level discussions with the European Commission on how they wanted to do something concrete to address antibiotic resistance  (Press release).  The conclusions of these discussions led us to the Innovative Medicines Initiative (IMI homepage ) as the most immediately available source of funding.  IMI was set up in 2008 to support collaborative research projects between networks of industrial (EFPIA goal and membership) and academic experts to reduce drug discovery bottlenecks, and boost pharmaceutical innovation within Europe.  The effort applied to the project by the EFPIA companies is then matched with funding from IMI; this funding from IMI goes directly to European academics, institutions or small medium enterprises (SME) that have organized themselves into a consortium to address the goals of a research project.  All the EFPIA companies had the opportunity to participate in ND4BB.  The current topic text was the result of discussions amongst those EFPIA companies interested in participating (listed below), and developed in consultation with (and with input from) other stakeholders, such as the European Commission, IMI’s Scientific Committee, and IMI’s States Representatives Group.   

The first project (Topic 1) is focused on creating and enabling an antibiotic clinical trial network for evaluating the clinical efficacy and safety of novel antibacterials, initially from AZ and GSK.  In addition,  Topic 1 has opportunities for  institutions that have not previously run clinical trials to receive training to become compliant clinical trial sites for the future. Sites of particular interest are those in regions of high levels of resistance, or where a specific resistance mechanism predominates. This will create a footprint of compliant clinical trial sites that can be adapted to optimally evaluate new antibacterials against infections resistant to current standard of care antibacterials.

The second project (Topic 2) is focused on improving our understanding of how to design agents that will optimally penetrate Gram negative pathogens – we see the lack of rational approaches to this problem as a major barrier to creating a pipeline of Gram negative antibacterials . Overall, there is €16M available for a consortium of European academics to tackle this problem and EFPIA members will be providing tool compounds and additional support for the various projects. We encourage broad and innovative thinking to address the goals of this project.

So how does the funding work ?  Under IMI individuals can not apply for funding, applications have to be made as a consortium. For example, a consortium of clinical investigators and SMEs with a Principal Investigator need to apply to run the clinical trials in the proposal. Researchers across Europe are encouraged to connect with other interested parties to initiate a consortium and/or communicate their interests and expertise through the IMI Partnering Tool (Link to Partner Search) which can also be the genesis of a consortium. The optimal consortium is then selected by an expert panel consisting of independent academics appointed by IMI.  To ensure a fair application process, EFPIA representatives cannot directly communicate with prospective applicants, so any specific enquires should be emailed to the IMI offices (INFODESK@imi.europa.eu).

Essentially the way this will work for clinical trials is that IMI will provide funding for the European clinical trial sites and the sponsoring EFPIA company will fund an equal share of the cost.  As antibacterial clinical trials have never been run by such a consortium, the risks of added complexity could extend timelines. However, by initiating this project with their compounds, GSK and AZ hope to build confidence around the approach, create an established network of compliant clinical trials sites for future use, and establish Europe as a center of excellence for antibacterial clinical trials.  Those following David’s blog will appreciate that this type of funding support is key to maintaining and encouraging companies to commit to antibacterial R&D.

Finally, a major theme of the proposal will be that the EFPIA members and academic groups participating in ND4BB will share information on antibacterial R&D in a way that we have never done before. This will encompass everything from learnings from clinical trials to past experiences of why particular projects or compounds failed. The hope here is that we will increase the overall efficiency of antibacterial R&D and companies will have broader access to potential liabilities associated with different approaches, targets and novel chemical series to better inform their strategies.

The eagerness of the EC and IMI to play a role here is exemplary and this current proposal is an ambitious first step. Additional funding is available (the total amount could be up to €600M) and we are working on additional projects which will be the subject of future ‘Calls’. We hope ND4BB establishes a framework that will attract additional projects/clinical programs and other EFPIA companies to collaboratively participate in a new way of working collaboratively in antibacterial R&D.

GlaxoSmithKine

AstraZeneca

J&J

Basilea

Sanofi  

Europe Leads the Way!

The European Medicines Agency (EMA) has just released their long-awaited addendum to the antibacterial guidance they released late last year.  It is an amazing document compared to the guidance documents released in the last few years by the FDA in the US.  Clearly, this was the work of a very thoughtful group of smart individuals who kept trial feasibility high on the priority list of considerations.  They also worked hard to avoid the FDA trap of justifying non-inferiority margins at the expense of real-world considerations like trial numbers and endpoints.

In general, the EMA addendum uses clinical response at test of cure as their endpoint.  No fuss, no bother.  Their suggested non-inferiority margins for various indications are as follows:

Complicated UTI – 10%

Community-acquired Pneumonia – 10%

Complicated Skin and Skin Structure Infection – 5-10%

Complicated Intra-abdominal Infection – 12.5%

Hospital-Acquired Pneumonia and/or Ventilator Associated Pneumonia – 12.5%

In my view – these trial designs are all quite feasible in terms of patient numbers with two possible exceptions – anything less than a 10% margin (the 5-10% for skin infection) is probably not realistic and 12.5% for HAP/VAP is, in today’s world, is also probably not feasible.  There is even a feasible pathway forward for an oral only antibiotic for community-acquired pneumonia - an option that does not exist at the FDA (at least for now).

The EMA allows for up to 24 hours of prior antibiotic therapy within the 72 hours prior to enrollment.  They recommend that only a single dose be allowed for UTI and CAP patients – but that is still quite a feasible approach and stands in stark contrast to the FDA.   The EMA also suggest that sponsors perform an “exploratory” analysis of patients who received and did not receive antibiotics.  This suggests to me that this will not be a review issue at least for now – but it behooves sponsors to confirm this during their discussions with the EMA.

In another amazing coup – the EMA recognizes the efficacy of antibiotics for Acute Otitis Media in children similar to those studied in two placebo controlled trials as published in the New England Journal last year (see my blog on this).   This means trials (non-inferiority design) for antibiotics can once again be carried out in children with AOM – a situation that was going to be impossible under the requirement for a superiority design.  This is a critical move on the part of EMA because it opens an entry indication for treatment of pediatric infections that has been unavailable since 2003 or so.

Finally, in another startling development presaged by their general antibacterial guidance, the EMA opens the door for various superiority or open enrollment designs for the approval of drugs that target pathogens rarely causing infection where the medical need is high.  This will include antibiotics active against specific pathogens where resistance is a major problem and antibiotics tackling key resistance mechanisms that may still be rare today.  In their addendum, the EMA clearly recognizes the difficulties in carrying out such trials and the inherent risks in approving such therapies, even with a limited label, based on small numbers of treated patients.  But they also recognize the public health risk of the lack of antibiotics to address these highly resistant pathogens and are paving a pathway forward for sponsors to develop these needed products. The EMA notes (as does the FDA actually) that it is up to sponsors to come forward with specific proposals – but this addendum clearly shows that the EMA is open for business and, more importantly, for protecting the health and safety of patients around the world.  The FDA has to reboot their entire approach to achieve what the EMA has already done – and we’re not there yet!

So – the antibiotic waters in Europe are warm!  Come on in!!

Next week – the Innovative Medicines Initiative explained.

David Livermore on EUCAST and Breakpoints

David Livermore University of East Anglia

As the EU’s grand confection – a single currency for diverging economies– draws towards its denouement, it comes as some relief to point to the success of a less ambitious but more successful harmonisation: EUCAST. This has brought useful agreement, provided a little employment and may even spread a healthy contagion beyond Europe’s borders… 

Specifically, EUCAST – the European Committee on Antimicrobial Susceptibility Testing has two major achievements to its credit:

First, it has brought a harmonisation of breakpoints across Europe so that single definitions of susceptible, intermediate and resistance are now accepted throughout the continent, whereas previously there were separate national committees with different breakpoints in Norway, Sweden, the UK, France and Germany, whilst most of the southern Europe followed CLSI.   Despite slow incorporation onto certain automated testing systems, EUCAST values are increasingly adopted for day-to-day laboratory testing

Second, and in contrast to the protracted territorial squabble between CLSI and the FDA, EUCAST has reached a Memorandum of Understanding with the European Medicines Agency – the drug regulator – and serves as their advisor on breakpoints.  Decisions on indications and pathogen spectrum remain firmly with the Agency.  This agreement has functioned for 5 years, through the licensing of tigecycline, daptomycin and telavancin, with ceftaroline pending.   It precludes the unfortunate situation, not unknown across the Atlantic, where pharmaceutical company X, with a generous breakpoint from the FDA, omits to talk with the CLSI, for fear of a lower value. It also prevents the problem where device manufacturer Y is obliged to comply with FDA breakpoints to have its product licensed, whilst its customers demand a panel that tests to CLSI’s criteria, which are becoming more conservative than the FDA’s.

This article isn’t to detail the organisational structure of EUCAST, which can be found on http://www.eucast.org/organization.   Briefly, it operates with funding from the European Centres for Disease Control (ECDC) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). Its Steering Committee, which makes the primary decisions on breakpoints, comprises representatives from European national breakpoint committees whilst its General Committee, which reviews proposals, has wider representation from across EU and non-EU Europe, also Russia, Turkey and Australia. Representatives of pharmaceutical and device manufacturers are invited to present data for review by the Steering Committee when they seek to license new agents or indications, but they do not sit on EUCAST’s decision-making committees.

Breakpoint decisions are largely predicated on pharmacodynamics, as increasingly are those of the CLSI whilst the FDA puts more weight on clinical outcomes in relation to MIC.  These pharmacodynamic breakpoints may be adjusted by a dilution up or down, to ensure that they do not slice through the MIC distribution for wild-type isolates of major species groups. They may also be adjusted on the basis of clinical evidence and experience. A category of ‘Insufficient evidence’ is noted for drugs that might be of interest against a pathogen but where clinical data are scant (e.g. daptomycin vs. enterococci), whilst low non-species-specific breakpoints are included for obscure species. Last, an epidemiological cut off (‘ECOFF’) is specified, defining the upper edge of the normal distribution of MICs for isolates without any diminution of susceptibility.  This corresponds to what others call a biological breakpoint, though EUCAST is at pains to avoid the term. ‘Intermediate’ is taken as ‘may respond at high dose’ and, for some marginal agents (e.g. macrolides against haemophili or ciprofloxacin against pneumococci) nearly all isolates count as intermediate.  This differs somewhat from CLSI, where intermediate is viewed more as a buffer to minimise errors between MIC and disc categorisations.   Once assigned – and ratified by EMA for agents  – EUCAST publishes breakpoints on its website, along with a brief rationale, a summary of which also appears in Clinical Microbiology and Infection as ESCMID’s journal of record.   Values are not set in stone (as with the FDA) and can be reviewed at the request of the manufacturer, professional societies or the regulator. There is a low bar to initiating a review, but strong justification is needed for a change.

Is the system perfect? Personally – and this comment applies as much to CLSI – I believe that the pendulum in defining resistance has swung too far from mechanisms towards pharmacodynamics, with excessive optimism in the precision of MICs.  Second, I find it incongruous that EUCAST breakpoints are allowed to split populations with common modes of resistance despite a determination not to split wild type distributions. Third, there is the unfortunate ‘loss’ (perhaps to be rectified in the future!) of the higher breakpoints used previously in the UK and elsewhere for urinary infections; as a result laboratories are suddenly finding 40% resistance to amoxicillin-clavulanate in urinary E. coli whereas they previously found 5-10%---- with no evidence that the extra ‘resistant’ isolates are associated with poor outcomes.  

But, these are lesser cavils; overall, the EUCAST system is a major improvement over the country-specific breakpoints that went before.   These never had much logic when bacteria and pharmacokinetics didn’t respect political boundaries (different currencies for countries with different economic cultures and traditions is quite another matter, though…).   Which begs the question as to whether EUCAST and CLSI breakpoints too will coalesce, especially as both organisations base their values primarily on pharmacodynamics. In the short term the answer seems to be ‘no’. Although both have recently reviewed cephalosporin and carbapenem breakpoints they’ve achieved answers a dilution or two apart.  What’s more, if both committees ever do agree completely, there will be an embarrassing little problem, for CLSI’s income derives from selling its Standards, whilst EUCAST’s guidance is available free gratis, over the internet.

Generic Antibiotics - Which Way is Up?

In a number of previous blogs, I have noted the apparently hypocritical and inconsistent approach taken by the FDA regarding old approvals of generic antibiotics.  Recently, the FDA was awakened from its long sleep by an article in the New England Journal of Medicine on an old macrolide antibiotic, azithromycin.  In the study, the authors show that there is an elevated, but very small risk of cardiac arrhythmias from taking azithromycin – a potential already recognized by the FDA and already noted in all labeling for macrolide antibiotics.  The FDA responded to the article by noting its intention to relabel azithromycin and other macrolide antibiotics.  But at the same time, the FDA reasserts its approval of use of azithromycin and other macrolide antibiotics for

·      Acute bacterial exacerbations of chronic bronchitis

·      Acute bacterial sinusitis

·      Uncomplicated skin infections.

But – STOP THE PRESSES!  Uncomplicated skin infection no longer exists as an indication for the FDA.  The so called mild respiratory infections now require placebo-controlled trials to prove benefit over risk – while here the FDA is noting increased risk but they already state that for these mild respiratory infections – no placebo-controlled trial = no proof of benefit.  Therefore, these indications should logically now be withdrawn for all macrolide antibiotics.  And here is the perfect opportunity – an example of potentially increased risk.   What is the FDA doing?

Of course the FDA is completely and totally aware of the apparent paradox in their approach to generics – but they refuse to do anything.  There is nothing new about this.  The only thing new here is the reminder that, in fact, the reality is that they will not touch generics in any meaningful way while, at the same time, they restrict entry of new antibiotics to indications that physicians and patients still find useful even if the FDA does not (acute otitis media – great entry into pediatrics; acute bacterial sinusitis and acute bacterial exacerbations of COPD).  Without some drugs approved to treat these infections – all use – and there is a ton of it – would be off label.  We wouldn’t want that (or would we?).

By the way – in this case, the FDA in the US and the EMA in Europe are on the same page – I just think it’s the wrong page.

If you are confused by the approach of the regulatory agencies to generic antibiotics – welcome to my world. 

Antibiotic Investment - Alice in Wonderland!

I spend a good deal of time talking with investors and even more time with pharmaceutical companies large and small and with the regulatory agencies.  I am beginning to notice a trend among the three groups of clients that I would like to share.

In the antibiotics world, there seem to be two general classes of investor.  There are those who want to invest in “early” stage companies – usually preclinical through phase I – and those interested in “late” stage opportunities – those that are phase III ready or even later.  Everything in between is up for grabs between the two groups and depends on the size of the fund, experience of investors and, in fact, the financial situation of the opportunity.

But I am always confused by all this.  Take Novexel for example.  Novexel was acquired by Astra-Zeneca for up to $500MM prior to completion of its phase II trials – so the acquisition was based mainly on preclinical  and phase I data.  There is still the possibility for such acquisitions to occur given the reliability of these early data.  In fact, Novexel raised a late round of funding during the phase II trials to position itself to be ready to go to phase III but also to strengthen its negotiating position during potential M&A discussions. Two new investors came in at this point and did very well since the AZ buyout occurred within about a year to their investment.  Is Novexel an example of something between early and late?

The world is now about to completely change.  It is clear, at least conceptually, that there will be a regulatory pathway for the development of antibiotics for “unmet” medical needs. For me, this means the treatment of patients with serious infections caused by pathogens resistant to reliable efficacious therapy – so called extensively-resistant or pan-resistant strains of Gram-negative bacilli. The development pathways being discussed would allow for rapid testing of a small number of such patients leading to some sort of approval with a restricted label.  At the same time, companies would have to demand a high price for such products since the target population will be small and therefore the margin for each course of therapy would have to be high.  Have we seen this approach before?  Of course – think oncology. But in the case of antibiotics – we can actually save lives whereas for oncology products we mainly prolong life by some rather small amount of time.

Every company and both the EMA and FDA are actively engaged in planning for the development of new antibiotics along these lines. Thus, this year, we will see successful negotiations on such trial designs in Europe certainly – but I am optimistic that we will see this at the FDA as well.

When I speak to investors, they seem completely unaware of this paradigm shift in the antibiotic world.  They are still thinking about traditional “early” and “late” stage development.  And, for some opportunities, it is clear that has not changed.  But for others, the world is topsy-turvy.  Early is late!  So – investors – the antibiotic waters are warming quickly.  Time to get wet!  And not only investors – all you pharma companies that got out of antibiotics to jump into oncology – take another look!  Antibiotics are oncology only better!  BMS, Roche-Genentech, Lilly, Abbott, J&J, Novartis, Merck, - I’m talking to you!  Pfizer – I think its not a good time to speak to you . . .

Upcoming Guest Blogs – David Livermore on Breakpoints at EUCAST and David Payne on Explaining the Innovative Medicines Initiative.  Stay tuned. 

Antibiotic News

First, I have to apologize for being so long in contributing a blog since my last one.  I have a couple of excuses.  I’ve been busy.  The antibiotic news lately has been scant and much of it I don’t even understand as noted below.

The GAIN act passed both the senate and the house in the US over the past couple of weeks. It was attached to the PDUFA reauthorization legislation that allows the FDA to continue to charge companies more and more money to carry out efficient reviews of New Drug Applications among other tasks. PDUFA was highly sought by both FDA and the pharmaceutical industry – so – win-win.  GAIN, however, to my eyes, is more controversial.  The main piece of GAIN that has attracted attention is the “incentive” for industry to continue or restart antibiotic R&D by extending the patent exclusivity of antibiotics active against resistant pathogens.  But this incentive, for the most part, isn’t. The extension seems designed only to help those companies, mainly biotech and perhaps some academic groups, who are developing drugs with very short patent lives.  Otherwise, the benefit of the exclusivity extension is completely gone when discounted for inflation over the years of exclusivity of most newly marketed antibiotics.  So – as an incentive for large pharmaceutical companies – I just don’t get it. And we need the large pharmaceutical companies to get into the game so that they can help fund biotech and academia so that phase III trials can be accomplished.  Luckily, the markets may do that for us – thus GAIN becomes, as far as incentives go, a very limited step forward.

GAIN might accomplish two things.  It allows congress folks like Dick Blumenthal to crow about how they are helping provide needed new antibiotics for Americans without spending government money.  GAIN also has a vague clause that states that the FDA has to provide new guidance for antibiotic development.  This might actually provide the FDA cover from congress itself as it seeks new, more rapid but also more risky development pathways for antibiotics that target unmet medical needs like activity against superbugs.

Logo (Photo credit: Wikipedia)

In another bit of news last week, the Innovative Medicines Initiative announced a new public private partnership to foster R&D for new antibiotics.  They are targeting the development of new clinical trial designs for antibiotics for unmet medical needs and new discovery pathways for antibiotics active against Gram-negative pathogens.  This is all well and good and we all welcome this effort.  But, as always, the devil is in the details.   And in spite of trying to carefully study and understand the details as presented in all the documents on the IMI website, I find I am completely confused.  It looks like all the large funding blocks have already been committed to the two largest European PhARMA (EFPIA) contributors, GSK and AZ. So, if another company wanted sufficient funding to support phase III trials, I am not sure it would be there in any case.  It also looks like the partnership is designed to partner companies or academics with EFPIA members and that opportunities for R&D outside the EFPIA group is limited. It looks like I am not the only one with questions on this front. Finally, it looks like the research awards will be similar to those done within the context of the European Framework grants – NO!  NOT THAT!!!  Anything but that!!!

So – consider this a plea for clarity.  Can someone from IMI explain all this?

In another piece of news closer to my heart, Nabriva announced a deal with Forest. Hopefully, their novel IV/oral Gram-positive and RTI compound active against resistant pathogens will ultimately see the light of day.

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